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Atrial fibrillation; Oral anticoagulants; Adherence; Persistence; Electronic health records Fibrilación auricular; Tratamiento anticoagulante oral; Adherencia; Persistencia; Registros electrónicos de salud Fibril·lació auricular; Tractament anticoagulant oral; Adherència; Persistència; Registres electrònics de salut Objective: We aimed to describe sociodemographic, comorbidities, co-medication and risk of thromboembolic events and bleeding in patients with NVAF initiating oral anticoagulants (OAC) for stroke prevention, and to estimate adherence and persistence to OAC. Setting: Primary Health Care (PHC) in the Catalan Health Institute (ICS), Catalunya, Spain. Participants: All NVAF adult patients initiating OAC for stroke prevention in August 2013---December 2015. Methods: Population-based cohort study. Persistence was measured in patients initiating OAC in August 2013---December 2014. Data source: SIDIAP, which captures electronic health records from PHC in the (ICS), covering approximately 5.8 million people. Results: 51,690 NVAF patients initiated OAC; 47,197 (91.3%) were naive to OAC and 32,404 (62.7%) initiated acenocoumarol. Mean age was 72.8 years (SD 12.3) and 49.4% were women. Platelet-aggregation inhibitors were taken by 9105 (17.6%) of the patients. Persistence and adherence were estimated up to the end of follow-up. For 22,075 patients, persistence was higher among the non-naive patients [n = 258 (61.7%)] than among the naive [n = 11,502 (53.1%)]. Adherence was estimated for patients initiating DOAC and it was similar in naive and non-naive patients. Among the naive to DOAC treatment, those starting rivaroxaban showed a highest proportion [(n = 360 (80.1%)] of good adherence at implementation (MPR > 80%) while patients starting dabigatran were less adherent [n = 203 (47.8%)]. Conclusions: Acenocoumarol was the most frequently prescribed OAC as first therapy in NVAF patients. Non-naive to DOAC showed better persistence than naive. Rivaroxaban showed higher proportion of adherent patients during the implementation phase than apixaban and dabigatran the lowest. Objetivo: Describir datos sociodemográficos, comorbilidades, comedicaciones y riesgo de eventos tromboembólicos y hemorrágicos de los pacientes con fibrilación auricular no valvular (FANV) que inician tratamiento anticoagulante por vía oral (TAO) para prevención del ictus. Estimar adherencia y persistencia al TAO. Emplazamiento: Atención primaria (AP) del Instituto Catalán de Salud (ICS), Cataluña, España. Participantes: Adultos con FANV que inician TAO para prevención de ictus entre agosto del 2013 y diciembre del 2015. Métodos: Estudio de cohortes de base poblacional. Adherencia y persistencia se midieron en pacientes que iniciaban TAO entre agosto del 2013 y diciembre del 2014. Fuente de datos: SIDIAP, base de datos procedentes de registros electrónicos de AP del ICS, que cubre aproximadamente una población de 5,8 millones de personas. Resultados: Cincuenta y un mil seiscientos noventa pacientes con FANV iniciaron TAO, 47.197 (91,3%) eran naïve al TAO y 32.404 (62,7%) iniciaron acenocumarol. Su edad media era 72,8 años (DE 12,3) y el 49,4% eran mujeres; 90105 (17,6%) recibían tratamiento antiagregante plaquetario. Persistencia y adherencia se estimaron hasta el final del seguimiento. La persistencia a anticoagulantes orales directos (ACOD) fue mayor en no naïve que en naïve (61,7% vs. 53,1%). La adherencia a ACOD fue similar en los 2 grupos. Entre los naïve, los pacientes que iniciaban rivaroxabán (80,1%) mostraron mayor adherencia en la implementación (MPR > 80%), mientras que los que iniciaban dabigatrán fueron menos adherentes (47,8%). Conclusiones: Acenocumarol fue el anticoagulante más prescrito. Los pacientes no naïve mostraron mejor persistencia al tratamiento que los naïve. Rivaroxabán mostró mayores tasas de adherencia que apixabán y dabigatrán, las menores.

Objective: To evaluate the association between prematurity (by the gestational week [gw]) and ADHD during childhood. Method: Observational, matched cohort study using data from children born in a tertiary-level hospital (Hospital Universitari Vall d'Hebron, Catalonia, Spain) during 1995-2007 and data from the Information System for the Development of Research in Primary Health Care (SIDIAP database, Catalonia, Spain). Results: Prevalence of ADHD increases as gestational age decreases, 12.7% for those born =28 gw, compared to 3.2% for those born after the 37 gw. The risk of developing ADHD in the non-premature children tends to increase as the gw decreases (35-36 gw, hazard ratio [HR] = 1.70, 95% confidence interval [CI] [1.19, 2.44]; 33-34 gw, HR = 3.38, 95% CI [2.08, 5.50]; 29-32 gw, HR = 2.37, 95% CI [1.54, 3.63]; and =28 gw, HR = 5.57, 95% CI [2.49, 12.46]) Conclusion: Being born preterm is associated with a risk of developing ADHD, also in late preterm children (35-36 gw). Attention when taking care of these infants regarding their mental health must be made.

