Reviewing Atrial Fibrillation Pathophysiology from a Network Medicine Perspective: The Relevance of Structural Remodeling, Inflammation, and the Immune System.

Atrial fibrillation (AF) is the most common type of sustained arrhythmia. The numerous gaps concerning the knowledge of its mechanism make improving clinical management difficult. As omics technologies allow more comprehensive insight into biology and disease at a molecular level, bioinformatics encompasses valuable tools for studying systems biology, as well as combining and modeling multi-omics data and networks. Network medicine is a subarea of network biology where disease traits are considered perturbations within the interactome. With this approach, potential disease drivers can be revealed, and the effect of drugs, novel or repurposed, used alone or in combination, may be studied. Thus, this work aims to review AF pathology from a network medicine perspective, helping researchers to comprehend the disease more deeply. Essential concepts involved in network medicine are highlighted, and specific research applying network medicine to study AF is discussed. Additionally, data integration through literature mining and bioinformatics tools, with network building, is exemplified. Together, all of the data show the substantial role of structural remodeling, the immune system, and inflammation in this disease etiology. Despite this, there are still gaps to be filled about AF.

Cilostazol attenuates cardiac oxidative stress and inflammation in hypercholesterolemic rats.

Atherosclerosis is a multifactorial chronic disease associated with pro-inflammatory and pro-oxidative cardiovascular states. Cilostazol, a selective phosphodiesterase 3 inhibitor (PDE3), is clinically used in the treatment of intermittent claudication and secondary prevention of cerebral infarction. The aim of this study was to evaluate the cardioprotective effects of cilostazol and the molecular mechanisms involved in hypercholesterolemic rats. Male Wistar rats were divided into four groups: control group (C) and control + cilostazol group (C+CILO), that were fed a standard chow diet, and hypercholesterolemic diet group (HCD) and HCD + cilostazol (HCD+CILO) that were fed a hypercholesterolemic diet. Cilostazol treatment started after 30 days for C+CILO and HCD+CILO groups. Animals were administered cilostazol once a day for 15 days. Subsequently, serum and left ventricles were extracted for evaluation of lipid profile, inflammatory, and oxidative biomarkers. The HCD group displayed increased serum lipid levels, inflammatory cytokines production, and cardiac NF-kB protein expression and decreased cardiac Nrf2-mediated antioxidant activity. Conversely, the cilostazol treatment improved all these cardiac deleterious effects, inhibiting NF-kB activation and subsequently decreasing inflammatory mediators, reestablishing the antioxidant properties through Nrf2-mediated pathway, including increased SOD, GPx, and catalase expression. Taken together, our results indicated that cilostazol protects hypercholesterolemia-induced cardiac damage by molecular mechanisms targeting the crosstalk between Nrf2 induction and NF-kB inhibition in the heart.

Evaluation of the effects produced by subacute tributyltin administration on vascular reactivity of male wistar rats.

Tributyltin chloride (TBT) is an organotin compound widely used in several high biocides for agroindustrial applications, such as fungicides, and marine antifouling paints leading to endocrine disrupting actions, such as imposex development in mollusks. In female rats, TBT has been shown to promote ovarian dysfunction, reduction of estrogen protective effect in the vascular morphophysiology, at least in part by oxidative stress consequences. Estrogen causes coronary endothelium-dependent and independent vasodilation. However, the TBT effects on cardiovascular system of male rats are not fully understood. The aim of this study was to evaluate the effects of subacute TBT exposure in aorta vascular reactivity from male wistar rats. Rats were randomly divided into three groups: control (C), TBT 500 ng/kg/day and TBT 1000 ng/kg/day. TBT was administered daily for 30 days by oral gavage. We found that TBT exposure enhanced testosterone serum levels and it was also observed obesogenic properties. TBT exposure evoked an increase in endothelium-dependent and independent phenylephrine-induced contraction, associated to an inhibition in eNOS activity. On the other hand, it was observed an enhancement of iNOS and NF-kB protein expression. We also observed an increase in oxidative stress parameters, such as superoxide dismutase (SOD) and catalase expression, and also an increase in malondialdehyde production. Finally, TBT exposure produced aortic intima-media thickness. Taken together, these data suggest a potential cardiovascular toxicological effect after subacute TBT exposure in male rats.

