Influence of nonalcoholic fatty liver disease severity on carotid adventitial vasa vasorum.

Introduction: Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the world's population and encompasses a spectrum of liver conditions, from non-alcoholic steatohepatitis (NASH) to inflammation and fibrosis. In addition, NAFLD also links to extrahepatic conditions like diabetes or obesity. However, it remains unclear if NAFLD independently correlates with the onset and progression of atherosclerosis. Material and methods: This cross-sectional study aimed to explore the relationship between NAFLD severity, assessed via liver biopsy, and early atherosclerosis using adventitial vasa vasorum (VV) density. It included 44 patients with obesity (33 with steatosis, 11 with NASH) undergoing bariatric surgery. Results: Results revealed no significant differences in adventitial VV density between steatosis and NASH groups, neither in the mean values [0.759 ± 0.104 vs. 0.780 ± 0.043, P=0.702] nor left-right sides. Similarly, carotid intima-media thickness (cIMT) did not vary between these groups. Additionally, no linear correlation existed between VV density and cIMT. Only gender showed an association with VV density. Conclusion: These findings suggest that NASH severity doesn't independently drive early atherosclerosis or affects cIMT. Gender might play a role in early atherosclerotic disease in NAFLD, impacting VV density and cIMT. This highlights the need to consider other risk factors when evaluating cardiovascular risk in NAFLD patients.

Role of Advanced Glycation End Products as New Biomarkers in Systemic Lupus Erythematosus.

Advanced glycation end-products (AGEs) may play a relevant role as inducers in the chronic inflammatory pathway present in immune-mediated diseases, such as systemic lupus erythematosus (SLE). AGEs concentrations have been associated, with discrepant results to date, with some parameters such as disease activity or accrual damage, suggesting their potential usefulness as biomarkers of the disease. Our objectives are to confirm differences in AGEs levels measured by cutaneous autofluorescence between SLE patients and healthy controls (HC) and to study their correlation with various disease parameters. Cross-sectional study, where AGEs levels were measured by skin autofluorescence, and SLE patients' data were compared with those of sex- and age-matched HC in a 1:3 proportion through a multiple linear regression model. Associations of AGEs levels with demographic and clinical data were analyzed through ANOVA tests. Both analyses were adjusted for confounders. AGEs levels in SLE patients were significantly higher than in HC (p < 0.001). We found statistically significant positive associations with SLE disease activity index (SLEDAI) and damage index (SDI), physician and patient global assessment, C-reactive protein, leukocyturia, complement C4, IL-6 and oral ulcers. We also found a negative statistically significant association with current positivity of anti-nuclear and anti-Ro60 antibodies. AGEs seem to have a contribution in LES pathophysiology, being associated with activity and damage and having a role as a new management and prognosis biomarker in this disease. The association with specific antibodies and disease manifestations may indicate a specific clinical phenotype related to higher or lower AGEs levels.

Association between adherence to the mediterranean diet, physical activity, and sleep apnea-hypopnea syndrome (SAHS) in a middle-aged population with cardiovascular risk: Insights from the ILERVAS cohort.

INTRODUCTION: Sleep Apnea-Hypopnea Syndrome (SAHS) is a common sleep disorder influenced by factors like age, gender, and obesity. The Mediterranean Diet (MedDiet) and physical activity have shown health benefits in lung diseases, but their effects on SAHS remain underexplored. METHODS: In a cross-sectional analysis of 678 middle-aged individuals with low-to-moderate cardiovascular risk from the ILERVAS cohort, we assessed adherence to the MedDiet and physical activity levels using validated tools. Sleep parameters, SAHS severity, and excessive daytime sleepiness were evaluated through non-attended cardiorespiratory polygraphy and the Epworth Sleepiness Scale. Multinomial logistic regression models were employed to assess the relationship between MedDiet adherence, physical activity, and SAHS severity. RESULTS: The prevalence of severe, moderate, and mild SAHS was 15.5%, 23.2% and 36.1%, respectively. We found no significant associations between adherence to the MedDiet, physical activity levels, and the presence or severity of SAHS. However, we noted a significant interaction between MedDiet and physical activity with minimum SpO2 values (p = 0.049). Notably, consuming more than one serving of red meat per day was independently associated with a higher risk of moderate SAHS [OR = 2.65 (1.29-5.44), p = 0.008]. CONCLUSION: Individually, MedDiet adherence and physical activity did not show independent correlations with SAHS. However, when considered together, a minimal but significant effect on minimum SpO2 was observed. Additionally, red meat consumption was associated with a moderate risk of SAHS. Further research is necessary to comprehend the intricate connections between lifestyle factors and sleep-breathing disorders, with a focus on personalized approaches for high-risk populations.