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase statistical power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data-set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data-sharing mechanisms. This system was developed for the National Heart, Lung, and Blood Institute’s Trans-Omics for Precision Medicine (TOPMed) program, which is generating genomic and other -omics data for more than 80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants (recruited in 1948–2012) from up to 17 studies per phenotype. Here we discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include 1) the software code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify, or extend these harmonizations to additional studies, and 2) the results of labeling thousands of phenotype variables with controlled vocabulary terms.

© 2019 Elsevier. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ Objectives The objective of the study was to identify factors affecting the use of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement, specifically authors’ attitudes toward and experiences with it. Study Design and Setting An online survey was distributed to authors of observational studies recruited via social media, personal network snowballing, and mass mailings using targeted search strategies. Data on demographics, awareness, motivators, and usage were collected in conjunction with a modified Unified Theory of Acceptance and Use of Technology (UTAUT) scale on which confirmatory factor analysis (CFA) was performed. Results One thousand fifteen participants completed the survey. Of these, 185 (18.2%) indicated they had never heard of STROBE nor used it previously, 195 (19.2%) had heard of it but never used it, and 635 (62.6%) had used it. Journals promoting STROBE were both key motivators and awareness mechanisms; peers and educational workshops were also important influencing factors to a lesser degree. The internal consistency of the modified UTAUT scale was strong (Cronbach's alpha = 0.94). CFA supported a four-factor model with 23 questions. Conclusion The endorsement of STROBE by journals is key to authors’ awareness and use of the guideline. We tested and validated our scale which can guide future research on reporting guidelines. The authors would like to acknowledge the Methods in Research on Research (MiRoR) network for their support and guidance. The authors would also like to thank Dr. Michail Kovanis for assistance gathering author emails and Ms. Alice Biggane for her assistance with the recruitment strategy.

Objective: Patient recruitment in clinical trials is challenging with failure to recruit to time and target sample size common. This may be caused by unanticipated problems or by overestimation of the recruitment rate. This study is a systematic review of statistical models to predict recruitment at the design stage of clinical trials. Study Design and Setting: The Online Resource for Recruitment research in Clinical triAls database was searched to identify articles published between 2008 and 2016. Articles published before 2008 were identified from a relevant systematic review. Google search was used to find potential methods in gray literature. Results: Thirteen eligible articles were identified of which, 11 focused on stochastic approaches, one on deterministic models, and one included both stochastic and deterministic methods. Models varied considerably in the factors included and in their complexity. Key aspects included their ability to condition on time; whether they used average or center-specific recruitment rates; and assumptions around center initiation rates. Lack of flexibility of some models restricts their implementation. Conclusion: Deterministic models require specification of few parameters but are likely unrealistic although easy to implement. Increasingly, stochastic models require greater parameter specification, which, along with greater complexity may be a barrier to their implementation.

International audience; Objective: Identify the current practice for recruitment prediction and monitoring within clinical trials.Study Design and Setting: Chief investigators (CIs) were surveyed to identify data sources and adjustments made to support recruitment prediction. Statisticians were surveyed to determine methods and adjustments used when predicting and monitoring recruitment. Participants were identified from the National Institute for Health Research recently funded studies, the UK Clinical Research Collaboration registered Clinical Trial Units network or by the European Clinical Research Infrastructure Network.Results: A total of 51 CIs (UK = 32, ECRIN = 19) and 104 statisticians (UK = 51, ECRIN = 53) were contacted. Response rates varied (CIs UK = 53% ECRIN = 32%; statisticians UK = 98% ECRIN = 36%).Multiple data sources are used to support recruitment rates, most commonly audit data from multiple sites. Variation in individual site recruitment rates are frequently incorporated, but staggered site openings were featured more commonly among UK respondents. Simple prediction methods are preferred to rarely used statistical models. Lack of familiarity with statistical methods are barriers to their use with evidence needed to justify the time required to support their implementation.Conclusion: Simplistic methods will continue as the mainstay of prediction; however, generation of evidence supporting the benefits of complex statistical models should promote their implementations. Multiple data sources to support recruitment prediction are being used, and further work on the quality of these data is needed. Pressure to be optimistic about recruitment rates for the trial to be attractive to funders was felt by a sizable minority. (C) 2020 The Authors. Published by Elsevier Inc.

