Showing papers by "Federal University of São Paulo published in 2018"

Minimal information for studies of extracellular vesicles 2018 (MISEV2018) : a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

Abstract: The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.

Analysis of shared heritability in common disorders of the brain

Abstract: Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology

Abstract: The International League Against Epilepsy (ILAE) classification of the epilepsies has been updated to reflect the gain in understanding of the epilepsies and their underlying mechanisms following the major scientific advances that have taken place since the last ratified classification in 1989. As a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking, yet robust and translatable to all areas of the globe. Its primary purpose is for the clinical diagnosis of patients but it is also critical for epilepsy research, development of antiepileptic treatment and communication around the world. The new classification is based on a draft document submitted for public comments in 2013, which was revised to incorporate extensive feedback from the international epilepsy community over several rounds of consultation. It consists of three levels starting with seizure type, where it is assumed that the epileptic seizures of the patient are defined by the new 2017 ILAE seizure classification. After diagnosis of the seizure type, the next step is the diagnosis of the epilepsy type, which includes focal epilepsy, generalized epilepsy, combined generalized and focal epilepsy and also an unclassified epilepsy group. At the third level the disease is assigned to a specific epilepsy syndrome. The new classification incorporates etiology at each stage, emphasizing the need to consider etiology at each step of the diagnosis, as it often carries significant treatment implications. The various etiologies can be assigned to six subgroups, defined with respect to the potential therapeutic consequences. New terminology is introduced, such as developmental and epileptic encephalopathy. The term benign is replaced by the terms self-limiting and pharmacoresponsive, to be used where appropriate. It is hoped that this new framework will assist in improving epilepsy care and research in the twenty-first century.

The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria.

Abstract: This evidence- and consensus-based guideline was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. The conference was held on 1 December 2016. It is a joint initiative of the Dermatology Sectionof the European Academy of Allergology and Clinical Immunology (EAACI), the EU-founded network of excellence, the Global Allergy and Asthma European Network (GA(2)LEN), the European Dermatology Forum (EDF) and the World Allergy Organization (WAO) with the participation of 48 delegates of 42 national and international societies. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell-driven disease, presenting with wheals, angioedema, or both. The lifetime prevalence for acute urticaria is approximately 20%. Chronic spontaneous urticaria and other chronic forms of urticaria are disabling, impair quality of life and affect performance at work and school. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. In addition, it outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria.

Pattern Recognition Receptors and the Host Cell Death Molecular Machinery

Abstract: Pattern Recognition Receptors (PRRs) are proteins capable of recognizing molecules frequently found in pathogens (the so-called Pathogen-Associated Molecular Patterns-PAMPs), or molecules released by damaged cells (the Damage-Associated Molecular Patterns-DAMPs). They emerged phylogenetically prior to the appearance of the adaptive immunity and, therefore, are considered part of the innate immune system. Signals derived from the engagement of PRRs on the immune cells activate microbicidal and pro-inflammatory responses required to eliminate or, at least, to contain infectious agents. Molecularly controlled forms of cell death are also part of a very ancestral mechanism involved in key aspects of the physiology of multicellular organism, including the elimination of unwanted, damaged or infected cells. Interestingly, each form of cell death has its particular effect on inflammation and on the development of innate and adaptive immune responses. In this review article, we discuss some aspects of the molecular interplay between the cell death machinery and signals initiated by the activation of PRRs by PAMPs and DAMPs.

mhGAP Intervention guide for mental, neurological and substance use disorders in non-specialized health settings: version 2.0

