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BACKGROUND: Treatment with dasatinib, a highly potent BCR-ABL kinase inhibitor, has resulted in high rates of complete cytogenetic response and progression-free survival among patients with chronic myeloid leukemia (CML) in the chronic phase, after failure of imatinib treatment. We assessed the efficacy and safety of dasatinib, as compared with imatinib, for the first-line treatment of chronic-phase CML. METHODS: In a multinational study, 519 patients with newly diagnosed chronic-phase CML were randomly assigned to receive dasatinib at a dose of 100 mg once daily (259 patients) or imatinib at a dose of 400 mg once daily (260 patients). The primary end point was complete cytogenetic response by 12 months, confirmed on two consecutive assessments at least 28 days apart. Secondary end points, including major molecular response, were tested at a significance level of 0.0001 to adjust for multiple comparisons. RESULTS: After a minimum follow-up of 12 months, the rate of confirmed complete cytogenetic response was higher with dasatinib than with imatinib (77% vs. 66%, P=0.007), as was the rate of complete cytogenetic response observed on at least one assessment (83% vs. 72%, P=0.001). The rate of major molecular response was higher with dasatinib than with imatinib (46% vs. 28%, P<0.0001), and responses were achieved in a shorter time with dasatinib (P<0.0001). Progression to the accelerated or blastic phase of CML occurred in 5 patients who were receiving dasatinib (1.9%) and in 9 patients who were receiving imatinib (3.5%). The safety profiles of the two treatments were similar. CONCLUSIONS: Dasatinib, administered once daily, as compared with imatinib, administered once daily, induced significantly higher and faster rates of complete cytogenetic response and major molecular response. Since achieving complete cytogenetic response within 12 months has been associated with better long-term, progression-free survival, dasatinib may improve the long-term outcomes among patients with newly diagnosed chronic-phase CML. (ClinicalTrials.gov number, NCT00481247.)

OBJECTIVES: The phase III RADIATE study examined the efficacy and safety of tocilizumab, an anti-IL-6 receptor monoclonal antibody in patients with rheumatoid arthritis (RA) refractory to tumour necrosis factor (TNF) antagonist therapy. METHODS: 499 patients with inadequate response to one or more TNF antagonists were randomly assigned to receive 8 mg/kg or 4 mg/kg tocilizumab or placebo (control) intravenously every 4 weeks with stable methotrexate for 24 weeks. ACR20 responses, secondary efficacy and safety endpoints were assessed. RESULTS: ACR20 was achieved at 24 weeks by 50.0%, 30.4% and 10.1% of patients in the 8 mg/kg, 4 mg/kg and control groups, respectively (less than p<0.001 both tocilizumab groups versus control). At week 4 more patients achieved ACR20 in 8 mg/kg tocilizumab versus controls (less than p = 0.001). Patients responded regardless of most recently failed anti-TNF or the number of failed treatments. DAS28 remission (DAS28 <2.6) rates at week 24 were clearly dose related, being achieved by 30.1%, 7.6% and 1.6% of 8 mg/kg, 4 mg/kg and control groups (less than p = 0.001 for 8 mg/kg and p = 0.053 for 4 mg/kg versus control). Most adverse events were mild or moderate with overall incidences of 84.0%, 87.1% and 80.6%, respectively. The most common adverse events with higher incidence in tocilizumab groups were infections, gastrointestinal symptoms, rash and headache. The incidence of serious adverse events was higher in controls (11.3%) than in the 8 mg/kg (6.3%) and 4 mg/kg (7.4%) groups. CONCLUSION: Tocilizumab plus methotrexate is effective in achieving rapid and sustained improvements in signs and symptoms of RA in patients with inadequate response to TNF antagonists and has a manageable safety profile. TRIAL REGISTRATION NUMBER: NCT00106522.

Abstract Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40–50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes 1 . Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel 2 ) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10–20% (14–24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

