High-risk non-muscle-invasive bladder cancer (NMIBC) presents high recurrence and progression rates. Despite the use of Bacillus Calmette-Guérin gold-standard immunotherapy and the recent irruption of anti-PD-1/PD-L1 drugs, we are missing a comprehensive understanding of the tumor microenvironment (TME) that may help us find biomarkers associated to treatment outcome. Here, we prospectively analyzed TME composition and PD-L1 expression of tumor and non-tumoral tissue biopsies from 73 NMIBC patients and used scRNA-seq, transcriptomic cohorts and tissue micro-array to validate the prognostic value of cell types of interest. Compared to non-tumoral tissue, NMIBC presented microvascular alterations, increased cancer-associated fibroblast (CAF) and myofibroblast (myoCAF) presence, and varied immune cell distribution, such as increased macrophage infiltration. Heterogeneous PD-L1 expression was observed across subsets, with macrophages showing the highest expression levels, but cancer cells as the primary potential anti-PD-L1 binding targets. Unbiased analysis revealed that myoCAF and M2-like macrophages are specifically enriched in high-grade NMIBC tumors. The topological distribution of these two cell types changed as NMIBC progresses, as shown by immunofluorescence. Only myoCAFs were associated with higher rates of progression and recurrence in three independent cohorts (888 total patients), reaching prediction values comparable to transcriptomic classes, which we further validated using tissue micro-array. Our study provides a roadmap to establish the landscape of the NMIBC TME, highlighting myoCAFs as potential prognostic markers.

The CORDELIA Study (Collaborative Cohorts Reassembled Data to Study Mechanisms and Long-term Incidence of Chronic Diseases) combines 35 Spanish population cohorts to investigate the clinical, environmental, genetic, and omics determinants of cardiovascular disease in the Southern European population. It aims to conduct the largest genome-wide association study to date on cardiovascular disease in this population, improve predictions of cardiovascular incidence using genomic and clinical data, and identify subgroups that would benefit most from targeted pharmacological and lifestyle interventions. CORDELIA includes 196,632 individuals (ages 18–84, 54

BACKGROUND:Mycosis fungoides (MF) and Sézary syndrome (SS) are chronic malignant diseases that typically necessitate diverse strategies to achieve remission. Systemic interferon (IFN)-α (subtypes 2a and 2b) has been used to treat MF/SS since 1984; however, its production was recently stopped. The recombinant pegylated (PEG) form of IFN-α-2a remains the only alternative IFN treatment, although it has not been approved for use in MF/SS. OBJECTIVES:To assess the effectiveness and safety of PEG-IFN-α-2a in monotherapy and in combination with other treatments using time to next treatment (TTNT) as a measure of clinical therapeutic benefit in a real-world setting. METHODS:We conducted an international, multicentre retrospective study of patients with MF and SS (of any stage) treated with PEG-IFN-α-2a from July 2012 to February 2022. Patients were included across 11 centres in 10 countries. The primary endpoints were to determine the TTNT of PEG-IFN-α-2a and adverse events (AEs) in MF/SS. RESULTS:In total, 105 patients were included [mean (SD) age 61 (13.1) years]; 42 (40.0%) had stage IA-IIA and 63 (60.0%) had stage IIB-IVB disease. PEG-IFN-α-2a was combined with other therapies in 67 (63.8%) patients, most commonly with extracorporeal photopheresis (36%) and bexarotene (22%). Patients with stage I-IIA disease achieved an overall response rate (ORR) of 57%; the ORR in those with stage IIB-IVB disease was 51%. Combination treatment resulted in a median TTNT of 10.4 months (range 0.6-50.7) vs. 7.0 months (range 0.7-52.4) for those who received monotherapy (P < 0.01). Overall, the mean (SD) TTNT was 9.2 (10.6) months and the ORR was 53.3% (n = 56). A complete response was seen in 13% of patients and a partial response in 40%. AEs were described in 68.6% (n = 72) of patients. Flu-like symptoms (n = 28; 26.7%), lymphopenia (n = 24; 22.9%) and elevated liver function (n = 10; 9.5%) were the most frequently reported. Grade 3-4 AEs were reported in 23 (21.9%) patients, mostly related to myelosuppression. CONCLUSIONS:PEG-IFN-α-2a for MF/SS resulted in an ORR of 53.3% and a mean (SD) TTNT of 9.2 (10.6) months. Combination regimens were superior to monotherapy and doses of 180 µg PEG-IFN-α-2a weekly were related to a higher ORR.