Abstract: Em todo o mundo existe uma enorme diferença entre o número de pessoas que vivem com transtornos mentais e o número de pessoas que recebem qualquer tipo de tratamento. Mais de 45% da população mundial reside em países onde existe menos de um psiquiatra para cada 100.000 pessoas, e o número de neurologistas é ainda menor. O número pequeno de profissionais especialistas em saúde mental, aliado à desigualdade na distribuição territorial desses profissionais, não permite que essa diferença seja superada apenas pelos serviços especializados. Esta é uma publicação da Organização Mundial da Saúde e se insere no mhGAP (“Mental Health Gap Action Plan”), plano para reduzir desigualdades em saúde mental global. Atualmente existe um consenso de que é necessário haver boa evidência sobre o que funciona na prática para que se possam desenvolver programas efetivos, especialmente em regiões onde os recursos sejam escassos. Pesquisas demonstram a efetividade das intervenções farmacológicas e psicossociais desenvolvidas na atenção primária. Sendo assim, um livro que aborde estratégias de cuidado em saúde mental para não especialistas é de extrema importância, especialmente nas capacitações realizadas pelos psiquiatras aos profissionais da Estratégia Saúde da Família. A primeira versão deste Manual (lançada em 2010) foi utilizada por mais de 80 países e traduzida em mais de 20 idiomas. A atual versão (lançada em 2016) traz 23 novas recomendações que constituem um conjunto de ferramentas para o generalista lidar com situações diversas. As novas recomendações são abrangentes, envolvendo desde intervenções no estado nutricional dos pacientes diagnosticados com demência, até o treinamento dos cuidadores para o manejo de crianças e adolescentes com transtornos globais do desenvolvimento. Trata-se de um guia de orientações baseadas em evidências, composto de algoritmos, diagramas e fluxogramas que permitem ao profissional não especialista o diagnóstico e tratamento dos transtornos mentais considerados prioritários (com base nos critérios de mortalidade, morbidade e incapacidade). O módulo 1 traz princípios essenciais do cuidado em saúde mental, incluindo a atenção aos familiares e cuidadores. É dividido em duas seções. A primeira abrange as bases de uma boa aliança terapêutica, reforçando a importância do cuidado ser oferecido em um ambiente sem julgamentos e não estigmatizante. A segunda apresenta elementos essenciais da prática clínica em saúde mental em contextos comunitários. Os sete módulos seguintes tratam individualmente de cada condição prioritária para WHO: depressão,

Modulation of the interleukin-6 signalling pathway and incidence rates of atherosclerotic events and all-cause mortality: Analyses from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS)

Abstract: Aims Canakinumab, a monoclonal antibody targeting interleukin (IL)-1β, reduces rates of recurrent cardiovascular events without lowering lipids. It is uncertain, however, to what extent these beneficial cardiovascular outcomes are mediated through interleukin-6 (IL-6) signalling, an issue with substantial pathophysiologic consequences and therapeutic implications. Methods and results A total of 4833 stable atherosclerosis patients in the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) had IL-6 levels measured before randomization and after treatment with placebo or one of three doses of canakinumab (50 mg, 150 mg, or 300 mg) given subcutaneously once every 3 months. Participants were followed for up to 5 years (median follow-up 3.7 years). Compared with those allocated to placebo, CANTOS participants receiving canakinumab who achieved on-treatment IL-6 levels below the study median value of 1.65 ng/L experienced a 32% reduction in major adverse cardiovascular events [MACE, multivariable adjusted hazard ratio (HRadj) 0.68, 95% confidence interval (CI) 0.56-0.82; P < 0.0001], a 30% reduction in MACE plus the additional endpoint of hospitalization for unstable angina requiring urgent revascularization (MACE+, HRadj 0.70, 95% CI 0.59-0.84; P < 0.0001), a 52% reduction in cardiovascular mortality (HRadj 0.48, 95% CI 0.34-0.68; P < 0.0001), and a 48% reduction in all-cause mortality (HRadj 0.52, 95% CI 0.40-0.68; P < 0.0001) with prolonged treatment. In contrast, those with on-treatment IL-6 levels equal to or above 1.65 ng/L after taking the first dose of canakinumab had no significant benefit for any of these endpoints. These differential findings based on the magnitude of IL-6 response were seen in analyses alternatively based on tertiles of on-treatment IL-6 levels, and in analyses using a statistical inference approach to estimate the effect of treatment among individuals who would achieve a targeted IL-6 level. Conclusion CANTOS provides proof of concept evidence in humans that modulation of the IL-6 signalling pathway, at least with canakinumab, associates with reduced cardiovascular event rates, independent of lipid lowering. Clinical trial registration ClinicalTrials.gov NCT01327846.

Ultra-Processed Food Consumption and Chronic Non-Communicable Diseases-Related Dietary Nutrient Profile in the UK (2008⁻2014).