Matrix Gla protein polymorphism rs1800802 is associated with atheroma plaque progression and with cardiovascular events in a chronic kidney disease cohort.

Background: Chronic kidney disease (CKD) is associated with increased atherosclerotic burden and higher risk for cardiovascular events (CVE). Atherosclerosis has a significant genetic component and, in CKD, it is influenced by mineral metabolism alterations. Therefore, genetic modifications of mineral metabolism-related proteins could affect atherosclerosis in CKD patients. In the present study we investigated the role of single nucleotide polymorphisms (SNPs) of the matrix gamma-carboxy glutamic acid protein (MGP) on atherosclerosis progression and CVE in a CKD cohort. Methods: A total of 2187 CKD patients from the Observatorio Nacional de Aterosclerosis en Nefrologia (NEFRONA) study were genotyped for SNPs present in the matrix gamma-carboxy glutamic acid (Gla) protein (MGP) gene. Atheromatosis was detected by vascular ultrasound. Progression of atheromatosis, defined as an increase in territories with plaque, was assessed after 24 months. Patients were followed for 48 months for CVE. Association of SNPs with plaque progression was assessed by logistic regression and their capacity to predict CVE by Cox regression. Results: Three SNPs of the MGP gene were analyzed. No association of the rs4236 or the rs1800801 SNPs was detected with any of the outcomes. However, patients homozygotes for the minor allele of the rs1800802 SNP showed higher adjusted risk for plaque progression [odds ratio 2.3 (95% confidence interval 1.06-4.9)] and higher risk of suffering a CVE [hazard ratio 2.16 (95% confidence interval 1.13-4.12)] compared with the rest of genotypes. No association of the SNP with total or dp-ucMGP levels was found in a subsample. Conclusions: The rs1800802 polymorphism of MGP is associated with plaque progression and CVE in CKD patients.

Gender-specific risk factors and outcomes of hyperkalemia in CKD patients: smoking as a driver of hyperkalemia in men.

Background: Hyperkalemia is common among patients with chronic kidney disease (CKD) but there is scarce information on differential risk factors and outcomes for men and women. For instance, smoking has been suggested to be a risk factor for hyperkalemia, but specific analysis of the sex-specific impact of smoking on hyperkalemia in CKD is lacking. Methods: We studied serum potassium levels in 2891 participants from the NEFRONA cohort: 483 controls (47% women) and 2408 CKD patients (38% women) without prior cardiovascular disease (CVD), assessing whether smoking is a risk factor for hyperkalemia, and if hyperkalemia is associated with outcomes separately for men and women. Results: Median potassium levels and prevalence of hypo and hyperkalemia were higher in CKD participants than in controls. Serum potassium levels were higher and hyperkalemia and severe hyperkalemia more prevalent in men than in women with non-dialysis CKD (G3-G5). The highest prevalence of hyperkalemia for each gender was found in CKD G4-G5 and hemodialysis patients for men (46%) and in hemodialysis (54%) for women. Gender-specific etiological multivariate analysis identified current smoking as a risk factor for hyperkalemia only in men. Hyperkalemia was independently associated with stopping RAASi, an outcome which was more common in women. Hyperkalemia was also associated to higher risk of cardiovascular events within 4 years in men. In conclusion, hyperkalemia is common among men and women with CKD, but the prevalence, risk factors and outcomes may differ by gender. Specifically, current smoking is a driver of hyperkalemia in men.

Validation of an in vivo transit dosimetry algorithm using Monte Carlo simulations and ionization chamber measurements.