AIMS:The 2021 European Society of Cardiology prevention guidelines recommend the use of (lifetime) risk prediction models to aid decisions regarding initiation of prevention. We aimed to update and systematically recalibrate the LIFEtime-perspective CardioVascular Disease (LIFE-CVD) model to four European risk regions for the estimation of lifetime CVD risk for apparently healthy individuals. METHODS AND RESULTS:The updated LIFE-CVD (i.e. LIFE-CVD2) models were derived using individual participant data from 44 cohorts in 13 countries (687 135 individuals without established CVD, 30 939 CVD events in median 10.7 years of follow-up). LIFE-CVD2 uses sex-specific functions to estimate the lifetime risk of fatal and non-fatal CVD events with adjustment for the competing risk of non-CVD death and is systematically recalibrated to four distinct European risk regions. The updated models showed good discrimination in external validation among 1 657 707 individuals (61 311 CVD events) from eight additional European cohorts in seven countries, with a pooled C-index of 0.795 (95% confidence interval 0.767-0.822). Predicted and observed CVD event risks were well calibrated in population-wide electronic health records data in the UK (Clinical Practice Research Datalink) and the Netherlands (Extramural LUMC Academic Network). When using LIFE-CVD2 to estimate potential gain in CVD-free life expectancy from preventive therapy, projections varied by risk region reflecting important regional differences in absolute lifetime risk. For example, a 50-year-old smoking woman with a systolic blood pressure (SBP) of 140 mmHg was estimated to gain 0.9 years in the low-risk region vs. 1.6 years in the very high-risk region from lifelong 10 mmHg SBP reduction. The benefit of smoking cessation for this individual ranged from 3.6 years in the low-risk region to 4.8 years in the very high-risk region. CONCLUSION:By taking into account geographical differences in CVD incidence using contemporary representative data sources, the recalibrated LIFE-CVD2 model provides a more accurate tool for the prediction of lifetime risk and CVD-free life expectancy for individuals without previous CVD, facilitating shared decision-making for cardiovascular prevention as recommended by 2021 European guidelines.

Introduction The consensus on recovery from alcohol use disorder (AUD) has shifted toward encompassing psychological wellbeing and quality of life dimensions. However, few studies have explored the long-term recovery process and its dimensions, timing, styles, and modes. The aim of this study was to investigate the extent, timing, and process of psychological wellbeing and quality of life recovery in alcohol use disorder (AUD) patients, as well as the relationship with classic dimensions of AUD recovery. Method A cross-sectional study has been carried out with 348 participants with AUD, in different abstinence periods (1 month–28 years), and 171 control subjects. Participants underwent a psychological evaluation, which included self-informed measures of psychological wellbeing, quality of life, negative emotionality, and coping strategies related to alcohol consumption avoidance. Statistical analysis included linear and non-linear regression models between psychological dimensions and maintenance of abstinence, as well as matching the scores of the sample with AUD to those of controls. Scatter plots were used to explore inflection points. In addition, mean comparison tests were performed between participants with AUD and controls and by gender. Results In general, according to the regression models, there were pronounced increases in indices of wellbeing and coping strategies (and pronounced decreases in negative emotionality) during the first 5 years of abstinence, followed by less pronounced improvements. The matching of AUD subjects in wellbeing and negative emotionality indices with controls occurs at different times: (a) 1 year or less: physical health; (b) 1–4 years: psychological health; (c) 4–10 years: social relationships, wellbeing, and negative emotionality; and (d) more than 10 years: autonomy and self-acceptance. There are statistically significant differences by gender for the negative emotionality and physical health variables. Conclusion Recovery from AUD is a long process that involves improvements in wellbeing and quality of life. Four stages can be described in this process, with the most pronounced changes occurring during the first 5 years of abstinence. However, AUD patients take more time to obtain similar scores to controls in several psychological dimensions.

BACKGROUND AND OBJECTIVE:Reusing Electronic Health Records (EHRs) for Machine Learning (ML) leads on many occasions to extremely incomplete and sparse tabular datasets, which can hinder the model development processes and limit their performance and generalization. In this study, we aimed to characterize the most effective data imputation techniques and ML models for dealing with highly missing numerical data in EHRs, in the case where only a very limited number of data are complete, as opposed to the usual case of having a reduced number of missing values.METHODS:We used a case study including full blood count laboratory data, demographic and survival data in the context of COVID-19 hospital admissions and evaluated 30 processing pipelines combining imputation methods with ML classifiers. The imputation methods included missing mask, translation and encoding, mean imputation, k-nearest neighbors' imputation, Bayesian ridge regression imputation and generative adversarial imputation networks. The classifiers included k-nearest neighbors, logistic regression, random forest, gradient boosting and deep multilayer perceptron.RESULTS:Our results suggest that in the presence of highly missing data, combining translation and encoding imputation-which considers informative missingness-with tree ensemble classifiers-random forest and gradient boosting-is a sensible choice when aiming to maximize performance, in terms of area under curve.CONCLUSIONS:Based on our findings, we recommend the consideration of this imputer-classifier configuration when constructing models in the presence of extremely incomplete numerical data in EHR.