Abstract: We described the contribution of ultra-processed foods in the U.K. diet and its association with the overall dietary content of nutrients known to affect the risk of chronic non-communicable diseases (NCDs). Cross-sectional data from the U.K. National Diet and Nutrition Survey (2008–2014) were analysed. Food items collected using a four-day food diary were classified according to the NOVA system. The average energy intake was 1764 kcal/day, with 30.1% of calories coming from unprocessed or minimally processed foods, 4.2% from culinary ingredients, 8.8% from processed foods, and 56.8% from ultra-processed foods. As the ultra-processed food consumption increased, the dietary content of carbohydrates, free sugars, total fats, saturated fats, and sodium increased significantly while the content of protein, fibre, and potassium decreased. Increased ultra-processed food consumption had a remarkable effect on average content of free sugars, which increased from 9.9% to 15.4% of total energy from the first to the last quintile. The prevalence of people exceeding the upper limits recommended for free sugars and sodium increased by 85% and 55%, respectively, from the lowest to the highest ultra-processed food quintile. Decreasing the dietary share of ultra-processed foods may substantially improve the nutritional quality of diets and contribute to the prevention of diet-related NCDs.

Technical challenges of working with extracellular vesicles

Abstract: Extracellular Vesicles (EVs) are gaining interest as central players in liquid biopsies, with potential applications in diagnosis, prognosis and therapeutic guidance in most pathological conditions. These nanosized particles transmit signals determined by their protein, lipid, nucleic acid and sugar content, and the unique molecular pattern of EVs dictates the type of signal to be transmitted to recipient cells. However, their small sizes and the limited quantities that can usually be obtained from patient-derived samples pose a number of challenges to their isolation, study and characterization. These challenges and some possible options to overcome them are discussed in this review.

Melatonin as a hormone: new physiological and clinical insights

Abstract: Melatonin is a ubiquitous molecule present in almost every live being from bacteria to humans. In vertebrates, besides being produced in peripheral tissues and acting as an autocrine and paracrine signal, melatonin is centrally synthetized by a neuroendocrine organ, the pineal gland. Independently of the considered species, pineal hormone melatonin is always produced during the night and its production and secretory episode duration are directly dependent on the length of the night. As its production is tightly linked to the light/dark cycle, melatonin main hormonal systemic integrative action is to coordinate behavioral and physiological adaptations to the environmental geophysical day and season. The circadian signal is dependent on its daily production regularity, on the contrast between day and night concentrations, and on specially developed ways of action. During its daily secretory episode, melatonin coordinates the night adaptive physiology through immediate effects and primes the day adaptive responses through prospective effects that will only appear at daytime, when melatonin is absent. Similarly, the annual history of the daily melatonin secretory episode duration primes the central nervous/endocrine system to the seasons to come. Remarkably, maternal melatonin programs the fetuses' behavior and physiology to cope with the environmental light/dark cycle and season after birth. These unique ways of action turn melatonin into a biological time-domain-acting molecule. The present review focuses on the above considerations, proposes a putative classification of clinical melatonin dysfunctions, and discusses general guidelines to the therapeutic use of melatonin.

Reward Processing in Depression: A Conceptual and Meta-Analytic Review Across fMRI and EEG Studies.

Abstract: Objective:A role for aberrant reward processing in the pathogenesis of depression has long been proposed. However, no review has yet examined its role in depression by integrating conceptual and qu...

Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases

Abstract: The recently discovered histone post-translational modification crotonylation connects cellular metabolism to gene regulation. Its regulation and tissue-specific functions are poorly understood. We characterize histone crotonylation in intestinal epithelia and find that histone H3 crotonylation at lysine 18 is a surprisingly abundant modification in the small intestine crypt and colon, and is linked to gene regulation. We show that this modification is highly dynamic and regulated during the cell cycle. We identify class I histone deacetylases, HDAC1, HDAC2, and HDAC3, as major executors of histone decrotonylation. We show that known HDAC inhibitors, including the gut microbiota-derived butyrate, affect histone decrotonylation. Consistent with this, we find that depletion of the gut microbiota leads to a global change in histone crotonylation in the colon. Our results suggest that histone crotonylation connects chromatin to the gut microbiota, at least in part, via short-chain fatty acids and HDACs.

Autophagy and Alzheimer's Disease: From Molecular Mechanisms to Therapeutic Implications.