Effects of Chloroquine and Hydroxychloroquine on the Cardiovascular System - Limitations for Use in the Treatment of COVID-19

Abstract Chloroquine (CQ) and Hydroxychloroquine (HCQ) are antimalarial drugs, with anti-inflammatory properties that justify their use in the treatment of systemic lupus erythematosus and rheumatic diseases. A pandemic caused by the new coronavirus led the entire world's scientific community to look for drugs already available on the market, capable of exercising beneficial actions in the fight against the disease. Preliminary studies in patients, as well as in vitro studies, suggested possible therapeutic effects associated with the use of HCQ and CQ in the treatment of COVID-19. Despite controversies over the effects of these drugs in combating the "cytokine storm" associated with COVID and the dismal of results in different clinical trials in Brazil, their use has been encouraged and several ongoing investigative studies are underway. In addition to the possible beneficial effects on the prognosis of patients with SARS-CoV-2, such drugs include varied effects on the cardiovascular system, ranging from positive developments related to their vasodilator properties to potential negative effects, such as cardiotoxicity. This work presents the main effects exerted by these drugs on the cardiovascular system, in order to contribute to a scientific discussion about the repurposing of these drugs in the context of COVID-19.

Nutrition and Cardiovascular Diseases: Programming and Reprogramming

Abstract The Developmental Origin of Health and Disease (DOHaD) is an area of science dedicated to studying the processes by which insults during critical periods of mammals development leading to physiological changes resultig in diseases throughout life. Studies point to a complex interaction between nutritional status in early life and cardiovascular system homeostasis in which maternal malnutrition during gestation and/or lactation, as well as early weaning, are associated with development of cardiovascular diseases in adulthood. In this context, epigenetic changes, such as DNA methylation, histone acetylation, and change in microRNA expression have been considered molecular bases of cellular plasticity, which can also be gender-dependent. Experimental studies have demonstrated that interventions encompassing the consumption of functional food/bioactive compounds, as well as energetic and nutrients adjustments on the diet, may attenuate or even prevent consequences associated with plasticity of development, improving cardiovascular health. This review aimed to gather and discuss the findings within this context, published over the last ten years.

Leptin administration during lactation leads to different nutritional, biometric, hemodynamic, and cardiac outcomes in prepubertal and adult female Wistar rats.

Literature reports that insults, such as hormonal disturbances, during critical periods of development may modulate organism physiology and metabolism favoring cardiovascular diseases (CVDs) later in life. Studies show that leptin administration during lactation leads to cardiovascular dysfunction in young and adult male Wistar rats. However, there are sex differences regarding CVD. Thus, the present work aimed to investigate neonatal leptin administration's consequences on different outcomes in female rats at prepubertal and adult age. Newborn Wistar female rats were divided into two groups, Leptin and Control, receiving daily subcutaneous injections of this adipokine (8 µg/100 g) or saline for the first 10 of 21 d of lactation. Nutritional, biometric, hemodynamic, and echocardiographic parameters, as well as maximal effort ergometer performance, were determined at postnatal days (PND) 30 and 150. Leptin group presented lower food intake (p = 0.0003) and higher feed efficiency (p = 0.0058) between PND 21 and 30. Differences concerning echocardiographic parameters revealed higher left ventricle internal diameter (LVID) in systole (p = 0.0051), as well as lower left ventricle ejection fraction (LVEF) (p = 0.0111) and fractional shortening (FS) (p = 0.0405) for this group at PND 30. Older rats treated with leptin during lactation presented only higher LVID in systole (p = 0.0270). Systolic blood pressure and maximum effort ergometer test performance was similar between groups at both ages. These data suggest that nutritional, biometric, and cardiac outcomes due to neonatal leptin administration in female rats are age-dependent.