PURPOSE: Transit dosimetry is a safety tool based on the transit images acquired during treatment. Forward-projection transit dosimetry software, as PerFRACTION, compares the transit images acquired with an expected image calculated from the DICOM plan, the CT, and the structure set. This work aims to validate PerFRACTION expected transit dose using PRIMO Monte Carlo simulations and ionization chamber measurements, and propose a methodology based on MPPG5a report. METHODS: The validation process was divided into three groups of tests according to MPPG5a: basic dose validation, IMRT dose validation, and heterogeneity correction validation. For the basic dose validation, the fields used were the nine fields needed to calibrate PerFRACTION and three jaws-defined. For the IMRT dose validation, seven sweeping gaps fields, the MLC transmission and 29 IMRT fields from 10 breast treatment plans were measured. For the heterogeneity validation, the transit dose of these fields was studied using three phantoms: 10 , 30 , and a 3 cm cork slab placed between 10 cm of solid water. The PerFRACTION expected doses were compared with PRIMO Monte Carlo simulation results and ionization chamber measurements. RESULTS: Using the 10 cm solid water phantom, for the basic validation fields, the root mean square (RMS) of the difference between PerFRACTION and PRIMO simulations was 0.6%. In the IMRT fields, the RMS of the difference was 1.2%. When comparing respect ionization chamber measurements, the RMS of the difference was 1.0% both for the basic and the IMRT validation. The average passing rate with a γ(2%/2 mm, TH = 20%) criterion between PRIMO dose distribution and PerFRACTION expected dose was 96.0% ± 5.8%. CONCLUSION: We validated PerFRACTION calculated transit dose with PRIMO Monte Carlo and ionization chamber measurements adapting the methodology of the MMPG5a report. The methodology presented can be applied to validate other forward-projection transit dosimetry software.

PRIMO Monte Carlo software as a tool for commissioning of an external beam radiotherapy treatment planning system.

Background: The purpose was to validate the PRIMO Monte Carlo software to be used during the commissioning of a treatment planning system (TPS). Materials and methods: The Acuros XB v. 16.1 algorithm of the Eclipse was configured for 6 MV and 6 MV flattening-filter-free (FFF) photon beams, from a TrueBeam linac equipped with a high-definition 120-leaf multileaf collimator (MLC). PRIMO v. 0.3.64.1814 software was used with the phase space files provided by Varian and benchmarked against the reference dosimetry dataset published by the Imaging and Radiation Oncology Core-Houston (IROC-H). Thirty Eclipse clinical intensity-modulated radiation therapy (IMRT)/volumetric modulated arc therapy (VMAT) plans were verified in three ways: 1) using the PTW Octavius 4D (O4D) system; 2) the Varian Portal Dosimetry system and 3) the PRIMO software. Clinical validation of PRIMO was completed by comparing the simulated dose distributions on the O4D phantom against dose measurements for these 30 clinical plans. Agreement evaluations were performed using a 3% global/2 mm gamma index analysis. Results: PRIMO simulations agreed with the benchmark IROC-H data within 2.0% for both energies. Gamma passing rates (GPRs) from the 30 clinical plan verifications were (6 MV/6MV FFF): 99.4% ± 0.5%/99.9% ± 0.1%, 99.8% ± 0.4%/98.9% ± 1.4%, 99.7% ± 0.4%/99.7% ± 0.4%, for the 1), 2) and 3) verification methods, respectively. Agreement between PRIMO simulations on the O4D phantom and 3D dose measurements resulted in GPRs of 97.9% ± 2.4%/99.7% ± 0.4%. Conclusion: The PRIMO software is a valuable tool for dosimetric verification of clinical plans during the commissioning of the primary TPS.

Calprotectin is a contributor to and potential therapeutic target for vascular calcification in chronic kidney disease.

Vascular calcification is an important risk factor for cardiovascular (CV) mortality in patients with chronic kidney disease (CKD). It is also a complex process involving osteochondrogenic differentiation of vascular smooth muscle cells (VSMCs) and abnormal deposition of minerals in the vascular wall. In an observational, multicenter European study, including 112 patients with CKD from Spain and 171 patients on dialysis from France, we used serum proteome analysis and further validation by ELISA to identify calprotectin, a circulating damage-associated molecular pattern protein, as being independently associated with CV outcome and mortality. This was confirmed in an additional cohort of 170 patients with CKD from Sweden, where increased serum calprotectin concentrations correlated with increased vascular calcification. In primary human VSMCs and mouse aortic rings, calprotectin exacerbated calcification. Treatment with paquinimod, a calprotectin inhibitor, as well as pharmacological inhibition of the receptor for advanced glycation end products and Toll-like receptor 4 inhibited the procalcifying effect of calprotectin. Paquinimod also ameliorated calcification induced by the sera of uremic patients in primary human VSMCs. Treatment with paquinimod prevented vascular calcification in mice with chronic renal failure induced by subtotal nephrectomy and in aged apolipoprotein E-deficient mice as well. These observations identified calprotectin as a key contributor of vascular calcification, and increased circulating calprotectin was strongly and independently associated with calcification, CV outcome, and mortality in patients with CKD. Inhibition of calprotectin might therefore be a promising strategy to prevent vascular calcification in patients with CKD.