Abstract: Alzheimer’s disease (AD) is the most common cause of progressive dementia in the elderly. It is characterized by a progressive and irreversible loss of cognitive abilities and formation of senile plaques, composed mainly of amyloid β (Aβ), and neurofibrillary tangles (NFTs), composed of tau protein, in the hippocampus and cortex of afflicted humans. In brains of AD patients the metabolism of Aβ is dysregulated, which leads to the accumulation and aggregation of Aβ. Metabolism of Aβ and tau proteins is crucially influenced by autophagy. Autophagy is a lysosome-dependent, homeostatic process, in which organelles and proteins are degraded and recycled into energy. Thus, dysfunction of autophagy is suggested to lead to the accretion of noxious proteins in the AD brain. In the present review, we describe the process of autophagy and its importance in AD. Additionally, we discuss mechanisms and genes linking autophagy and AD, i.e., the mTOR pathway, neuroinflammation, endocannabinoid system, ATG7, BCL2, BECN1, CDK5, CLU, CTSD, FOXO1, GFAP, ITPR1, MAPT, PSEN1, SNCA, UBQLN1, and UCHL1. We also present pharmacological agents acting via modulation of autophagy that may show promise in AD therapy. This review updates our knowledge on autophagy mechanisms proposing novel therapeutic targets for the treatment of AD.

Genomic and epidemiological monitoring of yellow fever virus transmission potential

Abstract: The yellow fever virus (YFV) epidemic in Brazil is the largest in decades. The recent discovery of YFV in Brazilian Aedes species mosquitos highlights a need to monitor the risk of reestablishment of urban YFV transmission in the Americas. We use a suite of epidemiological, spatial, and genomic approaches to characterize YFV transmission. We show that the age and sex distribution of human cases is characteristic of sylvatic transmission. Analysis of YFV cases combined with genomes generated locally reveals an early phase of sylvatic YFV transmission and spatial expansion toward previously YFV-free areas, followed by a rise in viral spillover to humans in late 2016. Our results establish a framework for monitoring YFV transmission in real time that will contribute to a global strategy to eliminate future YFV epidemics.

The 2018 ISDE achalasia guidelines

Abstract: Achalasia is a relatively rare primary motor esophageal disorder, characterized by absence of relaxations of the lower esophageal sphincter and of peristalsis along the esophageal body As a result, patients typically present with dysphagia, regurgitation and occasionally chest pain, pulmonary complication and malnutrition New diagnostic methodologies and therapeutic techniques have been recently added to the armamentarium for treating achalasia With the aim to offer clinicians and patients an up-to-date framework for making informed decisions on the management of this disease, the International Society for Diseases of the Esophagus Guidelines proposed and endorsed the Esophageal Achalasia Guidelines (I-GOAL) The guidelines were prepared according the Appraisal of Guidelines for Research and Evaluation (AGREE-REX) tool, accredited for guideline production by NICE UK A systematic literature search was performed and the quality of evidence and the strength of recommendations were graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Given the relative rarity of this disease and the paucity of high-level evidence in the literature, this process was integrated with a three-step process of anonymous voting on each statement (DELPHI) Only statements with an approval rate >80% were accepted in the guidelines Fifty-one experts from 11 countries and 3 representatives from patient support associations participated to the preparations of the guidelines These guidelines deal specifically with the following achalasia issues: Diagnostic workup, Definition of the disease, Severity of presentation, Medical treatment, Botulinum Toxin injection, Pneumatic dilatation, POEM, Other endoscopic treatments, Laparoscopic myotomy, Definition of recurrence, Follow up and risk of cancer, Management of end stage achalasia, Treatment options for failure, Achalasia in children, Achalasia secondary to Chagas' disease

Incidence, predictors, and clinical outcomes of coronary obstruction following transcatheter aortic valve replacement for degenerative bioprosthetic surgical valves: insights from the VIVID registry