RATIONALE: Baseline characteristics and management have changed over time in patients requiring mechanical ventilation; however, the impact of these changes on patient outcomes is unclear. OBJECTIVES: To estimate whether mortality in mechanically ventilated patients has changed over time. METHODS: Prospective cohort studies conducted in 1998, 2004, and 2010, including patients receiving mechanical ventilation for more than 12 hours in a 1-month period, from 927 units in 40 countries. To examine effects over time on mortality in intensive care units, we performed generalized estimating equation models. MEASUREMENTS AND MAIN RESULTS: We included 18,302 patients. The reasons for initiating mechanical ventilation varied significantly among cohorts. Ventilatory management changed over time (P < 0.001), with increased use of noninvasive positive-pressure ventilation (5% in 1998 to 14% in 2010), a decrease in tidal volume (mean 8.8 ml/kg actual body weight [SD = 2.1] in 1998 to 6.9 ml/kg [SD = 1.9] in 2010), and an increase in applied positive end-expiratory pressure (mean 4.2 cm H2O [SD = 3.8] in 1998 to 7.0 cm of H2O [SD = 3.0] in 2010). Crude mortality in the intensive care unit decreased in 2010 compared with 1998 (28 versus 31%; odds ratio, 0.87; 95% confidence interval, 0.80-0.94), despite a similar complication rate. Hospital mortality decreased similarly. After adjusting for baseline and management variables, this difference remained significant (odds ratio, 0.78; 95% confidence interval, 0.67-0.92). CONCLUSIONS: Patient characteristics and ventilation practices have changed over time, and outcomes of mechanically ventilated patients have improved. Clinical trials registered with www.clinicaltrials.gov (NCT01093482).

Air pollution is a complex mixture of gases (e.g., ozone), particulate matter, and organic compounds present in outdoor and indoor air. Dogs exposed to severe air pollution exhibit chronic inflammation and acceleration of Alzheimer's-like pathology, suggesting that the brain is adversely affected by pollutants. We investigated whether residency in cities with high levels of air pollution is associated with human brain inflammation. Expression of cyclooxygenase-2 (COX2), an inflammatory mediator, and accumulation of the 42-amino acid form of beta-amyloid (Abeta42), a cause of neuronal dysfunction, were measured in autopsy brain tissues of cognitively and neurologically intact lifelong residents of cities having low (n:9) or high (n:10) levels of air pollution. Genomic DNA apurinic/apyrimidinic sites, nuclear factor-kappaB activation and apolipoprotein E genotype were also evaluated. Residents of cities with severe air pollution had significantly higher COX2 expression in frontal cortex and hippocampus and greater neuronal and astrocytic accumulation of Abeta42 compared to residents in low air pollution cities. Increased COX2 expression and Abeta42 accumulation were also observed in the olfactory bulb. These findings suggest that exposure to severe air pollution is associated with brain inflammation and Abeta42 accumulation, two causes of neuronal dysfunction that precede the appearance of neuritic plaques and neurofibrillary tangles, hallmarks of Alzheimer's disease.

Abstract Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes 1,2 and molecular mechanisms that are often specific to cell type 3,4 . Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance ( P &lt; 5 × 10 −8 ) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores 5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

BACKGROUND: The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy. METHODS: We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites. RESULTS: Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00). CONCLUSIONS: Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; ClinicalTrials.gov number, NCT01064284; EudraCT number, 2009-011186-88.).

Hereditary angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1 inhibitor (type 1) and HAE with dysfunctional C1 inhibitor (type 2), by providing guidance on common and important clinical issues, such as: (1) How should HAE be diagnosed? (2) When should HAE patients receive prophylactic on top of on-demand treatment and what treatments should be used? (3) What are the goals of treatment? (4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast-feeding women? and (5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients.

Outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) have improved because of advancements in equipment and techniques. With global collaboration and knowledge sharing, we have identified 7 common principles that are widely accepted as best practices for CTO-PCI. 1. Ischemic symptom improvement is the primary indication for CTO-PCI. 2. Dual coronary angiography and in-depth and structured review of the angiogram (and, if available, coronary computed tomography angiography) are key for planning and safely performing CTO-PCI. 3. Use of a microcatheter is essential for optimal guidewire manipulation and exchanges. 4. Antegrade wiring, antegrade dissection and reentry, and the retrograde approach are all complementary and necessary crossing strategies. Antegrade wiring is the most common initial technique, whereas retrograde and antegrade dissection and reentry are often required for more complex CTOs. 5. If the initially selected crossing strategy fails, efficient change to an alternative crossing technique increases the likelihood of eventual PCI success, shortens procedure time, and lowers radiation and contrast use. 6. Specific CTO-PCI expertise and volume and the availability of specialized equipment will increase the likelihood of crossing success and facilitate prevention and management of complications, such as perforation. 7. Meticulous attention to lesion preparation and stenting technique, often requiring intracoronary imaging, is required to ensure optimum stent expansion and minimize the risk of short- and long-term adverse events. These principles have been widely adopted by experienced CTO-PCI operators and centers currently achieving high success and acceptable complication rates. Outcomes are less optimal at less experienced centers, highlighting the need for broader adoption of the aforementioned 7 guiding principles along with the development of additional simple and safe CTO crossing and revascularization strategies through ongoing research, education, and training.

