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Supplementary Table S6. Normalized expression values from the 90 miRNAs analyzed.

Supplementary Table and Figure Legend. Legends for Supplementary Tables S1-S8 and Supplementary Figures S1-S2.

Better knowledge of the biology of breast cancer has allowed the use of new targeted therapies, leading to improved outcome. High-throughput technologies allow deepening into the molecular architecture of breast cancer, integrating different levels of information, which is important if it helps in making clinical decisions. microRNA (miRNA) and protein expression profiles were obtained from 71 estrogen receptor–positive (ER+) and 25 triple-negative breast cancer (TNBC) samples. RNA and proteins obtained from formalin-fixed, paraffin-embedded tumors were analyzed by RT-qPCR and LC/MS-MS, respectively. We applied probabilistic graphical models representing complex biologic systems as networks, confirming that ER+ and TNBC subtypes are distinct biologic entities. The integration of miRNA and protein expression data unravels molecular processes that can be related to differences in the genesis and clinical evolution of these types of breast cancer. Our results confirm that TNBC has a unique metabolic profile that may be exploited for therapeutic intervention. Cancer Res; 75(11); 2243–53. ©2015 AACR.

Supplementary Figure S2. Hypothesis about how miR449a exerts its regulatory effect over cellular metabolism.

Colorectal cancer (CRC) is a molecular and clinically heterogeneous disease. In 2015, the Colorectal Cancer Subtyping Consortium classified CRC into four consensus molecular subtypes (CMS), but these CMS have had little impact on the clinical practice. The purpose of this study is to deepen into the molecular characterization of CRC. A novel approach, based on probabilistic graphical models (PGM) and sparse k-means-Consensus Cluster layer analyses was applied in order to functionally characterize CRC tumors. First, PGM was used to functionally characterize CRC, and then, sparse k-means-Consensus cluster was used to explore layers of biological information and establish classifications. To this aim, gene expression and clinical data of 805 CRC samples from three databases were analyzed. Tree different layers based on biological features were identified: adhesion, immune and molecular. The adhesion layer divided patients into high and low adhesion groups, with prognostic value. The immune layer divided patients into immune-high and immune-low groups, according to the expression of immune-related genes. The molecular layer established four molecular groups related to stem cells, metabolism, Wnt signalling pathway and extracellular functions. Immune-high patients, with a higher expression of immune-related genes and genes involved in viral mimicry response may be benefit for immunotherapy and viral mimicry-related therapies. Additionally, several possible therapeutic targets have been identified in each molecular group. Therefore, this improved CRC classification could be useful for searching new therapeutic targets and specific therapeutic strategies in CRC disease.Simple summaryColorectal cancer is a heterogeneous disease. Several efforts have been done to characterize this heterogeneity but they have not impact in clinic. In this work, we used a novel analysis approach based on identifying layers of information using expression data from colorectal tumors and characterize three different layers of information: one layer related to adhesion with prognostic value, one related to immune characteristics and one related to molecular features. The molecular layer divided colorectal tumors in stem cell, Wnt, metabolic, and extracellular groups. These molecular groups suggested some possible therapeutic targets for each group. Additionally, immune characteristics divided tumors in tumors with a high expression of immune and viral mimicry response genes and with a low expression, suggesting immunotherapy and viral mimicry related therapies as suitable for these immune-high patients.

Since the introduction of modern antiretroviral treatment for HIV and hepatitis C virus (HCV), the pattern of autoimmune diseases (AD) in people living with HIV (PWH) might have changed.A retrospective study in a cohort of 5665 PWH at the HIV Clinic of Hospital Universitario La Paz (Spain) to study the prevalence of AD from January 1990 to June 2020. We divided the timeline in four periods:1996, 1996-2006, 2006-2015, 2015-2020.369 participants were diagnosed with at least one AD, with a prevalence of 5.3% (95% CI 4.7-5.9). 302 (81%) participants were diagnosed simultaneously or after HIV diagnosis. Most prevalent diseases were immune thrombopenia (n=90), cutaneous psoriasis (n=52), autoimmune thyroid disorders (n=36), spondylarthritis (n=24), and inflammatory bowel disease (n=21). There was a significant trend for more AD in recent periods (p=0.037). In recent years participants with AD were older, had a long time since HIV diagnosis, and had higher CD4+ T-cell count and higher CD4+ T-cell nadir (temporal linear trend p0.001). There was a change in the pattern of AD over time with a decrease in immune thrombopenia and an increase in spondylarthritis, arthritis, inflammatory bowel disease, and thyroid disorders. One hundred thirty-nine participants (46%) were coinfected with HCV, with a steady decline throughout the study period. Only cryoglobulinemia was statistically associated with HCV infection.AD increases over time in PWH with reasonable immune virological control. We observed a higher frequency of spondylarthritis, arthritis, autoimmune thyroid disorders, and inflammatory bowel disease in recent years.