Abstract: Aims: There are limited data on coronary obstruction following transcatheter valve-in-valve (ViV) implantation inside failed aortic bioprostheses The objectives of this study were to determine the incidence, predictors, and clinical outcomes of coronary obstruction in transcatheter ViV procedures Methods and results: A total of 1612 aortic procedures from the Valve-in-Valve International Data (VIVID) Registry were evaluated Data were subject to centralized blinded corelab computed tomography (CT) analysis in a subset of patients The virtual transcatheter valve to coronary ostium distance (VTC) was determined A total of 37 patients (23%) had clinically evident coronary obstruction Baseline clinical characteristics in the coronary obstruction patients were similar to controls Coronary obstruction was more common in stented bioprostheses with externally mounted leaflets or stentless bioprostheses than in stented with internally mounted leaflets bioprostheses (61% vs 37% vs 08%, respectively; P < 0001) CT measurements were obtained in 20 (54%) and 90 (54%) of patients with and without coronary obstruction, respectively VTC distance was shorter in coronary obstruction patients in relation to controls (324 ± 222 vs 630 ± 234, respectively; P < 0001) Using multivariable analysis, the use of a stentless or stented bioprosthesis with externally mounted leaflets [odds ratio (OR): 767; 95% confidence interval (CI): 314-187; P < 0001] associated with coronary obstruction for the global population In a second model with CT data, a shorter VTC distance predicted this complication (OR: 022 per 1 mm increase; 95% CI: 009-051; P < 0001), with an optimal cut-off level of 4 mm (area under the curve: 0943; P < 0001) Coronary obstruction was associated with a high 30-day mortality (529% vs 39% in the controls, respectively; P < 0001) Conclusion: Coronary obstruction following aortic ViV procedures is a life-threatening complication that occurred more frequently in patients with prior stentless or stented bioprostheses with externally mounted leaflets and in those with a short VTC

Childhood Obesity and Firmicutes/Bacteroidetes Ratio in the Gut Microbiota: A Systematic Review.

Abstract: Background: The aim of the present study was to undertake a systematic review exploring the relationship between childhood obesity and fecal microorganisms, to answer the following questio

A brief review about melatonin, a pineal hormone

Abstract: Melatonin is a ubiquitous molecule in nature, being locally synthesized in several cells and tissues, besides being a hormone that is centrally produced in the pineal gland of vertebrates, particularly in mammals. Its pineal synthesis is timed by the suprachiasmatic nucleus, that is synchronized to the light-dark cycle via the retinohypothalamic tract, placing melatonin synthesis at night, provided its dark. This unique trait turns melatonin into an internal synchronizer that adequately times the organism's physiology to the daily and seasonal demands. Besides being amphiphilic, melatonin presents specific mechanisms and ways of action devoted to its role as a time-giving agent, being widely spread in the organism. The present review aims to focus on melatonin as a pineal hormone with specific mechanisms and ways of action, besides presenting the clinical syndromes related to its synthesis and/or function disruptions.

A Novel Synthesis Route of Mesoporous γ-Alumina from Polyoxohydroxide Aluminum

Abstract: Mesoporous gamma-aluminas (γ-Al2O3) were synthesized starting from an unusual precursor of polyoxohydroxide aluminum (POHA). This precursor was obtained from aluminum oxidation in alkaline water-ethanol solvent in the presence of d-glucose that induces the formation of a gel, which leads to the POAH powder after ethanolic treatment. Precipitated POHAs were calcined at different temperatures (300, 400, 700 and 900 °C) resulting in the metastable γ-Al2O3 phase. Whereas at 300 °C no γ-Al2O3 phase was formed, unexpectedly, mesoporous γ-Al2O3 was obtained at 400 oC having a high specific surface area (282 m2/g) and a narrow pore size distribution. At higher temperatures, the aluminas had the expected decrease in surface area: 166 m2/g (700 °C) and 129 m2/g (900 °C), respectively. The structural change from POHA to alumina calcined at 400 oC occurs directly without the need to isolate the hydroxide or oxyhydroxide aluminum precursors. Both POHA and transition aluminas were characterized by Fourier Transform Infrared spectroscopy (FTIR), X-ray diffraction (XRD), N2 sorption and Scanning Electron Microscopy (SEM). These findings show an alternative route to produce high standard aluminas.

Diretriz Brasileira de Insuficiência Cardíaca Crônica e Aguda.

Abstract: Parte 1: Diretriz Brasileira de Insuficiencia Cardiaca Cronica […] Diretriz Brasileira de Insuficiencia Cardiaca Cronica e Aguda

