Guideline-directed medical therapies for comorbidities among patients with atrial fibrillation: results from GARFIELD-AF.

AIMS: This study aimed to identify relationships in recently diagnosed atrial fibrillation (AF) patients with respect to anticoagulation status, use of guideline-directed medical therapy (GDMT) for comorbid cardiovascular conditions (co-GDMT), and clinical outcomes. The Global Anticoagulant Registry in the FIELD (GARFIELD)-AF is a prospective, international registry of patients with recently diagnosed non-valvular AF at risk of stroke (NCT01090362). METHODS AND RESULTS: Guideline-directed medical therapy was defined according to the European Society of Cardiology guidelines. This study explored co-GDMT use in patients enrolled in GARFIELD-AF (March 2013-August 2016) with CHA2DS2-VASc ≥ 2 (excluding sex) and ≥1 of five comorbidities-coronary artery disease, diabetes mellitus, heart failure, hypertension, and peripheral vascular disease (n = 23 165). Association between co-GDMT and outcome events was evaluated with Cox proportional hazards models, with stratification by all possible combinations of the five comorbidities. Most patients (73.8%) received oral anticoagulants (OACs) as recommended; 15.0% received no recommended co-GDMT, 40.4% received some, and 44.5% received all co-GDMT. At 2 years, comprehensive co-GDMT was associated with a lower risk of all-cause mortality [hazard ratio (HR) 0.89 (0.81-0.99)] and non-cardiovascular mortality [HR 0.85 (0.73-0.99)] compared with inadequate/no GDMT, but cardiovascular mortality was not significantly reduced. Treatment with OACs was beneficial for all-cause mortality and non-cardiovascular mortality, irrespective of co-GDMT use; only in patients receiving all co-GDMT was OAC associated with a lower risk of non-haemorrhagic stroke/systemic embolism. CONCLUSION: In this large prospective, international registry on AF, comprehensive co-GDMT was associated with a lower risk of mortality in patients with AF and CHA2DS2-VASc ≥ 2 (excluding sex); OAC therapy was associated with reduced all-cause mortality and non-cardiovascular mortality, irrespective of co-GDMT use. CLINICAL TRIAL REGISTRATION: Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Adherence to recommendations by infectious disease consultants and its influence on outcomes of intravenous antibiotic-treated hospitalized patients

BACKGROUND: Consultation to infectious diseases specialists (ID), although not always performed by treating physicians, is part of hospital's daily practice. This study analyses adherence by treating physicians to written ID recommendations (inserted in clinical records) and its effect on outcome in hospitalized antibiotic-treated patients in a tertiary hospital in Spain. METHODS: A prospective, randomized, one-year study was performed. Patients receiving intravenous antimicrobial therapy prescribed by treating physicians for 3 days were identified and randomised to intervention (insertion of written ID recommendations in clinical records) or non-intervention. Appropriateness of empirical treatments (by treating physicians) was classified as adequate, inadequate or unnecessary. In the intervention group, adherence to recommendations was classified as complete, partial or non-adherence. RESULTS: A total of 1173 patients were included, 602 in the non-intervention and 571 in the intervention group [199 (34.9%) showing complete adherence, 141 (24.7%) partial adherence and 231 (40.5%) non-adherence to recommendations]. In the multivariate analysis for adherence (R2 Cox=0.065, p=0.009), non-adherence was associated with prolonged antibiotic prophylaxis (p=0.004; OR=0.37, 95%CI=0.19-0.72). In the multivariate analysis for clinical failure (R2 Cox=0.126, p<0.001), Charlson index (p<0.001; OR=1.19, 95%CI=1.10-1.28), malnutrition (p=0.006; OR=2.00, 95%CI=1.22-3.26), nosocomial infection (p<0.001; OR=4.12, 95%CI=2.27-7.48) and length of hospitalization (p<0.001; OR=1.01, 95%CI=1.01-1.02) were positively associated with failure, while complete adherence (p=0.001; OR=0.35, 95%CI=0.19-0.64) and adequate initial treatment (p=0.010; OR=0.39, 95%CI=0.19-0.80) were negatively associated. CONCLUSIONS: Adherence to ID recommendations by treating physicians was associated with favorable outcome, in turn associated with shortened length of hospitalization. This may have important health-economic benefits and stimulates further investigation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN83234896. http://www.controlled-trials.com/isrctn/sample_documentation.asp

TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts

Eukaryotic topoisomerase 1 (TOP1) regulates DNA topology to ensure efficient DNA replication and transcription. TOP1 is also a major driver of endogenous genome instability, particularly when its catalytic intermediate—a covalent TOP1-DNA adduct known as a TOP1 cleavage complex (TOP1cc)—is stabilised. TOP1ccs are highly cytotoxic and a failure to resolve them underlies the pathology of neurological disorders but is also exploited in cancer therapy where TOP1ccs are the target of widely used frontline anti-cancer drugs. A critical enzyme for TOP1cc resolution is the tyrosyl-DNA phosphodiesterase (TDP1), which hydrolyses the bond that links a tyrosine in the active site of TOP1 to a 3’ phosphate group on a single-stranded (ss)DNA break. However, TDP1 can only process small peptide fragments from ssDNA ends, raising the question of how the ~90 kDa TOP1 protein is processed upstream of TDP1. Here we find that TEX264 fulfils this role by forming a complex with the p97 ATPase and the SPRTN metalloprotease. We show that TEX264 recognises both unmodified and SUMO1-modifed TOP1 and initiates TOP1cc repair by recruiting p97 and SPRTN. TEX264 localises to the nuclear periphery, associates with DNA replication forks, and counteracts TOP1ccs during DNA replication. Altogether, our study elucidates the existence of a specialised repair complex required for upstream proteolysis of TOP1ccs and their subsequent resolution

