Real-World Management and Clinical Outcomes of Stroke Survivors With Atrial Fibrillation: A Population-Based Cohort in Spain

Antiplatelets; Atrial fibrillation; Treatment strategiesAntiplaquetarios; Fibrilación auricular; Estrategias de tratamientoAntiplaquetàries; Fibril·lació auricular; Estratègies de tractamentObjective: Despite the continuous update of clinical guidelines, little is known about the real-world management of patients with atrial fibrillation (AF) who survived a stroke. We aimed to assess patterns of therapeutic management of stroke survivors with AF and clinical outcomes using data from routine practice in a large population-based cohort. Methods: A population-based retrospective cohort study of all patients with AF who survived a stroke, from January 2010 to December 2017 in the Valencia region, Spain (n = 10,986), was carried out. Treatment strategies and mean time to treatment initiation are described. Temporal trends are shown by the management pattern during the study period. Factors associated with each pattern (including no treatment) vs. oral anticoagulant (OAC) treatment were identified using logistic multivariate regression models. Incidence rates of clinical outcomes (mortality, stroke/TIA, GI bleeding, and ACS) were also estimated by the management pattern. Results: Among stroke survivors with AF, 6% were non-treated, 23% were prescribed antiplatelets (APT), 54% were prescribed OAC, and 17% received OAC + APT at discharge. Time to treatment was 8.0 days (CI 7.6–8.4) for APT, 9.86 (CI 9.52–10.19) for OAC, and 16.47 (CI 15.86–17.09) for OAC + APT. Regarding temporal trends, management with OAC increased by 20%, with a decrease of 50% for APT during the study period. No treatment and OAC + APT remained relatively stable. The strongest predictor of no treatment and APT treatment was having the same management strategy pre-stroke. Those treated with APT had the highest rates of GI bleeding and recurrent stroke/TIA, and untreated patients showed the highest rates of mortality. Conclusion: In this large population-based cohort using real-world data, nearly 30% of AF patients who suffered a stroke were untreated or treated with APT, which overall is not recommended. Treatment was started within 2 weeks as recommended, except for OAC + APT, which was started later. The strong association of APT treatment or non-treatment with the same treatment strategy before stroke occurrence suggests a strong therapeutic inertia and opposes recommendations. Patients under these two strategies had the highest rates of adverse outcomes. An inadequate prescription poses a great risk on patients with AF and stroke; thus monitoring their management is necessary and should be setting-specific.CR-B was funded at the start of this work by the Instituto de Salud Carlos III, Spanish Ministry of Health, co-financed by the European Regional Development Fund (grant number RD16/0001/0011) and currently through a competitive grant (Sara Borrell CD19/00137). FS-S was funded by the Instituto de Salud Carlos III, Spanish Ministry of Health through the REDISSEC network (grant number RD16/0001/0011). The views presented here are those of the authors and not necessarily those of the FISABIO Foundation, the Valencia Ministry of Health or the study sponsors

Enhancing the effects of neurofeedback training: the motivational value of the reinforcers

The brain activity that is measured by electroencephalography (EEG) can be modified through operant conditioning, specifically using neurofeedback (NF). NF has been applied to several disorders claiming that a change in the erratic brain activity would be accompanied by a reduction of the symptoms. However, the expected results are not always achieved. Some authors have suggested that the lack of an adequate response may be due to an incorrect application of the operant conditioning principles. A key factor in operant conditioning is the use of reinforcers and their value in modifying behavior, something that is not always sufficiently taken into account. This work aims to clarify the relevance of the motivational value versus the purely informational value of the reinforcer. In this study, 113 subjects were randomly assigned two different reinforcer conditions: a selected reinforcer—the subjects subjectively selected the reinforcers—or an imposed reinforcer— the reinforcers were assigned by the experimenter—and both groups undertook NF sessions to enhance the sensorimotor rhythm (SMR). In addition, the selected reinforcer group was divided into two subgroups: one receiving real NF and the other one sham NF. There were no significant differences between the groups at baseline in terms of SMR amplitude. After the intervention, only those subjects belonging to the selected reinforcer group and receiving real NF increased their SMR. Our results provide evidence for the importance of the motivational value of the reinforcer in Neurofeedback succes

Chitosan: poly (vinyl) alcohol composite alkaline membrane incorporating organic ionomers and layered silicate materials into a PEM electrochemical reactor