BACKGROUND:Mammographic density (MD), defined as the percentage of dense fibroglandular tissue in the breast, is a modifiable marker of the risk of developing breast cancer. Our objective was to evaluate the effect of residential proximity to an increasing number of industrial sources in MD. METHODS:A cross-sectional study was conducted on 1225 premenopausal women participating in the DDM-Madrid study. We calculated distances between women's houses and industries. The association between MD and proximity to an increasing number of industrial facilities and industrial clusters was explored using multiple linear regression models. RESULTS:We found a positive linear trend between MD and proximity to an increasing number of industrial sources for all industries, at distances of 1.5 km (p-trend = 0.055) and 2 km (p-trend = 0.083). Moreover, 62 specific industrial clusters were analyzed, highlighting the significant associations found between MD and proximity to the following 6 industrial clusters: cluster 10 and women living at ≤1.5 km (β = 10.78, 95 % confidence interval (95%CI) = 1.59; 19.97) and at ≤2 km (β = 7.96, 95%CI = 0.21; 15.70); cluster 18 and women residing at ≤3 km (β = 8.48, 95%CI = 0.01; 16.96); cluster 19 and women living at ≤3 km (β = 15.72, 95%CI = 1.96; 29.49); cluster 20 and women living at ≤3 km (β = 16.95, 95%CI = 2.90; 31.00); cluster 48 and women residing at ≤3 km (β = 15.86, 95%CI = 3.95; 27.77); and cluster 52 and women living at ≤2.5 km (β = 11.09, 95%CI = 0.12; 22.05). These clusters include the following industrial activities: surface treatment of metals/plastic, surface treatment using organic solvents, production/processing of metals, recycling of animal waste, hazardous waste, urban waste-water treatment plants, inorganic chemical industry, cement and lime, galvanization, and food/beverage sector. CONCLUSIONS:Our results suggest that women living in the proximity to an increasing number of industrial sources and those near certain types of industrial clusters have higher MD.

Background The statistical analysis of composite outcomes is challenging. The Clinical Outcomes, HEalthcare REsource utilizatioN, and relaTed costs (COHERENT) model was developed to describe and compare all components (incidence, timing and duration) of composite outcomes, but its statistical analysis remained unsolved. The aim of the study is to assess a multi-State Markov model as one statistical solution for the COHERENT model. Methods A cohort of 3280 patients admitted to the emergency department or hospital for heart failure during year 2018 were followed during one year. The state of the patient was registered at the end of each day during 365 days as: home, emergency department (ED), hospital, re-hospital, re-ED, and death. Outcomes of patients with or without severe renal disease (sRD) were compared as an example. A Multi-State Markov model was developed to explain transitions to and from these states during follow-up. Results A Multi-State Markov model showed, adjusted for age and sex, a significantly lower likelihood of patients with sRD to return home regardless of the state in which they were (ED → HOME (HR, 0.72; 95%CI, 0.54-0.95), RE-ED → HOME (HR, 0.83; 95%CI, 0.75-0.93), HOSPITAL → HOME (HR, 0.77; 95%CI, 0.69-0.86), RE-HOSPITAL → HOME (HR, 0.82; 95%CI, 0.74-0.92) and a higher mortality risk, in particular at the hospital and at home (HOME → Death [HR, 1.54; 95%CI, 1.01-2.37] and HOSPITAL → Death [HR, 1.71; 95%CI, 1.30-2.24]. Conclusion Multi-state Markov models offer a statistical solution for the comprehensive analysis of composite outcomes assessed as transitions from different clinical states. Clinical Perspective ### Competing Interest Statement This study was an investigator initiative sponsored by AstraZeneca Spain. Dr. Bueno receives research funding from the Instituto de Salud Carlos III, Spain (PIE16/00021 & PI17/01799, PI21/01572), Sociedad Española de Cardiología, AstraZeneca, Boehringer Ingelheim, Janssen, and Novartis; has received consulting/speaking fees from Astra-Zeneca, Novartis, Novo Nordisk and Organon: and was a scientific advisor for MEDSCAPE-the heart.org. Beatriz Palacios, Miriam Villarreal, and Margarita Capel are employees of AstraZeneca Spain. ### Clinical Trial N/A ### Funding Statement This work was supported by AstraZeneca Farmacéutica Spain, S.A ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the Hospital Universitario 12 de Octubre institutional review board. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Original data come from the hospital information system. This is not available. Data from the anonimzed edited database may be accessible after reasonable request. * HF : Heart failure COHERENT : Clinical Outcomes, HEalthcare REsource utilizatioN, and relaTed costs CI : Confidence Interval ED : Emergency department sRD: Severe renal disease