This study demonstrates a unique and crucial role of plasmacytoid dendritic cells (pDCs) and pDC-derived type I interferons (IFNs) in the pathogenesis of mouse coronavirus infection. pDCs controlled the fast replicating mouse hepatitis virus (MHV) through the immediate production of type I IFNs. Recognition of MHV by pDCs was mediated via TLR7 ensuring a swift IFN-alpha production following encounter with this cytopathic RNA virus. Furthermore, the particular type I IFN response pattern was not restricted to the murine coronavirus, but was also found in infection with the highly cytopathic human severe acute respiratory syndrome (SARS) coronavirus. Taken together, our results suggest that rapid production of type I IFNs by pDCs is essential for the control of potentially lethal coronavirus infections.

OBJECTIVES: A systematic review was conducted to explore the immunogenicity of biologic agents across inflammatory diseases and its potential impact on efficacy/safety. METHODS: Literature searches were conducted through November 2016 to identify controlled and observational studies of biologics/biosimilars administered for treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS), non-radiographic axial spondyloarthritis (nr-axSpA), psoriasis (Ps), Crohn's disease, and ulcerative colitis. RESULTS: Of >21,000 screened publications, 443 were included. Anti-drug antibody (ADAb) rates varied widely among biologics across diseases (and are not directly comparable because of immunoassay heterogeneity); the highest overall rates were reported with infliximab (0-83%), adalimumab (0-54%), and infliximab biosimilar CT-P13 (21-52%), and the lowest with secukinumab (0-1%), ustekinumab (1-11%), etanercept (0-13%), and golimumab (0-19%). Most ADAbs were neutralizing, except those to abatacept and etanercept. ADAb+ versus ADAb- patients had lower rates of clinical response to adalimumab (RA, PsA, JIA, AS, Ps), golimumab (RA), infliximab (RA, PsA, AS, Ps), rituximab (RA), ustekinumab (Ps), and CT-P13 (RA, AS). Higher rates of infusion-related reactions were reported in infliximab- and CT-P13-treated ADAb+ patients. Background immunosuppressives/anti-proliferatives reduced biologic immunogenicity across diseases. CONCLUSIONS: Based on reviewed reports, biologic/biosimilar immunogenicity differs among agents, with the highest rates observed with infliximab and adalimumab. As ADAb formation in biologic-/biosimilar-treated patients may increase the risk of lost response, the immunogenicity of these agents is an important (albeit not the only) consideration in the treatment decision-making process.

The annual cycle of plankton was studied over 14 years from 1984 to 2000 at a coastal station in the Gulf of Naples, with the aim of assessing seasonal patterns and interannual trends. Phytoplankton biomass started increasing over the water column in February-early March, and generally achieved peak values in the upper layers in late spring. Another peak was often recorded in autumn. Diatoms and phytoflagellates dominated for the largest part of the year. Ciliates showed their main peaks in phase with phytoplankton and were mainly represented by small (&lt; 30 mm) naked choreotrichs. Mesozooplankton increased in March-April, reaching maximum concentrations in summer. Copepods were always the most abundant group, followed by cladocerans in summer. At the interannual scale, a high variability and a decreasing trend were recorded over the sampling period for autotrophic biomass. Mesozooplankton biomass showed a less marked interannual variability. From 1995 onwards, phytoplankton populations increased in cell number but decreased in cell size, with intense blooms of small diatoms and undetermined coccoid species frequently observed in recent years. In spite of those interannual variations, the different phases of the annual cycle and the occurrence of several plankton species were remarkably regular.

Gallstone ileus is a mechanical intestinal obstruction due to gallstone impaction within the gastrointestinal tract. Less than 1% of cases of intestinal obstruction are derived from this etiology. The symptoms and signs of gallstone ileus are mostly nonspecific. This entity has been observed with a higher frequency among the elderly, the majority of which have concomitant medical illness. Cardiovascular, pulmonary, and metabolic diseases should be considered as they may affect the prognosis. Surgical relief of gastrointestinal obstruction remains the mainstay of operative treatment. The current surgical procedures are: (1) simple enterolithotomy; (2) enterolithotomy, cholecystectomy and fistula closure (one-stage procedure); and (3) enterolithotomy with cholecystectomy performed later (two-stage procedure). Bowel resection is necessary in certain cases after enterolithotomy is performed. Large prospective laparoscopic and endoscopic trials are expected.

