Multi-omic analysis of Esophageal Adenocarcinoma uncovers candidate therapeutic targets and cancer-selective post-transcriptional regulation.

BACKGROUND: Efforts to address the poor prognosis associated with esophageal adenocarcinoma (EAC) have been hampered by a lack of biomarkers to identify early disease and therapeutic targets. Despite extensive efforts to understand the somatic mutations associated with EAC over the past decade, a gap remains in understanding how the atlas of genomic aberrations in this cancer impacts the proteome and which somatic variants are of importance for the disease phenotype. METHODS: We performed a quantitative proteomic analysis of 23 EACs and matched adjacent normal esophageal and gastric tissues. We explored the correlation of transcript and protein abundance using tissue-matched RNA-seq and proteomic data from 7 patients and further integrated these data with a cohort of EAC RNA-seq data (n=264 patients), EAC whole-genome sequencing (n=454 patients) and external published datasets. CENTRAL FINDINGS: We quantified protein expression from 5879 genes in EAC and patient-matched normal tissues. Several biomarker candidates with EAC-selective expression were identified including the transmembrane protein GPA33. We further verified the EAC-enriched expression of GPA33 in an external cohort of 115 patients and confirm this as an attractive diagnostic and therapeutic target. To further extend the insights gained from our proteomic data, an integrated analysis of protein and RNA expression in EAC and normal tissues revealed several genes with poorly correlated Protein and RNA abundance, suggesting post-transcriptional regulation of protein expression. These outlier genes including SLC25A30, TAOK2, and AGMAT, only rarely demonstrated somatic mutation suggesting post-transcriptional drivers for this EAC-specific phenotype. AGMAT was demonstrated to be over-expressed at the protein level in EAC compared to adjacent normal tissues with an EAC-selective, post-transcriptional mechanism of regulation of protein abundance proposed. CONCLUSIONS: By quantitative proteomic analysis we have identified GPA33 as an EAC-selective biomarker. Integrated analysis of proteome, transcriptome, and genome in EAC has revealed several genes with tumor-selective, post-transcriptional regulation of protein expression which may be an exploitable vulnerability.

NLRP3 inflammasome activation and symptom burden in KRAS-mutated CMML patients is reverted by IL-1 blocking therapy.

Chronic myelomonocytic leukemia (CMML) is frequently associated with mutations in the rat sarcoma gene (RAS), leading to worse prognosis. RAS mutations result in active RAS-GTP proteins, favoring myeloid cell proliferation and survival and inducing the NLRP3 inflammasome together with the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which promote caspase-1 activation and interleukin (IL)-1ß release. Here, we report, in a cohort of CMML patients with mutations in KRAS, a constitutive activation of the NLRP3 inflammasome in monocytes, evidenced by ASC oligomerization and IL-1ß release, as well as a specific inflammatory cytokine signature. Treatment of a CMML patient with a KRASG12D mutation using the IL-1 receptor blocker anakinra inhibits NLRP3 inflammasome activation, reduces monocyte count, and improves the patient's clinical status, enabling a stem cell transplant. This reveals a basal inflammasome activation in RAS-mutated CMML patients and suggests potential therapeutic applications of NLRP3 and IL-1 blockers.

Statement of the Spanish Interdisciplinary Vascular Prevention Committee on the updated European Guidelines on Cardiovascular Disease Prevention.

We present the Spanish adaptation of the 2021 European Guidelines on Cardiovascular Disease (CVD) prevention in clinical practice. The current guidelines besides the individual approach greatly emphasize on the importance of population level approaches to the prevention of cardiovascular diseases. Systematic global CVD risk assessment is recommended in individuals with any major vascular risk factor. Regarding LDL-Cholesterol, blood pressure, and glycemic control in patients with diabetes mellitus, goals and targets remain as recommended in previous guidelines. However, it is proposed a new, stepwise approach (Step 1 and 2) to treatment intensification as a tool to help physicians and patients pursue these targets in a way that fits patient profile. After Step 1, considering proceeding to the intensified goals of Step 2 is mandatory, and this intensification will be based on 10-year CVD risk, lifetime CVD risk and treatment benefit, comorbidities and patient preferences. The updated SCORE algorithm-SCORE2, SCORE-OP- is recommended in these guidelines, which estimates an individual's 10-year risk of fatal and non-fatal CVD events (myocardial infarction, stroke) in healthy men and women aged 40-89 years. Another new and important recommendation is the use of different categories of risk according different age groups (< 50, 50-69, ≥70 years). Different flow charts of CVD risk and risk factor treatment in apparently healthy persons, in patients with established atherosclerotic CVD, and in diabetic patients are recommended. Patients with chronic kidney disease are considered high risk or very high-risk patients according to the levels of glomerular filtration rate and albumin-to-creatinine ratio. New lifestyle recommendations adapted to the ones published by the Spanish Ministry of Health as well as recommendations focused on the management of lipids, blood pressure, diabetes and chronic renal failure are included.

