Neurohormonal modulation: The new paradigm of pharmacological treatment of heart failure

The current paradigm of medical therapy for heart failure with reduced ejection fraction (HFrEF) is triple neurohormonal blockade with an angiotensin-converting enzyme inhibitor (ACEI), a beta-blocker (BB) and a mineralocorticoid receptor antagonist (MRA). However, three-year mortality remains over 30%. Stimulation of counter-regulatory systems in addition to neurohormonal blockade constitutes a new paradigm, termed neurohormonal modulation. Sacubitril/valsartan is the first element of this new strategy. PARADIGM-HF was the largest randomized clinical trial conducted in HFrEF. It included 8442 patients and compared the efficacy and safety of sacubitril/valsartan versus enalapril. The primary endpoint was the composite of cardiovascular mortality and hospitalization due to HF, which occurred in 914 (21.8%) patients receiving sacubitril/valsartan and in 1117 (26.5%) patients receiving enalapril (HR 0.8, 95% CI 0.73-0.87, p=0.0000002; NNT 21). Sacubitril/valsartan reduced both primary endpoint components, as well as sudden cardiac death, death due to worsening HF, and death from all causes. Patients on sacubitril/valsartan reported less frequent deterioration of HF and of quality of life, and discontinued study medication less frequently because of an adverse event. PARADIGM-HF demonstrated the superiority of sacubitril/valsartan over enalapril, with a 20% greater impact on cardiovascular mortality compared to ACEIs. Accordingly, in 2016, the European (ESC) and American (ACC/AHA/HFSA) cardiology societies simultaneously issued a class I recommendation for the replacement of ACEIs by sacubitril/valsartan in patients resembling PARADIGM-HF trial participants.info:eu-repo/semantics/publishedVersio

o novo paradigma do tratamento farmacológico da Insuficiência Cardíaca

The current paradigm of medical therapy for heart failure with reduced ejection fraction (HFrEF) is triple neurohormonal blockade with an angiotensin-converting enzyme inhibitor (ACEI), a beta-blocker (BB) and a mineralocorticoid receptor antagonist (MRA). However, three-year mortality remains over 30%. Stimulation of counter-regulatory systems in addition to neurohormonal blockade constitutes a new paradigm, termed neurohormonal modulation. Sacubitril/valsartan is the first element of this new strategy. PARADIGM-HF was the largest randomized clinical trial conducted in HFrEF. It included 8442 patients and compared the efficacy and safety of sacubitril/valsartan versus enalapril. The primary endpoint was the composite of cardiovascular mortality and hospitalization due to HF, which occurred in 914 (21.8%) patients receiving sacubitril/valsartan and in 1117 (26.5%) patients receiving enalapril (HR 0.8, 95% CI 0.73-0.87, p=0.0000002; NNT 21). Sacubitril/valsartan reduced both primary endpoint components, as well as sudden cardiac death, death due to worsening HF, and death from all causes. Patients on sacubitril/valsartan reported less frequent deterioration of HF and of quality of life, and discontinued study medication less frequently because of an adverse event. PARADIGM-HF demonstrated the superiority of sacubitril/valsartan over enalapril, with a 20% greater impact on cardiovascular mortality compared to ACEIs. Accordingly, in 2016, the European (ESC) and American (ACC/AHA/HFSA) cardiology societies simultaneously issued a class I recommendation for the replacement of ACEIs by sacubitril/valsartan in patients resembling PARADIGM-HF trial participants.publishersversionpublishe

(I)Migrantes, diversidades e desigualdades no sistema educativo português : balanço e perspectivas

O objectivo do presente artigo consiste em procurar transmitir um olhar sociologicamente informado no que concerne à situação portuguesa no domínio das políticas educativas públicas e investigações produzidas relacionadas com o sistema educativo e a (i)migração, ou seja, com a tentativa de construção de uma educação intercultural. Neste sentido, será realizada uma análise descritiva e compreensivo-interpretativa da evolução desta problemática em Portugal desde que a mesma se tornou objecto de reflexão por parte de investigadores/as e políticos nos finais da década de oitenta, início da década de noventa do século XX. Nesta análise, será dada ênfase às investigações e quadros teóricos produzidos e às medidas legislativas e políticas educativas no domínio do tratamento da diferença cultural dentro do sistema educativo português.The aim of this article consists in attempting to transmit a sociologically informed view in what the Portuguese situation in the field of public policies and research related to the educational system and (im)migration are concerned, that is, in attempting to construct an intercultural education. In this way, a descriptive and comprehensiveinterpretative analysis of the evolution of this problem in Portugal will be realized, since the latter became an object of reflection on the part of researchers and politicians towards the end of the 80s, the beginning of the 90s of the XXth century. In this analysis, emphasis will be given on the research and theoretical frameworks produced and on the legislative measures and educational policies in the field of treating cultural difference in the Portuguese educational system

A sterol-like odorant in the urine of mozambique tilapia males likely signals social dominance to females