Could cilostazol be beneficial in COVID-19 treatment? Thinking about phosphodiesterase-3 as a therapeutic target.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) that has emerged and rapidly spread across the world. The COVID-19 severity is associated to viral pneumonia with additional extrapulmonary complications. Hyperinflammation, dysfunctional immune response and hypercoagulability state are associated to poor prognosis. Therefore, the repositioning of multi-target drugs to control the hyperinflammation represents an important challenge for the scientific community. Cilostazol, a selective phosphodiesterase type-3 inhibitor (PDE-3), is an antiplatelet and vasodilator drug, that presents a range of pleiotropic effects, such as antiapoptotic, anti-inflammatory, antioxidant, and cardioprotective activities. Cilostazol also can inhibit the adenosine uptake, which enhances intracellular cAMP levels. In the lungs, elevated cAMP promotes anti-fibrotic, vasodilator, antiproliferative effects, as well as mitigating inflammatory events. Interestingly, a recent study evaluated antiplatelet FDA-approved drugs through molecular docking-based virtual screening on viral target proteins. This study revealed that cilostazol is a promising drug against COVID-19 by inhibiting both main protease (Mpro) and Spike glycoprotein, reinforcing its use as a promising therapeutic approach for COVID-19. Considering the complexity associated to COVID-19 pathophysiology and observing its main mechanisms, this article raises the hypothesis that cilostazol may act on important targets in development of the disease. This review highlights the importance of drug repurposing to address such an urgent clinical demand safely, effectively and at low cost, reinforcing the main pharmacological actions, to support the hypothesis that a multi-target drug such as cilostazol could play an important role in the treatment of COVID-19.

Estudo do Uso do Dabigatrana em Hospital Público Brasileiro Especializado em Cardiologia / Study of Dabigatran Use in a Brazilian Public Hospital Specialized in Cardiology

Fundamentos: Durante a comercialização de novos medicamentos, efeitos inéditos podem ser descobertos. O dabigratana é um anticoagulante aprovado pela ANVISA em 2008. Objetivos: Avaliar segurança, efetividade, perfil de eventos adversos e adesão terapêutica ao dabigatrana (110 e 150 mg) prescrito para pacientes com fibrilação atrial não valvar. Métodos: Pacientes em uso de dabigatrana foram submetidos a entrevistas ao longo do primeiro ano de tratamento, avaliando-se a prescrição em função da dose, idade, gênero e fatores de risco, bem como a prevalência de eventos adversos e o perfil dos pacientes envolvidos. Resultados: O estudo começou com 139 pacientes havendo redução do número de sujeitos em uso do anticoagulante ao final (10% dose 110 mg e 30% dose 150 mg), sem variação nas proporções dos indivíduos quanto ao gênero (homens@65%), faixa etária (idade inferior a 75 anos@80%), escores de risco para eventos tromboembólicos (CHA2 DS2-VASc≥2 @80%) e hemorrágicos (HASBLED<3 @50% dose 110mg e @85% dose 150 mg). O evento adverso mais comum foi a dispepsia (≥10%), independentemente do gênero, porém com menor frequência na faixa etária superior a 75 anos (@20% dos casos). A dispepsia relacionada ao dabigatrana foi principalmente associada a sua combinação com betabloqueadores (@70%), porém, minoritariamente com antidiabéticos (@20%), antiplaquetários (@10%), inibidores da bomba de prótons (@30%) e antagonistas de receptores H2 (@3%). A adesão foi de @60%, independentemente dos eventos adversos relatados. Não foram observados casos de evento tromboembólico e nem sangramento maior

Background: During its commercialization phase, unprecedented effects of new medicaments can be discovered. Dabigatran is an anticoagulant approved by Brazilian National Health Surveillance Agency in 2008. Objectives: To assess safety, effectiveness adverse event profile and adherence to dabigatran (110 mg and 150 mg) prescribed for patients with non-valvular atrial fibrillation. Methods: Patients taking dabigatran were subjected to interviews during the first year of treatment, evaluating the prescription depending on the dose, age, gender and risk factors as well as the prevalence of adverse events and the profile of the patients involved. Results: Between the beginning and the end of the study there was a reduction in the number of subjects using this anticoagulant (10% for the dose of 110 mg and 30% for the dose of 150 mg), without changes in the proportions of individuals regarding to gender (men @65%), age (age <75 anos @80%), anticoagulation previous history (@85%) and risk scores for thromboembolic (CHA2DS2≥VASc = 2 @80%) and bleeding (HASBLED <3 @50% dose 110 mg and @85% dose 150 mg) events. The most common adverse event was dyspepsia (≥10%), regardless of gender, but less frequently in patients over 75 years of age (@20% of cases). Dyspepsia related to dabigatran was mainly associated to its combination with beta-blockers (@70%), but minoritarily with oral hypoglycemic (@20%), antiplatelet agents (@10%), proton pump inhibitors (@30%) and antagonists H2 (@3%). Therapeutic adherence was @60% regardless of the described adverse events. There were no cases of thromboembolic event and major bleeding. Conclusions: Dabigatran has shown to be safe and effective in the evaluated conditions