Purpose: To explore the tumor proteome of patients diagnosed with localized clear cell renal cancer (ccRCC) and treated with surgery. Material and methods: A total of 165 FFPE tumor samples from patients diagnosed with ccRCC were analyzed using DIA-proteomics. Proteomics ccRCC subtypes were defined using a consensus cluster algorithm (CCA) and characterized by a functional approach using probabilistic graphical models and survival analyses. Results: We identified and quantified 3091 proteins, including 2026 high-confidence proteins. Two proteomics subtypes of ccRCC (CC1 and CC2) were identified by CC using the high-confidence proteins only. Characterization of molecular differences between CC1 and CC2 was performed in two steps. First, we defined 514 proteins showing differential expression between the two subtypes using a significance analysis of microarrays analysis. Proteins overexpressed in CC1 were mainly related to translation and ribosome, while proteins overexpressed in CC2 were mainly related to focal adhesion and membrane. Second, a functional analysis using probabilistic graphical models was performed. CC1 subtype is characterized by an increased expression of proteins related to glycolysis, mitochondria, translation, adhesion proteins related to cytoskeleton and actin, nucleosome, and spliceosome, while CC2 subtype showed higher expression of proteins involved in focal adhesion, extracellular matrix, and collagen organization. Conclusions: ccRCC tumors can be classified in two different proteomics subtypes. CC1 and CC2 present specific proteomics profiles, reflecting alterations of different molecular pathways in each subtype. The knowledge generated in this type of studies could help in the development of new drugs targeting subtype-specific deregulated pathways.

AimsHyponatraemia is the most common body fluid disorders but often goes unnoticed. Our laboratory incorporated a standardised procedure to help clinicians detect moderate/severe hyponatraemia. The study aims were to evaluate the outcomes on patient care and clinicians’ satisfaction.MethodsThe study, observational and retrospective, included 1839 cases, adult and paediatric patients, with sodium concentration ResultsThe median hyponatraemia length decreased significantly from 4.95 hours (2.08–16.57) in the first period to 2.17 hours (1.06–5.39) in the second period. The lack of hyponatraemia patients follow-up was significantly less after the procedure implementation. The survey was answered by 92 (60 senior specialists and 32 residents) out of 110 clinicians surveyed. Ninety of them (98%) answered positively.ConclusionsWe have demonstrated the reduction in the time for diagnosing and management by physicians, the higher uniformity in the time required to solve hyponatraemia episodes following our laboratory procedure and the clinicians’ satisfaction.

We investigated B-cell-activating factor (BAFF) in relation to response to treatment with TNF inhibitors (TNFis) in rheumatoid arthritis (RA). This was a longitudinal study including 158 patients with RA treated with TNFis and followed up for 6 months. Clinical response at 6 months of treatment was defined according to the EULAR criteria for good responders (GRs). BAFF concentration was measured in serum samples, collected at baseline and at 6 months. Associations with EULAR response were evaluated using univariable and multivariable logistic regression models. ROC analysis was performed to determine the optimal threshold of serum BAFF concentration associated with good EULAR response to treatment. After 6 months of TNFi treatment, 24% of patients were GRs. They had a lower BMI, lower baseline DAS28 and lower baseline serum BAFF concentration than non-responders. After 6 months of TNFi treatment, autoantibody-positive patients who attained GR had significantly lower serum BAFF concentrations compared with patients who did not. Serum BAFF < 968 pg/mL at 6 months represented the concentration likely to best discriminate between GR and non-GR at 6 months of TNFi treatment. Autoantibody-seropositive patients who had serum BAFF < 968 pg/mL at 6 months demonstrated a more than four-fold increased probability to be GRs compared with patients with higher BAFF concentrations. In conclusion, serum BAFF concentrations were associated with response to TNFis in seropositive RA patients, corroborating the importance of the B-cell compartment in RA.

BackgroundChildren with juvenile idiopathic arthritis (JIA) might be at a higher risk of infection. Our objectives are to describe and compare infection rates in patients with JIA vs. healthy patients.MethodsA prospective, multicenter observational study was performed in Spain from January 2017 to June 2019. Patients with JIA from 7 participating hospitals and children without JIA (siblings of patients with JIA, and non-JIA children from primary health centers) were followed up with quarterly questionnaires to record infection episodes. Tuberculosis, herpes zoster, and infections requiring hospital admission were considered severe infections. Rates of infection (episodes/patient/year) were compared using a generalized estimating equations model.ResultsA total of 371 children (181 with and 190 without JIA) were included. The median age was 8.8 years (IQR 5.5–11.3); 75% of the patients with JIA received immunosuppressive treatment (24% methotrexate, 22% biologic, 26% both). A total of 667 infections were recorded; 15 (2.2%) were considered severe. The infection rate was 1.31 (95%CI 1.1–1.5) in JIA and 1.12 (95%CI 0.9–1.3) in non-JIA participants (p = 0.19). Age p < 0.001) in both groups. The most frequent infection sites were upper respiratory (62.6% vs. 74.5%) and gastrointestinal (18.8% vs. 11.4%). There were no differences in severe infections (2.5% vs. 2%, p = 0.65) between the groups. In children with JIA, younger age and higher disease activity (JADAS71) were associated with a higher infection rate.ConclusionWe found no differences in the infection rate or infection severity between patients with and without JIA. Most infections were mild. An age younger than 4 years increased the infection risk in both groups. Higher disease activity was associated with a higher infection rate.