IFITM proteins: Understanding their diverse roles in viral infection, cancer, and immunity.

Interferon-induced transmembrane proteins (IFITMs) are broad spectrum antiviral factors that inhibit the entry of a wide range of clinically important pathogens including influenza A virus, HIV-1, and Dengue virus. IFITMs are thought to act primarily by antagonizing virus-cell membrane fusion in this regard. However, recent work on these proteins has uncovered novel post-entry viral restriction mechanisms. IFITMs are also increasingly thought to have a role regulating immune responses, including innate antiviral and inflammatory responses as well as adaptive T-cell and B-cell responses. Further, IFITMs may have pathological activities in cancer, wherein IFITM expression can be a marker of therapeutically resistant and aggressive disease courses. In this review, we summarize the respective literatures concerning these apparently diverse functions with a view to identifying common themes and potentially yielding a more unified understanding of IFITM biology.

Highly Active and Stable Ni/La-Doped Ceria Material for Catalytic CO2 Reduction by Reverse Water-Gas Shift Reaction.

The design of an active, effective, and economically viable catalyst for CO2 conversion into value-added products is crucial in the fight against global warming and energy demand. We have developed very efficient catalysts for reverse water-gas shift (rWGS) reaction. Specific conditions of the synthesis by combustion allow the obtention of macroporous materials based on nanosized Ni particles supported on a mixed oxide of high purity and crystallinity. Here, we show that Ni/La-doped CeO2 catalysts─with the "right" Ni and La proportions─have an unprecedented catalytic performance per unit mass of catalyst for the rWGS reaction as the first step toward CO2 valorization. Correlations between physicochemical properties and catalytic activity, obtained using a combination of different techniques such as X-ray and neutron powder diffraction, Raman spectroscopy, in situ near ambient pressure X-ray photoelectron spectroscopy, electron microscopy, and catalytic testing, point out to optimum values for the Ni loading and the La proportion. Density functional theory calculations of elementary steps of the reaction on model Ni/ceria catalysts aid toward the microscopic understanding of the nature of the active sites. This finding offers a fundamental basis for developing economical catalysts that can be effectively used for CO2 reduction with hydrogen. A catalyst based on Ni0.07/(Ce0.9La0.1Ox)0.93 shows a CO production of 58 × 10-5 molCO·gcat-1·s-1 (700 °C, H2/CO2 = 2; selectivity to CO > 99.5), being stable for 100 h under continuous reaction.

Comparison of the Ammonia Trapping Performance of Different Gas-Permeable Tubular Membrane System Configurations.

The technology of gas-permeable tubular membranes (GPMs) is promising in reducing ammonia emissions from livestock manure, capturing NH3 in an acidic solution, and obtaining final products suitable for valorization as fertilizers, in line with the principles of the circular economy. This study aimed to evaluate the performance of several e-PTFE membrane systems with different configurations for the recovery of NH3 released from pig slurry. Ten different configurations were tested: only a submerged membrane, only a suspended membrane in the same chamber, only a suspended membrane in an annex chamber, a submerged membrane + a suspended membrane in the same chamber, and a submerged membrane + a suspended membrane in an annex chamber, considering in each case the scenarios without and with agitation and aeration of the slurry. In all tests, sulfuric acid (1N H2SO4) was used as the NH3 capture solution, which circulated at a flow rate of 2.1 L·h-1. The results showed that NH3-N removal rates ranged from 36-39% (for systems with a single submerged or suspended membrane without agitation or aeration of the slurry) to 70-72% for submerged + suspended GPM systems with agitation and aeration. In turn, NH3-N recovery rates were found to be between 44-54% (for systems with a single membrane suspended in an annex compartment) and 88-91% (for systems based on a single submerged membrane). However, when choosing a system for farm deployment, it is essential to consider not only the capture and recovery performance of the system, but also the investment and operating costs (ranging from 9.8 to 21.2 €/kg N recovered depending on the selected configuration). The overall assessment suggests that the simplest systems, based on a single membrane, may be the most recommendable.

Emergent Role of IFITM1/3 towards Splicing Factor (SRSF1) and Antigen-Presenting Molecule (HLA-B) in Cervical Cancer.

