The free plasma amyloid Aß1-42/Aß1-40 ratio predicts conversion to dementia for subjects with mild cognitive impairment with performance equivalent to that of the total plasma Aß1-42/Aß1-40 ratio. The BALTAZAR study.

BACKGROUND AND PURPOSE: Blood-based biomarkers are a non-invasive solution to predict the risk of conversion of mild cognitive impairment (MCI) to dementia. The utility of free plasma amyloid peptides (not bound to plasma proteins and/or cells) as an early indicator of conversion to dementia is still debated, as the results of studies have been contradictory. In this context, we investigated whether plasma levels of the free amyloid peptides Aß1-42 and Aß1-40 and the free plasma Aß1-42/Aß1-40 ratio are associated with the conversion of MCI to dementia, in particular AD, over three years of follow-up in a subgroup of the BALTAZAR cohort. We also compared their predictive value to that of total plasma Aß1-42 and Aß1-40 levels and the total plasma Aß1-42/Aß1-40 ratio. METHODS: The plasma Aß1-42 and Aß1-40 peptide assay was performed using the INNO-BIA kit (Fujirebio Europe). Free amyloid levels (defined by the amyloid fraction directly accessible to antibodies of the assay) were obtained with the undiluted plasma, whereas total amyloid levels were obtained after the dilution of plasma (1/3) with a denaturing buffer. Free and total Aß1-42 and Aß1-40 levels were measured at inclusion for a subgroup of participants (N = 106) with mild cognitive impairment (MCI) from the BALTAZAR study (a large-scale longitudinal multicenter cohort with a three-year follow-up). Associations between conversion and the free/total plasma Aß1-42 and Aß1-40 levels and Aß1-42/Aß1-40 ratio were analyzed using logistic and Cox Proportional Hazards models. Demographic, clinical, cognitive (MMSE, ADL and IADL), APOE, and MRI characteristics (relative hippocampal volume) were compared using non-parametric (Mann-Whitney) or parametric (Student) tests for quantitative variables and Chi-square or Fisher exact tests for qualitative variables. RESULTS: The risk of conversion to dementia was lower for patients in the highest quartile of free plasma Aß1-42/Aß1-40 (≥ 25.8%) than those in the three lower quartiles: hazard ratio = 0.36 (95% confidence interval [0.15-0.87]), after adjustment for age, sex, education, and APOE ε4 (p-value = 0.022). This was comparable to the risk of conversion in the highest quartile of total plasma Aß1-42/Aß1-40: hazard ratio = 0.37 (95% confidence interval [0.16-0.89], p-value = 0.027). However, while patients in the highest quartile of total plasma Aß1-42/Aß1-40 showed higher MMSE scores and a higher hippocampal volume than patients in the three lowest quartiles of total plasma Aß1-42/Aß1-40, as well as normal CSF biomarker levels, the patients in the highest quartile of free plasma Aß1-42/Aß1-40 did not show any significant differences in MMSE scores, hippocampal volume, or CSF biomarker levels relative to the three lowest quartiles of free plasma Aß1-42/Aß1-40. CONCLUSION: The free plasma Aß1-42/Aß1-40 ratio is associated with a risk of conversion from MCI to dementia within three years, with performance comparable to that of the total plasma Aß1-42/Aß1-40 ratio. Threshold levels of the free and total plasma Aß1-42/Aß1-40 ratio could be determined, with a 60% lower risk of conversion for patients above the threshold than those below.

Association between type 2 diabetes and depressive symptoms after a 1-year follow-up in an older adult Mediterranean population.