Background Although switching antiretroviral therapy (ART) in people with human immunodeficiency virus experiencing insomnia due to dolutegravir-related neurotoxicity is well founded upon evidence, there is a lack of proof in regard to the outcome of stopping dolutegravir-based ART in people without insomnia but reporting poor sleep quality. Methods This is a randomized, multicenter, open-label study to evaluate the reversibility of patient-reported sleep disturbances in patients on dolutegravir/lamivudine/abacavir without insomnia after switching to darunavir/cobicistat/emtricitabine/tenofovir alafenamide. The participants were randomized to switch ART at baseline or at week 4 and then completed 8 weeks of darunavir/cobicistat/emtricitabine/tenofovir alafenamide. Our primary objective was to compare changes in sleep quality between arms at week 4. Secondary objectives were to compare changes in mood and neuropsychiatric symptoms (NS) at week 4 and 4 and 8 weeks after switching to darunavir/cobicistat/emtricitabine/tenofovir alafenamide. The participants completed a survey, including the Pittsburgh Sleep Quality Index (PSQI), the Hospital Anxiety and Depression scale (HADS), and specific questions to explore NS, at each visit to assess those objectives. Results We included 72 participants. The results show that study arms were similar at baseline; however, at week 4, PSQI scores remained unchanged with dolutegravir/lamivudine/abacavir, whereas patients improved significantly after switching to darunavir/cobicistat/emtricitabine/tenofovir alafenamide. Similar differences between arms were also observed in HADS and NS changes. At weeks 4 and 8 after all participants switched to darunavir/cobicistat/emtricitabine/tenofovir alafenamide, we have observed significant improvements in PSQI and HAD scores and in NS. Conclusions In patients reporting subclinical sleep disturbances without insomnia, switching from dolutegravir/lamivudine/abacavir to darunavir/cobicistat/emtricitabine/tenofovir alafenamide was associated with better sleep quality and improvements in mood and NS.

We have previously demonstrated the safety and feasibility of adoptive cell therapy with CD45RAWe performed a longitudinal analysis from previously severe acute respiratory syndrome coronavirus 2-infected and infection-naïve individuals covering 21 months from infection and 10 months after full vaccination with the BNT162b2 Pfizer/BioNTech vaccine.We observed that cellular responses are maintained over time. Humoral responses increased after vaccination but were gradually lost. In addition, dexamethasone did not alter cell functionality or proliferation of CD45RAOur results suggest that the best donors for adoptive cell therapy would be recovered individuals and 2 months after vaccination, although further studies with larger cohorts would be needed to confirm this finding. Dexamethasone did not affect the characteristics of the memory T cells at a concentration used in the clinical practice and IL-15 showed a positive effect on SARS-CoV-2-specific CD45RA

Context.— Point-of-care testing allows rapid analysis and short turnaround times. To the best of our knowledge, the present study assesses, for the first time, clinical, operative, and economic outcomes of point-of-care blood gas analysis in a nephrology department. Objective.— To evaluate the impact after implementing blood gas analysis in the nephrology department, considering clinical (differences in blood gas analysis results, critical results), operative (turnaround time, elapsed time between consecutive blood gas analysis, preanalytical errors), and economic (total cost per process) outcomes. Design.— A total amount of 3195 venous blood gas analyses from 688 patients of the nephrology department before and after point-of-care blood gas analyzer installation were included. Blood gas analysis results obtained by ABL90 FLEX PLUS were acquired from the laboratory information system. Statistical analyses were performed using SAS 9.3 software. Results.— During the point-of-care testing period, there was an increase in blood glucose levels and a decrease in pCO2, lactate, and sodium as well as fewer critical values (especially glucose and lactate). The turnaround time and the mean elapsed time were shorter. By the beginning of this period, the number of preanalytical errors increased; however, no statistically significant differences were found during year-long monitoring. Although there was an increase in the total number of blood gas analysis requests, the total cost per process decreased. Conclusions.— The implementation of a point-of-care blood gas analysis in a nephrology department has a positive impact on clinical, operative, and economic terms of patient care.

Background Standard oncology tools are inadequate to distinguish which older patients are at higher risk of developing chemotherapy-related complications. Materials and Methods Patients over 70 years of age starting new chemotherapy regimens were prospectively included in a multicenter study. A prechemotherapy assessment that included sociodemographics, tumor/treatment variables, and geriatric assessment variables was performed. Association between these factors and the development of grade 3–5 toxicity was examined by using logistic regression. Results A total of 551 patients were accrued. Chemotherapy doses (odds ratio [OR] 1.834; 95% confidence interval [CI] 1.237–2.719) and creatinine clearance (OR 0.989; 95% CI 0.981–0.997) were the only factors independently associated with toxicity. Only 19% of patients who received reduced doses of chemotherapy and had a creatinine clearance ≥40 mL/minute had grade 3–4 toxicity, compared with 38% of those who received standard doses or had a creatinine clearance Conclusion Chemotherapy doses and renal function were identified as the major risk factors for developing severe toxicity in the older patient. These factors should be considered when planning to initiate a new chemotherapy regimen and should also lead to a closer follow-up in these patients.