The IFITM restriction factors play a role in cancer cell progression through undefined mechanisms. We investigate new protein-protein interactions for IFITM1/3 in the context of cancer that would shed some light on how IFITM1/3 attenuate the expression of targeted proteins such as HLA-B. SBP-tagged IFITM1 protein was used to identify an association of IFITM1 protein with the SRSF1 splicing factor and transporter of mRNA to the ribosome. Using in situ proximity ligation assays, we confirmed a predominant cytosolic protein-protein association for SRSF1 and IFITM1/3. Accordingly, IFITM1/3 interacted with HLA-B mRNA in response to IFNγ stimulation using RNA-protein proximity ligation assays. In addition, RT-qPCR assays in IFITM1/IFITM3 null cells and wt-SiHa cells indicated that HLA-B gene expression at the mRNA level does not account for lowered HLA-B protein synthesis in response to IFNγ. Complementary, shotgun RNA sequencing did not show major transcript differences between IFITM1/IFITM3 null cells and wt-SiHa cells. Furthermore, ribosome profiling using sucrose gradient sedimentation identified a reduction in 80S ribosomal fraction an IFITM1/IFITM3 null cells compared to wild type. It was partially reverted by IFITM1/3 complementation. Our data link IFITM1/3 proteins to HLA-B mRNA and SRSF1 and, all together, our results begin to elucidate how IFITM1/3 catalyze the synthesis of target proteins. IFITMs are widely studied for their role in inhibiting viruses, and multiple studies have associated IFITMs with cancer progression. Our study has identified new proteins associated with IFITMs which support their role in mediating protein expression; a pivotal function that is highly relevant for viral infection and cancer progression. Our results suggest that IFITM1/3 affect the expression of targeted proteins; among them, we identified HLA-B. Changes in HLA-B expression could impact the presentation and recognition of oncogenic antigens on the cell surface by cytotoxic T cells and, ultimately, limit tumor cell eradication. In addition, the role of IFITMs in mediating protein abundance is relevant, as it has the potential for regulating the expression of viral and oncogenic proteins.

Statement of the Spanish Interdisciplinary Vascular Prevention Committee on the updated European Guidelines on Cardiovascular Disease Prevention. / Comentario del CEIPV a las nuevas Guías Europeas de Prevención Cardiovascular 2021.

We present the Spanish adaptation of the 2021 European Guidelines on Cardiovascular Disease Prevention in Clinical Practice. The current guidelines besides the individual approach greatly emphasize on the importance of population level approaches to the prevention of cardiovascular diseases. Systematic global cardiovascular disease risk assessment is recommended in individuals with any major vascular risk factor. Regarding LDL-cholesterol, blood pressure, and glycemic control in patients with diabetes mellitus, goals and targets remain as recommended in previous guidelines. However, it is proposed a new, stepwise approach (steps 1 and 2) to treatment intensification as a tool to help physicians and patients pursue these targets in a way that fits patient profile. After step 1, considering proceeding to the intensified goals of step 2 is mandatory, and this intensification will be based on 10-year cardiovascular disease risk, lifetime cardiovascular disease risk and treatment benefit, comorbidities and patient preferences. The updated SCORE algorithm ?SCORE2, SCORE2-OP? is recommended in these guidelines, which estimates an individual's 10-year risk of fatal and non-fatal cardiovascular disease events (myocardial infarction, stroke) in healthy men and women aged 40-89 years. Another new and important recommendation is the use of different categories of risk according to different age groups (<50, 50-69, ≥70 years). Different flow charts of cardiovascular disease risk and risk factor treatment in apparently healthy persons, in patients with established atherosclerotic cardiovascular disease, and in diabetic patients are recommended. Patients with chronic kidney disease are considered high risk or very high-risk patients according to the levels of glomerular filtration rate and albumin-to-creatinine ratio. New lifestyle recommendations adapted to the ones published by the Spanish Ministry of Health as well as recommendations focused on the management of lipids, blood pressure, diabetes and chronic renal failure are included.

Evaluation of Different Capture Solutions for Ammonia Recovery in Suspended Gas Permeable Membrane Systems.

Gas permeable membranes (GPM) are a promising technology for the capture and recovery of ammonia (NH3). The work presented herein assessed the impact of the capture solution and temperature on NH3 recovery for suspended GPM systems, evaluating at a laboratory scale the performance of eight different trapping solutions (water and sulfuric, phosphoric, nitric, carbonic, carbonic, acetic, citric, and maleic acids) at 25 and 2 °C. At 25 °C, the highest NH3 capture efficiency was achieved using strong acids (87% and 77% for sulfuric and nitric acid, respectively), followed by citric and phosphoric acid (65%) and water (62%). However, a remarkable improvement was observed for phosphoric acid (+15%), citric acid (+16%), maleic acid (+22%), and water (+12%) when the capture solution was at 2 °C. The economic analysis showed that water would be the cheapest option at any working temperature, with costs of 2.13 and 2.52 €/g N (vs. 3.33 and 3.43 €/g N for sulfuric acid) in the winter and summer scenarios, respectively. As for phosphoric and citric acid, they could be promising NH3 trapping solutions in the winter months, with associated costs of 3.20 and 3.96 €/g N, respectively. Based on capture performance and economic and environmental considerations, the reported findings support that water, phosphoric acid, and citric acid can be viable alternatives to the strong acids commonly used as NH3 adsorbents in these systems.

