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Zika virus (ZikV) is a flavivirus that infects neural tissues, causing congenital microcephaly. ZikV has evolved multiple mechanisms to restrict proliferation and enhance cell death, although the underlying cellular events involved remain unclear. Here we show that the ZikV-NS5 protein interacts with host proteins at the base of the primary cilia in neural progenitor cells, causing an atypical non-genetic ciliopathy and premature neuron delamination. Furthermore, in human microcephalic fetal brain tissue, ZikV-NS5 persists at the base of the motile cilia in ependymal cells, which also exhibit a severe ciliopathy. Although the enzymatic activity of ZikV-NS5 appears to be dispensable, the amino acids Y25, K28, and K29 that are involved in NS5 oligomerization are essential for localization and interaction with components of the cilium base, promoting ciliopathy and premature neurogenesis. These findings lay the foundation for therapies that target ZikV-NS5 multimerization and prevent the developmental malformations associated with congenital Zika syndrome., The work in E.M.’s laboratory was supported by grants BFU2016-77498-P, BFU2016-77498-P, and La Maratò de TV3 foundation 201833-10. M.S. holds a Ramón Y Cajal fellowship (RYC2018-025379-I). J.B.-A is a recipient of a BES-2017-080050 PhD scholarship. The work in N.V.’s laboratory was supported by grants BIO2017-83906-P, Maria de Maeztu Unit of Excellence MDM-2014-0435 (MCIU), and La Maratò de TV3 foundation 201833-10. The work in N.A.’s laboratory was supported by NIH/NINDS R00NS089859 and IDDRC-NPDA (CHOP/Penn).

We present 783 surgical resections of typical and atypical carcinoid tumors of the lung identified in the pathology files of 20 different pathology departments. All cases were critically reviewed for clinical and pathological features and further correlated with clinical outcome. Long-term follow-up was obtained in all the patients and statistically analyzed to determine significance of the different parameters evaluated. Of the histopathological features analyzed, the presence of mitotic activity of 4 mitoses or more per 2mm2, necrosis, lymphatic invasion and lymph node metastasis were identified as statistically significant. Tumors measuring 3 cm or more were also identified as statistically significant and correlate with clinical outcome. Based on our analysis, we consider that the separation of low and intermediate grade neuroendocrine neoplasms of the lung needs to be readjusted in terms of mitotic count as the risk of over grading these neoplasms exceeds 10% under the current criteria. We also consider that tumor size is an important feature to be considered in the assessment of these neoplasms and together with the histological grade of the tumor offers important features that can be correlated with clinical outcome.

Background Vulvar and vaginal cancers are considered rare cancers in women. Human Papillomavirus is responsible for 30–76% of them. The aim of this study was to describe the burden of hospital admissions by malignant neoplasia (MN) and in situ carcinoma (ISC) of vulva and vagina from 2009 to 2013, in Spain Methods This observational, descriptive study used discharge information obtained from the national surveillance system for hospital data, Conjunto Mínimo Básico de Datos, CMBD, provided by the Ministry of Health. Results From 2009–2013, we found 9,896 hospitalizations coded as MN or ISC of vulva and vagina. Mean age of hospitalization was 69.94 ± 15.16 years; average length of hospital stay (ALOS) was 10.02 ± 12.40 days, and mean hospitalization costs were 5,140.31 ± 3,220.61 euros. Mean hospitalization rate was 9.874 per 100,000 women aged >14 years old (95% CI: 9.689–10.058); mean mortality rate was 0.932 per 100,000 women aged >14 years old (95% CI: 0.872–0.991) and mean case fatality rate was 9.438% (95% CI: 8.862–10.014). Conclusion MN and ISC of vulva and vagina are responsible for a considerable hospitalization burden. Information about these hospitalizations could be useful for cost effectiveness analysis and monitoring of HPV vaccination effectiveness., Highlights • 9896 hospitalizations due to NM and ISC were recorded during 2009–2013. • Mean hospitalization rate was 9.874 per 100,000 women >14 years old. • Most of these hospitalizations are related to vulva diseases. • Estimated annual hospital costs due to vagina/vulva NM/ISC are 10.3 million euros.