Envelhecimento e alterações cardíacas, bioquímica, moleculares e funcionais: estudo experimental / Aging and Cardiac, Biochemical, Molecular and functional changes: an experimental study

Fundamentos: O envelhecimento abrange mudanças físicas e psicológicas que reduzem a capacidade de adaptação do idoso à sociedade, sendo o maior fator de risco para doenças cardiovasculares. Objetivo: Investigar alterações do sistema cardiovascular decorrentes do processo de envelhecimento em ratos. Métodos: Parâmetros murinométricos/nutricionais, ecocardiográficos e hemodinâmicos foram determinados em ratos machos com um, cinco e 12 meses de idade. A expressão de proteínas importantes na dinâmica do cálcio intracelular ena sinalização da leptina foram investigadas em homogenato de coração de rato, bem como a atividade das ATPases cardíacas. Os dados foram apresentados como média±erro-padrão e analisados pelo teste one way ANOVA (*p<0,05 vs. 1 mês e #p<0,05 vs. 5 meses). Resultados: Enquanto o índice de massa corporal aumentou (0,46±0,01 g/cm2 ; 0,75±0,01 g/cm2*; 0,78±0,01 g/cm2*), ocoeficiente de eficácia alimentar (0,431±0,013; 0,035±0,003*; 0,003±0,001*#), a velocidade máxima desenvolvida em teste de esforço (3,36±0,34 km/h; 1,38±0,04 km/h*;1,20±0,13 km/h*) e a frequência cardíaca (410,2±5,9 bpm; 375,9±7,6 bpm*;376,6±3,3 bpm*) diminuíram com a idade. Foram observadas hipertrofia do ventrículo esquerdo e disfunção diastólicaem paralelo à redução da expressão do receptor para leptina (2,1±0,4; 1,9±0,2; 0,8±0,2*#) e da atividade da bomba decálcio da família SERCA (1981±77 nmol Pi/mg de proteína/h; 2385±205 nmol Pi/mg de proteína/h; 1148±152 nmol Pi/mg de proteína/h#) no coração.Conclusões: O envelhecimento está associado a risco cardiometabólico, sendo a infrarregulação de receptores para leptina e a redução da atividade da bomba de cálcio no coração provavelmente mecanismos subjacentes à disfunção diastólica do ventrículo esquerdo e a consequente intolerância ao exercício.

Background: Aging involves physical and psychological changes that reduce the elderly’s ability to adapt themselves to society, which is the leading risk factor for cardiovascular diseases. Objective: To investigate changes in the cardiovascular system resulting from the aging process in rats. Methods: Murinometric/nutritional, echocardiographic and hemodynamic parameters were determined in 1, 5 and 12-month aged male rats. The expression of proteins that are critical to intracellular calcium dynamics and leptin signaling, as well as cardiac ATPase activity, was investigated in cardiac homogenates of rats. Data were expressed as mean ± standard error and analyzed by ANOVA one-way test (* p <0.05 vs. one month and #p <0.05 vs. 5 months). Results: Whereas the body mass index increased (0.46±0.01 g/cm2; 0.75±0.01 g/cm2 *,0.78±0.01 g/cm2*), the food efficiency ratio(0.431±0.013; 0.035±0.003*; 0.003±0.001*#), maximum speed during maximal exercise stress testing (3.36±0.34 km/h; 1.38±0.04 km/h*;1.20±0.13 km/h*) and heart rate (410.2±5.9bpm; 375.9±7.6 bpm*; 376.6±3,3 bpm*) decreased with age. Left ventricular hypertrophy and diastolic dysfunction along with reduced leptin receptor expression (2.1±0.4; 1.9±0.2; 0.8±0.2*#) and SERCA-type calcium pump activity (1981±77 nmol Pi/mg protein/h; 2385±205 nmol Pi/mg protein/h; 1148±152 nmol Pi/mg protein/h#) were observed in the hearts.Conclusions: Aging process is related to cardiometabolic risk, with cardiac leptin receptor downregulation and reduced cardiac SERCA2 calcium pump activity presumably being mechanisms underlying the left ventricular diastolic dysfunction and consequent exercise intolerance.