Background Data about safety and efficacy of the mRNA SARS-CoV-2 vaccine in adolescents with rheumatic diseases (RD) is scarce and whether these patients generate a sufficient immune response to the vaccine remains an outstanding question. Objective To evaluate safety and humoral and cellular immunity of the BNT162b2 vaccine in adolescents 12 to 18 years with RD and immunosuppressive treatment compared with a healthy control group. Methods Adolescents from 12 to 18 years with RD followed at Hospital La Paz in Madrid (n = 40) receiving the BNT162b2 mRNA vaccination were assessed 3 weeks after complete vaccination. Healthy adolescents served as controls (n = 24). Humoral response was measured by IgG antiSpike antibodies, and cellular response by the quantity of IFN-γ and IL-2 present in whole blood stimulated with SARS-CoV-2 Spike and M proteins. Results There were no differences in spike-specific humoral or cellular response between groups (median IFN-γ response to S specific protein; 528.80 pg/ml in controls vs. 398.44 in RD patients, p 0.78, and median IL-2 response in controls: 635.68 pg/ml vs. 497.30 in RD patients, p 0.22. The most frequent diagnosis was juvenile idiopathic arthritis (26/40, 65%) followed by Lupus (6/40, 15%). 60% of cases (23/40) received TNF inhibitors and 35% (14/40) methotrexate. 40% of patients (26/64) had previous SARS-CoV-2 infection, 9 in the control group and 17 in the RD patients without differences. Of note, 70% of infections were asymptomatic. A higher IFN-γ production was found in COVID-19 recovered individuals than in naive subjects in both groups (controls: median 859 pg/ml in recovered patients vs. 450 in naïve p 0.017, and RD patients: 850 in recovered vs. 278 in naïve p 0.024). No serious adverse events or flares were reported following vaccination. Conclusions We conclude that standard of care treatment for adolescents with RD including TNF inhibitors and methotrexate did not affect the humoral and the cellular immunity to BNT162b2 mRNA vaccination compared to a healthy control group. The previous contact with SARS-CoV-2 was the most relevant factor in the immune response.

The diagnostic approach to eosinophilia is complex, given the numerous reported etiologies. Intestinal parasites (especially helminths) are a concern in children from high-burden settings. We describe the diagnostic approach and clinical management of eosinophilia in a cohort of migrant children.We conducted a retrospective observational study that included children diagnosed with eosinophilia at a reference center for pediatric tropical diseases from 2014 to 2018. All patients were screened according to a unified protocol, including direct microbiologic and serologic tests.A total of 163 children presented with eosinophilia during the study period [median age, 7.7 years (4.1-12.2); 57.1% boys], mostly from Asia (27.6%) and South America (22.1%). Most were internationally adopted children (43.6%) or migrants (26.4%). Only 34.4% of the children were symptomatic, and the main etiology for eosinophilia was helminths (56.4%). After a sequential diagnostic approach, no etiology was found for 40.5% of the patients. The independent risk factors for an unexplained etiology were younger age (≤2 years: odds ratio, 3.6; 95% CI, 1.3-10.2; P = 0.015), absence of symptoms (odds ratio, 4.8; 95% CI, 1.8-12.5; P = 0.001) and mild eosinophilia (1000/µL: odds ratio, 4.2; 95% CI, 4.5-11.7; P = 0.005). Only 6 children were treated empirically. In those children with an identified cause and in those treated empirically, the eosinophilia resolved in 52% in a median of 7 months (5-9).Helminths are the main cause of eosinophilia in migrant children and need to be hunted, especially in older children with eosinophil counts1000 eosinophils/µL.

Introduction Triple negative breast cancer (TNBC) accounts for 15-20% of the breast cancer and is characterized by an aggressive phenotype and worst prognosis. TNBC does not benefit from any targeted therapy, so further characterization would be needed to define subgroups with potential therapeutic value. Material and methods 125 TNBC paraffin samples were analyzed using high-throughput proteomics based on SWATH-MS. Survival analyses and a prognostic predictor were done using BRB Array Tools. Proteins related with disease-free survival were established and, then, a prognostic signature was built based on their p-values. Results and discussion Using SWATH-MS, 1,206 proteins were identified in a cohort of 125 TNBC tumors. Of these 1,206 proteins, 29 proteins were related with disease-free survival. In addition, a prognostic signature based on the expression of two proteins, RMB3 and NIPSNAP1, was defined. The predictor split our population into a low-risk and a high-risk group (p=0.0002, HR= 6.519). Multivariate analysis showed that the prognostic signature based on the expression of these two proteins supplied significant information to the clinical parameters. Conclusion SWATH-MS proteomics demonstrates its utility in the analysis of TNBC paraffin samples. Moreover, this proteomics data allows us to build a prognostic signature based on the expression of two proteins (RBM3 and NIPSNAP1). This prognostic signature could be used in the future to identify a population with a high-risk of relapse that may be directed to a clinical trial. Citation Format: Pilar Zamora Auñon, Silvia García Adrián, Lucia Trilla-Fuertes, Angelo Gámez-Pozo, Guillermo Prado-Vázquez, Andrea Zapater-Moros, Mariana Díaz- Almirón, Rocío López Vacas, Cristina Chiva, Cristina Chiva, Eduard Sabidó, Enrique Espinosa Arranz, Juan Ángel Fresno Vara. Disease-free survival prognostic signature in triple-negative breast cancer based on high-throughput proteomics data [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-42.

Background Tracheostomy is one of the most frequent techniques in intensive care units (ICU). Fiberoptic bronchoscopy (FB) is a safety measure when performing a percutaneous dilatational tracheostomy (PDT), but the controversy surrounding the routine use of FB as part of the procedure remains open. National surveys in some European countries showed that the use of FB is non-standardized. Retrospective studies have not shown a significant difference in complications between procedures performed with or without a bronchoscope. International guidelines have not been able to establish recommendations regarding the use of FB in PDT due to lack of evidence. Design This is a multicenter (three centers at the time of publishing this paper) randomized controlled clinical trial to examine the safety of percutaneous tracheostomy using FB. We will include all consecutive adult patients admitted to the ICU in whom percutaneous tracheostomy for prolonged mechanical ventilation is indicated and with no exclusion criteria for using FB. Eligible patients will be randomly assigned to receive blind PDT or PDT under endoscopic guidance. All procedures will be performed by experienced intensivists in PDT and FB. A Data Safety and Monitoring Board (DSMB) will monitor the trial. The primary outcome is the incidence of perioperative complications. Discussion FB is a safe technique when performing PDT although its use is not universally accepted in all ICUs as a routine practice. Should PDT be monitored routinely with endoscopic guidance? This study will assess the role of FB monitoring during PDT. Trial registration ClinicalTrials.gov NCT04265625. Registered on February 11, 2020