The 5-year survival rate of patients with pancreatic ductal adenocarcinoma (PDAC) is around 5% due to the fact that the majority of patients present with advanced disease that is treatment resistant. Familial pancreatic cancer (FPC) is a rare disorder that is defined as a family with at least two affected first degree relatives, with an estimated incidence of 4%-10%. The genetic basis is unknown in the majority of families although around 10%-13% of families carry germline mutations in known genes associated with hereditary cancer and pancreatitis syndromes. Panel sequencing was performed of 35 genes associated with hereditary cancer in 43 PDAC cases from families with an apparent hereditary pancreatic cancer syndrome. Pathogenic variants were identified in 19% (5/26) of PDAC cases from pure FPC families in the genes MLH1, CDKN2A, POLQ and FANCM. Low frequency potentially pathogenic VUS were also identified in 35% (9/26) of PDAC cases from FPC families in the genes FANCC, MLH1, PMS2, CFTR, APC and MUTYH. Furthermore, an important proportion of PDAC cases harboured more than one pathogenic, likely pathogenic or potentially pathogenic VUS, highlighting the multigene phenotype of FPC. The genetic basis of familial or hereditary pancreatic cancer can be explained in 21% of families by previously described hereditary cancer genes. Low frequency variants in other DNA repair genes are also present in 35% of families which may contribute to the risk of pancreatic cancer development. This study was funded by the Instituto de Salud Carlos III (Plan Estatal de I + D + i 2013-2016): ISCIII (PI09/02221, PI12/01635, PI15/02101 and PI18/1034) and co-financed by the European Development Regional Fund ''A way to achieve Europe'' (ERDF), the Biomedical Research Network in Cancer: CIBERONC (CB16/12/00446), Red Temática de investigación cooperativa en cáncer: RTICC (RD12/0036/0073) and La Asociación Española contra el Cáncer: AECC (Grupos Coordinados Estables 2016). This study was funded by the Instituto de Salud Carlos III (Plan Estatal de I+D+i 2013-2016): ISCIII (PI09/02221, PI12/01635, PI15/02101 and PI18/1034) and co-financed by the European Development Regional Fund "A way to achieve Europe'' (ERDF), the Biomedical Research Network in Cancer: CIBERONC (CB16/12/00446), Red Tematica de investigacion cooperativa en cancer: RTICC (RD12/0036/0073) and La Asociacion Espanola contra el Cancer: AECC (Grupos Coordinados Estables 2016). Sí

The life and work of Santiago Ramon y Cajal (1852–1934), whose scientific achievements have provided the pillars of modern neuroscience, are presented. Cajal strenuously fought the reticularist view of the nervous system as a continuous fiber network, which was prevailing when he initiated his studies on the nervous system using the Golgi silver stain. Paladin of the neuron doctrine, Cajal viewed the nervous system as made by morphologically and functionally distinct cells polarized to convey information and interconnected in neural circuits. He also provided key contributions to developmental neurobiology and neuroplasticity. In 1906, Cajal received with Camillo Golgi the Nobel Prize in Physiology or Medicine.

Articulo biográfico sobre el doctor D. Pedro Ramón y Cajal.

Brolucizumab; Intraocular inflammation; Patient management Brolucizumab; Inflamación intraocular; Manejo del paciente Brolucizumab; Inflamació intraocular; Maneig del pacient Purpose: Brolucizumab, a new generation anti-VEGF, has demonstrated efficacy and safety in AMD in the pivotal HAWK and HARRIER trials. Post-marketing, previously undetected adverse events related to intraocular inflammation have been reported. An independent post hoc review of the pivotal trials puts the rate of IOI at 4.6%. The aim of this paper is to propose a set of recommendations for implementing the management of brolucizumab in clinical practice. Methods: The recommendations made by the authors are based on their clinical experience, critical review of (i) the pivotal trials, the post-hoc analysis of the Safety Review Committee, (ii), and (iii) the published literature. Results: In the pivotal trials, brolucizumab showed sustained functional gains, superior anatomical outcomes with potentially longer intervals between injections and a well-tolerated overall safety profile. Adverse events reported post-marketing include retinal vasculitis and retinal vascular occlusion. Based on the available information, experts recommend (i) ruling out non-recommended patient profiles (prior history of ORI), (ii) screening the patient prior to each injection to rule out active ORI, (iii) monitoring the patient for early warning signs, and (iv) treating immediately should any adverse events develop. Conclusions: The adverse events reported are rare, but may be associated with severe and irreversible loss of visual acuity. The recommendations made are intended to facilitate the management of brolucizumab in the routine practice of retinologists, to ensure patient safety and, should any adverse events occur, to minimise their impact on vision. Objetivo Brolucizumab, un anti-VEGF de nueva generación, ha demostrado su eficacia y seguridad en degeneración macular asociada a la edad neovascular exudativa (DMAEn) en los ensayos pivotales HAWK y HARRIER. Tras su comercialización, se han reportado eventos adversos relacionados con la inflamación intraocular no detectados previamente. Una revision post hoc independiente de los ensayos pivotales cifra la tasa de IIO en 4,6%. El objetivo de este trabajo es proponer una serie de recomendaciones para implementar el manejo de brolucizumab en la práctica clínica. Método Las recomendaciones realizadas por los autores se han basado en su experiencia clínica y la revisión crítica de: 1) los ensayos pivotales; 2) el análisis post hoc del Comité de Revisión de Seguridad, y 3) la literatura publicada. Resultados En los ensayos pivotales, brolucizumab mostró ganancias funcionales sostenidas, resultados anatómicos superiores con intervalos entre inyecciones potencialmente más prolongados y un perfil de seguridad global bien tolerado. Los eventos adversos reportados tras la comercialización incluyen vasculitis retiniana y la oclusión vascular retiniana. De acuerdo con la información disponible, los expertos recomiendan 1) descartar los perfiles de pacientes no recomendados (historial previo de IIO), 2) explorar al paciente antes de cada inyección para descartar la presencia de IIO activa, 3) monitorizar al paciente para detectar precozmente los signos de alerta, y 4) tratar de inmediato en el caso de que se desarrolle algún evento adverso. Conclusiones Los eventos adversos reportados son poco frecuentes, pero pueden estar asociados con una pérdida severa e irreversible de agudeza visual. Las recomendaciones realizadas pretenden facilitar el manejo de brolucizumab en la práctica habitual de los retinólogos, garantizar la seguridad del paciente y, en caso de que se produzca alguno de los eventos adversos, minimizar su impacto sobre la visión.