This is the peer reviewed version of the following article: Forns, J. [et al.]. Validity of ICD-9 and ICD-10 codes used to identify acute liver injury: a study in three European data sources. "Pharmacoepidemiology and drug safety", 6 Juny 2019, vol. 28, núm. 7, p. 965-975, which has been published in final form at 10.1002/pds.4803. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving." Purpose Validating cases of acute liver injury (ALI) in health care data sources is challenging. Previous validation studies reported low positive predictive values (PPVs). Methods Case validation was undertaken in a study conducted from 2009 to 2014 assessing the risk of ALI in antidepressants users in databases in Spain (EpiChron and SIDIAP) and the Danish National Health Registers. Three ALI definitions were evaluated: primary (specific hospital discharge codes), secondary (specific and nonspecific hospital discharge codes), and tertiary (specific and nonspecific hospital and outpatient codes). The validation included review of patient profiles (EpiChron and SIDIAP) and of clinical data from medical records (EpiChron and Denmark). ALI cases were confirmed when liver enzyme values met a definition by an international working group. Results Overall PPVs (95% CIs) for the study ALI definitions were, for the primary ALI definition, 84% (60%-97%) (EpiChron), 60% (26%-88%) (SIDIAP), and 74% (60%-85%) (Denmark); for the secondary ALI definition, 65% (45%-81%) (EpiChron), 40% (19%-64%) (SIDIAP), and 70% (64%-77%) (Denmark); and for the tertiary ALI definition, 25% (18%-34%) (EpiChron), 8% (7%-9%) (SIDIAP), and 47% (42%-52%) (Denmark). The overall PPVs were higher for specific than for nonspecific codes and for hospital discharge than for outpatient codes. The nonspecific code “unspecified jaundice” had high PPVs in Denmark. Conclusions PPVs obtained apply to patients using antidepressants without preexisting liver disease or ALI risk factors. To maximize validity, studies on ALI should prioritize hospital specific discharge codes and should include hospital codes for unspecified jaundice. Case validation is required when ALI outpatient cases are considered.

Summary Background & aims Individuals with Down syndrome (DS) have higher rates of obesity. In the general population green tea extracts, and in particular epigallocatechin gallate (EGCG), have been studied for their antiobesogenic effects. The aim of this study is to elucidate the effect of EGCG on body weight in young DS adults and whether it could be related to changes in lipid profile. Methods In the context of a double-blind phase II clinical trial comparing the effect of EGCG to that of placebo, the body composition of 77 young adults with DS was analyzed through bioelectrical impedance analysis. Lipids were analyzed using standard laboratory procedures. The factors tested in the ANCOVA model for the differences from baseline were treatment, sex as well as their interaction as independent variables. Baseline values were included in the models as covariates. Results Individuals receiving placebo showed an increase in body weight and body mass index (BMI) that was not detected in those with EGCG treatment. EGCG effect on body composition was mainly observed in males, with significant differences between the EGCG and the placebo group after 12 months for weight (estimated adjusted mean difference (AMD) = −2.34, 95% CI = [−4.21, −0.48]; p = 0.015) and body fat (estimated AMD = −1.23, 95% CI = [−2.43,−0.04], p = 0.043). The changes detected in body composition were associated with changes in lipid profile. Conclusions Our results suggest that EGCG could have a modest beneficial effect on weight management in DS. Furthermore, EGCG has also a sex-dependent effect on lipid profile that is related to changes in body mass and composition.

Introduction: Community-acquired pneumonia (CAP) is treated with penicillin in some northern European countries. Objectives: To evaluate whether high-dose penicillin V is as effective as high-dose amoxicillin for the treatment of non-severe CAR. Design: Multicentre, parallel, double-blind, controlled, randomized clinical trial. Setting: 31 primary care centers in Spain. Participants: Patients from 18 to 75 years of age with no significant associated comorbidity and with symptoms of lower respiratory tract infection and radiological confirmation of CAP were randomized to receive either penicillin V 1.6 million units, or amoxicillin 1000 mg three times per day for 10 days. Main measurements: The main outcome was clinical cure at 14 days, and the primary hypothesis was that penicillin V would be non-inferior to amoxicillin with regard to this outcome, with a margin of 15% for the difference in proportions. EudraCT register 2012-003511-63. Results: A total of 43 subjects (amoxicillin: 28; penicillin: 15) were randomized. Clinical cure was observed in 10 (90.9%) patients assigned to penicillin and in 25 (100%) patients assigned to amoxicillin with a difference of -9.1% (95% CI, -41.3% to 6.4%; p=.951) for non-inferiority. In the intention-to-treat analysis, amoxicillin was found to be 28.6% superior to penicillin (95% CI, 7.3-58.1%; p =.009 for superiority). The number of adverse events was similar in both groups. Conclusions: There was a trend favoring high-dose amoxicillin versus high-dose penicillin in adults with uncomplicated CAR The main limitation of this trial was the low statistical power due to the low number of patients included., The project received a research grant from the Carlos III Institute of Health, Ministry of Economy and Competitiveness (Spain), awarded in the 2011 call under the Health Strategy Action 2013-2016, within the National Research Program oriented to Societal Challenges, within the Technical, Scientific and Innovation Research National Plan 2008-2011, with reference PI11/02471, co-funded with European Union ERDF funds. It was also supported by the Spanish Clinical Research Network (SCReN), PT13/0002/0030. The funding bodies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Background: From 2005 to 2010, we conducted 2 randomized studies on a journal (Medicina Clínica), where we took manuscripts received for publication and randomly assigned them to either the standard editorial process or to additional processes. Both studies were based on the use of methodological reviewers and reporting guidelines (RG). Those interventions slightly improved the items reported on the Manuscript Quality Assessment Instrument (MQAI), which assesses the quality of the research report. However, masked evaluators were able to guess the allocated group in 62% (56/90) of the papers, thus presenting a risk of detection bias. In this post-hoc study, we analyse whether those interventions that were originally designed for improving the completeness of manuscript reporting may have had an effect on the number of citations, which is the measured outcome that we used. Methods: Masked to the intervention group, one of us used the Web of Science (WoS) to quantify the number of citations that the participating manuscripts received up December 2016. We calculated the mean citation ratio between intervention arms and then quantified the uncertainty of it by means of the Jackknife method, which avoids assumptions about the distribution shape. Results: Our study included 191 articles (99 and 92, respectively) from the two previous studies, which all together received 1336 citations. In both studies, the groups subjected to additional processes showed higher averages, standard deviations and annual rates. The intervention effect was similar in both studies, with a combined estimate of a 43% (95% CI: 3 to 98%) increase in the number of citations. Conclusions: We interpret that those effects are driven mainly by introducing into the editorial process a senior methodologist to find missing RG items. Those results are promising, but not definitive due to the exploratory nature of the study and some important caveats such as: the limitations of using the number of citations as a measure of scientific impact; and the fact that our study is based on a single journal. We invite journals to perform their own studies to ascertain whether or not scientific repercussion is increased by adhering to reporting guidelines and further involving statisticians in the editorial process. DGA, JAG and EC belong to MiRoR (Methods in Research on Research), which has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 676207. EC and JC are partially supported by the grants MTM2015–64465-C2–1-R (MINECO/FEDER, UE) from the Secretaría de Estado de Investigación, Desarrollo e Innovación del Ministerio de Economía y Competitividad (Spain) and through grant 2017 SGR 622 from the Departament d’Economia i Coneixement de la Generalitat de Catalunya (Spain). The funding bodies had no role in the study design, data collection and analysis, results interpretation, or in writing the manuscript.