Globalization has pushed population movements in the last decades, turning imported diseases into the focus. Due to behavioral habits, children are at higher risk of acquiring parasitosis. This study aims to investigate the prevalence of parasites in migrant children and factors associated with parasitic diseases.Retrospective cross-sectional study (2014-2018) including children diagnosed with parasitosis. The diagnosis was based on serology and/or microscopic stool-sample evaluation. Epidemiological and clinical data were recorded.Out of 813 migrant children screened, 241 (29.6%) presented at least one parasite, and 89 (10.9%) more than one. The median age was 6.6 years (IQR: 3.1-11.9) and 58.9% were males. Most cases were referred for a health exam; only 52.3% of children were symptomatic, but 43.6% had eosinophilia. The most common diagnosis were giardiasis (35.3%), schistosomiasis (19.1%), toxocariasis (15.4%), and strongyloidiasis (9.1%). After the multivariate analysis, African origin and presenting with eosinophilia were the main risk factors for parasitism.parasitosis are frequent among migrant children. Children are often asymptomatic, and thus active screening for parasitosis should be considered among high-risk populations. Eosinophilia can be useful to guide complimentary tests, as well as geographical origin, but normal eosinophil count does not exclude parasitosis.

In 2017, a worldwide survey was conducted on compliance with the practices promoted by Neo-BFHI (Baby-friendly Hospital Initiative expansion to neonatal wards).To present the results of the Spanish wards that participated in the global survey and compare them with those obtained internationally.Cross-sectional study through a survey on compliance with the Neo-BFHI ("Three basic principles", "Ten steps adapted to neonatal wards" and "the compliance with the International Code of Marketing of Breast-milk Substitutes" and subsequent relevant World Health Assembly resolutions). Compliance was calculated as the mean in each indicator and a final mean score for each neonatal unit. For the partial and final scores for each country and at the international level, the median was used. All scores ranged between 0 and 100.The response rate in Spain was 90%. The range of the national mean for neonatal wards were from 37 to 99, with no differences in the final score according to the level of care. The global score for Spain (72) is below the international median (77) and this also occurs in 8 of 14 items. The neonatal wards from BFHI designated hospitals, obtained a significantly higher mean global score, and in 9 of 14 items than the non-accredited ones.Both international and national results indicate an improvement in breast feeding practices in neonatal units. The benefits of the BFHI accreditation of maternity reach neonatal wards. Spain has several key points below the international score.

Background: Estimation of life expectancy in older patients is relevant to select the best treatment strategy. We aimed to develop and validate a score to predict early mortality in older patients with cancer. Patients and Methods: A total of 749 patients over 70 years starting new chemotherapy regimens were prospectively included. A prechemotherapy assessment that included sociodemographic variables, tumor/treatment variables, and geriatric assessment variables was performed. Association between these factors and early death was examined using multivariable logistic regression. Score points were assigned to each risk factor. External validation was performed on an independent cohort. Results: In the training cohort, the independent predictors of 6-month mortality were metastatic stage (OR 4.8, 95% CI [2.4–9.6]), ECOG-PS 2 (OR 2.3, 95% CI [1.1–5.2]), ADL≤5 (OR 1.7, 95% CI [1.1–3.5]), serum albumin levels ≤ 3.5 g/dL (OR 3.4, 95% CI [1.7–6.6]), BMI &lt, 23 kg/m2 (OR 2.5, 95% CI [1.3–4.9]), and hemoglobin levels &lt, 11 g/dL (OR 2.4, 95% CI (1.2–4.7)). With these results, we built a prognostic score. The area under the ROC curve was 0.78 (95% CI, 0.73 to 0.84), and in the validation set, it was 0.73 (95% CI: 0.67–0.79). Conclusions: This simple and highly accurate tool can help physicians making decisions in elderly patients with cancer who are planned to initiate chemotherapy treatment.

[Objective]: Describe the GETH haploidentical stem cell transplantation (haplo‐HSCT) activity in non‐malignant disease (NMDs)., [Methods]: We retrospectively analyzed data from children with NMDs who underwent haplo‐HSCT., [Results]: From January 2001 to December 2016, 26 pediatric patients underwent 31 haplo‐HSCT through ex vivo T cell‐depleted (TCD) graft platforms or post‐transplantation cyclophosphamide (PT‐Cy) at 7 Spanish centers. Five cases employed unmanipulated PT‐Cy haplo‐HSCT, 16 employed highly purified CD34+ cells, and 10 employed ex vivo TCD grafts manipulated either with CD3+CD19+ depletion, TCRαβ+CD19+ selection or naive CD45RA+ T‐cell depletion. Peripheral blood stem cells were the sole source for patients following TCD haplo‐HSCT, and bone marrow was the source for one PT‐Cy haplo‐HSCT. The most common indications for transplantation were primary immunodeficiency disorders (PIDs), severe aplastic anemia, osteopetrosis, and thalassemia. The 1‐year cumulative incidence of graft failure was 27.4%. The 1‐year III‐IV acute graft‐versus‐host disease (GvHD) and 1‐year chronic GvHD rates were 34.6% and 16.7%, respectively. The 2‐year overall survival was 44.9% for PIDs, and the 2‐year graft‐versus‐host disease‐free and relapse‐free survival rate was 37.6% for the other NMDs. The transplantation‐related mortality at day 100 was 30.8%., [Conclusion]: Although these results are discouraging, improvements will come if procedures are centralized in centers of expertise., This work was supported in part by the National Health Service of Spain, Carlos III Health Institute (ISCIII), FONDOS FEDER grant (FIS) PI18/01301, the CRIS Cancer Foundation (http://criscancer.org), and the Association Pablo Ugarte (http://www.asociacionpablougarte.es/).