OBJECTIVES: To examine the cross-sectional association between baseline depressive symptoms and the presence of type 2 diabetes (T2D), and its association with glycated hemoglobin (HbA1c) and other metabolic variables, and the prospective association of depressive symptoms and HbA1c after 1 year of follow-up. METHODS: n = 6224 Mediterranean older adults with overweight/obesity and metabolic syndrome (48% females, mean age 64.9 ± 4.9 years) were evaluated in the framework of the PREDIMED-Plus study cohort. Depressive symptoms were assessed using the Beck Depression Inventory-II and HbA1c was used to measure metabolic control. RESULTS: The presence of T2D increased the likelihood of higher levels of depressive symptoms (χ2 = 15.84, p = 0.001). Polynomial contrast revealed a positive linear relationship (χ2 = 13.49, p = 0.001), the higher the depressive symptoms levels, the higher the prevalence of T2D. Longitudinal analyses showed that the higher baseline depressive symptoms levels, the higher the likelihood of being within the HbA1c ≥ 7% at 1-year level (Wald-χ2 = 24.06, df = 3, p < .001, for the full adjusted model). Additionally, depressive levels at baseline and duration of T2D predicted higher HbA1c and body mass index, and lower physical activity and adherence to Mediterranean Diet at 1 year of follow-up. CONCLUSIONS: This study supports an association between T2D and the severity of depressive symptoms, suggesting a worse metabolic control from mild severity levels in the short-medium term, influenced by lifestyle habits related to diabetes care. Screening for depressive symptoms and a multidisciplinary integrative therapeutic approach should be ensured in patients with T2D.

Impact of mediterranean diet promotion on environmental sustainability: a longitudinal analysis.

OBJECTIVE: This article aims to estimate the differences in environmental impact (greenhouse gas [GHG] emissions, land use, energy used, acidification and potential eutrophication) after one year of promoting a Mediterranean diet (MD). METHODS: Baseline and 1-year follow-up data from 5800 participants in the PREDIMED-Plus study were used. Each participant's food intake was estimated using validated semi-quantitative food frequency questionnaires, and the adherence to MD using the Dietary Score. The influence of diet on environmental impact was assessed through the EAT-Lancet Commission tables. The influence of diet on environmental impact was assessed through the EAT-Lancet Commission tables. The association between MD adherence and its environmental impact was calculated using adjusted multivariate linear regression models. RESULTS: After one year of intervention, the kcal/day consumed was significantly reduced (-125,1 kcal/day), adherence to a MD pattern was improved (+0,9) and the environmental impact due to the diet was significantly reduced (GHG: -361 g/CO2-eq; Acidification:-11,5 g SO2-eq; Eutrophication:-4,7 g PO4-eq; Energy use:-842,7 kJ; and Land use:-2,2 m2). Higher adherence to MD (high vs. low) was significantly associated with lower environmental impact both at baseline and one year follow-up. Meat products had the greatest environmental impact in all the factors analysed, both at baseline and at one-year follow-up, in spite of the reduction observed in their consumption. CONCLUSIONS: A program promoting a MD, after one year of intervention, significantly reduced the environmental impact in all the factors analysed. Meat products had the greatest environmental impact in all the dimensions analysed.

High accuracy of a blood ctDNA-based multimodal test to detect colorectal cancer.

BACKGROUND: Detection of circulating tumor DNA (ctDNA) is a minimally invasive and convenient blood-based screening strategy that may increase effectiveness of colorectal cancer (CRC) screening. PATIENTS AND METHODS: A novel multimodal ctDNA-based blood assay that integrates genomics, epigenomics and fragmentomics, as well as proteomics in a refined version, was tested in blood samples from two cohorts: (i) consecutive fecal immunochemical test (FIT)-positive individuals from the CRC Barcelona stool-based screening program; (ii) patients diagnosed with CRC. Primary endpoint was the performance of the test to detect CRC at different tumor-node-metastasis (TNM) stages. Secondary endpoint was the ability of the test to detect advanced precancerous lesions (advanced adenoma or advanced serrated lesion). RESULTS: A total of 623 blood samples were analyzed in the primary analysis. Sensitivity and specificity of the assay to detect CRC was 93% and 90%, respectively. The sensitivity of CRC detection according to TNM stages was 84% for stage I, 94% for stage II and 96% for stage III (70/73) (P< 0.024). Sensitivity to detect advanced precancerous lesions was 23% with a refined version of the test (including protein and updating bioinformatic thresholding). CONCLUSION: A blood-based multimodal ctDNA assay detected CRC with high accuracy. This minimally invasive, accessible and convenient assay may help to increase the effectiveness of CRC screening.