El objetivo de este estudio fue describir la localización anatómica, el tipo y la gravedad de las lesiones ocurridas en las competiciones oficiales de las ligas de verano masculinas (2005-2015) de Lucha Leonesa. Al objeto de realizar un análisis más profundo, se tuvo en cuenta, el perfil del luchador. Se produjeron un total de 401 lesiones, siendo los luchadores de mayor nivel los que menos número de lesiones sufrieron. Las contusiones fueron las lesiones más frecuentes (41,4%) pero entre las graves fueron los esguinces (42,3%). Los miembros inferiores fueron la localización más frecuente en el total de lesiones (38,2%) y entre las graves (45,4%). La rodilla, el tórax y el hombro acumulaban casi la mitad de las lesiones y el 68% de las lesiones graves. Los resultados obtenidos sugieren que las características de las lesiones que se pueden observar en la lucha leonesa son similares a las de otros deportes de combate, This study aimed at describing the anatomical location, type and severity of the sport injuries observed during the Leonese Wrestling “masculine summer leagues” official tournaments (2005-2015). The wrestler’s profile was taken into account as a way to achieve a deep analysis. A total of 401 injuries were registered. The best wrestlers were the ones that suffered the least number of injuries. Contusions were the type of injuries more frequently registered (41.4%), while sprains were the most common cause of severe injury (42.3%). The most frequent anatomical location affected and the one in which a great number of severe injuries occurred were the lower limbs (38.2% and 45.4%). The knee, thorax, and shoulder accounted for almost half of the total injuries and represented 68% of the severe injuries. The obtained results suggest that Leonese Wrestling show a similar injury pattern to the one observed in other combat sports, Este trabajo contó con financiación parcial de la Diputación de León, la Federación Territorial de Castilla y León de Lucha y CIBERESP (MTM2015-64465-C2-1-R; MINECO / FEDER)

© 2018 Elsevier. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ The objective of this study is to analyze the effect of different imaging modalities in treatment decision making in proximal humeral fractures. After evaluation of 116 consecutive proximal humeral fractures, observers were asked to give treatment recommendation (conservative vs. surgery). If surgery was proposed, they were told to select surgery of choice. When 3D imaging was added, complexity of fractures significantly increased (p¿

OBJECTIVE: To evaluate the effect of effervescent paracetamol on office and ambulatory blood pressure (BP) compared with noneffervescent paracetamol in hypertensive patients. DESIGN: This was a multicenter open crossover randomized clinical trial. SETTING: Primary care centers in Catalonia and the Basque Country. PARTICIPANTS: Inclusion criteria were office BP 150/95¿mmHg or less and daytime ambulatory BP 140/90¿mmHg or less, stable pharmacologic or nonpharmacologic antihypertensive treatment, and concomitant chronic osteoarticular pain. INTERVENTIONS: Baseline randomized assignment to 3-week periods of effervescent paracetamol (1¿g three times a day) first and noneffervescent paracetamol later, or inversely, during a 7-week study period. At the start and end of each treatment period, 24-h ambulatory BP monitoring was performed. MAIN OUTCOME MEASURES: Differences in 24-h SBP between baseline and end of both treatment periods. The main analyses were performed according to the intention-to-treat principle. RESULTS: In intention-to-treat analysis, 46 patients were analyzed, 21 were treated with paracetamol effervescent and noneffervescent later, and 25 followed the opposite sequence. The difference in 24-h SBP between the two treatments was 3.99¿mmHg (95% confidence interval 1.35-6.63; P¿=¿0.004), higher in the effervescent paracetamol treatment period. Similarly, the per-protocol analysis showed a difference in 24-h SBP between the two groups of 5.04¿mmHg (95% confidence interval 1.80-8.28; P¿=¿0.004), higher in the effervescent paracetamol treatment period. Self-reported pain levels did not differ between groups and did not vary by treatment period. No serious adverse events were reported in either study arm. CONCLUSION: Effervescent paracetamol tablets are responsible for a significant daytime and overall increase in ambulatory 24-h SBP. TRIAL REGISTRATION: NCT: 02514538 EudraCT: 2010-023485-53.