Covid-19, caused by the SARS-CoV-2 virus, has reached the category of a worldwide pandemic. Even though intensive efforts, no effective treatments or a vaccine are available. Molecular characterization of the transcriptional response in Covid-19 patients could be helpful to identify therapeutic targets. In this study, RNAseq data from peripheral blood mononuclear cell samples from Covid-19 patients and healthy controls was analyzed from a functional point of view using probabilistic graphical models. Two networks were built: one based on genes differentially expressed between healthy and infected individuals and another one based on the 2,000 most variable genes in terms of expression in order to make a functional characterization. In the network based on differentially expressed genes, two inflammatory response nodes with different tendencies were identified, one related to cytokines and chemokines, and another one related to bacterial infections. In addition, differences in metabolism, which were studied in depth using Flux Balance Analysis, were identified. SARS-CoV2-infection caused alterations in glutamate, methionine and cysteine, and tetrahydrobiopterin metabolism. In the network based on 2,000 most variable genes, also two inflammatory nodes with different tendencies between healthy individuals and patients were identified. Similar to the other network, one was related to cytokines and chemokines. However, the other one, lower in Covid-19 patients, was related to allergic processes and self-regulation of the immune response. Also, we identified a decrease in T cell node activity and an increase in cell division node activity. In the current absence of treatments for these patients, functional characterization of the transcriptional response to SARS-CoV-2 infection could be helpful to define targetable processes. Therefore, these results may be relevant to propose new treatments.

Introduction To study antibiotic susceptibility in bacterial keratitis (BK), its profile over 10 years and its influence on ophthalmological practice. Methods Retrospective review of BK with positive corneal scraping over a 10-year period. Risk factors for keratitis, visual acuity (VA), empirical topical treatment, corneal infection characteristics and outcomes were analyzed for BK due to Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Pseudomonas aeruginosa and Propionibacterium acnes. Results 389 positive corneal scrapings were collected. All Gram-positive bacteria were susceptible to vancomycin. P. aeruginosa demonstrated >90% sensitivity to the most-commonly-used topical antibiotics. Susceptibility to methicillin was 90.2% for S. aureus and 66.3% for S. epidermidis. The results of 215 patients were available. 1.9% required enucleation and 2.8% required surgical treatments. Final VA improved after treatment in keratitis due to S. aureus (p = 0.026) and S. epidermidis (p = 0.005). There was a correlation between S. aureus resistance to methicillin (p = 0.002) and levofloxacin (p = 0.043) and enucleation (20% and 10%, respectively) compared with a 0% rate of enucleation in S. aureus-susceptible keratitis. Conclusions BK due to S. pneumoniae is very aggressive irrespective of antibiotic sensitivity. S. aureus was frequently isolated in patients with systemic diseases. It causes severe keratitis and remains moderately resistant to methicillin and levofloxacin. For this reason, keeping vancomycin in empirical regimens is believed to be necessary.

BACKGROUND Patients with asthma exacerbations and frequent relapses that require admission to the emergency department (ED) often have more severe disease, worse quality of life, and higher use of health care resources. OBJECTIVE The aim of this study was to identify potential predictors of relapse after patients are treated in an ED for an asthma exacerbation. METHODS A retrospective, noninterventional cohort study was conducted in adult patients who attended the ED of a tertiary hospital in 2014 for an asthma exacerbation. We analyzed the subpopulation who experienced at least one relapse (returned to the ED < 15 days after the previous event). RESULTS Fifty-two of 831 patients experienced 66 relapses after going to the ED (mean ± standard deviation [SD] age, 58.5 ± 23.4 years). The average ± SD probability of a relapse was 6 ± 0.8%. The frequency of episodes was higher in May and November. Twenty-four patients had ≥260 blood eosinophils/μL, including 17 who had ≥400 eosinophils/μL. Only 15% of the patients were referred to an asthma specialist at discharge. Factors related to a higher probability of relapse were the following: having multiple visits to the ED in 1 year, uncontrolled asthma, wheezing in the pulmonary auscultation, peripheral eosinophilia with ≥400 eosinophils/ μL, and being discharged in the first visit to the ED (p < 0.01 for all). CONCLUSION In this population, patients who had multiple ED visits in 1 year, those with uncontrolled asthma, wheezing, ≥400 blood eosinophils/μL, or who had been discharged at the first ED visit are at higher risk of relapse.