ABSTRACT BACKGROUND Non-muscle-invasive bladder cancer (NMIBC) poses clinical challenges due to its high recurrence and progression rates. While Bacillus Calmette-Guérin (BCG) remains as the gold standard treatment for high-risk NMIBC, recent irruption of anti-PD-1/PD-L1 drugs claims for a comprehensive understanding of the tumour microenvironment (TME) of these tumors. METHODS The present prospective study consisted on the analysis 98 fresh NMIBC samples, tumor and non-pathological tissue, via flow cytometry. Final analysis included distribution of 11 cell types and the expression of PD-L1 in 66 tumor and 62 non-pathological tissue biopsies from 73 NMIBC patients (84.4% paired samples). The results were validated using publicly available transcriptomic data, and histology. RESULTS In comparison to non-pathological tissue, the TME of NMIBC presented microvascular alterations, increased cancer-associated fibroblast (CAF) and myofibroblast (myoCAF) presence, and varied immune cell distribution. Heterogeneous PD-L1 expression was observed across subsets, with cancer cells as primary potential anti-PD-L1 binding targets. Unbiased analysis revealed that myoCAF and M2-like macrophages are enriched in high grade NMIBC tumors, but only myoCAF were associated with higher rates of progression and recurrence, as we confirmed in three independent transcriptomic cohorts (888 total patients). We further validated the prognostic value of myoCAFs by tissue micro-array. CONCLUSION This comprehensive analysis provides a roadmap to establish the full landscape of the NMIBĆs TME, highlighting myoCAFs as potential prognostic markers. FUNDING This study was funded by FC AECC (INVES222946GARC), Consejería de Educación, Ciencia y Universidades de la CAM (2018-T2/BMD-10342), Hoffmann-La Roche, Ministerio de Ciencia e Innovación (INMUNOEPIBLA) and ISCIII/FEDER (CIBERONC CB16/12/00489)

Studies specifically designed to determine the profile of psychiatric symptoms among COVID-19 patients are limited and based on case series, self-report questionnaires, and surveys. The objective of the study was to identify and classify the neuropsychological symptoms of hospitalized COVID-19 patients during the first wave of the pandemic in one of the most important front-line tertiary hospitals from Spain, and to analyze its correlation with diagnosed mental disorders, as well as to explore potential risk factors associated with mental health problems. This observational, cohort study involved data from COVID-19 patients at the University Hospital 12 de Octubre (Madrid, Spain) from February to May 2020. First, patients underwent a semistructured phone interview (screening phase), based on the Mini International Neuropsychiatric Interview (MINI). Then the confirmation of the diagnosis (confirmation phase) was performed in patients who reported a mental disorder development or worsening. A factorial analysis was performed to identify groups of symptoms. A tetrachoric matrix was created, and factorial analysis, by a principal component analysis, was employed upon it. Factors showing values >1.0 were selected, and a varimax rotation was applied to these factors. Symptoms most frequently identified in patients were anosmia/ageusia (54.6%), cognitive complaints (50.3%), worry/nervousness (43.8%), slowing down (36.2%), and sadness (35.4%). Four factors were identified after the screening phase. The first ("anxiety/depression") and second ("executive dysfunction") factors explained 45.4 and 11.5% of the variance, respectively. Women, age between 50 and 60 years, duration in the hospital (more than 13 days), and psychiatric history showed significant higher levels (number of symptoms) in the factors. This study reports the factor structure of the psychiatric symptoms developed by patients with a confirmed diagnosis of SARS-CoV2 during the first wave of the COVID-19. Three item domains (anxiety, depression, and posttraumatic stress disorder symptoms) were loaded together on one factor, whereas sleep disturbance stood up as a separate factor. Interestingly, the item anosmia/ageusia was not captured by any factor. In conclusion, an increase in neuropsychiatric morbidity is expected in the upcoming months and years. Therefore, screening for early symptoms is the first step to prevent mental health problems associated with this pandemic.

This systematic review aims to evaluate the effect of continuous glucose monitoring (CGM) on maternal and neonatal outcomes in gestational diabetes mellitus (GDM).

