Pontifícia Universidade Católica do Rio Grande do Sul

BACKGROUND: Trastuzumab, a recombinant monoclonal antibody against HER2, has clinical activity in advanced breast cancer that overexpresses HER2. We investigated its efficacy and safety after excision of early-stage breast cancer and completion of chemotherapy. METHODS: This international, multicenter, randomized trial compared one or two years of trastuzumab given every three weeks with observation in patients with HER2-positive and either node-negative or node-positive breast cancer who had completed locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy. RESULTS: Data were available for 1694 women randomly assigned to two years of treatment with trastuzumab, 1694 women assigned to one year of trastuzumab, and 1693 women assigned to observation. We report here the results only of treatment with trastuzumab for one year or observation. At the first planned interim analysis (median follow-up of one year), 347 events (recurrence of breast cancer, contralateral breast cancer, second nonbreast malignant disease, or death) were observed: 127 events in the trastuzumab group and 220 in the observation group. The unadjusted hazard ratio for an event in the trastuzumab group, as compared with the observation group, was 0.54 (95 percent confidence interval, 0.43 to 0.67; P<0.0001 by the log-rank test, crossing the interim analysis boundary), representing an absolute benefit in terms of disease-free survival at two years of 8.4 percentage points. Overall survival in the two groups was not significantly different (29 deaths with trastuzumab vs. 37 with observation). Severe cardiotoxicity developed in 0.5 percent of the women who were treated with trastuzumab. CONCLUSIONS: One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with HER2-positive breast cancer. (ClinicalTrials.gov number, NCT00045032.)

Abstract Cloud computing is a recent advancement wherein IT infrastructure and applications are provided as ‘services’ to end‐users under a usage‐based payment model. It can leverage virtualized services even on the fly based on requirements (workload patterns and QoS) varying with time. The application services hosted under Cloud computing model have complex provisioning, composition, configuration, and deployment requirements. Evaluating the performance of Cloud provisioning policies, application workload models, and resources performance models in a repeatable manner under varying system and user configurations and requirements is difficult to achieve. To overcome this challenge, we propose CloudSim: an extensible simulation toolkit that enables modeling and simulation of Cloud computing systems and application provisioning environments. The CloudSim toolkit supports both system and behavior modeling of Cloud system components such as data centers, virtual machines (VMs) and resource provisioning policies. It implements generic application provisioning techniques that can be extended with ease and limited effort. Currently, it supports modeling and simulation of Cloud computing environments consisting of both single and inter‐networked clouds (federation of clouds). Moreover, it exposes custom interfaces for implementing policies and provisioning techniques for allocation of VMs under inter‐networked Cloud computing scenarios. Several researchers from organizations, such as HP Labs in U.S.A., are using CloudSim in their investigation on Cloud resource provisioning and energy‐efficient management of data center resources. The usefulness of CloudSim is demonstrated by a case study involving dynamic provisioning of application services in the hybrid federated clouds environment. The result of this case study proves that the federated Cloud computing model significantly improves the application QoS requirements under fluctuating resource and service demand patterns. Copyright © 2010 John Wiley &amp; Sons, Ltd.