The Spanish Society of Cardiovascular & Endovascular Surgery presents the 2012-2020 report of the activity in congenital cardiovascular surgery, based on a voluntary and anonymous registration involving the most of Spanish centres. This article is complementary to the 2020 cardiovascular surgery annual report, and they are published together. In 2020, seriously damaged by the COVID-19 pandemic related to all sanitary fields, we observe a 14% drop in our congenital activity compared with 2019. Data from the previous 9 years are included, in order to obtain real information related to our activity in the serelatively scarce pathologies. In the last nine years, a total of 18526 congenital heart surgeries were performed, accounting for 9.6% of major surgery (congenital + acquired) performed in Spain during that period. Of these surgeries, 81% of them required extracorporeal circulation and 19% not. We highlight the interventions in neonates and adult patients, which represent respectively 19% and 21% of the whole activity and are a real challenge. The most prevalent congenital heart pathologies operated on were septal defects in cases requiring extracorporeal circulation, and ductus in patients not requiring extracorporeal circulation. The presented data are adjusted to the basic Aristotle score of preoperative surgical risk. The observed mortality of surgeries with extracorporeal circulation was 3.1% (Aristotle-6.48), and without cardiopulmonary bypass 2.41% (Aristotle-4.81). This data analysis shows accurate and reliable information about our surgery for congenital heart disease and allow us to compare ourselves within an international framework, and to organize strategies directed to improve our results. (C) 2022 Published by Elsevier Espana, S.L.U. on behalf of Sociedad Espanola de Cirugia Cardiovascular y Endovascular.

The Spanish Society of Cardiovascular and Endovascular Surgery (SECCE) reports the results of the 2019 registry of the surgical activity in our country. This year represents the 31th consecutive year in which this report is published. The participation in this registry is anonymous and voluntary, and it is based on the analysis of the information gathered from 57 centers with activity in cardiovascular surgery in our country, and the confidentiality of the individual data of each center is warranted. For the first time, in the last 15 years, a tendency is broken and fewer hospitals have communicated their activity. In certain cases, estimations have to be calculated in order to make comparisons possible. The registry reports the global activity in our country, the observed mortality and the estimated mortality risk, stratified in different types of procedures.The global cardiac surgical activity in our country remains stable, with an observed mortality that is adequately adjusted to the estimated surgical risk.During 2019, a total of 33,660 procedures of cardiovascular surgery were performed. Major heart surgery was performed in 21,525 cases, among which 19,657 procedures of adult cardiac surgery and 1,868 procedures of congenital cardiac surgery. Out of those, 19,221 procedures were performed under extracorporeal circulation (CEC). Congenital and transplant registries are specifically analysed in their corresponding reports.Among the 19,720 procedures of acquired major cardiac surgery, isolated valve surgery was predominant (8,607 procedures), followed by coronary by-pass surgery (4,734), aorta surgery (2,315) and combined coronary-valvular surgery (1,983). Vascular surgery and transcatheter activity are also reported.The information derived from this national registry allows to know the state-of-the-art of the surgical specialty in our country, through the knowledge of the surgical activity, the risk profile and the observed results, which is a keystone for an adequate evaluation of the quality of the health care that we deliver to the patients affected with cardiovascular pathologies. Risk adjusted mortality seems adequately adjusted, though important local differences are observed. (C) 2021 Sociedad Espanola de Cirugia Cardiovascular y Endovascular. Published by Elsevier Espana, S.L.U.