Weight Loss and Vitamin D Improve Hyporesponsiveness to Corticosteroids in Obese Asthma.

BACKGROUND AND OBJECTIVES: Obesity negatively impacts on the response of asthma patients to inhaled corticosteroids. The mechanisms underlying this impact are unknown. Objective: To demonstrate that the poor response to inhaled corticosteroids in obese asthma patients is associated with impaired anti-inflammatory activity of corticosteroids and vitamin D deficiency, both of which are improved by weight loss. METHODS: The study population comprised 23 obese asthma patients (OA) (18 females; median (IQR) age 56 [51-59] years), 14 nonobese asthma patients (NOA) (11 females; 53 [43-60] years), 15 obese patients (OP) (13 females; 47 [45-60] years), and 19 healthy controls (HC) (14 females; 43 [34-56] years). Ten OA and 11 OP were evaluated at baseline (V1) and 6 months after bariatric surgery (V2). Corticosteroid response was measured using dexamethasone-induced inhibition of peripheral blood mononuclear cell (PBMC) proliferation. Lung function and serum levels of leptin, adiponectin, and vitamin D were measured at V1 and V2. RESULTS: We found a reduced response to dexamethasone in PBMCs of OP and OA with respect to NOA and HC; this inversely correlated with the adiponectin/leptin ratio and vitamin D levels. Bariatric surgery improved corticosteroid responses in OP and OA and normalized the adiponectin/leptin ratio and vitamin D levels. Exposure of PBMCs to vitamin D potentiated the antiproliferative effects of corticosteroids. Dexamethasone and vitamin D induced similar MKP1 expression in OP and OA. CONCLUSION: The efficacy of weight loss to improve symptoms and lung function in OA may be due, at least in part, to the recovered anti-inflammatory effects of corticosteroids. Vitamin D deficiency may contribute to corticosteroid hyporesponsiveness in OA.

The genus Gautieria (Gomphales) in Europe and the Mediterranean Basin: a morphological and phylogenetic taxonomic revision.

Type material and additional collections of 11 taxa of Gautieria described in Europe and North Africa have been studied, namely G. dubia, G. graveolens, G. morchelliformis var. globispora, G. morchelliformis var. magnicellaris, G. morchelliformis var. morchelliformis, G. morchelliformis var. stenospora, G. otthii, G. pseudovestita, G. retirugosa, G. trabutii and G. villosa. At the same time, morphological and genetic studies on recent and herbarium collections from several European countries have been carried out. This enabled clarification of sections within Gautieria and differentiation of 28 taxa, of which 21 are new to science. However, the deeper relationships and nomenclature changes related to the phylogenetic position of the genus Gautieria within Gomphaceae will not be addressed in this study because they would require a more complete molecular analysis together with that of related genera, e.g., Gomphus, Turbinellus, and the four subgenera of Ramaria. In addition, a lectotype for G. villosa var. villosa and reference specimens for G. graveolens and G. morchelliformis var. morchelliformis are selected, and the new combination G. morchelliformis var. dubia is proposed. Detailed descriptions, macro- and microphotographs and distribution maps of all taxa are provided, as well as extensive information on their ecology, chorology and phylogeny. A key is included to facilitate identification of taxa. Citation: Vidal JM, Cseh P, Merényi Z, et al. 2023. The genus Gautieria (Gomphales) in Europe and the Mediterranean Basin: a morphological and phylogenetic taxonomic revision. Persoonia 50: 48 -122. https://doi.org/10.3767/persoonia.2023.50.03.