Antihypertensive Effects of an Optimized Aged Garlic Extract in Subjects with Grade I Hypertension and Antihypertensive Drug Therapy: A Randomized, Triple-Blind Controlled Trial.

The use of garlic (Allium sativum) for treating arterial hypertension has been recognized as effective for several decades. However, tolerance to treatment is low, and several technological modifications have been developed to improve its tolerability, such as the aging process at controlled temperature and humidity. This study aims to validate the antihypertensive effects of an optimized extract of aged black garlic with low doses of s-allyl-cysteine (SAC) in a Grade I hypertensive population with drug treatment. A randomized, triple-blind, placebo-controlled parallel trial was developed, where a daily supplementation with 0.25 mg/day of SAC for 12 weeks was performed. A reduction in systolic and diastolic blood pressure of 1.8 mmHg (0.7 to 4.1 95% CI) and 1.5 mmHg (0.3 to 3.0 95% CI), respectively, was observed. Similarly, an increase in blood nitric oxide (10.3 µM, 1.1 to 19.5 95% CI) and antioxidant capacity (7 × 10-3 µM TE/min, (1.2 to 13 × 10-3 95% CI) and a reduction in uric acid levels (-0.3 mg/dL, -0.5 to -0.001 95% CI) and ACE activity (-9.3 U/L; -18.4 to -0.4 95% CI) were observed. No changes in endothelial function and inflammatory cytokines were observed. It was concluded that low-dose SAC supplementation in an optimized black-garlic extract allows for an extra-significant reduction in blood pressure in a Grade I hypertensive population receiving drug treatment.

Low adherence to the Mediterranean diet is associated with increased prevalence and number of atherosclerotic plaques in the ILERVAS cohort.

BACKGROUND AND AIMS: Current research on the association between dietary patterns and subclinical atherosclerotic disease (SAD) is still limited, and published results are inconsistent and often consist of small population sizes. We aimed to evaluate the association between the Mediterranean diet (MDiet) and SAD in a large cohort of Mediterranean individuals. METHODS: This was a cross-sectional study that included 8116 subjects from the ILERVAS cohort. The presence of atherosclerotic plaques (AP) was assessed by ultrasound examination. Adherence to the MDiet was assessed using the 14-item Mediterranean Diet Adherence Score (MEDAS). Inclusion criteria were subjects with at least one cardiovascular risk factor. Exclusion criteria were a clinical history of diabetes, chronic kidney disease, or a prior cardiovascular event. Bivariable and multivariable models were performed. RESULTS: Compared with subjects without SAD, participants with SAD were older and had a higher frequency of smoking habit, hypertension, dyslipidemia, HbA1c and waist circumference. The adjusted multivariable analysis showed that a higher MEDAS was associated with a lower risk of AP (incidence rate ratios [IRR] 0.97, 95% CI [0.96-0.98]; p<0.001). Furthermore, moderate or high adherence to the MDiet was associated with a lower number of AP compared with a low MDiet adherence (IRR 0.90, 95% CI [0.87-0.94]; p<0.001). In both models, female sex was associated with a lower risk of AP. CONCLUSIONS: Our findings point to a potentially protective role of MDiet for SAD in a Mediterranean population with low-to-moderate cardiovascular risk. Further research is needed to establish a causal relationship between both variables.

Cumulative tobacco consumption has a dose-dependent effect on atheromatosis burden and improves severe atheromatosis prediction in asymptomatic middle-aged individuals: The ILERVAS study.