Surviving sepsis campaign: research priorities for sepsis and septic shock

Abstract: To identify research priorities in the management, epidemiology, outcome and underlying causes of sepsis and septic shock. A consensus committee of 16 international experts representing the European Society of Intensive Care Medicine and Society of Critical Care Medicine was convened at the annual meetings of both societies. Subgroups had teleconference and electronic-based discussion. The entire committee iteratively developed the entire document and recommendations. Each committee member independently gave their top five priorities for sepsis research. A total of 88 suggestions (ESM 1 - supplemental table 1) were grouped into categories by the committee co-chairs, leading to the formation of seven subgroups: infection, fluids and vasoactive agents, adjunctive therapy, administration/epidemiology, scoring/identification, post-intensive care unit, and basic/translational science. Each subgroup had teleconferences to go over each priority followed by formal voting within each subgroup. The entire committee also voted on top priorities across all subgroups except for basic/translational science. The Surviving Sepsis Research Committee provides 26 priorities for sepsis and septic shock. Of these, the top six clinical priorities were identified and include the following questions: (1) can targeted/personalized/precision medicine approaches determine which therapies will work for which patients at which times?; (2) what are ideal endpoints for volume resuscitation and how should volume resuscitation be titrated?; (3) should rapid diagnostic tests be implemented in clinical practice?; (4) should empiric antibiotic combination therapy be used in sepsis or septic shock?; (5) what are the predictors of sepsis long-term morbidity and mortality?; and (6) what information identifies organ dysfunction? While the Surviving Sepsis Campaign guidelines give multiple recommendations on the treatment of sepsis, significant knowledge gaps remain, both in bedside issues directly applicable to clinicians, as well as understanding the fundamental mechanisms underlying the development and progression of sepsis. The priorities identified represent a roadmap for research in sepsis and septic shock.

Everolimus with Reduced Calcineurin Inhibitor Exposure in Renal Transplantation

Abstract: Background Everolimus permits reduced calcineurin inhibitor (CNI) exposure, but the efficacy and safety outcomes of this treatment after kidney transplant require confirmation.Methods In a multicenter noninferiority trial, we randomized 2037 de novo kidney transplant recipients to receive, in combination with induction therapy and corticosteroids, everolimus with reduced-exposure CNI (everolimus arm) or mycophenolic acid (MPA) with standard-exposure CNI (MPA arm). The primary end point was treated biopsy-proven acute rejection or eGFR<50 ml/min per 1.73 m2 at post-transplant month 12 using a 10% noninferiority margin.Results In the intent-to-treat population (everolimus n=1022, MPA n=1015), the primary end point incidence was 48.2% (493) with everolimus and 45.1% (457) with MPA (difference 3.2%; 95% confidence interval, -1.3% to 7.6%). Similar between-treatment differences in incidence were observed in the subgroups of patients who received tacrolimus or cyclosporine. Treated biopsy-proven acute rejection, graft loss, or death at post-transplant month 12 occurred in 14.9% and 12.5% of patients treated with everolimus and MPA, respectively (difference 2.3%; 95% confidence interval, -1.7% to 6.4%). De novo donor-specific antibody incidence at 12 months and antibody-mediated rejection rate did not differ between arms. Cytomegalovirus (3.6% versus 13.3%) and BK virus infections (4.3% versus 8.0%) were less frequent in the everolimus arm than in the MPA arm. Overall, 23.0% and 11.9% of patients treated with everolimus and MPA, respectively, discontinued the study drug because of adverse events.Conclusions In kidney transplant recipients at mild-to-moderate immunologic risk, everolimus was noninferior to MPA for a binary composite end point assessing immunosuppressive efficacy and preservation of graft function.

CrossFit Overview: Systematic Review and Meta-analysis

Abstract: CrossFit is recognized as one of the fastest growing high-intensity functional training modes in the world. However, scientific data regarding the practice of CrossFit is sparse. Therefore, the objective of this study is to analyze the findings of scientific literature related to CrossFit via systematic review and meta-analysis. Systematic searches of the PubMed, Web of Science, Scopus, Bireme/MedLine, and SciELO online databases were conducted for articles reporting the effects of CrossFit training. The systematic review followed the PRISMA guidelines. The Oxford Levels of Evidence was used for all included articles, and only studies that investigated the effects of CrossFit as a training program were included in the meta-analysis. For the meta-analysis, effect sizes (ESs) with 95% confidence interval (CI) were calculated and heterogeneity was assessed using a random-effects model. Thirty-one articles were included in the systematic review and four were included in the meta-analysis. However, only two studies had a high level of evidence at low risk of bias. Scientific literature related to CrossFit has reported on body composition, psycho-physiological parameters, musculoskeletal injury risk, life and health aspects, and psycho-social behavior. In the meta-analysis, significant results were not found for any variables. The current scientific literature related to CrossFit has few studies with high level of evidence at low risk of bias. However, preliminary data has suggested that CrossFit practice is associated with higher levels of sense of community, satisfaction, and motivation.