Seguridad del paciente; Errores médicos; Atención Primaria; Calidad asistencial; Estudio de cohortes Seguretat del pacient; Errors mèdics; Atenció Primària; Qualitat assistencial; Estudi de cohorts Patient safety; Medical errors; Primary Care; Care quality; Cohort study Objetivo Determinar la frecuencia de eventos adversos evitables (EAE) en atención primaria (AP). Diseño Estudio retrospectivo de cohortes. Emplazamiento consultas de medicina de familia y pediatría de Andalucía, Aragón, Castilla La Mancha, Cataluña, Madrid, Navarra y Comunidad Valenciana. Participantes Se determinó revisar un mínimo de 2.397 historias clínicas (nivel de confianza del 95% y una precisión del 2%). La muestra se estratificó por grupos de edad de forma proporcional a su frecuentación y con revisión paritaria de historias de hombres y mujeres. Mediciones principales Número y gravedad de los EAE identificados entre febrero de 2018 y septiembre de 2019. Resultados Se revisaron un total de 2.557 historias clínicas (1.928, 75.4% de pacientes adultos y 629, 24.6% pediátricos). Se identificaron 182 EAE que afectaron a 168 pacientes (7,1%, IC 95% 6,1-8,1%); en adultos 7,6% (IC 95% 6,4-8,8%) y 5,7% (IC 95% 3,9-7,5%) en pacientes pediátricos. Las mujeres sufrieron más EAE que los hombres (p = 0,004). La incidencia de EAE en niños y niñas fue similar (p = 0,3). 6 (4.1%) de los EAE supusieron un daño permanente en pacientes adultos. Conclusiones Buscar fórmulas para incrementar la seguridad en AP, particularmente en pacientes mujeres, debe seguir siendo un objetivo prioritario incluso en pediatría. Uno de cada 24 EAE supone un daño grave y permanente en el adulto. Objective To determine the frequency of avoidable adverse events (AAEs) in Primary Care (PC). Design Retrospective cohort study. Location Family medicine and paediatric clinics in Andalusia, Aragon, Castilla-La Mancha, Catalonia, Madrid, Navarre, and Valencia. Participants A review was performed on a designated sample of 2,397 medical records (95% confidence level and 2% accuracy). The sample was stratified by age group as regards the frequency of physician consultations and considering equal distribution of male and female patients. Main measurements Number and severity of identified AAEs from February 2018 to September 2019. Results A total of 2,557 medical records were reviewed (1,928, 75.4% of adult patients, and 629, 24.6% paediatrics). A total of 182 (7.1%, 95% CI 6.1-8.1%) AAEs that affected 168 patients were identified, which included 7.6% (95% CI 6.4-8.8%) in adults and 5.7% (95% CI 3.9-7.5%) in paediatric patients. The number of AAEs in women was higher than in men (P = 0.006). The incidence of AAEs in boys and girls was similar (P = 0.3). Permanent damage was caused by AAEs in 6 (4.1%) adult patients. Conclusions Seeking formulas to increase patient safety in PC should remain a priority objective, particularly in female patients and in paediatrics. One in 24 AAEs causes serious and permanent damage in adults.

Although titanium is widely used as biomaterial, the control of the interface properties between its surface and the surrounding physiological environment (like bone, other tissues or biofluids) results crucial to achieve a successful osseointegration and good biomechanical and functional performance. In this work, commercially pure titanium (Grade IV) discs obtained by conventional powder metallurgy were coated with 1–3 µm of Ti6Al4V (Grade V) alloy using DC-pulsed or high-power impulse magnetron sputtering (HiPIMS) technique with the aim of improving their biomedical performance. SEM, confocal microscopy, X-ray diffraction, nanoindentation and wetting measurements are used to evaluate the bio-interface role of the titanium-coated implants. Conformal Ti6Al4V coatings with controlled nano-roughness can be deposited with enhanced mechanical (H = 5–8 GPa; E = 140–160 GPa) and hydrophobic properties thanks to a dense columnar structure. The increased Ti-O bonding at the interface helps to prevent the corrosion due to the formation of a surface passivation layer. Particularly in the case of the HiPIMS process, the surface modification of titanium implants (chemistry, morphology and structure) appears as an effective strategy for satisfying the biomedical requirements and functionality, with enhanced mechanical properties and nanostructuration for prevention of bacteria colonization. University of Seville through the VI PPIT-US

Non-target screening (NTS) methods are rapidly gaining in popularity, empowering researchers to search for an ever-increasing number of chemicals. Given this possibility, communicating the confidence of identification in an automated, concise and unambiguous manner is becoming increasingly important. In this study, we compiled several pieces of evidence necessary for communicating NTS identification confidence and developed a machine learning approach for classification of the identifications as reliable and unreliable. The machine learning approach was trained using data generated by four laboratories equipped with different instrumentation. The model discarded substances with insufficient identification evidence efficiently, while revealing the relevance of different parameters for identification. Based on these results, a harmonized IP-based system is proposed. This new NTS-oriented system is compatible with the currently widely used five level system. It increases the precision in reporting and the reproducibility of current approaches via the inclusion of evidence scores, while being suitable for automation., PGF acknowledges his Ramon y Cajal fellowship (RYC2019-027913-I) from the AEI-MICI. ELS is supported by the Luxembourg National Research Fund (FNR) for project A18/BM/12341006.