Gorham-Stout case report: a multi-omic analysis reveals recurrent fusions as new potential drivers of the disease.

BACKGROUND: Gorham-Stout disease is a rare condition characterized by vascular proliferation and the massive destruction of bone tissue. With less than 400 cases in the literature of Gorham-Stout syndrome, we performed a unique study combining whole-genome sequencing and RNA-Seq to probe the genomic features and differentially expressed pathways of a presented case, revealing new possible drivers and biomarkers of the disease. CASE PRESENTATION: We present a case report of a white 45-year-old female patient with marked bone loss of the left humerus associated with vascular proliferation, diagnosed with Gorham-Stout disease. The analysis of whole-genome sequencing showed a dominance of large structural DNA rearrangements. Particularly, rearrangements in chromosomes seven, twelve, and twenty could contribute to the development of the disease, especially a gene fusion involving ATG101 that could affect macroautophagy. The study of RNA-sequencing data from the patient uncovered the PI3K/AKT/mTOR pathway as the most affected signaling cascade in the Gorham-Stout lesional tissue. Furthermore, M2 macrophage infiltration was detected using immunohistochemical staining and confirmed by deconvolution of the RNA-seq expression data. CONCLUSIONS: The way that DNA and RNA aberrations lead to Gorham-Stout disease is poorly understood due to the limited number of studies focusing on this rare disease. Our study provides the first glimpse into this facet of the disease, exposing new possible therapeutic targets and facilitating the clinicopathological diagnosis of Gorham-Stout disease.

[Statement of the Spanish Interdisciplinary Vascular Prevention Committee on the updated European Guidelines on Cardiovascular Disease Prevention.] / Comentario del CEIPV a las nuevas Guías Europeas de Prevención Cardiovascular 2021.

We present the Spanish adaptation of the 2021 European Guidelines on Cardiovascular Disease (CVD) prevention in clinical practice. The current guidelines besides the individual approach greatly emphasize on the importance of population level approaches to the prevention of cardiovascular diseases. Systematic global CVD risk assessment is recommended in individuals with any major vascular risk factor. Regarding LDL-Cholesterol, blood pressure, and glycemic control in patients with diabetes mellitus, goals and targets remain as recommended in previous guidelines. However, it is proposed a new, stepwise approach (Step 1 and 2) to treatment intensification as a tool to help physicians and patients pursue these targets in a way that fits patient profile. After Step 1, considering proceeding to the intensified goals of Step 2 is mandatory, and this intensification will be based on 10-year CVD risk, lifetime CVD risk and treatment benefit, comorbidities and patient preferences. The updated SCORE algorithm (SCORE2, SCORE-OP) is recommended in these guidelines, which estimates an individual's 10-year risk of fatal and non-fatal CVD events (myocardial infarction, stroke) in healthy men and women aged 40-89 years. Another new and important recommendation is the use of different categories of risk according different age groups (<50, 50-69, >70 years). Different flow charts of CVD risk and risk factor treatment in apparently healthy persons, in patients with established atherosclerotic CVD, and in diabetic patients are recommended. Patients with chronic kidney disease are considered high risk or very high-risk patients according to the levels of glomerular filtration rate and albumin-to-creatinine ratio. New lifestyle recommendations adapted to the ones published by the Spanish Ministry of Health as well as recommendations focused on the management of lipids, blood pressure, diabetes and chronic renal failure are included.

Presentamos la adaptación española de las Guías Europeas de Prevención Cardiovascular 2021. En esta actualización además del abordaje individual, se pone mucho más énfasis en las políticas sanitarias como estrategia de prevención poblacional. Se recomienda el cálculo del riesgo vascular de manera sistemática a todas las personas adultas con algún factor de riesgo vascular. Los objetivos terapéuticos para el colesterol LDL, la presión arterial y la glucemia no han cambiado respecto a las anteriores guías, pero se recomienda alcanzar estos objetivos de forma escalonada (etapas 1 y 2). Se recomienda llegar siempre hasta la etapa 2, y la intensificación del tratamiento dependerá del riesgo a los 10 años y de por vida, del beneficio del tratamiento, de las comorbilidades, de la fragilidad y de las preferencias de los pacientes. Las guías presentan por primera vez un nuevo modelo para calcular el riesgo (SCORE2 y SCORE2 OP) de morbimortalidad vascular en los próximos 10 años (infarto de miocardio, ictus y mortalidad vascular) en hombres y mujeres entre 40 y 89 años. Otra de las novedades sustanciales es el establecimiento de diferentes umbrales de riesgo dependiendo de la edad (<50, 50-69, >70 años). Se presentan diferentes algoritmos de cálculo del riesgo vascular y tratamiento de los factores de riesgo vascular para personas aparentemente sanas, pacientes con diabetes y pacientes con enfermedad vascular aterosclerótica. Los pacientes con enfermedad renal crónica se considerarán de riesgo alto o muy alto según la tasa del filtrado glomerular y el cociente albúmina/creatinina. Se incluyen innovaciones en las recomendaciones sobre los estilos de vida, adaptadas a las recomendaciones del Ministerio de Sanidad, así como aspectos novedosos relacionados con el control de los lípidos, la presión arterial, la diabetes y la insuficiencia renal crónica.