Non-linear models for black carbon exposure modelling using air pollution datasets.

Black carbon (BC) is a product of incomplete combustion, present in urban aerosols and sourcing mainly from road traffic. Epidemiological evidence reports positive associations between BC and cardiovascular and respiratory disease. Despite this, BC is currently not regulated by the EU Air Quality Directive, and as a result BC data are not available in urban areas from reference air quality monitoring networks in many countries. To fill this gap, a machine learning approach is proposed to develop a BC proxy using air pollution datasets as an input. The proposed BC proxy is based on two machine learning models, support vector regression (SVR) and random forest (RF), using observations of particle mass and number concentrations (N), gaseous pollutants and meteorological variables as the input. Experimental data were collected from a reference station in Barcelona (Spain) over a 2-year period (2018-2019). Two months of additional data were available from a second urban site in Barcelona, for model validation. BC concentrations estimated by SVR showed a high degree of correlation with the measured BC concentrations (R2 = 0.828) with a relatively low error (RMSE = 0.48 µg/m3). Model performance was dependent on seasonality and time of the day, due to the influence of new particle formation events. When validated at the second station, performance indicators decreased (R2 = 0.633; RMSE = 1.19 µg/m3) due to the lack of N data and PM2.5 and the smaller size of the dataset (2 months). New particle formation events critically impacted model performance, suggesting that its application would be optimal in environments where traffic is the main source of ultrafine particles. Due to its flexibility, it is concluded that the model can act as a BC proxy, even based on EU-regulatory air quality parameters only, to complement experimental measurements for exposure assessment in urban areas.

[ISO 9001 quality approach in Sterilization Unit and developing the skills of agents: Contribution of a multi-support, transdisciplinary and multi-professional training plan]. / Démarche qualité ISO 9001 en stérilisation et développement des compétences des agents : apports d'un plan de formation multi-support, transdisciplinaire et pluri-professionnel.

OBJECTIVES: The Sterilization Unit of the Narbonne Hospital Center (France) has decided to embark on a process of NF EN ISO 9001: 2015 certification. The objective is to describe how the working group has appropriated the provisions relating to staff training in order to build a skills development plan for its Sterilization agents. METHODS: A multi-professional working group has been set up. After a preliminary inventory, an inventory of skills needs, expectations of the agents, available means, and a bibliographical research, the group drew up a training plan with the support of a quality engineer from the Hospital Centre. The training plan was validated by a review of the management of the establishment. RESULTS: Several teaching aids were chosen: a serious game developed by the working group, the planning of instrumentation sessions, quality meetings and feedback committees. The principle of transdisciplinarity and recourse to multi-professional exchanges is the common thread in the elaboration of the training plan. CONCLUSION: The use of the selected materials is formalised in the form of a skills development plan indexed in the institution's quality management system. The application of the requirements of the ISO 9001 standard in terms of training in our Sterilization quality management system enables risk control and continuous improvement of the training plan to comply with technical and regulatory changes in the profession.

Dosage Individualization of Linezolid: Precision Dosing of Linezolid To Optimize Efficacy and Minimize Toxicity.