Background Osteoporotic fractures still remain very infrequent and physicians rarely evaluate bone health. We wanted to assess the magnitude of this problem in the near future by determining the risk and likelihood of progression to osteoporosis. Methods We estimated the risk of progression to osteopenia/osteoporosis among HIV-infected patients with at least 2 DXA scans (3726 scans from 875 patients). Time-non-homogeneous bidirectional multistate models based on three states (normal bone mineral density, osteopenia and osteoporosis) were used to model the progression of bone mineral density as a function of age and to study the association between the risk of bone loss and antiretroviral use. Results The HRs associated with age (>45 versus ≤45 years) were: (i) from normal bone mineral density to osteopenia, 0.71 (95% CI 0.45-1.11) for men and 1.06 (95% CI 0.55-2.05) for women; and (ii) from osteopenia to osteoporosis, 0.83 (95% CI 0.51-1.35) for men and 0.99 (95% CI 0.38-2.56) for women. The transition probabilities from osteopenia to osteoporosis over 10 years among men aged 30 and 50 years were 14.9% (95% CI 10.5%-20.4%) and 19% (95% CI 14.3%-24.3%), respectively; and for women, 6.9% (95% CI 3.1%-14.4%) and 30.1% (95% CI 19.8%-41.8%), respectively. An increased osteoporosis risk was observed for PIs and PIs + tenofovir disoproxil fumarate; darunavir was associated with a higher risk of osteoporosis among men (HR 3.9; 95% CI 2-7.5) and women (HR 4.5; 95% CI 1.4-14.7); and atazanavir was associated with a higher risk of osteoporosis among women (HR 4.2; 95% CI 1.3-14). Conclusions Our results highlight the importance of monitoring bone mineral density given the high probability of progression to osteopenia/osteoporosis, especially in women. In the future, changes in antiretrovirals other than tenofovir, such as PIs, should be recommended to reduce the risk of fracture.

Background: Precision medicine is the Holy Grail of interventions that are tailored to a patient’s individual characteristics. However, conventional clinical trials are designed to find differences in averages, and interpreting these differences depends on untestable assumptions. Although only an ideal, a constant effect of treatment would facilitate individual management. A direct consequence of a constant effect is that the variance of the outcome measure would be the same in the treated and control arms. We reviewed the literature to explore the similarity of these variances as a foundation for examining whether and how often precision medicine is definitively required. Methods: We reviewed parallel clinical trials with numerical primary endpoints published in 2004, 2007, 2010 and 2013. We collected the baseline and final standard deviations of the main outcome measure. We assessed homoscedasticity by comparing the variance of the primary endpoint between arms through the outcome variance ratio (treated to control group). Results: The review provided 208 articles with enough information to conduct the analysis. One out of five studies (n = 40, 19.2%) had statistically different variances between groups, implying a non-constant-effect. The adjusted point estimate of the mean outcome variance ratio (treated to control group) is 0.89 (95% CI 0.81 to 0.97). Conclusions: The mean variance ratio is significantly lower than 1 and the lower variance was found more often in the intervention group than in the control group, suggesting it is more usual for treated patients to be stable. This observed reduction in variance might also imply that there could be a subgroup of less ill patients who derive no benefit from treatment. This would require further study as to whether the treatment effect outweighs the side effects as well as the economic costs. We have shown that there are ways to analyze the apparently unobservable constant effect.

Summary Background The REVASCAT trial and other studies have shown that the neurovascular thrombectomy improves outcomes at 90 days post stroke. However, whether the observed benefit is sustained in the long term remains unknown. We report the results of the prespecified 12-month analysis of the REVASCAT trial. Methods Patients with acute ischaemic stroke who could be treated within 8 h of symptom onset were randomly assigned to medical therapy (including intravenous alteplase when eligible) and neurovascular thrombectomy with Solitaire FR or medical therapy alone. The main secondary outcome measure at 1 year follow-up was disability, measured using the modified Rankin Scale (mRS), ranging from 0 (no symptoms) to 6 (death) with categories 5 (severe disability) and 6 (death) collapsed into one category (severe disability or death), analysed as the distribution of the mRS. Additional prespecified secondary outcome measures included health-related quality of life measured with the EuroQol five dimensions questionnaire (EQ-5D) utility index (ranging from −0·3 to 1, higher values indicate better quality of life), the rate of functional independence (mRS 0–2), and cognitive function measured with the Trail Making Test (reported elsewhere). Treatment allocation was open label but endpoints at 12 months were assessed by masked investigators. The trial was registered at ClinicalTrials.gov, number NCT01692379. Findings From Nov 24, 2012, to Dec 12, 2014, 206 patients were randomly assigned to medical therapy plus endovascular treatment (n=103) or medical treatment alone (n=103), at four centres in Catalonia, Spain. At 12 months post randomisation, based on 205 of 206 outcomes available at 12 months, thrombectomy reduced disability over the range of the mRS (common adjusted odds ratio [aOR] 1·80, 95% CI 1·09–2·99), and improved functional independence (mRS=0–2; 45 [44%] of 103 patients vs 31 [30%] of 103 patients; aOR 1·86, 95% CI 1·01–3·44). Health-related quality of life was superior in the thrombectomy group (mean EQ-5D utility index score, 0·46 [SD 0·38] in the thrombectomy group vs 0·33 [0·33] in the control group, difference 0·12 [95% CI 0·03–0·22]; p=0·01). 1-year mortality was 23% (24 of 103 patients) in the thrombectomy group versus 24% (25 of 103 patients) in the control group. Interpretation At 12 months follow-up, neurovascular thrombectomy reduced post-stroke disability and improved health-related quality of life, indicating sustained benefit. These findings have important clinical and public health implications for evaluating the cost-effectiveness of the intervention in the long term. Funding Fundacio Ictus Malaltia Vascular through an unrestricted grant from Medtronic.