Pilot Plant for the Capture of Ammonia from the Atmosphere of Pig and Poultry Farms Using Gas-Permeable Membrane Technology.

Gas-permeable membrane (GPM) technology is a possible solution to reduce ammonia (NH3) emissions from livestock housing. This paper presents the results obtained with an NH3-capture prototype based on the use of expanded polytetrafluoroethylene (ePTFE) membranes in real conditions in a gestating sow house and a free-range laying hen house, comparing them with the results obtained in controlled laboratory conditions for the same type of waste. The NH3 present in the air of the livestock housing was captured by reaction with an acidic solution flowing inside the membranes. The periods of continuous operation of the pilot plant were 232 days at the pig farm and 256 days at the poultry farm. The NH3 recovery rate at the end of those periods was 2.3 and 0.4 g TAN·m-2·d-1 in the pig and the poultry farms, respectively. The limiting factor for the capture process was the NH3 concentration in the air, with the highest recovery occurring in the most concentrated atmosphere. Differences in NH3 capture were observed between seasons and farms, with capture efficiencies of 1.62 and 0.33 g·m-2·d-1 in summer and 3.85 and 1.20 g·m-2·d-1 in winter for pig and poultry farms, respectively. The observed differences were mainly due to the higher ventilation frequency in the summer months, which resulted in a lower NH3 concentration inside the houses compared to the winter months. This is especially important when considering the real applicability of this technology. The results obtained suggest that GPM technology holds promise for limiting NH3 emissions from livestock housing with NH3 ambient concentrations close to 20 ppm or as part of manure storage facilities, given that it allows for recovery of nitrogen in a stable and concentrated solution, which can be used as a fertilizer.

Functional Interfaces, Biological Pathways, and Regulations of Interferon-Related DNA Damage Resistance Signature (IRDS) Genes.

Interferon (IFN)-related DNA damage resistant signature (IRDS) genes are a subgroup of interferon-stimulated genes (ISGs) found upregulated in different cancer types, which promotes resistance to DNA damaging chemotherapy and radiotherapy. Along with briefly discussing IFNs and signalling in this review, we highlighted how different IRDS genes are affected by viruses. On the contrary, different strategies adopted to suppress a set of IRDS genes (STAT1, IRF7, OAS family, and BST2) to induce (chemo- and radiotherapy) sensitivity were deliberated. Significant biological pathways that comprise these genes were classified, along with their frequently associated genes (IFIT1/3, IFITM1, IRF7, ISG15, MX1/2 and OAS1/3/L). Major upstream regulators from the IRDS genes were identified, and different IFN types regulating these genes were outlined. Functional interfaces of IRDS proteins with DNA/RNA/ATP/GTP/NADP biomolecules featured a well-defined pharmacophore model for STAT1/IRF7-dsDNA and OAS1/OAS3/IFIH1-dsRNA complexes, as well as for the genes binding to GDP or NADP+. The Lys amino acid was found commonly interacting with the ATP phosphate group from OAS1/EIF2AK2/IFIH1 genes. Considering the premise that targeting IRDS genes mediated resistance offers an efficient strategy to resensitize tumour cells and enhances the outcome of anti-cancer treatment, this review can add some novel insights to the field.

Statement of the Spanish Interdisciplinary Vascular Prevention Committee on the updated European Cardiovascular Prevention Guidelines. / Comentario del CEIPV a la actualización de las Guías Europeas de Prevención Vascular en la Práctica Clínica.