Attenuated viral vaccines can be generated by targeting essential pathogenicity factors. We report here the rational design of an attenuated recombinant coronavirus vaccine based on a deletion in the coding sequence of the non-structural protein 1 (nsp1). In cell culture, nsp1 of mouse hepatitis virus (MHV), like its SARS-coronavirus homolog, strongly reduced cellular gene expression. The effect of nsp1 on MHV replication in vitro and in vivo was analyzed using a recombinant MHV encoding a deletion in the nsp1-coding sequence. The recombinant MHV nsp1 mutant grew normally in tissue culture, but was severely attenuated in vivo. Replication and spread of the nsp1 mutant virus was restored almost to wild-type levels in type I interferon (IFN) receptor-deficient mice, indicating that nsp1 interferes efficiently with the type I IFN system. Importantly, replication of nsp1 mutant virus in professional antigen-presenting cells such as conventional dendritic cells and macrophages, and induction of type I IFN in plasmacytoid dendritic cells, was not impaired. Furthermore, even low doses of nsp1 mutant MHV elicited potent cytotoxic T cell responses and protected mice against homologous and heterologous virus challenge. Taken together, the presented attenuation strategy provides a paradigm for the development of highly efficient coronavirus vaccines.

Ces recherches prolongent l’axiomatique des fonctions harmoniques de M. Brelot. Dans un espace <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mi>Ω</mml:mi> </mml:math> localement compact, connexe et localement connexe, qu’on supposera le plus souvent à base dénombrable, les fonctions harmoniques satisfont à trois axiomes : le 1er est un axiome de faisceau ; le 2e pose l’existence d’une base de la topologie formée de domaines réguliers, c’est-à-dire pour lesquels le problème de Dirichlet admet une solution unique, croissant avec la donnée ; le 3e est une propriété de convergence par croissance, qui, pour certaines questions, est renforcée en une propriété du type de Harnack. Les fonctions surharmoniques sont alors définies comme dans le cas classique, à l’aide des domaines réguliers et de la solution du problème de Dirichlet correspondant. Soit <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msup> <mml:mi>S</mml:mi> <mml:mo>+</mml:mo> </mml:msup> </mml:math> l’ensemble des fonctions surharmoniques <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:mo>≥</mml:mo> <mml:mn>0</mml:mn> </mml:mrow> </mml:math> dans <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mi>Ω</mml:mi> </mml:math> ; on suppose qu’il existe au moins une fonction <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:mo>∈</mml:mo> <mml:msup> <mml:mi>S</mml:mi> <mml:mo>+</mml:mo> </mml:msup> </mml:mrow> </mml:math> , non harmonique dans <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mi>Ω</mml:mi> </mml:math> . Une première partie de ces recherches est centrée sur un théorème de partition, permettant de décomposer toute fonction <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:mo>∈</mml:mo> <mml:msup> <mml:mi>S</mml:mi> <mml:mo>+</mml:mo> </mml:msup> </mml:mrow> </mml:math> en deux autres, dont l’une est harmonique dans un ouvert <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mi>ω</mml:mi> </mml:math> donné et l’autre harmonique dans le complémentaire de <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mover> <mml:mi>ω</mml:mi> <mml:mo>¯</mml:mo> </mml:mover> </mml:math> . Ce théorème est le point de départ de la représentation intégrale des fonctions <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:mo>∈</mml:mo> <mml:msup> <mml:mi>S</mml:mi> <mml:mo>+</mml:mo> </mml:msup> </mml:mrow> </mml:math> , que l’on effectue en appliquant la théorie de G. Choquet sur les représentations intégrales, dans les cônes convexes, à l’aide des points extrémaux. On définit, pour cela, une topologie sur <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msup> <mml:mi>S</mml:mi> <mml:mo>+</mml:mo> </mml:msup> </mml:math> , rendant ce cône métrisable et localement compact. Une autre partie de ces recherches définit et étudie, sous des hypothèses un peu plus restreintes, les fonctions harmoniques adjointes à un système donné de fonctions harmoniques, généralisant les solutions de l’équation adjointe à une équation aux dérivées partielles du second ordre, de type elliptique : <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:mi>L</mml:mi> <mml:mi>u</mml:mi> <mml:mo>=</mml:mo> <mml:mn>0</mml:mn> </mml:mrow> </mml:math> . Le dernier chapitre est consacré à l’étude des fonctions harmoniques, et harmoniques adjointes, associées à l’équation <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:mi>L</mml:mi> <mml:mi>u</mml:mi> <mml:mo>=</mml:mo> <mml:mn>0</mml:mn> </mml:mrow> </mml:math> .