BACKGROUND AND AIMS: Sex-specific impact of cumulative tobacco consumption (CTC) on atheromatosis extension and total plaque area remains unknown. We aimed to determine the impact of CTC in atheromatosis localization and burden. METHODS: We performed a cross-sectional analysis in 8330 asymptomatic middle-aged individuals. 12-territory vascular ultrasounds in carotid and femoral arteries were performed to detect atheromatous plaque presence and to measure total plaque area. Adjusted regressions and conditional predictions by smoking habit or CTC (stratified in terciles as low (≤13.53), medium (13.54-29.3), and high (>29.3 packs-year)) were calculated. Severe atheromatosis (SA, ≥3 territories with atheroma plaque) was predicted with the Systematic COronary Risk Evaluation 2 (SCORE2) model. The improvement of SA prediction after adding CTC was evaluated. RESULTS: CTC was associated with an increased risk of atheromatosis, stronger in femoral than in carotid artery, but similar in both sexes. A dose-dependent effect of CTC on the number of territories with atheroma plaque and total plaque area was observed. Addition of CTC to the SCORE2 showed a higher sensitivity, accuracy, and negative predictive value in males, and a higher specificity and positive predictive value in females. In both sexes, the new SCORE2-CTC model showed a significant increase in AUC (males: 0.033, females: 0.038), and in the integrated discrimination index (males: 0.072; females: 0.058, p < 0.001). Age and CTC were the most important clinical predictors of SA in both sexes. CONCLUSIONS: CTC shows a dose-dependent association with atheromatosis burden, impacts more strongly in femoral arteries, and improves SA prediction.

Gamma passing rates of daily EPID transit images correlate to PTV coverage for breast cancer IMRT treatment plans.

PURPOSE: The use of the transit image obtained with the electronic portal-imaging device (EPID) is becoming an extended method to perform in-vivo dosimetry. The transit images acquired during each fraction can be compared with a predicted image, if available, or with a baseline image, usually the obtained in the first fraction. This work aims to study the dosimetric impact of the failing fractions and to evaluate the appropriateness of using a baseline image in breast plans. MATERIAL AND METHODS: Twenty breast patients treated in a Halcyon were retrospectively selected. For each patient and fraction, the treatment plan was calculated over the daily CBCT image. For each fraction, the differences respect to the treatment plan values of OARs and PTV dosimetric parameters were analyzed: ΔDmean , ΔD95%, ΔD98%, ΔD2%, ΔV36Gy, ΔV38.5Gy, and ΔV43.5Gy. Daily fractions were ranked according to the differences found in the dosimetric parameters between the treatment plan and the daily CBCT to establish the best fraction. The daily transit images acquired in every fraction were compared to the first fraction using the global gamma index with the Portal Dosimetry tool. The comparison was repeated using the best fraction image as a baseline. We assessed the correlation of the dosimetric differences obtained from the CBCT images-based treatment plans with the gamma index passing rates obtained using first fraction and best fraction as baseline. RESULTS: Average values of -11.6% [-21.4%, -3.3%] and -3.2% [-1.0%, -10.3%] for the ∆PTVD98% and ∆PTVD95% per every 10% decrease in the passing rate were found, respectively. When using the best fraction as baseline patients were detected with failing fractions that were not detected with the first fraction as baseline. CONCLUSION: The gamma passing rates of daily transit images correlate with the coverage loss parameters in breast IMRT plans. Using first fraction image as baseline can lead to the non-detectability of failing fractions.

Treatment time of image-guided radiotherapy with a Halcyon 2.0 system.

INTRODUCTION: The treatment fraction time is a key indicator of the external beam radiotherapy process. The Halcyon system was designed to improve the clinical workflow, according to the manufacturer (Varian Medical Systems). Few works studied the actual delivery efficiency of the Halcyon system. This work analyzed the treatment time on a Halcyon 2.0 unit for a variety of sites along a period of 9 months. MATERIALS AND METHODS: Treatment time included patient setup, image acquisition, image-guided online couch correction, and radiation delivery time. Data were extracted from the ARIA oncology information system and were studied as a function of the treatment site, the delivery modality, and the time from the first day of treatments with the Halcyon 2.0 system in our institution. RESULTS: A total of 8599 fractions were delivered during the analyzed period (69.5% from VMAT plans, and 30.5% from IMRT plans). The number of fractions by site ranged from 30 for anal canal to 1933 for prostate. Five sites (prostate, lung, pelvis with prostate, breast, and gynecological sites) accounted for the 84% of the fractions. After a 2-week adaptation period of the staff, the daily mean treatment time was reduced to less than 12 min. The mean treatment time of all the fractions amounted to 10.5 ± 3.8 min. CONCLUSIONS: The Halcyon 2.0 allowed delivering online image-guided radiation therapy in all fractions with total treatment time consistently below the 12-min standard time slot, for most of the analyzed treatment sites.