The consumption of ultra-processed foods (UPFs) has increased in recent decades, worldwide. Evidence on the negative impacts of food processing on health outcomes has also been steadily increasing. The aim of this study is to describe changes in consumption patterns of ultra-processed foods in the Spanish population over time and their geographical variability. Data from four representative cohorts of the Spanish population were used (1991–1996–2004–2008). Dietary information was collected using a validated frequency questionnaire and categorized using the NOVA classification. A total increase of 10.8% in UPF consumption between 1991 and 2008 was found in Spain (p-value < 0.001). The products contributing most to UPF consumption were sugar-sweetened beverages, processed meats, dairy products, and sweets. Those who consumed more ultra-processed foods were younger (p-value < 0.001) and female (p-value = 0.01). Significant differences between the different geographical areas of Spain were found. The eastern part of Spain was the area with the lowest UPF consumption, whereas the north-western part was the area with the highest increase in UPF consumption. Given the negative effect that the consumption of ultra-processed foods has on health, it is necessary to implement public health policies to curb this increase in UPF consumption.

OBJECTIVE:To determine the association between ultra-processed food (UPF) intake and all-cause mortality in a representative sample of Spanish population. DESIGN:Prospective cohort design in which follow-up lasted from baseline (1991) to mortality date or 31 December 2017, whichever was first. Dietary information was collected using a validated frequency questionnaire and categorised following the NOVA classification according to the extent of food processing. The association between consumption of UPF and mortality was analysed using Cox models. Isoenergetic substitution models were constructed to compare the health effects of the NOVA groups. SETTING:Cohort from the Diet and Risk of Cardiovascular Diseases (CVD) in Spain (DRECE) study, representative of the Spanish population. PARTICIPANTS:Totally, 4679 subjects between 5 and 59 years old. RESULTS:Average consumption of UPF was 370·8 g/d (24·4 % of energy intake). After a median follow-up of 27 years, 450 deaths occurred. Those who consumed the highest amount of UPF had higher risk of mortality. For every 10 % of the energy intake from UPF consumption, an increase of 15 % in the hazard of all-cause mortality was observed (HR 1·15; (95 % CI 1·03, 1·27); P-value = 0·012). Substitution of UPF with minimally processed foods was significantly associated with a decreased risk of mortality. CONCLUSIONS:An increase in UPF consumption was associated with higher risk of all-cause mortality in a representative sample of the Spanish population. Moreover, the theoretical substitution of UPF with unprocessed or minimally processed foods leads to a decrease in mortality. These results support the need to promote diets based on unprocessed or minimally processed foods.

Acromegaly is associated with increased vertebral fracture (VFs) risk not correlated to bone mineral density (BMD). Trabecular bone score (TBS), related to bone microarchitecture, provides information on bone strength. This cross‐sectional study considered the usefulness of TBS and BMD to assess bone status in long‐term controlled acromegalic patients.