The high interindividual variability in the pharmacokinetics (PK) of linezolid has been described, which results in an unacceptably high proportion of patients with either suboptimal or potentially toxic concentrations following the administration of a fixed regimen. The aim of this study was to develop a population pharmacokinetic model of linezolid and use this to build and validate alogorithms for individualized dosing. A retrospective pharmacokinetic analysis was performed using data from 338 hospitalized patients (65.4% male, 65.5 [±14.6] years) who underwent routine therapeutic drug monitoring for linezolid. Linezolid concentrations were analyzed by using high-performance liquid chromatography. Population pharmacokinetic modeling was performed using a nonparametric methodology with Pmetrics, and Monte Carlo simulations were employed to calculate the 100% time >MIC after the administration of a fixed regimen of 600 mg administered every 12 h (q12h) intravenously (i.v.). The dose of linezolid needed to achieve a PTA ≥ 90% for all susceptible isolates classified according to EUCAST was estimated to be as high as 2,400 mg q12h, which is 4 times higher than the maximum licensed linezolid dose. The final PK model was then used to construct software for dosage individualization, and the performance of the software was assessed using 10 new patients not used to construct the original population PK model. A three-compartment model with an absorptive compartment with zero-order i.v. input and first-order clearance from the central compartment best described the data. The dose optimization software tracked patients with a high degree of accuracy. The software may be a clinically useful tool to adjust linezolid dosages in real time to achieve prespecified drug exposure targets. A further prospective study is needed to examine the potential clinical utility of individualized therapy.

New duality results for evenly convex optimization problems.

We present new results on optimization problems where the involved functions are evenly convex. By means of a generalized conjugation scheme and the perturbation theory introduced by Rockafellar, we propose an alternative dual problem for a general optimization one defined on a separated locally convex topological space. Sufficient conditions for converse and total duality involving the even convexity of the perturbation function and c-subdifferentials are given. Formulae for the c-subdifferential and biconjugate of the objective function of a general optimization problem are provided, too. We also characterize the total duality by means of the saddle-point theory for a notion of Lagrangian adapted to the considered framework.

A real-time marker of object-based attention in the human brain. A possible component of a "gate-keeping mechanism" performing late attentional selection in the Ventro-Lateral Prefrontal Cortex.

The decision to process an incoming stimulus attentively - and to trigger a follow-up cascade of high-level processes - is strategic for the human brain as it becomes transiently unavailable to subsequent stimulus processing. In this study, we set to identify brain networks that carry out such evaluations. We therefore assessed the time-course of neural responses with intracerebral EEG in human patients during an attentional reading task, contrasting to-be-attended vs. to-be-ignored items. We measured High-Frequency Activity [50-150 â€‹Hz] as a proxy of population-level spiking activity and we identified a crucial component of a Gate-Keeping Mechanism bilateral in the mid-Ventro-Lateral Prefrontal Cortex (VLPFC), at the interplay of the Ventral and Dorsal Attention Networks, that selectively reacts before domain specialized cortical regions that engage in full stimulus analysis according to task demands.

Population Pharmacokinetics of Anidulafungin in Critically Ill Patients.

A two-compartment pharmacokinetic (PK) population model of anidulafungin was fitted to PK data from 23 critically ill patients (age, 65 years [range, 28 to 81 years]; total body weight [TBW], 75 kg [range, 54 to 168 kg]). TBW was associated with clearance and incorporated into a final population PK model. Simulations suggested that patients with higher TBWs had less-extensive MIC coverage. Dosage escalation may be warranted in patients with high TBWs to ensure optimal drug exposures for treatment of Candida albicans and Candida glabrata infections.

Ultra-selection of metastatic colorectal cancer patients using next-generation sequencing to improve clinical efficacy of anti-EGFR therapy.