We present the adaptation for Spain of the updated European Cardiovascular Prevention Guidelines. In this update, greater stress is laid on the population approach, and especially on the promotion of physical activity and healthy diet through dietary, leisure and active transport policies in Spain. To estimate vascular risk, note should be made of the importance of recalibrating the tables used, by adapting them to population shifts in the prevalence of risk factors and incidence of vascular diseases, with particular attention to the role of chronic kidney disease. At an individual level, the key element is personalised support for changes in behaviour, adherence to medication in high-risk individuals and patients with vascular disease, the fostering of physical activity, and cessation of smoking habit. Furthermore, recent clinical trials with PCSK9 inhibitors are reviewed, along with the need to simplify pharmacological treatment of arterial hypertension to improve control and adherence to treatment. In the case of patients with type 2 diabetes mellitus and vascular disease or high vascular disease risk, when lifestyle changes and metformin are inadequate, the use of drugs with proven vascular benefit should be prioritised. Lastly, guidelines on peripheral arterial disease and other specific diseases are included, as is a recommendation against prescribing antiaggregants in primary prevention.

[Statement of the Spanish Interdisciplinary Vascular Prevention Committee on the updated European Cardiovascular Prevention Guidelines]. / Comentario del CEIPV a la actualización de las Guías Europeas de Prevención Vascular en la Práctica Clínica.

We present the adaptation for Spain of the updated European Cardiovascular Prevention Guidelines. In this update, greater stress is laid on the population approach, and especially on the promotion of physical activity and healthy diet through dietary, leisure and active transport policies in Spain. To estimate vascular risk, note should be made of the importance of recalibrating the tables used, by adapting them to population shifts in the prevalence of risk factors and incidence of vascular diseases, with particular attention to the role of chronic kidney disease. At an individual level, the key element is personalised support for changes in behaviour, adherence to medication in high-risk individuals and patients with vascular disease, the fostering of physical activity, and cessation of smoking habit. Furthermore, recent clinical trials with PCSK9 inhibitors are reviewed, along with the need to simplify pharmacological treatment of arterial hypertension to improve control and adherence to treatment. In the case of patients with type 2 diabetes mellitus and vascular disease or high vascular disease risk, when lifestyle changes and metformin are inadequate, the use of drugs with proven vascular benefit should be prioritised. Lastly, guidelines on peripheral arterial disease and other specific diseases are included, as is a recommendation against prescribing antiaggregants in primary prevention.

[Statement of the Spanish Interdisciplinary Vascular Prevention Committee on the updated European Cardiovascular Prevention Guidelines.] / Comentario del CEIPV a la actualización de las Guías Europeas de Prevención Vascular en la Práctica Clínica.

We present the adaptation for Spain of the updated European Cardiovascular Prevention Guidelines. In this update, greater stress is laid on the population approach, and especially on the promotion of physical activity and healthy diet through dietary, leisure and active transport policies in Spain. To estimate vascular risk, note should be made of the importance of recalibrating the tables used, by adapting them to population shifts in the prevalence of risk factors and incidence of vascular diseases, with particular attention to the role of chronic kidney disease. At an individual level, the key element is personalised support for changes in behaviour, adherence to medication in high-risk individuals and patients with vascular disease, the fostering of physical activity, and cessation of smoking habit. Furthermore, recent clinical trials with PCSK9 inhibitors are reviewed, along with the need to simplify pharmacological treatment of arterial hypertension to improve control and adherence to treatment. In the case of patients with type 2 diabetes mellitus and vascular disease or high vascular disease risk, when lifestyle changes and metformin are inadequate, the use of drugs with proven vascular benefit should be prioritised. Lastly, guidelines on peripheral arterial disease and other specific diseases are included, as is a recommendation against prescribing antiaggregants in primary prevention.

Presentamos la adaptación para España de la actualización de las Guías Europeas de Prevención Vascular. En esta actualización se hace mayor énfasis en el abordaje poblacional, especialmente en la promoción de la actividad física y de una dieta saludable mediante políticas alimentarias y de ocio y transporte activo en España. Para estimar el riesgo vascular, se destaca la importancia de recalibrar las tablas que se utilicen, adaptándolas a los cambios poblaciones en la prevalencia de los factores de riesgo y en la incidencia de enfermedades vasculares, con particular atención al papel de la enfermedad renal crónica. A nivel individual resulta clave el apoyo personalizado para el cambio de conducta, la adherencia a la medicación en los individuos de alto riesgo y pacientes con enfermedad vascular, la promoción de la actividad física y el abandono del hábito tabáquico. Además, se revisan los ensayos clínicos recientes con inhibidores de PCKS9, la necesidad de simplificar el tratamiento farmacológico de la hipertensión arterial para mejorar su control y la adherencia al tratamiento. En los pacientes con diabetes mellitus 2 y enfermedad vascular o riesgo vascular alto, cuando los cambios de estilo de vida y la metformina resultan insuficientes, deben priorizarse los fármacos con demostrado beneficio vascular. Por último, se incluyen pautas sobre enfermedad arterial periférica y otras enfermedades específicas, y se recomienda no prescribir antiagregantes en prevención primaria.