Ivermectin as an inhibitor of the plasma membrane and the sarcoplasmic/endoplasmic reticulum Ca2+-ATPases in rat vas deferens / Ivermectina como um inibidor das Ca2+-ATPases de membrana plasmática e de retículo sarco/endoplasmático no ducto deferente de rato

Objective: The present work investigated the effect of ivermectin on Ca2+ content and on the Ca2+-ATPase activity (represented by the plasma membrane Ca2+-ATPase and the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase present in rat vas deferens. Methods: The assays were carried out using ultracentrifuged homogenate preparations from rat vas deferens in the presence or absence of the 12-kDa FK506-binding protein-Ca2+ release channel complex. Measures of Ca2+ content and Ca2+ ATPase activity were then carried out in function of different concentrations of ivermectin. Results: The data show that ivermectin (10 µM) reduces the sarcoplasmic reticulum Ca2+ content in FK506-binding protein (+) and FK506-binding protein (-) fractions of ultracentrifuged homogenate from rat vas deferens (inhibition of 50 and 40%, respectively, p<0.05) and inhibits both the activities of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase and plasma membrane Ca2+-ATPases pumps (33 and 16%, respectively, p<0.05). Conclusion: These data suggest that ivermectin effects Ca2+ handling in the rat vas deferens, indicating that this drug could alter the contractility of this smooth muscle. Therefore, ivermectin could be an interesting pharmacological tool to alter the physiological function of vas deferens and to manipulate the fertility status of male rats.

Objetivo: O presente trabalho investigou o efeito da ivermectina no conteúdo de Ca2+ e na atividade Ca2+-ATPásica (representada pela Ca2+-ATPase de membrana plasmática e pela Ca2+-ATPase de retículo sarco/endoplasmático presente no ducto deferente de rato. Métodos: Os ensaios foram realizados por meio de preparações de homogeneizado ultracentrifugado de duto deferente de rato na presença ou ausência do complexo proteína de ligação ao FK506 de 12 kDa-canal liberador de Ca2+. Após esse procedimento, avaliações do conteúdo de Ca2+ e da atividade Ca2+-ATPásica foram realizadas em função de diferentes concentrações de ivermectina. Resultados: Os dados mostram que a ivermectina (10 µM) reduz o conteúdo de cálcio no retículo sarcoplasmático de frações FK506-binding protein (+) e FK506-binding protein (-) de homogeneizado ultracentrifugado de duto deferente de rato (50 e 40% de inibição, respectivamente, p<0,05) e inibe as atividades das enzimas Ca2+-ATPase de retículo sarco/endoplasmático e Ca2+-ATPase de membrana plasmática (33 e 16%, respectivamente, p<0,05). Conclusão: Os dados sugerem que a ivermectina afeta a mobilização de cálcio no duto deferente de rato, o que indica que esse fármaco pode alterar a contratilidade desse músculo liso. Dessa forma, ivermectina pode ser ferramenta farmacológica interessante para alterar a função fisiológica do duto deferente e manipular o estado de fertilidade de ratos machos.

Variações interindividuais na farmacocinética clínica de cardiotônicos / Interindividual changes in cardiotonic clinical pharmacokinetics

A insuficiência cardíaca (IC) é uma síndrome clínica complexa cujo tratamento farmacológico consiste no uso de fármacos inibidores da ECA, BRA, betabloqueadores, diuréticos e antagonistas da aldosterona. Dentre os fármacos com atividade inotrópica, para uso na IC em fase crônica, o fármaco de eleição é a digoxina; já na IC descompensada são utilizados a dobutamina e a milrinona. A farmacocinética é a ciência que estuda a absorção, distribuição, biotransformação e excreção de fármacos; quando inserida na prática clínica, apresenta como hipótese fundamental a relação que existe entre os efeitos farmacológicos do fármaco e sua concentração no sangue ou no plasma. O estabelecimento de esquemas terapêuticos racionais de fármacos é feito apartir de seus parâmetros farmacocinéticos como biodisponibilidade, volume de distribuição, clearance e tempo de meia-vida, que podem ser modificados por inúmeros fatores. Neste estudo revisou-se a farmacocinética da digoxina, dobutamina e milrinona,avaliando-se as alterações de seus parâmetros farmacocinéticos em função de fatores como idade, sexo, presença de IC e interações medicamentosas. Este conhecimento aplicado aos diferentes grupos de indivíduos contribuirá para a racionalização da terapia, aproximando-se de um esquema terapêutico individualizado.