Chemotherapy; Geriatric assessment; Toxicity Quimioterapia; Evaluación geriátrica; Toxicidad Quimioteràpia; Avaluació geriàtrica; Toxicitat Introduction The GAH (Geriatric Assessment in Hematology) scale is a psychometrically valid tool aimed at identifying older patients with hematological malignancies at higher risk of treatment-related toxicity. Our objective in this study was to determine the weights for each dimension of the GAH scale and the cut-off point to reliably predict treatment tolerability in this population, estimated by a weighted receiver operating characteristic (ROC) analysis and quantified by the area under the curve (AUC). Material and Methods The RETROGAH was a retrospective cohort study including 126 patients who had previously participated in the GAH study. Patients were ≥ 65 years old with newly diagnosed myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), multiple myeloma (MM), or chronic lymphoid leukemia (CLL) and treated with standard front-line therapy within three months after having completed the GAH scale. Results The optimal cut-off value of the GAH total score to discriminate patients at higher risk of treatment toxicity was 42, with 68.5% sensitivity and 55.8% specificity. Using this value, 66.1% of patients evaluated were found to develop some type of toxicity. The AUC was 0.6259 (95% CI: 0.512–0.739; p = 0.035). Discussion The GAH scale not only would enable clinicians to individualize therapy based on individual risk of toxicity but also discriminate patients that will benefit most from intensive treatments from those requiring an adapted approach. While futures studies in clinical practice may improve the model and overcome its limitations, the GAH scale should not be used alone when making treatment decisions. This study was supported by Celgene España S.L.

Lurbinectedin; Neuroendocrine tumours; Small cell Lurbinectedina; Tumores neuroendocrinos; Célula pequeña Lurbinectedina; Tumors neuroendocrins; Cèl·lula petita Background Patients with neuroendocrine tumours (NETs) need alternative therapies after failure of first-line therapy. Patients and methods This phase II trial evaluated lurbinectedin, a selective inhibitor of oncogenic transcription, at 3.2 mg/m2 as a 1-h intravenous infusion every 3 weeks in 32 NETs patients treated in the second- or third-line setting. The primary efficacy endpoint was overall response rate (ORR) according to RECIST v1.1 assessed by the investigators. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Results Two of 31 evaluable patients had confirmed partial responses (ORR = 6.5%; 95%CI, 0.8–21.4%). Median DoR was 4.7 months (95% CI, 4.0–5.4 months), median PFS was 1.4 months (95% CI, 1.2–3.0 months) and median OS was 7.4 months (95% CI, 3.4–16.2 months). Lurbinectedin showed an acceptable, predictable and manageable safety profile. The most common grade 3/4 toxicity was neutropenia (40.6%; grade 4, 12.4%; febrile neutropenia, 3.1%). Conclusions Considering the exploratory aim of this trial that evaluated a heterogeneous population of NETs patients, and the signs of antitumour activity observed (two confirmed partial responses and seven long disease stabilisations), further development of lurbinectedin is warranted in a more selected NETs population.

Background and aim: COVID-19 patients with severe heart or respiratory failure are potential candidates for extracorporeal membrane oxygenation (ECMO). Indications and management of these patients are unclear. Our aim is to describe the results of a prospective registry of COVID-19 patients treated with ECMO.Methods: An anonymous prospective registry of COVID-19 patients treated with veno-arterial (V-A) or veno-venous (V-V) ECMO was created on march 2020. Clinical, analytical and respiratory preimplantation variables, implantation data and post-implantation course data were recorded. The primary endpoint was all cause in-hospital mortality. Secondary events were functional recovery and the combined endpoint of mortality and functional recovery in patients followed at least 3 months after discharge.Results: Three hundred and sixty-six patients from 25 hospitals were analyzed, 347 V-V ECMO and 18 V-A ECMO patients (mean age 52.7 and 49.5 years respectively). Patients with V-V ECMO were more obese, had less frequently organ damage other than respiratory failure and needed less inotropic support; Thirty three percent of V-A ECMO and 34.9% of V-A ECMO were discharged (P = NS). Hospital mortality was non-significantly different, 56.2% versus 50.9% respectively, mainly during ECMO therapy and mostly due to multiorgan failure. Other 51 patients (14%) remained admitted. Mean follow-up was 196 +/- 101.7 days (95%CI: 170.8-221.6). After logistic regression, body weight (OR 0.967, 95%CI: 0.95-0.99, P = 0.004) and ECMO implantation in the own centre (OR 0.48, 95%CI: 0.27-0.88, P = 0.018) were protective for hospital mortality. Age (OR 1.063, 95%CI: 1.005-1.12, P = 0.032), arterial hypertension (3.593, 95%CI: 1.06-12.19, P = 0.04) and global (2.44, 95%CI: 0.27-0.88, P = 0.019), digestive (OR 4,23, 95%CI: 1.27-14.07, P = 0.019) and neurological (OR 4.66, 95%CI: 1.39-15.62, P = 0.013) complications during ECMO therapy were independent predictors of primary endpoint occurrence. Only the post-discharge day at follow-up was independent predictor of both secondary endpoints occurrence.Conclusions: Hospital survival of severely ill COVID-19 patients treated with ECMO is near 50%. Age, arterial hypertension and ECMO complications are predictors of hospital mortality, and body weight and implantation in the own centre are protective. Functional recovery is only predicted by the follow-up time after discharge. A more homogeneous management of these patients is warranted for clinical results and future research optimization. (C) 2022 Sociedad Espanola de Cirugia Cardiovascular y Endovascular. Published by Elsevier Espana, S.L.U.