Serum Phosphate Levels Modify the Impact of FGF23 Levels on Hemoglobin in Chronic Kidney Disease.

Anemia is a complication of chronic kidney disease (CKD). Phosphate and fibroblast growth factor-23 (FGF23) have a close relationship, as both are related to the pathogenesis of anemia. However, the possible interplay between them regarding their effect on anemia has not been evaluated. This was a cross-sectional study of 896 participants from the NEFRONA study (273 CKD3, 246 CKD4-5, 282 dialysis and 95 controls). The levels of 25(OH) and 1,25(OH)2 vitamin D, intact FGF23 (iFGF23) and soluble Klotho were measured, together with standard blood biochemistries. Anemia was defined as hemoglobin levels < 13 g/dL in men and <12 g/dL in women. Patients with anemia (407, 45.4%) were younger, mostly men and diabetic; were in advanced CKD stages; had lower calcium, 1,25(OH)2 vitamin D and albumin levels; and had higher ferritin, phosphate, intact PTH, and iFGF23. An inverse correlation was observed between hemoglobin and both iFGF23 and phosphate. The multivariate logistic regression analyses showed that the adjusted risk of anemia was independently associated with higher serum phosphate and LogiFGF23 levels (ORs (95% CIs) of 4.33 (2.11−8.90) and 8.75 (3.17−24.2), respectively (p < 0.001)). A significant interaction between phosphate and iFGF23 (OR of 0.66 (0.53−0.83), p < 0.001) showed that the rise in the adjusted predicted risk of anemia with the increase in iFGF23 was steeper when phosphate levels were low. Phosphate levels acted as modifiers of the effect of iFGF23 concentration on anemia. Thus, the effect of the increase in iFGF23 levels was stronger when phosphate levels were low.

New Variants of Pseudomonas aeruginosa High-Risk Clone ST233 Associated with an Outbreak in a Mexican Paediatric Hospital.

Recent multidrug resistance in Pseudomonas aeruginosa has favoured the adaptation and dissemination of worldwide high-risk strains. In June 2018, 15 P. aeruginosa strains isolated from patients and a contaminated multi-dose meropenem vial were characterized to assess their association to an outbreak in a Mexican paediatric hospital. The strains were characterized by antibiotic susceptibility profiling, virulence factors' production, and biofilm formation. The clonal relationship among isolates was determined with pulse-field gel electrophoresis (PFGE) and multi-locus sequence typing (MLST) sequencing. Repressor genes for the MexAB-OprM efflux pump were sequenced for haplotype identification. Of the strains, 60% were profiled as extensively drug-resistant (XDR), 33% as multidrug-resistant (MDR), and 6.6% were classified as sensitive (S). All strains presented intermediate resistance to colistin, and 80% were sensitive to aztreonam. Pyoverdine was the most produced virulence factor. The PFGE technique was performed for the identification of the outbreak, revealing eight strains with the same electrophoretic pattern. ST235 and ten new sequence types (STs) were identified, all closely related to ST233. ST3241 predominated in 26.66% of the strains. Twenty-five synonymous and seventeen nonsynonymous substitutions were identified in the regulatory genes of the MexAB-OprM efflux pump, and nalC was the most variable gene. Six different haplotypes were identified. Strains from the outbreak were metallo-ß-lactamases and phylogenetically related to the high-risk clone ST233.

Monte Carlo-based independent dose verification of radiosurgery HyperArc plans.