Mixed matrix membranes (MMM) are prepared from equivalent blends of poly (vinyl alcohol) (PVA) and chitosan (CS) polymers doped with organic ionomers 4VP and AS4, or inorganic layered titanosilicate AM-4 and stannosilicate UZAR-S3, by solution casting to improve the mechanical and thermal properties, hydroxide conductivity and alcohol barrier effect to reduce the crossover. The structural properties, thermal stability, hydrolytic stability, transport and ionic properties of the prepared composite membranes were investigated by scanning electron microscopy (SEM), X-ray diffraction (XRD), thermogravimetric analysis (TGA), water uptake, water content, alcohol permeability, thickness, ion exchange capacity (IEC) and OH- conductivity measurements. The addition of both organic and inorganic fillers in a CS:PVA blend polymer enhances the thermal and ionic properties. All the membranes are homogenous, as revealed by the SEM and XRD studies, except when UZAR-S3 stannosilicate is used as filler, which leads to a dual layer structure, a top layer of UZAR-S3 lamellar particles bound together by the polymer matrix and a bottom layer composed mostly of polymer blend. The loss of crystallinity was especially remarkable in 4VP/CS:PVA membrane. Thus, the 4VP/CS:PVA membrane exhibits the best ionic conductivity, whereas the UZAR-S3/CS:PVA membrane the best reduced alcohol crossover. Finally, the performance of the CS:PVA-based membranes were tested in a Polymer Electrolyte Membrane Electrochemical Reactor (PEMER) for the feasibility use of alkaline anionic exchange membranes in electrosynthesis under alkaline conditions, showing the 4VP/CS:PVA and UZAR-S3/CS:PVA membranes the best performances in PEMER.We gratefully acknowledge the financial support from the Spanish Ministry of Economy and Competitiveness (MINECO) for CTQ2012-31229 project at the University of Cantabria, and MINECO-FEDER (Fondo Europeo de Desarrollo Regional (2014- 2020) through the CTQ2013-48280-C3-3-R project at the University of Alicante. C. C. C. also thanks the MINECO for the “Ramón y Cajal” program at the University of Cantabria (RYC2011-08550), and L. G. C. for her PhD fellowship BES-2011-045147 and the EEBB- 14-09094 mobility grant for the research stay at the University of Cantabria, respectively. Dr. César Rubio, Prof. Carlos Téllez and Prof. Joaquín Coronas from the University of Zaragoza are also warmly thanked for the UZAR-S3 sample

A GRFa2/Prop1/Stem (GPS) Cell Niche in the Pituitary

BACKGROUND: The adult endocrine pituitary is known to host several hormone-producing cells regulating major physiological processes during life. Some candidates to progenitor/stem cells have been proposed. However, not much is known about pituitary cell renewal throughout life and its homeostatic regulation during specific physiological changes, such as puberty or pregnancy, or in pathological conditions such as tumor development. PRINCIPAL FINDINGS: We have identified in rodents and humans a niche of non-endocrine cells characterized by the expression of GFRa2, a Ret co-receptor for Neurturin. These cells also express b-Catenin and E-cadherin in an oriented manner suggesting a planar polarity organization for the niche. In addition, cells in the niche uniquely express the pituitary-specific transcription factor Prop1, as well as known progenitor/stem markers such as Sox2, Sox9 and Oct4. Half of these GPS (GFRa2/Prop1/Stem) cells express S-100 whereas surrounding elongated cells in contact with GPS cells express Vimentin. GFRa2+-cells form non-endocrine spheroids in culture. These spheroids can be differentiated to hormone-producing cells or neurons outlining the neuroectoderm potential of these progenitors. In vivo, GPSs cells display slow proliferation after birth, retain BrdU label and show long telomeres in its nuclei, indicating progenitor/stem cell properties in vivo. SIGNIFICANCE: Our results suggest the presence in the adult pituitary of a specific niche of cells characterized by the expression of GFRa2, the pituitary-specific protein Prop1 and stem cell markers. These GPS cells are able to produce different hormone-producing and neuron-like cells and they may therefore contribute to postnatal pituitary homeostasis. Indeed, the relative abundance of GPS numbers is altered in Cdk4-deficient mice, a model of hypopituitarism induced by the lack of this cyclin-dependent kinase. Thus, GPS cells may display functional relevance in the physiological expansion of the pituitary gland throughout life as well as protection from pituitary disease

Understanding metric-related pitfalls in image analysis validation

Validation metrics are key for the reliable tracking of scientific progress and for bridging the current chasm between artificial intelligence (AI) research and its translation into practice. However, increasing evidence shows that particularly in image analysis, metrics are often chosen inadequately in relation to the underlying research problem. This could be attributed to a lack of accessibility of metric-related knowledge: While taking into account the individual strengths, weaknesses, and limitations of validation metrics is a critical prerequisite to making educated choices, the relevant knowledge is currently scattered and poorly accessible to individual researchers. Based on a multi-stage Delphi process conducted by a multidisciplinary expert consortium as well as extensive community feedback, the present work provides the first reliable and comprehensive common point of access to information on pitfalls related to validation metrics in image analysis. Focusing on biomedical image analysis but with the potential of transfer to other fields, the addressed pitfalls generalize across application domains and are categorized according to a newly created, domain-agnostic taxonomy. To facilitate comprehension, illustrations and specific examples accompany each pitfall. As a structured body of information accessible to researchers of all levels of expertise, this work enhances global comprehension of a key topic in image analysis validation.Comment: Shared first authors: Annika Reinke, Minu D. Tizabi; shared senior authors: Paul F. J\"ager, Lena Maier-Hei