BACKGROUND: N-terminal fragment of B-type natriuretic peptide (NT-proBNP) is a marker of both fluid volume overload and myocardial damage, and it has been useful as a predictor of mortality in patients with end-stage renal disease (ESRD). It has been suggested that continuous ambulatory peritoneal dialysis (CAPD), automated peritoneal dialysis (APD) and haemodialysis (HD) may have different effects on fluid volume and blood pressure control; however, whether the independent predictive value of NT-proBNP for mortality is preserved when analysed in conjunction with fluid overload and dialysis modality is not clear. METHODS: A prospective multicentre cohort of 753 prevalent adult patients on CAPD, APD and HD was followed up for 16 months. Plasmatic levels of NT-proBNP, extracellular fluid volume/total body water ratio (ECFv/TBW) and traditional clinical and biochemical markers for cardiovascular damage risk were measured, and their role as predictors of all-cause and cardiovascular mortality was analysed. RESULTS: NT-proBNP level, ECFv/TBW and other cardiovascular damage risk factors were not evenly distributed among the different dialysis modalities. NT-proBNP levels and ECFv/TBW were correlated with several inflammation, malnutrition and myocardial damage markers. Multivariate analysis showed that NT-proBNP levels and ECFv/TBW were predictors of both all-cause and cardiovascular mortality, independently of dialysis modality and the presence of other known clinical and biochemical risk factors. CONCLUSIONS: NT-proBNP is a reliable predictor of death risk independently of the effect of dialysis modality on fluid volume control, and the presence of other clinical and biochemical markers recognized as risk factors for all-cause and cardiovascular mortality. NT-pro-BNP is a good predictor of mortality independently of fluid volume overload and dialysis modality.

Rotational thromboelastometry (ROTEM) is a point-of-care viscoelastic method and enables to assess viscoelastic profiles of whole blood in various clinical settings. ROTEM-guided bleeding management has become an essential part of patient blood management (PBM) which is an important concept in improving patient safety. Here, ROTEM testing and hemostatic interventions should be linked by evidence-based, setting-specific algorithms adapted to the specific patient population of the hospitals and the local availability of hemostatic interventions. Accordingly, ROTEM-guided algorithms implement the concept of personalized or precision medicine in perioperative bleeding management ('theranostic' approach). ROTEM-guided PBM has been shown to be effective in reducing bleeding, transfusion requirements, complication rates, and health care costs. Accordingly, several randomized-controlled trials, meta-analyses, and health technology assessments provided evidence that using ROTEM-guided algorithms in bleeding patients resulted in improved patient's safety and outcomes including perioperative morbidity and mortality. However, the implementation of ROTEM in the PBM concept requires adequate technical and interpretation training, education and logistics, as well as interdisciplinary communication and collaboration.

OBJECTIVES: To assess the salivary flow rate, pH, and buffer capacity of healthy volunteers, and their relationships with age, gender, obesity, smoking, and alcohol consumption, and to establish the lower-end value of normal salivary flow (oligosialia). METHODS: A prospective study was conducted in 159 healthy volunteers (age > 18 years, absence of medical conditions that could decrease salivary flow). Unstimulated whole saliva was collected during ten minutes, and salivary flow rate (ml/min), pH, and bicarbonate concentration (mmol/l) were measured using a Radiometer ABL 520. The 5 percentile of salivary flow rate and bicarbonate concentration was considered the lower limit of normality. RESULTS: Median salivary flow rate was 0.48 ml/min (range: 0.1-2 ml/min). Age younger than 44 years was associated with higher flow rates (OR 2.10). Compared with women, men presented a higher flow rate (OR 3.19) and buffer capacity (OR 2.81). Bicarbonate concentration correlated with salivary flow rate. The lower-end values of normal flow rate and bicarbonate concentration were 0.15 ml/min and 1.800 mmol/l, respectively. The presence of obesity, smoking, and alcohol consumption did not influence salivary parameters. CONCLUSIONS: In healthy volunteers, salivary flow rate depends on age and gender, and correlates with buffer capacity. Obesity, smoking, and alcohol use do not influence salivary secretion.