BACKGROUND: Extended RAS analysis is mandatory in metastatic colorectal cancer (mCRC) patients. The optimal threshold of RAS mutated subclones to identify patients most likely to benefit from antiepidermal growth factor receptor (EGFR) therapy is controversial. Our aim was to assess the clinical impact of detecting mutations in RAS, BRAF, PIK3CA and EGFRS492R in basal tissue tumour samples by using a highly sensitive next-generation sequencing (NGS) technology in mCRC patients treated with chemotherapy plus anti-EGFR or anti-vascular endothelial growth factor. PATIENTS AND METHODS: Five hundred and eighty-one tumour samples from untreated mCRC patients from 7 clinical studies were collected. Mutational analysis was carried out by standard-of-care (therascreen pyro) with a sensitivity detection of 5% mutant allele fraction (MAF), and compared with NGS technology using 454GS Junior platform (Roche Applied Science, Germany) with a sensitivity of 1%. Molecular results were correlated with clinical outcomes. RESULTS: After quality assessment, 380 samples were evaluable for molecular analysis. Standard-of-care mutational analysis detected RAS, BRAFV600E or PIK3CA mutations in 56.05% of samples compared with 69.21% by NGS (P = 0.00018). NGS identified coexistence of multiple low-frequency mutant alleles in 96 of the 263 mutated cases (36.5%; range 2-7). Response rate (RR), progression-free survival (PFS) and overall survival (OS) were increasingly improved in patients with RAS wild-type, RAS/BRAF wild-type or quadruple (KRAS/NRAS/BRAF/PIK3CA) wild-type tumours treated with anti-EGFR, assessed by standard-of-care. No additional benefit in RR, PFS or OS was observed by increasing the detection threshold to 1% by NGS. An inverse correlation between the MAF of the most prevalent mutation detected by NGS and anti-EGFR response was observed (P = 0.039). EGFRS492Rmutation was not detected in untreated samples. CONCLUSIONS: No improvement in the selection of patients for anti-EGFR therapy was obtained by adjusting the mutation detection threshold in tissue samples from 5% to 1% MAF. Response to anti-EGFR was significantly better in patients with quadruple wild-type tumours.

Novel Method for the Direct Measurement of the τ Lepton Dipole Moments.

A novel method for the direct measurement of the elusive magnetic and electric dipole moments of the τ lepton is presented. The experimental approach relies on the production of τ^{+} leptons from D_{s}^{+}→τ^{+}ν_{τ} decays, originating in fixed-target collisions at the LHC. A sample of polarized τ^{+} leptons is kinematically selected and subsequently channeled in a bent crystal. The magnetic and electric dipole moments of the τ^{+} lepton are measured by determining the rotation of the spin-polarization vector induced by the intense electromagnetic field between crystal atomic planes. The experimental technique is discussed along with the expected sensitivities.

A phylogenetic and taxonomic revision of sequestrate Russulaceae in Mediterranean and temperate Europe.

A comprehensive morphological and genetic study of type material and new collections of sequestrate Russulales species formerly belonging to the genera Arcangeliella, Elasmomyces, Gymnomyces, Hydnangium, Hymenogaster, Macowanites, Martellia, Secotium and Zelleromyces is here undertaken, for the purpose of providing a complete taxonomical revision of sequestrate Russulaceae species in the Mediterranean and temperate regions of Europe. As a result, seven distinct taxa in the genus Lactarius and 18 in the genus Russula are identified. Six of them are new species: L. populicola, L. subgiennensis, R. bavarica, R. candidissima, R. hobartiae and R. mediterraneensis, and seven represent new combinations: L. josserandii (≡ Zelleromyces josserandii), L. soehneri (≡ Hydnangium soehneri), R. candida (≡ Hydnangium candidum), R. cerea (≡ Hydnangium cereum), R. messapica var. messapicoides (≡ Macowanites messapicoides), R. meridionalis (≡ Zelleromyces meridionalis) and R. neuhoffii (≡ Hydnangium neuhoffii). Twenty-two of the 25 taxa are illustrated, while descriptions, microscopy images, as well as extensive information on the ecology, chorology and phylogeny for all taxa are provided. A key is further included to facilitate their identification.

Analysis of the evolution of cortical and trabecular bone compartments in the proximal femur after spinal cord injury by 3D-DXA.