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Impact of the 2018 revised Pregnancy Prevention Programme by the European Medicines Agency on the use of oral retinoids in females of childbearing age in Denmark, Italy, Netherlands, and Spain: an interrupted time series analysis

Background: In March 2018, the European pregnancy prevention programme for oral retinoids was updated as part of risk minimisation measures (RMM), emphasising their contraindication in pregnant women. Objective: To measure the impact of the 2018 revision of the RMMs in Europe by assessing the utilisation patterns of isotretinoin, alitretinoin and acitretin, contraceptive measures, pregnancy testing, discontinuation, and pregnancy occurrence concomitantly with a retinoid prescription. Methods: An interrupted time series (ITS) analysis to compare level and trend changes after the risk minimisation measures implementation was conducted on a cohort of females of childbearing age (12-55 years of age) from January 2010 to December 2020, derived from six electronic health data sources in four countries: Denmark, Netherlands, Spain, and Italy. Monthly utilisation figures (incidence rates [IR], prevalence rates [PR] and proportions) of oral retinoids were calculated, as well as discontinuation rates, contraception coverage, pregnancy testing, and rates of exposed pregnancies to oral retinoids, before and after the 2018 RMMs. Results: From 10,714,182 females of child-bearing age, 88,992 used an oral retinoid at any point during the study period (mean age 18.9-22.2 years old). We found non-significant level and trend changes in incidence or prevalence of retinoid use in females of child-bearing age after the 2018 RMMs. The reason of discontinuation was unknown in >95% of cases. Contraception use showed a significant increase trend in Spain; for other databases this information was limited. Pregnancy testing was hardly recorded thus was not possible to model ITS analyses. After the 2018 RMM, rates of pregnancy occurrence during retinoid use, and start of a retinoid during a pregnancy varied from 0.0 to 0.4, and from 0.2 to 0.8, respectively. Conclusion: This study shows a limited impact of the 2018 RMMs on oral retinoids utilisation patterns among females of child-bearing age in four European countries. Pregnancies still occur during retinoid use, and oral retinoids are still prescribed to pregnant women. Contraception and pregnancy testing information was limited in most databases. Regulators, policymakers, prescribers, and researchers must rethink implementation strategies to avoid any pregnancy becoming temporarily related to retinoid use

Impact of the 2018 revised Pregnancy Prevention Programme by the European Medicines Agency on the use of oral retinoids in females of childbearing age in Denmark, Italy, Netherlands, and Spain: an interrupted time series analysis

Background: In March 2018, the European pregnancy prevention programme for oral retinoids was updated as part of risk minimisation measures (RMM), emphasising their contraindication in pregnant women.Objective: To measure the impact of the 2018 revision of the RMMs in Europe by assessing the utilisation patterns of isotretinoin, alitretinoin and acitretin, contraceptive measures, pregnancy testing, discontinuation, and pregnancy occurrence concomitantly with a retinoid prescription.Methods: An interrupted time series (ITS) analysis to compare level and trend changes after the risk minimisation measures implementation was conducted on a cohort of females of childbearing age (12–55 years of age) from January 2010 to December 2020, derived from six electronic health data sources in four countries: Denmark, Netherlands, Spain, and Italy. Monthly utilisation figures (incidence rates [IR], prevalence rates [PR] and proportions) of oral retinoids were calculated, as well as discontinuation rates, contraception coverage, pregnancy testing, and rates of exposed pregnancies to oral retinoids, before and after the 2018 RMMs.Results: From 10,714,182 females of child-bearing age, 88,992 used an oral retinoid at any point during the study period (mean age 18.9–22.2 years old). We found non-significant level and trend changes in incidence or prevalence of retinoid use in females of child-bearing age after the 2018 RMMs. The reason of discontinuation was unknown in &gt;95% of cases. Contraception use showed a significant increase trend in Spain; for other databases this information was limited. Pregnancy testing was hardly recorded thus was not possible to model ITS analyses. After the 2018 RMM, rates of pregnancy occurrence during retinoid use, and start of a retinoid during a pregnancy varied from 0.0 to 0.4, and from 0.2 to 0.8, respectively.Conclusion: This study shows a limited impact of the 2018 RMMs on oral retinoids utilisation patterns among females of child-bearing age in four European countries. Pregnancies still occur during retinoid use, and oral retinoids are still prescribed to pregnant women. Contraception and pregnancy testing information was limited in most databases. Regulators, policymakers, prescribers, and researchers must rethink implementation strategies to avoid any pregnancy becoming temporarily related to retinoid use