[Increasing compliance with a surgical antibiotic prophylaxis protocol in the Urology Service.] / Incremento del cumplimiento de un protocolo de profilaxis antibiótica quirúrgica en el Servicio de Urología.

INTRODUCTION: Surgical site infectionis the most common nosocomial infection in Spain. Theuse of surgical antibiotic prophylaxis (SAP) in clinical practice is frequently inadequate, confirming the need to adopt prevention strategies for this kind of infections. In this sense, promoting actions to improve the SAP in order to reduce surgical site infections is an unavoidable commitment of every surgical department. OBJECTIVE: To evaluate the adequacy of the PAQ after PAQ system implementation based on the use of prophylaxis protocols in compliance with the quality indicator sestablished in the Urology Department. MATERIALS AND METHODS: Retrospective observational study of the SAP of the surgical procedures performed in the Urology Service of a Spanish tertiary-level hospital. An intervention based on the introduction of the prophylaxis protocols was performed. Each prophylaxis kit contains sufficient antibiotic doses to perform an adequate PAQ with a registration form where the administration of doses is recorded. A period of pre-intervention (2005-2010) and post-intervention (2012-2017) were established  and the differences in the values were determined in the following six quality indicators: indication of SAP (indicated and administered prophylaxis), antibiotic selection (according to established protocol), dose and route of administration (therapeutic dose and intravenous route), time of administration of the first dose (between15 min and 1 hour before the surgical incision), intraoperative dose (necessary if the surgery is prolonged more than twice the half-life of the antibiotic or there is significant bleeding) and duration (not to exceed 24 hours). RESULTS: Compliance with the selection of the antibiotic,the time of administration of the first dose, the duration of prophylaxis and the overall adequacy of the SAP increased after the introduction of prophylaxis protocols (p <0.001). CONCLUSIONS: The use of prophylaxis protocols promotes an adequate SAP as it facilitates the appropriate antibiotic selection (active substance, dose and route) and helps to prevent SAP from being unnecessarily prolonged.

INTRODUCCIÓN: La infección de localización quirúrgica es la infección nosocomial más frecuente en España. El uso de la profilaxis antibiótica quirúrgica (PAQ) en la práctica clínica se realiza frecuentemente de manera inadecuada, lo cual pone de manifiesto la necesidad de desarrollar estrategias de prevención de este tipo de infecciones. En este sentido,la promoción de acciones de mejora de la PAQ con el fin de disminuir las infecciones de localización quirúrgica es un compromiso ineludible de todo servicio quirúrgico. OBJETIVO: Nuestro objetivo es evaluar el incremento de la adecuación de la PAQ tras la implantación de un sistema basado en la utilización de los kits de profilaxis conforme al cumplimiento de los indicadores de calidad establecidos en el Servicio de Urología.MATERIALES Y MÉTODOS: Estudio retrospectivo observacional de la PAQ de los procedimientos quirúrgicos realizados en un Servicio de Urología de un hospital español de nivel terciario. Se llevó a cabo una intervención basada en la introducción de los kits de profilaxis, cada kit de profilaxis contiene las dosis de antibiótico necesarias y suficientes para la realización de una adecuada PAQ junto con un impreso donde se registra la administración de dichas dosis. Se estableció un período pre-intervención (2005-2010) y post-intervención (2012-2017) y se determinaron las diferencias encontradas en los valores los siguientes seis indicadores de calidad: indicación de la PAQ (profilaxis indicada y administrada), selección del antibiótico (según protocolo establecido), dosis y vía de administración (dosis terapéutica y vía intravenosa), momento de la administración de la primera dosis (entre 15 min. y 1 hora antes de la incisión quirúrgica), dosis intraoperatoria (necesaria sI la cirugía se prolonga más de dos veces la vida media del antibiótico o hay hemorragia importante) y duración (no exceder 24 horas). RESULTADOS: El cumplimiento de la selección del antibiótico,el momento de administración de la primera dosis, la duración de la profilaxis y la adecuación global de la PAQ se incrementaron de manera estadísticamente significativa tras la introducción de los kits de profilaxis (p<0,001).CONCLUSIONES: La utilización kits de profilaxis constituye una estrategia de mejora que promueve la realización de una adecuada PAQ porque facilita que el antibiótico seleccionado sea el correcto (principio activo,dosis y vía) y ayuda a evitar que la PAQ se prolongue innecesariamente.

The effects of IFITM1 and IFITM3 gene deletion on IFNγ stimulated protein synthesis.