During the early months of 2020, the world experienced a novel, violent, and relentless pandemic era. By the end of the year more than seventy-seven million cases of COVID-19 had been reported around the globe. Due to it being a highly contagious disease, the recommended measures adopted by most nations to prevent infection include social distancing and quarantine. How did these measures affect people's relationship with alcohol consumption in cultures where alcohol plays an important social role? A questionnaire-based study, designed to follow the drinking behaviour of people before and during lockdown was applied to two different cultural groups impacted by the pandemic during the strict phase of lockdown. These are the British and Spanish populations (179 participants from each country were interviewed). Considering the frequency of consumption of the alcoholic beverages evaluated (wine, beer, cider, whisky and spirits), the results showed that a significant lockdown*country interaction was observed. Overall, Spanish participants consumed alcoholic beverages less frequently during lockdown than before, while British participants reported no change in their consumption habits. Spaniards’ decrease in alcohol consumption is related to the absence of a social contexts while Britons seems to have adapted their consumption to the modified context. Results suggest that, alcohol consumption is a central core of the British culture, while for the Spanish, socialization is more a cultural characteristic than the alcohol itself., MPSN acknowledges the Spanish National Research Agency, the Ministry of Science, Innovation, and Universities and the European Social Fund for her postdoctoral fellowship: Ramón y Cajal Program (RYC2019-027995-I/AEI/10.13039/501100011033). The authors warmly thank Mr. Jeremy Kerswell for his help on participants’ recruitment, Miss Dona Frost and Mister Philip Hedger for the English proof reading as well as all the anonymous participants in this study.

Summary Accumulation of topological stress in the form of DNA supercoiling is inherent to the advance of RNA polymerase II (Pol II) and needs to be resolved by DNA topoisomerases to sustain productive transcriptional elongation. Topoisomerases are therefore considered positive facilitators of transcription. Here, we show that, in contrast to this general assumption, human topoisomerase IIα (TOP2A) activity at promoters represses transcription of immediate early genes such as c-FOS, maintaining them under basal repressed conditions. Thus, TOP2A inhibition creates a particular topological context that results in rapid release from promoter-proximal pausing and transcriptional upregulation, which mimics the typical bursting behavior of these genes in response to physiological stimulus. We therefore describe the control of promoter-proximal pausing by TOP2A as a layer for the regulation of gene expression, which can act as a molecular switch to rapidly activate transcription, possibly by regulating the accumulation of DNA supercoiling at promoter regions., Graphical abstract, Highlights • Catalytic inhibition of TOP2A results in a global reduction in promoter-proximal pausing • Catalytic inhibition of TOP2A upregulates transcription of immediate early genes (IEGs) • IEG upregulation occurs independently of DNA breaks or cellular stress • IEG upregulation depends on the accumulation of negative supercoiling at promoter regions, Herrero-Ruiz et al. analyze the function of DNA topoisomerase II in transcriptional regulation. The results reveal that TOP2A activity favors promoter-proximal pausing of RNA polymerase II and repression of immediate early genes in a mechanism that is independent of DNA break formation and involves the control of DNA supercoiling at promoters.

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER); Red de Investigación Renal (RedInRen); European Renal Association-European Dialysis and Transplant Association (ERA-EDTA); Fundación Renal Iñigo Álvarez de Toledo (FRIAT); Fundación para la Investigación Biomédica Hospital 12 de Octubre (i+12); Centre National de la Recherche Scientifique; Fondation Maladies Rares (LAM-RD_20170304); National Research Agency (ANR, grants MNaims ANR-17-CE17-0012-01); "Investments for the Future" Laboratory of Excellence SIGNALIFE, a network for innovation on signal transduction pathways in life sciences (ANR-11-LABX-0028-01); Initiative of Excellence (IDEX; UCAJedi ANR-15-IDEX-01); Fondation pour la Recherche Médicale (FRM, ING20140129210, DEQ20180339193, FDT201805005509). A cyclical corticosteroid-cyclophosphamide regimen is recommended for patients with primary membranous nephropathy at high risk of progression. We hypothesized that sequential therapy with tacrolimus and rituximab is superior to cyclical alternating treatment with corticosteroids and cyclophosphamide in inducing persistent remission in these patients. This was tested in a randomized, open-label controlled trial of 86 patients with primary membranous nephropathy and persistent nephrotic syndrome after six-months observation and assigned 43 each to receive six-month cyclical treatment with corticosteroid and cyclophosphamide or sequential treatment with tacrolimus (full-dose for six months and tapering for another three months) and rituximab (one gram at month six). The primary outcome was complete or partial remission of nephrotic syndrome at 24 months. This composite outcome occurred in 36 patients (83.7%) in the corticosteroid-cyclophosphamide group and in 25 patients (58.1%) in the tacrolimus-rituximab group (relative risk 1.44; 95% confidence interval 1.08 to 1.92). Complete remission at 24 months occurred in 26 patients (60%) in the corticosteroid-cyclophosphamide group and in 11 patients (26%) in the tacrolimus-rituximab group (2.36; 1.34 to 4.16). Anti-PLA2R titers showed a significant decrease in both groups but the proportion of anti-PLA2R-positive patients who achieved immunological response (depletion of anti-PLA2R antibodies) was significantly higher at three and six months in the corticosteroid-cyclophosphamide group (77% and 92%, respectively), as compared to the tacrolimus-rituximab group (45% and 70%, respectively). Relapses occurred in one patient in the corticosteroid-cyclophosphamide group, and three patients in the tacrolimus-rituximab group. Serious adverse events were similar in both groups. Thus, treatment with corticosteroid-cyclophosphamide induced remission in a significantly greater number of patients with primary membranous nephropathy than tacrolimus-rituximab.