This is the peer reviewed version of the following article: Chacon, A., Mateu Jimenez, M., Langohr, K., Fermoselle, C., García Arumí, E., Andreu, A., Yelamos, J., Barreiro, E. Role of PARP activity in lung cancer-induced cachexia: effects on muscle oxidative stress, proteolysis, anabolic markers, and phenotype. "Journal of cellular physiology", Desembre 2017, vol. 232, núm. 12, p. 3744-3761, which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1002/jcp.25851/pdf. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. Strategies to treat cachexia are still at its infancy. Enhanced muscle protein breakdown and ubiquitin-proteasome system are common features of cachexia associated with chronic conditions including lung cancer (LC). Poly(ADP-ribose) polymerases (PARP), which play a major role in chromatin structure regulation, also underlie maintenance of muscle metabolism and body composition. We hypothesized that protein catabolism, proteolytic markers, muscle fiber phenotype, and muscle anabolism may improve in respiratory and limb muscles of LC-cachectic Parp-1-deficient (Parp-1-/-) and Parp-2-/- mice. In diaphragm and gastrocnemius of LC (LP07 adenocarcinoma) bearing mice (wild type, Parp-1-/-, and Parp-2-/-), PARP activity (ADP-ribose polymers, pADPr), redox balance, muscle fiber phenotype, apoptotic nuclei, tyrosine release, protein ubiquitination, muscle-specific E3 ligases, NF-¿B signaling pathway, markers of muscle anabolism (Akt, mTOR, p70S6K, and mitochondrial DNA) were evaluated along with body and muscle weights, and limb muscle force. Compared to wild type cachectic animals, in both respiratory and limb muscles of Parp-1-/- and Parp-2-/- cachectic mice: cancer induced-muscle wasting characterized by increased PARP activity, protein oxidation, tyrosine release, and ubiquitin-proteasome system (total protein ubiquitination, atrogin-1, and 20S proteasome C8 subunit) were blunted, the reduction in contractile myosin and atrophy of the fibers was attenuated, while no effects were seen in other structural features (inflammatory cells, internal or apoptotic nuclei), and markers of muscle anabolism partly improved. Activation of either PARP-1 or -2 is likely to play a role in muscle protein catabolism via oxidative stress, NF-¿B signaling, and enhanced proteasomal degradation in cancer-induced cachexia. Therapeutic potential of PARP activity inhibition deserves attention.

The Consolidated Standards of Reporting Trials (CONSORT) statement is a guideline designed to improve the transparency and quality of the reporting of randomised controlled trials (RCTs). In this article we present an extension to that statement for randomised pilot and feasibility trials conducted in advance of a future definitive RCT. The checklist applies to any randomised study in which a future definitive RCT, or part of it, is conducted on a smaller scale, regardless of its design (eg, cluster, factorial, crossover) or the terms used by authors to describe the study (eg, pilot, feasibility, trial, study). The extension does not directly apply to internal pilot studies built into the design of a main trial, non-randomised pilot and feasibility studies, or phase II studies, but these studies all have some similarities to randomised pilot and feasibility studies and so many of the principles might also apply. The development of the extension was motivated by the growing number of studies described as feasibility or pilot studies and by research that has identified weaknesses in their reporting and conduct. We followed recommended good practice to develop the extension, including carrying out a Delphi survey, holding a consensus meeting and research team meetings, and piloting the checklist. The aims and objectives of pilot and feasibility randomised studies differ from those of other randomised trials. Consequently, although much of the information to be reported in these trials is similar to those in randomised controlled trials (RCTs) assessing effectiveness and efficacy, there are some key differences in the type of information and in the appropriate interpretation of standard CONSORT reporting items. We have retained some of the original CONSORT statement items, but most have been adapted, some removed, and new items added. The new items cover how participants were identified and consent obtained; if applicable, the prespecified criteria used to judge whether or how to proceed with a future definitive RCT; if relevant, other important unintended consequences; implications for progression from pilot to future definitive RCT, including any proposed amendments; and ethical approval or approval by a research review committee confirmed with a reference number. This article includes the 26 item checklist, a separate checklist for the abstract, a template for a CONSORT flowchart for these studies, and an explanation of the changes made and supporting examples. We believe that routine use of this proposed extension to the CONSORT statement will result in improvements in the reporting of pilot trials. Editor’s note: In order to encourage its wide dissemination this article is freely accessible on the BMJ and Pilot and Feasibility Studies journal websites. Electronic supplementary material The online version of this article (doi:10.1186/s40814-016-0105-8) contains supplementary material, which is available to authorized users.