Marked trabecular and cortical bone loss was observed at the proximal femur short-term after spinal cord injury (SCI). 3D-DXA provided measurement of vBMD evolution at both femoral compartments and cortical thinning, thereby suggesting that this technique could be useful for bone analysis in these patients. INTRODUCTION: SCI is associated with a marked increase in bone loss and risk of osteoporosis development short-term after injury. 3D-DXA is a new imaging analysis technique providing 3D analysis of the cortical and trabecular bone from DXA scans. The aim of this study was to assess the evolution of trabecular macrostructure and cortical bone using 3D-DXA in patients with recent SCI followed over 12 months. METHODS: Sixteen males with recent SCI (< 3 months since injury) and without antiosteoporotic treatment were included. Clinical assessment, bone mineral density (BMD) measurements by DXA, and 3D-DXA evaluation at proximal femur (analyzing the integral, trabecular and cortical volumetric BMD [vBMD] and cortical thickness) were performed at baseline and at 6 and 12 months of follow-up. RESULTS: vBMD significantly decreased at integral, trabecular, and cortical compartments at 6 months (- 8.8, - 11.6, and - 2.4%), with a further decrease at 12 months, resulting in an overall decrease of - 16.6, - 21.9, and - 5.0%, respectively. Cortical thickness also decreased at 6 and 12 months (- 8.0 and - 11.4%), with the maximal decrease being observed during the first 6 months. The mean BMD losses by DXA at femoral neck and total femur were - 17.7 and - 21.1%, at 12 months, respectively. CONCLUSIONS: Marked trabecular and cortical bone loss was observed at the proximal femur short-term after SCI. 3D-DXA measured vBMD evolution at both femoral compartments and cortical thinning, providing better knowledge of their differential contributory role to bone strength and probably of the effect of therapy in these patients.

Demonstration of Single-Barium-Ion Sensitivity for Neutrinoless Double-Beta Decay Using Single-Molecule Fluorescence Imaging.

A new method to tag the barium daughter in the double-beta decay of ^{136}Xe is reported. Using the technique of single molecule fluorescent imaging (SMFI), individual barium dication (Ba^{++}) resolution at a transparent scanning surface is demonstrated. A single-step photobleach confirms the single ion interpretation. Individual ions are localized with superresolution (∼2 nm), and detected with a statistical significance of 12.9σ over backgrounds. This lays the foundation for a new and potentially background-free neutrinoless double-beta decay technology, based on SMFI coupled to high pressure xenon gas time projection chambers.

Fermented dairy products, diet quality, and cardio-metabolic profile of a Mediterranean cohort at high cardiovascular risk.

BACKGROUND AND AIMS: Fermented dairy products have been associated with a better diet quality and cardio-metabolic profile. However, in Mediterranean populations, these associations have not been well characterized. The aim of this study was to assess the diet quality and the associations between the consumption of total fermented dairy products and their subtypes and the prevalence of Metabolic Syndrome (MetS) components in a Mediterranean population at high cardiovascular risk. METHODS AND RESULTS: Baseline cross-sectional analyses were conducted on 6,572 men and women (mean age: 65 years) with overweight or obesity and MetS recruited into the PREDIMED-Plus cohort. A 143-item Food Frequency Questionnaire (FFQ) was used, and anthropometrical, biochemical, and blood pressure measurements were recorded. Multivariate-adjusted Cox regressions were fitted to analyze the association between quartiles of consumption of fermented dairy products and their subtypes and MetS components to estimate the relative risk (RR) and 95% confidence intervals (95% CIs). Participants who were high consumers of fermented dairy products reported a higher consumption of fruit, vegetables, fish, nuts, and whole bread and a lower consumption of white bread, alcohol, and cookies. Participants in the higher quartile showed a lower prevalence of the low HDL-cholesterol component of the MetS (RR=0.88; 95% CI: 0.78-0.98) than those in the lowest quartile of cheese consumption. Cheese consumption was inversely associated with the prevalence of hypertriglyceridemia. Total fermented dairy products, yogurt, and its types were not associated with any of the MetS components. CONCLUSIONS: Compared to nonconsumers, participants consuming fermented dairy products reported a better diet quality and, particularly, cheese consumers presented a lower prevalence of hypertriglyceridemia and low HDL-cholesterol plasma levels, which are MetS components.