A Relationship between Carotenoid Accumulation and the Distribution of Species of the Fungus Neurospora in Spain

The ascomycete fungus Neurospora is present in many parts of the world, in particular in tropical and subtropical areas, where it is found growing on recently burned vegetation. We have sampled the Neurospora population across Spain. The sampling sites were located in the region of Galicia (northwestern corner of the Iberian peninsula), the province of Cáceres, the city of Seville, and the two major islands of the Canary Islands archipelago (Tenerife and Gran Canaria, west coast of Africa). The sites covered a latitude interval between 27.88° and 42.74°. We have identified wild-type strains of N. discreta, N. tetrasperma, N. crassa, and N. sitophila and the frequency of each species varied from site to site. It has been shown that after exposure to light Neurospora accumulates the orange carotenoid neurosporaxanthin, presumably for protection from UV radiation. We have found that each Neurospora species accumulates a different amount of carotenoids after exposure to light, but these differences did not correlate with the expression of the carotenogenic genes al-1 or al-2. The accumulation of carotenoids in Neurospora shows a correlation with latitude, as Neurospora strains isolated from lower latitudes accumulate more carotenoids than strains isolated from higher latitudes. Since regions of low latitude receive high UV irradiation we propose that the increased carotenoid accumulation may protect Neurospora from high UV exposure. In support of this hypothesis, we have found that N. crassa, the species that accumulates more carotenoids, is more resistant to UV radiation than N. discreta or N. tetrasperma. The photoprotection provided by carotenoids and the capability to accumulate different amounts of carotenoids may be responsible, at least in part, for the distribution of Neurospora species that we have observed across a range of latitudes

How the Emotional Content of Discourse Affects Language Comprehension

Emotion effects on cognition have often been reported. However, only few studies investigated emotional effects on subsequent language processing, and in most cases these effects were induced by non-linguistic stimuli such as films, faces, or pictures. Here, we investigated how a paragraph of positive, negative, or neutral emotional valence affects the processing of a subsequent emotionally neutral sentence, which contained either semantic, syntactic, or no violation, respectively, by means of event-related brain potentials (ERPs). Behavioral data revealed strong effects of emotion; error rates and reaction times increased significantly in sentences preceded by a positive paragraph relative to negative and neutral ones. In ERPs, the N400 to semantic violations was not affected by emotion. In the syntactic experiment, however, clear emotion effects were observed on ERPs. The left anterior negativity (LAN) to syntactic violations, which was not visible in the neutral condition, was present in the negative and positive conditions. This is interpreted as reflecting modulatory effects of prior emotions on syntactic processing, which is discussed in the light of three alternative or complementary explanations based on emotion-induced cognitive styles, working memory, and arousal models. The present effects of emotion on the LAN are especially remarkable considering that syntactic processing has often been regarded as encapsulated and autonomous

Fractal Characteristics of May-Grünwald-Giemsa Stained Chromatin Are Independent Prognostic Factors for Survival in Multiple Myeloma

The use of computerized image analysis for the study of nuclear texture features has provided important prognostic information for several neoplasias. Recently fractal characteristics of the chromatin structure in routinely stained smears have shown to be independent prognostic factors in acute leukemia. In the present study we investigated the influence of the fractal dimension (FD) of chromatin on survival of patients with multiple myeloma.We analyzed 67 newly diagnosed patients from our Institution treated in the Brazilian Multiple Myeloma Study Group. Diagnostic work-up consisted of peripheral blood counts, bone marrow cytology, bone radiograms, serum biochemistry and cytogenetics. The International Staging System (ISS) was used. In every patient, at least 40 digital nuclear images from diagnostic May-Grünwald-Giemsa stained bone marrow smears were acquired and transformed into pseudo-3D images. FD was determined by the Minkowski-Bouligand method extended to three dimensions. Goodness-of-fit of FD was estimated by the R(2) values in the log-log plots. The influence of diagnostic features on overall survival was analyzed in Cox regressions. Patients that underwent autologous bone marrow transplantation were censored at the day of transplantation.Median age was 56 years. According to ISS, 14% of the patients were stage I, 39% were stage II and 47% were stage III. Additional features of a bad prognosis were observed in 46% of the cases. When stratifying for ISS, both FD and its goodness-of-fit were significant prognostic factors in univariate analyses. Patients with higher FD values or lower goodness-of-fit showed a worse outcome. In the multivariate Cox-regression, FD, R(2), and ISS stage entered the final model, which showed to be stable in a bootstrap resampling study.Fractal characteristics of the chromatin texture in routine cytological preparations revealed relevant prognostic information in patients with multiple myeloma

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field