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg was investigated through 96 weeks in EMERALD (NCT02269917). Virologically-suppressed, HIV-1-positive treatment-experienced adults (previous non-darunavir virologic failure [VF] allowed) were randomized (2:1) to D/C/F/TAF or boosted protease inhibitor (PI) plus emtricitabine/tenofovir-disoproxil-fumarate (F/TDF) over 48 weeks. At week 52 participants in the boosted PI arm were offered switch to D/C/F/TAF (late-switch, 44 weeks D/C/F/TAF exposure). All participants were followed on D/C/F/TAF until week 96. Efficacy endpoints were percentage cumulative protocol-defined virologic rebound (PDVR; confirmed viral load [VL] ≥50 copies/mL) and VL

This article explores the main factors that drive the adoption of e-participation. A weight and meta-analysis was carried out from previous quantitative research studies related to individual e-participation adoption published in journals and conferences over the last 17 years. A total of 60 studies were used for the weight and meta-analysis. We identify the ‘best’ and ‘promising’ predictors used in research models to study e-participation. The best predictors are: trust, effort expectancy, perceived usefulness, attitude, trust in government and social influence on intention to use, perceived ease of use on perceived usefulness, perceived usefulness on attitude, and intention to use on use. General public in urban areas account for the 69.78% of the respondents across all articles. Two thirds of all respondents belong to Asia and the Middle East. The countries with highest number of articles found are United States and Jordan. The article provides a wide view of the performance of the 483 relationships used in research models to study e-participation, which may allow researchers to identify trends, and highlights issues in the future use of some constructs. Implications for theory and practice, limitations and directions for future research are discussed.

Background Reducing the dose of biological therapy (BT) when patients with immune-mediated arthritis achieve a sustained therapeutic goal may help to decrease costs for national health services and reduce the risk of serious infection. However, there is little information about whether such a decision can be applied universally. Therefore, the objective of this study was to develop appropriateness criteria for reducing the dose of BT in patients with rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), and peripheral spondyloarthritis (pSpA). Methods The RAND/UCLA appropriateness method was coordinated by experts in the methodology. Five rheumatologists with clinical research experience in RA and/or SpA selected and precisely defined the variables considered relevant when deciding to reduce the dose of BT in the 3 diseases, in order to define patient profiles. Ten rheumatologists with experience in prescribing BT anonymously rated each profile on a scale of 1 (completely inappropriate) to 9 (completely appropriate) after revising a summary of the evidence obtained from 4 systematic literature reviews carried out specifically for this project. Findings A total of 2,304 different profiles were obtained for RA, 768 for axSpA, and 3,072 for pSpA. Only 327 (14.2%) patient profiles in RA, 80 (10.4%) in axSpA, and 154 (5%) in pSpA were considered appropriate for reducing the dose of BT. By contrast, 749 (32.5%) patient profiles in RA, 270 (35.3%) in axSpA, and 1,243 (40.5%) in pSpA were considered inappropriate. The remaining profiles were considered uncertain. Interpretation Appropriateness criteria for reducing the dose of BT were developed in 3 inflammatory conditions. These criteria can help clinicians treating these disorders to optimize the BT dose. However, further research is needed, since more than 50% of the profiles were considered uncertain and the real prevalence of each profile in daily clinical practice remains unknown.

8 páginas.-- 3 figuras.-- 1 tabla.-- 50 referencias.-- Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.foreco.2017.05.060, Tree species often exhibit considerable variability among individuals in seed crop size and averaged seed mass within the same year. However, very little is known about the consequences for seed consumers’ preferences of this potentially large between-individual variability. In this study we quantified seed production and seed manipulation rates by animals over three years in two coexisting oak species of southeast Mexico (Quercus germana and Q. xalapensis) with the principal aim of evaluating the influence of two relevant plant traits (individual crop size and seed mass) on the responses of two guilds of acorn consumers with contrasting foraging behaviors and dietary breadths (vertebrate versus granivorous insects). We detected interactive effects of these two plant traits on seed consumers’ preferences, with important differences between the two groups of acorn-feeding animals. In general, high densities of large-sized acorns triggered a negative density-dependent response (i.e. satiating effect) in granivorous insects and a positive response (i.e. attractive effect) in vertebrates, whereas the opposite occurred when considering the fraction of small-sized acorns. The potential consequences of producing bigger seeds will partly depend on the relative abundance of the two guilds of acorn consumers. Thus, in plant populations with overabundance of vertebrates, the higher attraction of large-sized seeds for these generalist consumers could counteract the satiating effect exercised on granivorous insects through multi-infestation. However, in forest sites with less abundance of vertebrates, the risk of seed predation (mostly by insects) could be reduced in those trees producing huge quantities of large-sized seeds. In summary, we found clear evidences that the direction and magnitude of density-dependent seed removal can differ not only between different groups of seed consumers but also among different fractions of seed size, which highlights the importance of considering this plant trait to better understand the complexity of mechanisms operating in these plant-animal interactions., This study was supported by the Ramón y Cajal Research Programme to IMPR [RYC-2013-13937] and the Consejo Nacional de Ciencia y Tecnología for the doctoral scholarship [No. 272172] awarded to Yureli García De La Cruz for studies at the Centro de Investigaciones Tropicales, Universidad Veracruzana, Mexico.