Down syndrome (DS) is an aneuploidy syndrome that is caused by trisomy for human chromosome 21 resulting in a characteristic cognitive and behavioral phenotype, which includes executive functioning and adaptive behavior difficulties possibly due to prefrontal cortex (PFC) deficits. DS also present a high risk for early onset of Alzheimer Disease-like dementia. The dopamine (DA) system plays a neuromodulatory role in the activity of the PFC. Several studies have implicated trait differences in DA signaling on executive functioning based on genetic polymorphisms in the genes encoding for the catechol-O-methyltransferase (COMTVal158Met) and the dopamine transporter (VNTR-DAT1). Since it is known that the phenotypic consequences of genetic variants are modulated by the genetic background in which they occur, we here explore whether these polymorphisms variants interact with the trisomic genetic background to influence gene expression, and how this in turn mediates DS phenotype variability regarding PFC cognition. We genotyped 69 young adults of both genders with DS, and found that VNTR-DAT1 was in Hardy-Weinberg equilibrium but COMTVal158Met had a reduced frequency of Met allele homozygotes. In our population, genotypes conferring higher DA availability, such as Met allele carriers and VNTR-DAT1 10-repeat allele homozygotes, resulted in improved performance in executive function tasks that require mental flexibility. Met allele carriers showed worse adaptive social skills and self-direction, and increased scores in the social subscale of the Dementia Questionnaire for People with Intellectual Disabilities than Val allele homozygotes. The VNTR-DAT1 was not involved in adaptive behavior or early dementia symptoms. Our results suggest that genetic variants of COMTVal158Met and VNTR-DAT1 may contribute to PFC-dependent cognition, while only COMTVal158Met is involved in behavioral phenotypes of DS, similar to euploid population. This work was supported by grants, donations and agreements from Fondation Jérôme Lejeune (Paris, France), Instituto de Salud Carlos III FEDER, (PI11/00744), MINECO (SAF2010-19434 and SAF2013-49129-C2-1-R), EU (Era Net Neuron PCIN-2013-060), DIUE de la Generalitat de Catalunya (SGR 2009/1450, 2014SGR 680, 2014 SGR 464, SGR 2009/718, and SGR 2014/1125). LdH is recipient of a pre-doctoral fellowship from ISCIII [FI12/00319]. CRG is Center of Excellence Severo Ochoa SEV-2012-0208.

To estimate treatment effects, trials are initiated by randomising patients to the interventions under study and finish by comparing patient evolution. In order to improve the trial report, the CONSORT statement provides authors and peer reviewers with a guide of the essential items that would allow research replication. Additionally, WebCONSORT aims to facilitate author reporting by providing the items from the different CONSORT extensions that are relevant to the trial being reported. WebCONSORT has been estimated to improve the proportion of reported items by 0.04 (95% CI, -0.02 to 0.10), interpreted as "no important difference", in accordance with the scheduled desired scenario of a 0.15 effect size improvement. However, in a non-scheduled analysis, it was found that, despite clear instructions, around a third of manuscripts selected for trials by the editorial staff were not actually randomised trials. We argue that surprises benefit science, and that further research should be conducted in order to improve the performance of editorial staff.Please see related research: http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0736-x.

The endocannabinoid (eCB) system can promote food intake by increasing odor detection in mice. The eCB system is over-active in human obesity. Our aim is to measure circulating eCB concentrations and olfactory capacity in a human sample that includes people with obesity and explore the possible interaction between olfaction, obesity and the eCB system. The study sample was made up of 161 females with five groups of body mass index sub-categories ranging from under-weight to morbidly obese. We assessed olfactory capacity with the “Sniffin´Sticks” test, which measures olfactory threshold-discrimination-identification (TDI) capacity. We measured plasma concentrations of the eCBs 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine or anandamide (AEA), and several eCB-related compounds, 2-acylglycerols and N-acylethanolamines. 2-AG and other 2-acylglycerols fasting plasma circulating plasma concentrations were higher in obese and morbidly obese subjects. AEA and other N-acylethanolamine circulating concentrations were lower in under-weight subjects. Olfactory TDI scores were lower in obese and morbidly obese subjects. Lower TDI scores were independently associated with higher 2-AG fasting plasma circulating concentrations, higher %body fat, and higher body mass index, after controlling for age, smoking, menstruation, and use of contraceptives. Our results show that obese subjects have a lower olfactory capacity than non-obese ones and that elevated fasting plasma circulating 2-AG concentrations in obesity are linked to a lower olfactory capacity. In agreement with previous studies we show that eCBs AEA and 2-AG, and their respective congeners have a distinct profile in relation to body mass index. The present report is the first study in humans in which olfactory capacity and circulating eCB concentrations have been measured in the same subjects. The work was supported by the following: Instituto Salud Carlos III, http://www.isciii.es, FIS PI11/210, FIS14/290; Centro de Investigación Biomédica en Red. Fisiopatología de la Obesidad y Nutrición (CIBEROB), http://www.ciberobn.es; and Agència de Gestió d´Ajuts Universitaris i de Recerca (AGAUR), www.gencat.cat/agaur/, 2014 SGR 1672. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. SI