Interferon-induced transmembrane proteins IFITM1 and IFITM3 (IFITM1/3) play a role in both RNA viral restriction and in human cancer progression. Using immunohistochemical staining of FFPE tissue, we identified subgroups of cervical cancer patients where IFITM1/3 protein expression is inversely related to metastasis. Guide RNA-CAS9 methods were used to develop an isogenic IFITM1/IFITM3 double null cervical cancer model in order to define dominant pathways triggered by presence or absence of IFITM1/3 signalling. A pulse SILAC methodology identified IRF1, HLA-B, and ISG15 as the most dominating IFNγ inducible proteins whose synthesis was attenuated in the IFITM1/IFITM3 double-null cells. Conversely, SWATH-IP mass spectrometry of ectopically expressed SBP-tagged IFITM1 identified ISG15 and HLA-B as dominant co-associated proteins. ISG15ylation was attenuated in IFNγ treated IFITM1/IFITM3 double-null cells. Proximity ligation assays indicated that HLA-B can interact with IFITM1/3 proteins in parental SiHa cells. Cell surface expression of HLA-B was attenuated in IFNγ treated IFITM1/IFITM3 double-null cells. SWATH-MS proteomic screens in cells treated with IFITM1-targeted siRNA cells resulted in the attenuation of an interferon regulated protein subpopulation including MHC Class I molecules as well as IFITM3, STAT1, B2M, and ISG15. These data have implications for the function of IFITM1/3 in mediating IFNγ stimulated protein synthesis including ISG15ylation and MHC Class I production in cancer cells. The data together suggest that pro-metastatic growth associated with IFITM1/3 negative cervical cancers relates to attenuated expression of MHC Class I molecules that would support tumor immune escape.

Health care and therapeutic education program for newly diagnosed type 2 diabetes: A new approach in primary care. / Programa de atención y educación terapéutica en el debut de la diabetes tipo 2: un nuevo modelo de abordaje en atención primaria.

INTRODUCTION: Despite the favorable evidence available, our public health care system has no specific programs including therapeutic education for patients newly diagnosed with type 2 diabetes (T2DM), which would be crucial for the subsequent course of the disease. OBJECTIVES: To assess the effectiveness of a "Health care and Therapeutic Education Program for newly diagnosed type 2 diabetes (PAET-Debut DM2)" agreed by the primary care centers and the reference hospital in a given geographical area. METHODS: A prospective pilot study in patients over 18 years of age diagnosed with T2DM between February 2012 and 2013. The PAET-DebutDM2 is planned and set up in four primary care centers in the area covered by Hospital Clínic in Barcelona. Reference persons (family doctor and nurse) are designated at each center and specific training is provided to standardize the clinical processes and therapeutic education methods. First results are assessed and compared at 6 and 12 months. RESULTS: The program was proposed to 345 patients, of which 191 (55.3%) were enrolled in it and 134 (70.2%) completed the program. At the end of the program, 84% achieved the control goal (HbA1c <7%) and 88% passed the screening of chronic complications. Improvements were seen in body weight, physical activity (p<0,001), and disease awareness (p<0.05), and there were less hospital emergencies due to DM as compared to patients not included in the program (p=0.023). CONCLUSION: The PAET-DebutDM2 standardizes intervention and education and is effective in terms of clinical and educational results and patient satisfaction. The program emphasizes the importance of early education and intervention, reorganizing resources without increasing care pressure in the primary care centers, thus reducing hospital care.

Auditing and Improving Surgical Antibiotic Prophylaxis.

BACKGROUND: There is extensive evidence of the efficacy of anti-microbial drugs in preventing infections from surgical efforts. Our objective was to describe the results obtained in our annual surgical antibiotic prophylaxis (SAP) audit in the years 2013-2017. METHODS: This was a retrospective observational study of SAP in surgical procedures carried out between 2013 and 2017 in a tertiary-level hospital. We examined the results from the services of general surgery, vascular surgery, neurosurgery, the breast unit, otolaryngology, maxillofacial surgery, traumatology, urology, pediatric surgery, gynecology, and plastic surgery. RESULTS: Establishment of six process quality indicators and their evaluation in the annual audit were carried out by the pharmacy service for approximately 500 operations. The indicators that had a high percentage of compliance were indication for SAP, choice of anti-microbial agent, dose and route of administration, and administration of an intra-operative dose when this was appropriate. In contrast, time of administration of the first dose and duration of prophylaxis had a worse percentage of compliance. CONCLUSIONS: Compliance with the SAP protocols in our hospital is high. We consider that these better results are attributable to the establishment of quality indicators of SAP and to the annual audit that evaluates said indicators. Communication of the results obtained in the audit to the surgical services, which have as part of their objectives included in their management contracts compliance with said SAP protocols, encourages improvement. The use of prophylaxis kits is an improvement strategy that facilitates the correct choice of anti-microbial agent and prevents SAP from being prolonged inappropriately.