The main hypotheses proposed to explain barrier formation separating populations and causing the differentiation of species in Amazonia during the course of geological history are based on different factors, as follow: (1) Changes in the distribution of land and sea or in the landscape due to tectonic movements or sea level fluctuations (Paleogeography hypothesis), (2) the barrier effect of Amazonian rivers (River hypothesis), (3) a combination of the barrier effect of broad rivers and vegetational changes in northern and southern Amazonia (River-refuge hypothesis), (4) the isolation of humid rainforest blocks near areas of surface relief in the periphery of Amazonia separated by dry forests, savannas and other intermediate vegetation types during dry climatic periods of the Tertiary and Quaternary (Refuge hypothesis), (5) changes in canopy-density due to climatic reversals (Canopy-density hypothesis) (6) the isolation and speciation of animal populations in small montane habitat pockets around Amazonia due to climatic fluctuations without major vegetational changes (Museum hypothesis), (7) competitive species interactions and local species isolations in peripheral regions of Amazonia due to invasion and counterinvasion during cold/warm periods of the Pleistocene (Disturbance-vicariance hypothesis) and (8) parapatric speciation across steep environmental gradients without separation of the respective populations (Gradient hypothesis). Several of these hypotheses probably are relevant to a different degree for the speciation processes in different faunal groups or during different geological periods. The basic paleogeography model refers mainly to faunal differentiation during the Tertiary and in combination with the Refuge hypothesis. Milankovitch cycles leading to global main hypotheses proposed to explain barrier formation separating populations and causing the differentiation of species in Amazonia during the course of geological history are based on different factors, as follow: (1) Changes in the distribution of land and sea or in the landscape due to tectonic movements or sea level fluctuations (Paleogeography hypothesis), (2) the barrier effect of Amazonian rivers (River hypothesis), (3) a combination of the barrier effect of broad rivers and vegetational changes in northern and southern Amazonia (River-refuge hypothesis), (4) the isolation of humid rainforest blocks near areas of surface relief in the periphery of Amazonia separated by dry forests, savannas and other intermediate vegetation types during dry climatic periods of the Tertiary and Quaternary (Refuge hypothesis), (5) changes in canopy-density due to climatic reversals (Canopy-density hypothesis) (6) the isolation and speciation of animal populations in small montane habitat pockets around Amazonia due to climatic fluctuations without major vegetational changes (Museum hypothesis), (7) competitive species interactions and local species isolations in peripheral regions of Amazonia due to invasion and counterinvasion during cold/warm periods of the Pleistocene (Disturbance-vicariance hypothesis) and (8) parapatric speciation across steep environmental gradients without separation of the respective populations (Gradient hypothesis). Several of these hypotheses probably are relevant to a different degree for the speciation processes in different faunal groups or during different geological periods. The basic paleogeography model refers mainly to faunal differentiation during the Tertiary and in combination with the Refuge hypothesis. Milankovitch cycles leading to global climatic-vegetational changes affected the biomes of the world not only during the Pleistocene but also during the Tertiary and earlier geological periods. New geoscientific evidence for the effect of dry climatic periods in Amazonia supports the predictions of the Refuge hypothesis. The disturbance-vicariance hypothesis refers to the presumed effect of cold/warm climatic phases of the Pleistocene only and is of limited general relevance because most extant species originated earlier and probably through paleogeographic changes and the formation of ecological refuges during the Tertiary.

BACKGROUND: Obesity is a very prevalent chronic disease worldwide and has been suggested to increase susceptibility of periodontitis. The aim of this paper was to provide a systematic review of the association between obesity and periodontal disease, and to determine the possible mechanisms underlying in this relationship. MATERIAL AND METHODS: A literature search was carried out in the databases PubMed-Medline and Embase. Controlled clinical trials and observational studies identifying periodontal and body composition parameters were selected. Each article was subjected to data extraction and quality assessment. RESULTS: A total of 284 articles were identified, of which 64 were preselected and 28 were finally included in the review. All the studies described an association between obesity and periodontal disease, except two articles that reported no such association. Obesity is characterized by a chronic subclinical inflammation that could exacerbate other chronic inflammatory disorders like as periodontitis. CONCLUSIONS: The association between obesity and periodontitis was consistent with a compelling pattern of increased risk of periodontitis in overweight or obese individuals. Although the underlying pathophysiological mechanism remains unclear, it has been pointed out that the development of insulin resistance as a consequence of a chronic inflammatory state and oxidative stress could be implicated in the association between obesity and periodontitis. Further prospective longitudinal studies are needed to define the magnitude of this association and to elucidate the causal biological mechanisms.