PURPOSE: To investigate the feasibility of using the free PRIMO Monte Carlo software for independent dose check of cranial SRS plans designed with the Varian HyperArc (HA) technique. MATERIALS AND METHODS: In this study, the PRIMO Monte Carlo software v. 0.3.64.1800 was used with the phase-space files (v. 2, Feb. 27, 2013) provided by Varian for 6 MV flattening-filter-free (FFF) photon beams from a Varian TrueBeam linear accelerator (linac), equipped with a Millennium 120 multileaf collimator (MLC). This configuration was validated by comparing the percentage depth doses (PDDs), lateral profiles and relative output factors (OFs) simulated in a water phantom against measurements for field sizes from 1 × 1 to 40 × 40 cm2. The agreement between simulated and experimental relative dose curves was evaluated using a global (G) gamma index analysis. In addition, the accuracy of PRIMO to model the MLC was investigated (dosimetric leaf gap, tongue and groove, leaf transmission and interleaf leakage). Thirty-five HA SRS plans computed in the Eclipse treatment planning system (TPS) were simulated in PRIMO. The Acuros XB algorithm v. 16.10 (dose to medium) was used in Eclipse. Sixty targets with diameters ranging from 6 to 33 mm were included. Agreement between the dose distributions given by Eclipse and PRIMO was evaluated in terms of 3D global gamma passing rates (GPRs) for the 2 %/2 mm criteria. RESULTS: Average GPR greater than 95 % with the 2 %(G)/1 mm criteria were obtained over the PDD and profiles of each field size. Differences between PRIMO calculated and measured OFs were within 0.5 % in all fields, except for the 1 × 1 cm2 with a discrepancy of 1.5 %. Regarding the MLC modeling in PRIMO, an agreement within 3 % was achieved between calculated and experimental doses. Excellent agreement between PRIMO and Eclipse was found for the 35 HA plans. The 3D global GPRs (2 %/2 mm) for the targets and external patient contour were 99.6 % ± 1.1 % and 99.8 % ± 0.5 %, respectively. CONCLUSIONS: According to the results described in this study, the PRIMO Monte Carlo software, in conjunction with the 6X FFF Varian phase-space files, can be used as secondary dose calculation software to check stereotactic radiosurgery plans from Eclipse using the HyperArc technique.

Development and Validation of a Personalized, Sex-Specific Prediction Algorithm of Severe Atheromatosis in Middle-Aged Asymptomatic Individuals: The ILERVAS Study.

Background: Although European guidelines recommend vascular ultrasound for the assessment of cardiovascular risk in low-to-moderate risk individuals, no algorithm properly identifies patients who could benefit from it. The aim of this study is to develop a sex-specific algorithm to identify those patients, especially women who are usually underdiagnosed. Methods: Clinical, anthropometrical, and biochemical data were combined with a 12-territory vascular ultrasound to predict severe atheromatosis (SA: ≥ 3 territories with plaque). A Personalized Algorithm for Severe Atheromatosis Prediction (PASAP-ILERVAS) was obtained by machine learning. Models were trained in the ILERVAS cohort (n = 8,330; 51% women) and validated in the control subpopulation of the NEFRONA cohort (n = 559; 47% women). Performance was compared to the Systematic COronary Risk Evaluation (SCORE) model. Results: The PASAP-ILERVAS is a sex-specific, easy-to-interpret predictive model that stratifies individuals according to their risk of SA in low, intermediate, or high risk. New clinical predictors beyond traditional factors were uncovered. In low- and high-risk (L&H-risk) men, the net reclassification index (NRI) was 0.044 (95% CI: 0.020-0.068), and the integrated discrimination index (IDI) was 0.038 (95% CI: 0.029-0.048) compared to the SCORE. In L&H-risk women, PASAP-ILERVAS showed a significant increase in the area under the curve (AUC, 0.074 (95% CI: 0.062-0.087), p-value: < 0.001), an NRI of 0.193 (95% CI: 0.162-0.224), and an IDI of 0.119 (95% CI: 0.109-0.129). Conclusion: The PASAP-ILERVAS improves SA prediction, especially in women. Thus, it could reduce the number of unnecessary complementary explorations selecting patients for a further imaging study within the intermediate risk group, increasing cost-effectiveness and optimizing health resources. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT03228459].

Prevalence of Obstructive Sleep Apnoea and Its Association With Atherosclerotic Plaques in a Cohort of Subjects With Mild–Moderate Cardiovascular Risk