Background: Apixaban is a direct oral anticoagulant, which inhibits factor Xa. It has demonstrated clinical efficacy in prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation and a better safety profile compared to warfarin. Objectives: (1) To describe the characteristics of patients with nonvalvular atrial fibrillation beginning treatment with apixaban, (2) to analyze concomitant prescriptions of medications that could potentially interact with apixaban, (3) to evaluate the level of appropriate usage according to the recommended dosage, and (4) to estimate the level of apixaban persistence among naive and non-naive patients. Methods: Cohort study using data from primary care (System for Research in Primary Care database, users of the Institut Català de la Salut; Catalonia, Spain) from August 2013 to December 2015. Results: Mean age for apixaban-treated patients was 71.8 years (standard deviation = 11.1) and 55.6% were male. In all, 3.2% of patients receiving apixaban were taking drugs described as potentially related to either pharmacokinetic or pharmacodynamic interactions. According to the summary of product characteristics, 81.1% of patients with a recommended dose of 2.5 mg twice daily and 51.8% with a recommended dose of 5 mg twice daily actually took this dose. After 1 year of follow-up, 62.6% of the apixaban users showed good adherence. Conclusion: The prescribed dose of apixaban did not fully follow the recommended dose, particularly in patients who were treatment naive. Patients with a prior history of anticoagulant treatment were more likely to remain persistent to treatment with apixaban.

Antidepressants; Comorbidity; Drug utilization study; Europe Antidepresivos; Comorbilidad; Estudio de utilización de medicamentos; Europa Antidepressius; Comorbiditat; Estudi d'utilització de medicaments; Europa Background We aimed to describe patterns of use and characteristics of 10 commonly used antidepressants for the period 2009–2014 in Denmark, Germany, Spain, and Sweden. Methods Adult initiators from 2009 to 2014 of each study antidepressant were identified in four countries using five data sources: the Danish National registers, GePaRD (Germany), EpiChron (Aragon, Spain), SIDIAP (Catalonia, Spain), and the Swedish National Registers. The study included 10 study antidepressants: citalopram, escitalopram, fluoxetine, paroxetine, sertraline, duloxetine, venlafaxine, amitriptyline, mirtazapine, and agomelatine. Results Citalopram was the most prescribed study antidepressant, followed by mirtazapine. Paroxetine and agomelatine were the least prescribed antidepressants. Mirtazapine was widely used among older antidepressant initiators with higher percentages of comorbidities at baseline, and fluoxetine was used among young patients. Citalopram and amitriptyline had the lowest percentage of multiple antidepressant use in the 12 months prior to the current treatment episode, while agomelatine, duloxetine, and venlafaxine had the highest percentage of multiple antidepressant use in the year prior to the current treatment episode. Limitations The most important limitations are exposure information based on filled prescriptions, focus on antidepressant initiators only, lack of information on the indication, and heterogeneity of the type of data across data sources. Conclusions Results of this study including 4.8 million study antidepressant initiators of study antidepressants suggest that citalopram and mirtazapine are the most commonly prescribed antidepressants. Agomelatine and paroxetine were the least used antidepressants in the participating populations. Mirtazapine was the antidepressant most commonly prescribed among older antidepressant initiators with high percentage of comorbidities at baseline, whereas fluoxetine was commonly used among young patients.

Introduction24-hour ambulatory blood pressure monitoring (ABPM) is the gold standard diagnostic method for hypertension, but has some shortcomings in clinical practice while clinical settings often lack sufficient devices to accommodate all patients with suspected hypertension. Home blood pressure monitoring (HBPM) and office blood pressure monitoring (OBPM) also have shortcomings, such as the white coat effect or a lack of accuracy. This study aims to study the validity of a new method of diagnosing hypertension consisting of monitoring blood pressure (BP) for 1 hour and comparing it with OBPM and HBPM and examining the sensitivity and specificity of this method compared with 24-hour ABPM. The patient experience will be examined in each method.Methods and analysisA minimum sample of 214 patients requiring a diagnostic test for hypertension from three urban primary healthcare centres will be included. Participants will undergo 24-hour ABPM, 1-hour BP measurement (1-BPM), OBPM for three consecutive weeks and HBPM. Patients will follow a random sequence to first receive 24-hour ABPM or 1-hour ABPM. Daytime 24-hour ABPM records will be compared with the other monitoring methods using the correlation coefficient and Bland Altman plots. The kappa concordance index and the sensitivity and specificity of the methods will be calculated. The patient’s experience will be studied, with selected indicators of efficiency and satisfaction calculated using parametric tests.Ethics and disseminationThe protocol has been authorised by the research ethics committee of the Hospital Clinic of Barcelona (Ref. HCB/2014/0615): protocol details and amendments will be recorded and reported to ClinicalTrials.com. The results will be disseminated in peer-reviewed literature, and to policy makers and healthcare partners.Trial registrationNCT03147573; Pre-results.