Many species of freshwater fish with relatively simple mating strategies release hormonally derived sex pheromones in urine. However, it is not known whether species with more complex reproductive strategies use specialized urinary chemical signals. We addressed this by using the Mozambique tilapia (Oreochromis mossambicus Peters 1852), a lek-breeding species in which males establish dominance hierarchies and visiting females mate preferentially with territorial/dominant males. We measured urination frequency of territorial males in social isolation and in the presence of females that were either ready to spawn or had finished spawning. In groups of fish, we monitored the volume of urine stored in subordinate and dominant males to determine if urine volume and olfactory potency (by recording electro-olfactograms, EOG, in females) are related to the male’s social rank. Dominant, territorial males stored more urine than subordinates and released it in short pulses, the frequency of which increased in the presence of females ready to spawn but not in the presence of post-spawn females. Urine from subordinate and dominant males was fractionated by liquid chromatography and fractions tested for olfactory potency by using the EOG, with the most potent fraction analyzed by mass spectrometry (MS). The olfactory system of females was sensitive to a urinary compound that was more abundant in the urine of dominant males than in that of subordinates. MS analysis suggested the compound is a sulfated aminosterol-like compound with a formula of C29H40N2O10S. Therefore, we suggest that dominant/territorial tilapia males dramatically increase urination frequency in the presence of females ready to spawn and that the urinary odorant acts as a pheromonal signal of dominance, thereby influencing female spawning

Real-world data from the Portuguese Nivolumab Expanded Access Program (EAP) in previously treated Non Small Cell Lung Cancer (NSCLC)

Objective: The main aim of the study was to evaluate the efficacy and safety profile of Nivolumab, an immune-checkpoint-inhibitor antibody, in advanced, previously treated, Non-Small Cell Lung Cancer (NSCLC) patients, in a real world setting. Methods: We performed a retrospective, multicentre data analysis of patients who were included in the Portuguese Nivolumab Expanded Access Program (EAP). Eligibility criteria included histologically or citologically confirmed NSCLC, stage IIIB and IV, evaluable disease, sufficient organ function and at least one prior line of chemotherapy. The endpoints included Overall Response Rate (ORR), Disease Control Rate (DCR), Progression Free Survival (PFS) and Overall Survival (OS). Safety analysis was performed with the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, and immune-related Adverse Events (irAEs) were treated according to protocol treatment guidelines. Tumour response was assessed using the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Data was analysed using SPSS, version 21.0 (IBM Statistics). Results: From June 2015 to December 2016, a total of 229 patients with advanced NSCLC were enrolled at 30 Portuguese centres. Clinical data were collected up to the end of July 2018. The baseline median age was 64 years (range 37-83) and the majority of patients were males (70.3%) and former/current smokers (69.4%). Patients with non-squamous histology predominated (88.1%), and 67.6% of the patients had received 2 or more prior lines of chemotherapy. Out of 229 patients, data was available for 219 patients (3 patients did not start treatment, while data was unavailable in 7 patients); of the 219 patients, 15.5% were not evaluated for radiological tumour assessment, 1.4% had complete response (CR), 21% partial response (PR), 31% stable disease (SD) and 31.1% progressive disease (PD). Thus, the ORR was 22.4% and DCR was 53.4% in this population. At the time of survival analysis the median PFS was 4.91 months (95% CI, 3.89-6.11) and median OS was 13.21 months (95% CI, 9.89-16.53). The safety profile was in line with clinical trial data. Conclusions: Efficacy and safety results observed in this retrospective analysis were consistent with observations reported in clinical trials and from other centres.info:eu-repo/semantics/publishedVersio

Social organization and endocrine profiles of Australoheros facetus, an exotic freshwater fish in southern Portugal

Australoheros facetus is a neotropical cichlid and an exotic species in the Guadiana and Odelouca basins (Southern Portugal). In this research, we aimed to characterize the main behavioural patterns and circulating hormones, 17 beta-estradiol (E-2) for females, and testosterone, 11-ketotestosterone (11KT) and cortisol for both sexes, during the formation of social groups, a crucial step in the life-history of A. facetus. A pair-breeding strategy with territorial behaviour and aggressive interactions was found, with a positive correlation between dominance and size for both sexes. There were no significant differences between non-territorial and territorial individuals in the baseline levels of hormones, but 11KT was higher in males when they became territorial, as E-2 for territorial females, while there was no clear pattern for testosterone. In contrast, cortisol was higher in non-territorial males and correlated negatively with social dominance. These results suggest that size is the main driver for social dominance and that formation of stable hierarchies result in higher circulating 11KT and lowers stress in territorial males. Related to A. facetus' behaviour, aggressiveness and biparental care may be an advantage during the invasion process of A. facetus, facilitating colonization of new habitats.National Council for Technological and Scientific Development of Brazil (CNPq), Program Science without Borders [245971/20122]FCT-Foundation for Science and Technology [UID/Multi/04326/2013, SFRH/BPD/67008/2009]info:eu-repo/semantics/publishedVersio