Introduction: Classic cardiovascular risk factors do not explain all the cardiovascular events. Obstructive sleep apnoea (OSA) has been proposed as a potential and prevalent cardiovascular risk factor. Our study aimed to describe the prevalence of OSA in a middle-aged cohort with mild–moderate cardiovascular risk and evaluate its association with atherosclerotic disease. Methods: This is an observational cross-sectional ancillary study of the ILERVAS project which was aimed to study subclinical arterial disease in a cohort with mild–moderate cardiovascular risk. In a sample of consecutive subjects, we performed a sleep study and evaluate OSA prevalence and its association with carotid and femoral atheroma plaques and atherosclerotic burden. Results: Overall, 966 subjects with a median age of 57 years (25–75th percentile; 52–62) and a body mass index (BMI) of 28.5kg/m2 (25.6–31.6) were included. Of these, 72.6% (69.7%–75.3%) had OSA (apnoea–hypopnoea index (AHI)≥5/h); 35.7% (32.8%–38.8%) had mild OSA (AHI 5–14.9/h) and 36.9% (33.9%–39.9%) had moderate/severe OSA (AHI≥15/h). Mean oxygen saturation and the percentage of time with oxygen saturation<90% (CT90) were associated with atherosclerotic burden (eβ (95%CI) 0.932 (0.892, 0.974); 1.005 (1.002, 1.009), respectively) and total plaque (OR (95%CI) 0.88 (0.797,0.971); 1.013 (1.004,1.021), respectively). No association with the AHI or oxygen desaturation index was found. Conclusions: This study confirms a high prevalence of OSA in patients with mild–moderate cardiovascular risk and shows an association between atherosclerotic burden, total and femoral plaque with CT90 and mean oxygen saturation, suggesting the importance of OSA-related hypoxaemia in the induction of atherosclerotic disease. (AU)

Weak Association between Skin Autofluorescence Levels and Prediabetes with an ILERVAS Cross-Sectional Study.

A large body of evidence demonstrates a relationship between hyperglycemia and increased concentrations of advanced glycation end-products (AGEs). However, there is little information about subcutaneous AGE accumulation in subjects with prediabetes, and whether or not this measurement could assist in the diagnosis of prediabetes is unclear. A cross-sectional study was conducted in 4181 middle-aged subjects without diabetes. Prediabetes (n = 1444) was defined as a glycosylated hemoglobin (HbA1c) level between 39 and 47 mmol/mol (5.7 to 6.4%), and skin autofluorescence (SAF) measurement was performed to assess AGEs. A multivariable logistic regression model and receiver operating characteristic curve were used. The cohort consisted of 50.1% women with an age of 57 [52;62] years, a BMI of 28.3 [25.4;31.6] kg/m2, and a prevalence of prediabetes of 34.5%. Participants with prediabetes showed higher SAF than control participants (2.0 [1.7;2.2] vs. 1.9 [1.7;2.2], p < 0.001). However, HbA1c was not significantly correlated with SAF levels (r = 0.026, p = 0.090). In addition, the SAF level was not independently associated with prediabetes (OR = 1.12 (0.96 to 1.30)). Finally, there was no good cutoff point for SAF to identify patients with prediabetes (AUC = 0.52 (0.50 to 0.54), sensitivity = 0.61, and 1-specificity = 0.56). Given all of this evidence, we can conclude that although there is an increase in SAF levels in participants with prediabetes, the applicability and clinical relevance of the results is low in this population.

Prediabetes Is Associated with Increased Prevalence of Sleep-Disordered Breathing.

Type 2 diabetes leads to severe nocturnal hypoxemia, with an increase in apnea events and daytime sleepiness. Hence, we assessed sleep breathing parameters in the prediabetes stage. A cross-sectional study conducted on 966 middle-aged subjects without known pulmonary disease (311 patients with prediabetes and 655 controls with normal glucose metabolism) was conducted. Prediabetes was defined by glycated hemoglobin (HbA1c), and a nonattended overnight home sleep study was performed. Participants with prediabetes (n = 311) displayed a higher apnea−hypopnea index (AHI: 12.7 (6.1;24.3) vs. 9.5 (4.2;19.6) events/h, p < 0.001) and hypopnea index (HI: 8.4 (4.0;14.9) vs. 6.0 (2.7;12.6) events/h, p < 0.001) than controls, without differences in the apnea index. Altogether, the prevalence of obstructive sleep apnea was higher in subjects with prediabetes than in controls (78.1 vs. 69.9%, p = 0.007). Additionally, subjects with prediabetes presented impaired measurements of the median and minimum nocturnal oxygen saturation, the percentage of time spent with oxygen saturations below 90%, and the 4% oxygen desaturation index in comparison with individuals without prediabetes (p < 0.001 for all). After adjusting for age, sex, and the presence of obesity, HbA1c correlated with the HI in the entire population (r = 0.141, p < 0.001), and the presence of prediabetes was independently associated with the AHI (B = 2.20 (0.10 to 4.31), p = 0.040) as well as the HI (B = 1.87 (0.61 to 3.14), p = 0.004) in the multiple linear regression model. We conclude that prediabetes is an independent risk factor for an increased AHI after adjusting for age, sex, and obesity. The enhanced AHI is mainly associated with increments in the hypopnea events.