Heart failure (HF) is a complex clinical syndrome whose pharmacological treatment includes the useof ACE inhibitors, ARBs, beta blockers, diuretics and aldosterone antagonists. Among drugs with inotropic activity, the drug of choice for use in chronic phase HF is digoxin, while dobutamine and milrinone are used for decompensated HF. Pharmacokinetics is the science studying the absorption, distribution,biotransformation and excretion of drugs. When inserted into clinical practice, its fundamental hypothesis is the relationship between the pharmacological effects of a drug and its concentration in the blood or plasma. The establishment of rational drug regimens is achieved through their pharmacokinetic parameters, such asbioavailability, distribution volume, clearance rate and half-life, which can be modified by count less factors. This study reviews the pharmacokinetics of digoxin, dobutamine and milrinone, assessing changes in their pharmacokinetic parameters that depend on factors such as age, gender, presence of HF and drug interactions. Applied to different groups of individuals, this knowledge will contribute to the rationalization of treatment, moving towards individualized regimens.

Farmacoepidemiologia e uso indevido de anti-hipertensivos no estado do Rio de Janeiro / Pharmacoepidemiology and antihypertensive drugs misuse at Rio de Janeiro state

Fundamentos: A Farmacoepidemiologia possibilita que se conheça e se entenda melhor a relação risco benefício do uso dos medicamentos em pacientes. Objetivo: Avaliar o uso de medicamentos por pessoa sem idade produtiva na área metropolitana do estado do Rio de Janeiro. Métodos: Estudo transversal realizado com voluntários domiciliados na região metropolitana do estado do Rio de Janeiro, em 2011. Os dados foram coletados utilizando-se questionário estruturado. Resultados: Anti-inflamatórios não esteroidais (40%), medicamentos usados em doenças cardiovasculares (23%) e anticoncepcionais orais (9%) foram as classes farmacológicas mais usadas pelos 235 entrevistados. Os anti-hipertensivos mais usados foram: inibidores da enzima conversora da angiotensina/bloqueadores do receptor de angiotensina (A, 29-33%), diuréticos (D,28%) e betabloqueadores (B, 21-35%), em 186 indivíduos na faixa etária de 20-60 anos. Conclusões: O controle farmacológico da hipertensão indicado para o grupo estudado abrange monoterapia com A ou B. O uso inadequado de nitrovasodilatadores(N), B e D devem ser evitados, especialmente em terapias combinadas, pois B e D favorecem a intolerância à glicose e hipertrigliceridemia. Mulheres hipertensas em idade reprodutiva devem evitar o uso de A e interações medicamentosas com contraceptivos orais. Assim, o uso de anti-hipertensivos não está plenamente de acordo com o consenso atual.

Background: Pharmacoepidemiology makes possible the better knowing and understanding of patients drugs use risk-benefit ratio. Objective: Our study aims to evaluate the use of drugs by people in productive ages that live in metropolitan area of Rio de Janeiro state. Data collection included as tructured questionnaire applied after an informed consent document signature. Results: Non steroidal antiinflammatories (40%),drugs used in cardiovascular diseases (23%) and oral contraceptives (9%) were the most used pharmacological classes by 235 respondents. Angiotensin converting enzyme inhibitors/angiotensin receptor blockers(A, 29-33%), diuretics (D, 28%) and -blockers (B, 21-35%) were the most antihypertensives used by 186 individuals aged from 20 to 60 years. Conclusions: The hypertension pharmacological management indicated for the studied group covers Aor B monotherapy. It is inappropriate to use N; B must be avoided, such as D, especially in combination therapy because B and D promote glucose intolerance and hypertrigly ceridemia. Hypertensive females in reproductive ages must avoid A and drug interaction with oral contraceptives. So the use of antihypertensive drugs is not entirely in agreement to current consensus.