Graphical abstract, Puntos clave•Las intervenciones en seguridad del paciente, como las prácticas seguras, buscan reducir el número de incidentes para la seguridad de los pacientes, particularmente el número de eventos adversos evitables.•El número de eventos adversos evitables en atención primaria en España se ha duplicado con respecto a los datos aportados por el estudio APEAS (Estudio de la Seguridad de los Pacientes en atención primaria de Salud) realizado en 2008.•Uno de cada 30 eventos adversos evitables supone un daño grave y permanente en el adulto., Objetivo Determinar la frecuencia de eventos adversos evitables (EAE) en atención primaria (AP). Diseño Estudio retrospectivo de cohortes. Emplazamiento consultas de medicina de familia y pediatría de Andalucía, Aragón, Castilla La Mancha, Cataluña, Madrid, Navarra y Comunidad Valenciana. Participantes Se determinó revisar un mínimo de 2.397 historias clínicas (nivel de confianza del 95% y una precisión del 2%). La muestra se estratificó por grupos de edad de forma proporcional a su frecuentación y con revisión paritaria de historias de hombres y mujeres. Mediciones principales Número y gravedad de los EAE identificados entre febrero de 2018 y septiembre de 2019. Resultados Se revisaron un total de 2.557 historias clínicas (1.928, 75.4% de pacientes adultos y 629, 24.6% pediátricos). Se identificaron 182 EAE que afectaron a 168 pacientes (7,1%, IC 95% 6,1-8,1%); en adultos 7,6% (IC 95% 6,4-8,8%) y 5,7% (IC 95% 3,9-7,5%) en pacientes pediátricos. Las mujeres sufrieron más EAE que los hombres (p = 0,004). La incidencia de EAE en niños y niñas fue similar (p = 0,3). 6 (4.1%) de los EAE supusieron un daño permanente en pacientes adultos. Conclusiones Buscar fórmulas para incrementar la seguridad en AP, particularmente en pacientes mujeres, debe seguir siendo un objetivo prioritario incluso en pediatría. Uno de cada 24 EAE supone un daño grave y permanente en el adulto.

Immunoterapia; Pembrolizumab; neoplàsies mamàries triple-negatives Inmunoterapia; Pembrolizumab; neoplasias mamarias triple-negativas Immunotherapy; Pembrolizumab; triple-negative breast neoplasms Background: Treatment options for previously treated metastatic triple-negative breast cancer (mTNBC) are limited. In cohort A of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as second or later line of treatment for patients with mTNBC. Patients and methods: Eligible patients had centrally confirmed mTNBC, ?1 systemic therapy for metastatic disease, prior treatment with anthracycline and taxane in any disease setting, and progression on or after the most recent therapy. Patients received pembrolizumab 200mg intravenously every 3 weeks for up to 2 years. Primary end points were objective response rate in the total and PD-L1–positive populations, and safety. Secondary end points included duration of response, disease control rate (percentage of patients with complete or partial response or stable disease for ?24 weeks), progression-free survival, and overall survival. Results: All enrolled patients (N¼170) were women, 61.8% had PD-L1–positive tumors, and 43.5% had received ?3 previous lines of therapy for metastatic disease. ORR (95% CI) was 5.3% (2.7–9.9) in the total and 5.7% (2.4–12.2) in the PD-L1–positive populations. Disease control rate (95% CI) was 7.6% (4.4–12.7) and 9.5% (5.1–16.8), respectively. Median duration of response was not reached in the total (range, 1.2þ–21.5þ) and in the PD-L1–positive (range, 6.3–21.5þ) populations. Median PFS was 2.0 months (95% CI, 1.9–2.0), and the 6-month rate was 14.9%. Median OS was 9.0 months (95% CI, 7.6–11.2), and the 6-month rate was 69.1%. Treatment-related adverse events occurred in 103 (60.6%) patients, including 22 (12.9%) with grade 3 or 4 AEs. There were no deaths due to AEs. Conclusions: Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with previously treated mTNBC and had a manageable safety profile. This work was supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.