We present a historic cohort study with 57 patients diagnosed with mycosis fungoides in early stages during the years 1999 to 2002. Our group performed a cDNA microarray on the diagnosis skin biopsies samples with the CNIO (oncologic investigation national center of Spain) Onco-Chip. This chip includes 6386 cancer-related clones. Since the samples were processed in two deferent years the initial set of 57 patients was divided in two groups of 29 and 28 patients due to the heterogeneity of the sample array results. The patients had a medium of 14 years of follow-up and were divided in two groups: progression (development of tumor, nodes, erythroderma, blood involvement or metastasis) and no progression. And we performed volcano pot analysis and GSEA to determine whether there are different genes expressions at diagnosis that determine prognosis. Several pathways were up and down regulated differently in patients progressing. We performed a GSEA analysis with the following results. Pathways related with progression: CXCR4 pathway (p=0.000) Normalized Enrichment Score (NES) 1.91 and FDR 0.027; genes: BCAR1, PXN, PIK3CA, PTK2, PIK3R1, PRKCA, HRAS, RAF1, CXCL12, PIK3C2G, GNB1. Other pathways with p<5% were: ERK5 pathway p=0.035, NES 1.15, FDR 0.92; genes: PIK3CA, PIK3R1, HRAS, RPS6KA1, SHC1. AKT pathway p=0.049, NES 1.52, FDR 0.70; genes: PIK3CA, PIK3R1, GHR, CASP9, YWHAH. Cytokine pathway p=0.034, NES 1.49, FDR 0.66; genes: SOCS6, SOD2, CCL2. PIK 3-CL1 pathway p=0.035, NES 1.39, FDR 0.63; genes: PIK3CA and PIK3CD INFAR1 pathway p=0.012, NES –1.51, FDR 1; genes: IFNAR1, JAK1, IFNAR2. P53 pathway p=0.032, NES –1.48, FDR 1; genes: MDM2, ABCB1, TP53. Pathways related with no progression: lymphocyte pathway p=0.000, FDR 0.31 NES –1.67; genes: ITGA, ITGB1, SELL, SELP. UV response pathway p=0.007, NES 1.62, FDR 0.40; genes: NTRK3, CCNE1, RAB27A, LYN, CEBPG, IL6ST, GAL, PSMC3, RRAD, ATF3, SOD2, BAK1, STIP1, GCH1, BMP2, PRKCD, RFC4, E2F2, IRF1, RASGRP1, BTG3, CDKN1C, ATP6V1F, CHKA, EIF5, POLE3, CDC5, UROD, CDC34, NR4A1, ENO2, JUNB, SLC6A8, DNAJB1, IGFB2, CDK2, PPIF, ABCB1, RXRB, PPT1, SPOP, KIT, MET, EIF5, FURIN. Other pathway with p<5% was: ERK pathway p=0.048, NES –1.48, FDR 0.93; genes: SRC, NGFB, HRAS; IGF1R, RPS6KA1, MYC, EGFR, RAF, SHC1, PDGFRA, GNB1, STAT3, NGFR, ITGB1, GNAS. We also performed a volcano pot study that showed overexpression of PPP1R3C a gene related with the mTOR pathway in the progression cases. Although our sample size was limited, we believe that pathways related with JAK/STAT, PIK/AKT/mTOR, MAPK, and cellular cycle can be differentially expressed in patients that have progression of the disease from the early stages of mycosis fungoides. Further studies are necessary to validate our results. We present a historic cohort study with 57 patients diagnosed with mycosis fungoides in early stages during the years 1999 to 2002. Our group performed a cDNA microarray on the diagnosis skin biopsies samples with the CNIO (oncologic investigation national center of Spain) Onco-Chip. This chip includes 6386 cancer-related clones. Since the samples were processed in two deferent years the initial set of 57 patients was divided in two groups of 29 and 28 patients due to the heterogeneity of the sample array results. The patients had a medium of 14 years of follow-up and were divided in two groups: progression (development of tumor, nodes, erythroderma, blood involvement or metastasis) and no progression. And we performed volcano pot analysis and GSEA to determine whether there are different genes expressions at diagnosis that determine prognosis. Several pathways were up and down regulated differently in patients progressing. We performed a GSEA analysis with the following results. Pathways related with progression: CXCR4 pathway (p=0.000) Normalized Enrichment Score (NES) 1.91 and FDR 0.027; genes: BCAR1, PXN, PIK3CA, PTK2, PIK3R1, PRKCA, HRAS, RAF1, CXCL12, PIK3C2G, GNB1. Other pathways with p<5% were: ERK5 pathway p=0.035, NES 1.15, FDR 0.92; genes: PIK3CA, PIK3R1, HRAS, RPS6KA1, SHC1. AKT pathway p=0.049, NES 1.52, FDR 0.70; genes: PIK3CA, PIK3R1, GHR, CASP9, YWHAH. Cytokine pathway p=0.034, NES 1.49, FDR 0.66; genes: SOCS6, SOD2, CCL2. PIK 3-CL1 pathway p=0.035, NES 1.39, FDR 0.63; genes: PIK3CA and PIK3CD INFAR1 pathway p=0.012, NES –1.51, FDR 1; genes: IFNAR1, JAK1, IFNAR2. P53 pathway p=0.032, NES –1.48, FDR 1; genes: MDM2, ABCB1, TP53. Pathways related with no progression: lymphocyte pathway p=0.000, FDR 0.31 NES –1.67; genes: ITGA, ITGB1, SELL, SELP. UV response pathway p=0.007, NES 1.62, FDR 0.40; genes: NTRK3, CCNE1, RAB27A, LYN, CEBPG, IL6ST, GAL, PSMC3, RRAD, ATF3, SOD2, BAK1, STIP1, GCH1, BMP2, PRKCD, RFC4, E2F2, IRF1, RASGRP1, BTG3, CDKN1C, ATP6V1F, CHKA, EIF5, POLE3, CDC5, UROD, CDC34, NR4A1, ENO2, JUNB, SLC6A8, DNAJB1, IGFB2, CDK2, PPIF, ABCB1, RXRB, PPT1, SPOP, KIT, MET, EIF5, FURIN. Other pathway with p<5% was: ERK pathway p=0.048, NES –1.48, FDR 0.93; genes: SRC, NGFB, HRAS; IGF1R, RPS6KA1, MYC, EGFR, RAF, SHC1, PDGFRA, GNB1, STAT3, NGFR, ITGB1, GNAS. We also performed a volcano pot study that showed overexpression of PPP1R3C a gene related with the mTOR pathway in the progression cases. Although our sample size was limited, we believe that pathways related with JAK/STAT, PIK/AKT/mTOR, MAPK, and cellular cycle can be differentially expressed in patients that have progression of the disease from the early stages of mycosis fungoides. Further studies are necessary to validate our results.