Breast cancer is the most frequent tumor in women and its incidence is increasing. Neoadjuvant chemotherapy has become standard of care as a complement to surgery in locally advanced or poor-prognosis early stage disease. The achievement of a complete response to neoadjuvant chemotherapy correlates with prognosis but it is not possible to predict who will obtain an excellent response. The molecular analysis of the tumor offers a unique opportunity to unveil predictive factors. In this work, gene expression profiling in 279 tumor samples from patients receiving neoadjuvant chemotherapy was performed and probabilistic graphical models were used. This approach enables addressing biological and clinical questions from a Systems Biology perspective, allowing to deal with large gene expression data and their interactions. Tumors presenting complete response to neoadjuvant chemotherapy had a higher activity of immune related functions compared to resistant tumors. Similarly, samples from complete responders presented higher expression of lymphocyte cell lineage markers, immune-activating and immune-suppressive markers, which may correlate with tumor infiltration by lymphocytes (TILs). These results suggest that the patient’s immune system plays a key role in tumor response to neoadjuvant treatment. However, future studies with larger cohorts are necessary to validate these hypotheses.

Background Cancer immunotherapy involving natural killer (NK) cells has gained interest. Here we report two methods to obtain interleukin (IL)-15-activated NK cells for clinical use. Study design and methods IL-15-activated NK cell products were obtained after 1) enrichment from healthy haploidentical donors' peripheral blood mononuclear cells (PBMNCs) collected by nonmobilized apheresis by a two-step magnetic procedure, depletion of CD3+ cells followed by selection of CD56+ cells and ex vivo overnight stimulation with IL-15 (NKIL15); and 2) expansion using the K562-mb15-41BBL cell line (NKAE), from autologous PBMNCs from patients with multiple myeloma or expansion from healthy haploidentical PBMNCs obtained from whole blood using the same previous cell line. We analyzed the NK cell recovery and expansion, T cell depletion, phenotype, cytotoxicity, safety, and genomic stability of two good manufacturing practices (GMP)-grade IL-15-activated NK cell products. Results The number of NK cells obtained from NKIL15 cell and NKAE cell products was similar; however, there were significantly fewer T cells in the NKIL15 cell product. The haploidentical NKAE cell product contained more T cells than the autologous NKAE cell product. The surface expression of the activating receptors CD69, CD25, natural killer group-2 member D receptor, NKp44, NKp46, NKp30, and DNA accessory molecule 1 was up regulated in both NK cell products. NKIL15 cell and NKAE cell products had significantly higher lytic activity than unstimulated NK cells and showed no lytic activity against PBMNCs from healthy donors. No genetic alterations or potential oncogenic effects were found. Conclusion Different GMP-grade procedures can be used to obtain large numbers of highly IL-15-activated NK cells with extremely low T cell content for clinical use.

Abiraterone and enzalutamide are two oral novel androgen receptor axis-targeted agents approved for the treatment of castration-resistant prostate cancer (mCRPC). Despite the availability of multiple treatments, there is a need to improve the knowledge and management of these drugs in the real-world setting, especially in patient groups under-represented in clinical trials. Our aim was to review the outcome of patients with chemotherapy-naïve mCRPC treated with abiraterone or enzalutamide in routine clinical practice in order to identify factors that are predictive for response.This observational retrospective study was performed in a Spanish tertiary hospital and included men with chemotherapy-naïve mCPRC who started treatment with abiraterone or enzalutamide between September 2012 and November 2018. The study end date was 30 October 2020.Ninety patients with mCRPC were included, 57 with abiraterone and 33 with enzalutamide. Median overall survival (OS) was 26.87 months (95% CI 19.68 to 34.05), with no difference found between the two treatment groups. Nine variables were related to increased OS in the univariate analysis: Eastern Cooperative Oncology Group (ECOG) performance status (0-1 vs 2), pain (need of opioids for cancer pain), visceral disease, ≥3 bone lesions, exclusively lymph node metastases, baseline prostate specific antigen (PSA) (50 vs ≥50 ng/dL and20 vs ≥20 ng/dL), haemoglobin (12 vs ≥12 g/dL) and alkaline phosphatase (≤116 vs116 IU/L). A PSA response50% was observed in 65 patients (76.5%). In the multivariate analysis, ECOG performance status, pain, visceral disease and alkaline phosphatase provided independent prognostic information. Median OS by Kaplan-Meier analysis was significantly longer for patients with a PSA response (32.1 vs 17.9 months; HR 0.46, 95% CI 0.27 to 0.78; p=0.003).This study assessed the efficacy of abiraterone and enzalutamide in a real-world setting, including patients under-represented in pivotal studies. Some clinical factors were correlated with improved OS in chemotherapy-naïve men with mCPRC treated with these drugs.

Introduction: Abdominal fat and its increment over time in particular has become a cardiovascular risk factor in uraemic patients. Objectives: To analyse changes in abdominal fat in haemodialysis patients over one year and study their possible correlation with the variation in adipocytokine serum levels. As a secondary objective, we tried to validate the data obtained by bioelectrical impedance analysis (BIA) with data obtained by dual X-ray absorptiometry (DXA). Material and methods: A prospective one-year study was performed in 18 patients on haemodialysis (HD). In each patient, body composition by BIA and DXA was estimated at baseline and after one year. Several adipocytokine and biochemical parameters were determined. Results: A significant increase in phase angle [4.8° (4.1–5.6) vs. 5.2° (4.4–5.8), p