Plasma ctDNA RAS mutation analysis for the diagnosis and treatment monitoring of metastatic colorectal cancer patients.

BACKGROUND: RAS assessment is mandatory for therapy decision in metastatic colorectal cancer (mCRC) patients. This determination is based on tumor tissue, however, genotyping of circulating tumor (ct)DNA offers clear advantages as a minimally invasive method that represents tumor heterogeneity. Our study aims to evaluate the use of ctDNA as an alternative for determining baseline RAS status and subsequent monitoring of RAS mutations during therapy as a component of routine clinical practice. PATIENTS AND METHODS: RAS mutational status in plasma was evaluated in mCRC patients by OncoBEAM™ RAS CRC assay. Concordance of results in plasma and tissue was retrospectively evaluated. RAS mutations were also prospectively monitored in longitudinal plasma samples from selected patients. RESULTS: Analysis of RAS in tissue and plasma samples from 115 mCRC patients showed a 93% overall agreement. Plasma/tissue RAS discrepancies were mainly explained by spatial and temporal tumor heterogeneity. Analysis of clinico-pathological features showed that the site of metastasis (i.e. peritoneal, lung), the histology of the tumor (i.e. mucinous) and administration of treatment previous to blood collection negatively impacted the detection of RAS in ctDNA. In patients with baseline mutant RAS tumors treated with chemotherapy/antiangiogenic, longitudinal analysis of RAS ctDNA mirrored response to treatment, being an early predictor of response. In patients RAS wt, longitudinal monitoring of RAS ctDNA revealed that OncoBEAM was useful to detect emergence of RAS mutations during anti-EGFR treatment. CONCLUSION: The high overall agreement in RAS mutational assessment between plasma and tissue supports blood-based testing with OncoBEAM™ as a viable alternative for genotyping RAS of mCRC patients in routine clinical practice. Our study describes practical clinico-pathological specifications to optimize RAS ctDNA determination. Moreover, OncoBEAM™ is useful to monitor RAS in patients undergoing systemic therapy to detect resistance and evaluate the efficacy of particular treatments.

Concordance of blood- and tumor-based detection of RAS mutations to guide anti-EGFR therapy in metastatic colorectal cancer.

BACKGROUND: Circulating tumor DNA (ctDNA) is a potential source for tumor genome analysis. We explored the concordance between the mutational status of RAS in tumor tissue and ctDNA in metastatic colorectal cancer (mCRC) patients to establish eligibility for anti-epidermal growth factor receptor (EGFR) therapy. PATIENTS AND METHODS: A prospective-retrospective cohort study was carried out. Tumor tissue from 146 mCRC patients was tested for RAS status with standard of care (SoC) PCR techniques, and Digital PCR (BEAMing) was used both in plasma and tumor tissue. RESULTS: ctDNA BEAMing RAS testing showed 89.7% agreement with SoC (Kappa index 0.80; 95% CI 0.71 - 0.90) and BEAMing in tissue showed 90.9% agreement with SoC (Kappa index 0.83; 95% CI 0.74 - 0.92). Fifteen cases (10.3%) showed discordant tissue-plasma results. ctDNA analysis identified nine cases of low frequency RAS mutations that were not detected in tissue, possibly due to technical sensitivity or heterogeneity. In six cases, RAS mutations were not detected in plasma, potentially explained by low tumor burden or ctDNA shedding. Prediction of treatment benefit in patients receiving anti-EGFR plus irinotecan in second- or third-line was equivalent if tested with SoC PCR and ctDNA. Forty-eight percent of the patients showed mutant allele fractions in plasma below 1%. CONCLUSIONS: Plasma RAS determination showed high overall agreement and captured a mCRC population responsive to anti-EGFR therapy with the same predictive level as SoC tissue testing. The feasibility and practicality of ctDNA analysis may translate into an alternative tool for anti-EGFR treatment selection.