BACKGROUND:Tumor mutational burden (TMB) is a recently proposed predictive biomarker for immunotherapy in solid tumors, including non-small cell lung cancer (NSCLC). Available assays for TMB determination differ in horizontal coverage, gene content and algorithms, leading to discrepancies in results, impacting patient selection. A harmonization study of TMB assessment with available assays in a cohort of patients with NSCLC is urgently needed. METHODS:We evaluated the TMB assessment obtained with two marketed next generation sequencing panels: TruSight Oncology 500 (TSO500) and Oncomine Tumor Mutation Load (OTML) versus a reference assay (Foundation One, FO) in 96 NSCLC samples. Additionally, we studied the level of agreement among the three methods with respect to PD-L1 expression in tumors, checked the level of different immune infiltrates versus TMB, and performed an inter-laboratory reproducibility study. Finally, adjusted cut-off values were determined. RESULTS:Both panels showed strong agreement with FO, with concordance correlation coefficients (CCC) of 0.933 (95% CI 0.908 to 0.959) for TSO500 and 0.881 (95% CI 0.840 to 0.922) for OTML. The corresponding CCCs were 0.951 (TSO500-FO) and 0.919 (OTML-FO) in tumors with <1% of cells expressing PD-L1 (PD-L1<1%; N=55), and 0.861 (TSO500-FO) and 0.722 (OTML-FO) in tumors with PD-L1≥1% (N=41). Inter-laboratory reproducibility analyses showed higher reproducibility with TSO500. No significant differences were found in terms of immune infiltration versus TMB. Adjusted cut-off values corresponding to 10 muts/Mb with FO needed to be lowered to 7.847 muts/Mb (TSO500) and 8.380 muts/Mb (OTML) to ensure a sensitivity >88%. With these cut-offs, the positive predictive value was 78.57% (95% CI 67.82 to 89.32) and the negative predictive value was 87.50% (95% CI 77.25 to 97.75) for TSO500, while for OTML they were 73.33% (95% CI 62.14 to 84.52) and 86.11% (95% CI 74.81 to 97.41), respectively. CONCLUSIONS:Both panels exhibited robust analytical performances for TMB assessment, with stronger concordances in patients with negative PD-L1 expression. TSO500 showed a higher inter-laboratory reproducibility. The cut-offs for each assay were lowered to optimal overlap with FO.

ObjectivesInternational growth charts have been used in the past decades to identify atypical growth and diagnose the nutritional status of individuals. The aim of this study was to construct and compare growth patterns of normo-nourished children between 6-59months from Afghanistan, Haiti, and the Democratic Republic of the Congo, to assess if it would be worth developing growth charts at a national level. MethodsWe used an international sample of 46466 subjects (53.7% female; 46.3% male) from the aforementioned regions. To create the growth charts, we used different statistical methodologies: the Lambda-Mu-Sigma (LMS), LMSP, and LMST models, and regression models based on fractional polynomials. The LMSP models were the ones that fitted our data best and were therefore the ones used to make comparisons between countries using percentiles (3rd, 50th, and 97th). ResultsWe found that Haitian children were both, taller and heavier than their Afghan and Congolese equals of the same ages. Moreover, differences were bigger in the highest percentiles (i.e., 97th percentile). These differences might be the result of the influence that genetics and diverse social and environmental contexts have on growth rates. ConclusionsUsing the same international reference standards for all populations could result in the overestimation or underestimation of the proportion of malnourished children. In light of our results, we recommend the future development of national and regional growth charts to provide health workers with more precise tools to evaluate the nutritional status in the child population.