espanolLa pandemia COVID-19 se ha propagado rapidamente por todo el mundo, produciendo una alta mortalidad; ha obligado a reorganizar todos los sistemas sanitarios. La Unidad de Cuidados Paliativos del Hospital Universitario La Paz se transformo en una unidad para la atencion a pacientes con infeccion por COVID-19 con el fi n de colaborar en la atencion a los mismos. Nos enfrentabamos al reto de asegurar un buen control de la sintomatologia, que pasaba por una valoracion lo mas sistematica posible, siendo conscientes de la difi cultad en el contexto del aislamiento y situacion clinica de los pacientes. Presentamos una revision narrativa sobre las manifestaciones sintomaticas y nuestra experiencia como Unidad de Cuidados Paliativos integrada en la atencion COVID-19 en un hospital de tercer nivel de Madrid. Se priorizo un perfi l de pacientes con enfermedad avanzada y comorbilidad alta para el ingreso en esta unidad. Esta integracion contribuyo signifi cativamente a tener una mayor infl uencia en la forma de actuacion en la atencion al fi nal de la vida en todo el hospital. Los cuidados paliativos deben formar parte de los equipos de atencion de cualquier emergencia sanitaria, como una pandemia. Es imprescindible para una adecuada atencion de la sintomatologia y del fi nal de la vida. Es necesaria la recogida sistematica de los sintomas por la repercusion clinica que tiene sobre el paciente, la necesidad de un tratamiento especifi co y su implicacion pronostica. EnglishThe COVID-19 pandemic has spread rapidly around the world, resulting in high mortality; it has forced a reorganization of all health systems. The Palliative Care Unit at Hospital Universitario La Paz was transformed into a unit for the care of patients with COVID-19 infection in order to collaborate in the care of these patients. We faced the challenge of ensuring good control of symptoms, which were assessed as systematically as possible, being aware of the difficulties entailed in the context of the isolation and clinical situation of patients. We present a narrative review of symptomatic manifestations and our experience as a palliative care unit integrated in COVID-19 care at a third-level hospital in Madrid. A profile of patients with advanced disease and high comorbidity was prioritized for admission in this unit. This integration contributed significantly to having a greater influence on the way end-of-life care is provided throughout the hospital. Palliative care should be part of the care teams in any health emergency, such as a pandemic. It is essential for adequate symptomatology and end-of-life care. A systematic collection of symptoms is necessary because of its clinical impact on patients, their need for specific treatment, and its prognostic implications.

A total of 192 pediatric patients, median age 8.6 years, with high‐risk hematological malignancies, underwent haploidentical stem cell transplantation (haplo‐HSCT) using post‐transplantation cyclophosphamide (PT‐Cy), or ex vivo T cell‐depleted (TCD) graft platforms, from January 1999 to December 2016 in 10 centers in Spain. Some 41 patients received an unmanipulated graft followed by PT‐Cy for graft‐vs‐host disease (GvHD) prophylaxis. A total of 151 patients were transplanted with CD3‐depleted peripheral blood stem cells (PBSCs) by either CD34+ selection, CD3+CD19+ depletion, TCRαβ+CD19+ depletion or CD45RA+ depletion, added to CD34+ selection for GvHD prophylaxis. The PBSCs were the only source in patients following ex vivo TCD haplo‐HSCT; bone marrow was the source in 9 of 41 patients following PT‐CY haplo‐HSCT. Engraftment was achieved in 91.3% of cases. A donor younger than 30 years, and the development of chronic GvHD were positive factors influencing survival, whereas positive minimal residual disease (MRD) before transplant and lymphoid disease were negative factors. The probability of relapse increased with lymphoid malignancies, a donor killer‐cell immunoglobulin‐like receptor (KIR) haplotype A and positive MRD pretransplant. No difference was found in overall survival, disease‐free survival or relapse incidence between the two platforms. Relapse is still of concern in both platforms, and it should be the focus of future efforts. In conclusion, both platforms for haplo‐HSCT were effective and could be utilized depending on the comfort level of the center., Research funding: National Health Service of Spain, Instituto de Salud Carlos III (ISCIII), FONDOS FEDER grant (FIS). Grant Number: PI18/01301, the CRIS Cancer Foundation, the Association Pablo Ugarte.

Breast cancer is a heterogeneous disease. In clinical practice, tumors are classified as hormonal receptor positive, Her2 positive and triple negative tumors. In previous works, our group defined a new hormonal receptor positive subgroup, the TN-like subtype, which had a prognosis and a molecular profile more similar to triple negative tumors. In this study, proteomics and Bayesian networks were used to characterize protein relationships in 96 breast tumor samples. Components obtained by these methods had a clear functional structure. The analysis of these components suggested differences in processes such as mitochondrial function or extracellular matrix between breast cancer subtypes, including our new defined subtype TN-like. In addition, one of the components, mainly related with extracellular matrix processes, had prognostic value in this cohort. Functional approaches allow to build hypotheses about regulatory mechanisms and to establish new relationships among proteins in the breast cancer context., PLoS ONE, 15 (6), ISSN:1932-6203

Aims:Differences in metabolism among breast cancer subtypes suggest that metabolism plays an important role in this disease. Flux Balance Analysis is used to explore these differences as well as drug response.Materials & Methods:Proteomics data from breast tumors were obtained by mass-spectrometry. Flux Balance Analysis was performed to study metabolic networks. Flux activities from metabolic pathways were calculated and used to build prognostic models.Results:Flux activities of vitamin A, tetrahydrobiopterin and beta-alanine metabolism pathways split our population into low- and high-risk patients. Additionally, flux activities of glycolysis and glutamate metabolism split triple negative tumors into low- and high-risk groups.Conclusions:Flux activities summarize Flux Balance Analysis data and can be associated with prognosis in cancer.