Front-of-pack labels can improve the ability of consumers to identify which foods are healthier, making them a useful public health tool. Nutri-Score is a front-of-pack labelling system adopted by several European countries. This system ranks foods according to their nutritional quality, but does not consider other dimensions such as the degree of food processing. The aim of this study is to compare the nutritional quality (as assessed by Nutri-Score) and the ultra-processing (as assessed by the NOVA classification) of foods in the Open Food Facts database. A simple correspondence analysis was carried out to study the relationship between the two systems. Ultra-processed foods (NOVA 4) were found in all Nutri-Score categories, ranging from 26.08% in nutritional category A, 51.48% in category B, 59.09% in category C, 67.39% in category D to up to 83.69% in nutritional category E. Given the negative effect that the consumption of ultra-processed foods has on different aspects of health, front-of-pack labelling with Nutri-Score should at least be accompanied by complementary labelling indicating the level of processing, such as the NOVA classification.

Background Available information about prognostic implications of potassium levels alteration in the setting of acute heart failure (AHF) is scarce. Objectives We aim to describe the prevalence of dyskalemia (hypo or hyperkalemia), its dynamic changes during AHF-hospitalization, and its long-term clinical impact after hospitalization. Methods We analyzed 1779 patients hospitalized with AHF who were included in the REDINSCOR II registry. Patients were classified in three groups, according to potassium levels both on admission and discharge: hypokalemia (potassium < 3.5 mEq/L), normokalemia (potassium = 3.5-5.0 mEq/L and, hyperkalemia (potassium > 5 mEq/L). Results The prevalence of hypokalemia and hyperkalemia on admission was 8.2 and 4.6%, respectively, and 6.4 and 2.7% at discharge. Hyperkalemia on admission was associated with higher in-hospital mortality (OR = 2.32 [95% CI: 1.04-5.21]p = 0.045). Among patients with hypokalemia on admission, 79% had normalized potassium levels at discharge. In the case of patients with hyperkalemia on admission, 89% normalized kalemia before discharge. In multivariate Cox regression, dyskalemia was associated with higher 12-month mortality, (HR = 1.48 [95% CI, 1.12-1.96],p = 0.005). Among all patterns of dyskalemia persistent hypokalemia (HR = 3.17 [95% CI: 1.71-5.88];p < 0.001), and transient hyperkalemia (HR = 1.75 [95% CI: 1.07-2.86];p = 0.023) were related to reduced 12-month survival. Conclusions Potassium levels alterations are frequent and show a dynamic behavior during AHF admission. Hyperkalemia on admission is an independent predictor of higher in-hospital mortality. Furthermore, persistent hypokalemia and transient hyperkalemia on admission are independent predictors of 12-month mortality.

Background: Self-reported data about environmental exposures can lead to measurement error. Objectives: To validate the self-reported perception of proximity to industrial facilities. Methods: MCC-Spain is a population-based multicase-control study of cancer in Spain that recruited incident cases of breast, colorectal, prostate, and stomach cancer. The participant's current residence and the location of the industries were geocoded, and the linear distance between them was calculated (gold standard). The epidemiological questionnaire included a question to determine whether the participants perceived the presence of any industry at <= 1 km from their residences. Sensitivity and specificity of individuals' perception of proximity to industries were estimated as measures of classification accuracy, and the area under the curve (AUC) and adjusted odds ratios (aORs) of misclassification were calculated as measures of discrimination. Analyses were performed for all cases and controls, and by tumor location, educational level, sex, industrial sector, and length of residence. Finally, aORs of cancer associated with real and self-reported distances were calculated to explore differences in the estimation of risk between these measures. Results: Sensitivity of the questionnaire was limited (0.48) whereas specificity was excellent (0.89). AUC was sufficient (0.68). Participants with breast (aOR(95%CI) = 2.03 (1.67;2.46)), colorectal (aOR(95%CI) = 1.41 (1.20;1.64)) and stomach (aOR(95%CI) = 1.59 (1.20;2.10)) cancer showed higher risk of misclassification than controls. This risk was higher for lower educational levels (aOR (< primary vs. university) (95%CI) = 1.78 (1.44;2.20)), among younger participants (aOR(22-54 years vs. 73-85 years) (95%CI) = 1.32 (1.09;1.60)), and for some industrial sectors: pharmaceutical (aOR(95%CI) = 29.02 (19.52;43.14)), galvanization (aOR(95%CI) = 14.14 (6.78;29.47)), and ceramic (aOR(95%CI) = 12.73 (7.22;22.44)). Participants living <= 1 year in the study area showed a lower risk of misclassification ((aOR(<= 1 vs. > 15 years) (95%CI) = 0.56 (0.36;0.85)). The use of self-reported proximity vs. real distance to industrial facilities biased the effect on cancer risk towards the nullity. Conclusions: Self-reported distance to industrial facilities can be a useful tool for hypothesis generation, but hypothesis-testing studies should use real distance to report valid conclusions. The sensitivity of the question might be improved with a more specific formulation.