BACKGROUND: Unresectable locally advanced or metastatic triple-negative (hormone-receptor-negative and human epidermal growth factor receptor 2 [HER2]-negative) breast cancer is an aggressive disease with poor outcomes. Nanoparticle albumin-bound (nab)-paclitaxel may enhance the anticancer activity of atezolizumab. METHODS: In this phase 3 trial, we randomly assigned (in a 1:1 ratio) patients with untreated metastatic triple-negative breast cancer to receive atezolizumab plus nab-paclitaxel or placebo plus nab-paclitaxel; patients continued the intervention until disease progression or an unacceptable level of toxic effects occurred. Stratification factors were the receipt or nonreceipt of neoadjuvant or adjuvant taxane therapy, the presence or absence of liver metastases at baseline, and programmed death ligand 1 (PD-L1) expression at baseline (positive vs. negative). The two primary end points were progression-free survival (in the intention-to-treat population and PD-L1-positive subgroup) and overall survival (tested in the intention-to-treat population; if the finding was significant, then it would be tested in the PD-L1-positive subgroup). RESULTS: Each group included 451 patients (median follow-up, 12.9 months). In the intention-to-treat analysis, the median progression-free survival was 7.2 months with atezolizumab plus nab-paclitaxel, as compared with 5.5 months with placebo plus nab-paclitaxel (hazard ratio for progression or death, 0.80; 95% confidence interval [CI], 0.69 to 0.92; P=0.002); among patients with PD-L1-positive tumors, the median progression-free survival was 7.5 months and 5.0 months, respectively (hazard ratio, 0.62; 95% CI, 0.49 to 0.78; P<0.001). In the intention-to-treat analysis, the median overall survival was 21.3 months with atezolizumab plus nab-paclitaxel and 17.6 months with placebo plus nab-paclitaxel (hazard ratio for death, 0.84; 95% CI, 0.69 to 1.02; P=0.08); among patients with PD-L1-positive tumors, the median overall survival was 25.0 months and 15.5 months, respectively (hazard ratio, 0.62; 95% CI, 0.45 to 0.86). No new adverse effects were identified. Adverse events that led to the discontinuation of any agent occurred in 15.9% of the patients who received atezolizumab plus nab-paclitaxel and in 8.2% of those who received placebo plus nab-paclitaxel. CONCLUSIONS: Atezolizumab plus nab-paclitaxel prolonged progression-free survival among patients with metastatic triple-negative breast cancer in both the intention-to-treat population and the PD-L1-positive subgroup. Adverse events were consistent with the known safety profiles of each agent. (Funded by F. Hoffmann-La Roche/Genentech; IMpassion130 ClinicalTrials.gov number, NCT02425891 .).

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G rowth of the human population, rising consumption, and rapid globalization have caused widespread degradation and disruption of natural systems, especially in the freshwater realm. Freshwater ecosystems have lost a greater proportion of their species and habitat than ecosystems on land or in the oceans, and they face increasing threats from dams, water withdrawals, pollution, invasive species, and overharvesting (MEA 2005 Freshwater ecosystems and the diverse communities of species found in lakes, rivers, and wetlands may be the most endangered of all (MEA 2005).

BACKGROUND: The efficacy and safety of the anti-programmed death ligand 1 (PD-L1) monoclonal antibody atezolizumab, as compared with those of platinum-based chemotherapy, as first-line treatment for patients with metastatic non-small-cell lung cancer (NSCLC) with PD-L1 expression are not known. METHODS: wild-type tumors, overall survival and progression-free survival were also prospectively assessed in subgroups defined according to findings on two PD-L1 assays as well as by blood-based tumor mutational burden. RESULTS: wild-type tumors who had the highest expression of PD-L1 (205 patients), the median overall survival was longer by 7.1 months in the atezolizumab group than in the chemotherapy group (20.2 months vs. 13.1 months; hazard ratio for death, 0.59; P = 0.01). Among all the patients who could be evaluated for safety, adverse events occurred in 90.2% of the patients in the atezolizumab group and in 94.7% of those in the chemotherapy group; grade 3 or 4 adverse events occurred in 30.1% and 52.5% of the patients in the respective groups. Overall and progression-free survival favored atezolizumab in the subgroups with a high blood-based tumor mutational burden. CONCLUSIONS: Atezolizumab treatment resulted in significantly longer overall survival than platinum-based chemotherapy among patients with NSCLC with high PD-L1 expression, regardless of histologic type. (Funded by F. Hoffmann-La Roche/Genentech; IMpower110 ClinicalTrials.gov number, NCT02409342.).

Previous analyses of relations, divergence times, and diversification patterns among extant mammalian families have relied on supertree methods and local molecular clocks. We constructed a molecular supermatrix for mammalian families and analyzed these data with likelihood-based methods and relaxed molecular clocks. Phylogenetic analyses resulted in a robust phylogeny with better resolution than phylogenies from supertree methods. Relaxed clock analyses support the long-fuse model of diversification and highlight the importance of including multiple fossil calibrations that are spread across the tree. Molecular time trees and diversification analyses suggest important roles for the Cretaceous Terrestrial Revolution and Cretaceous-Paleogene (KPg) mass extinction in opening up ecospace that promoted interordinal and intraordinal diversification, respectively. By contrast, diversification analyses provide no support for the hypothesis concerning the delayed rise of present-day mammals during the Eocene Period.

Advanced Breast Cancer (ABC) comprises both locally advanced breast cancer (LABC) and metastatic breast cancer (MBC) [1.Cardoso F. Costa A. Norton L. ESO-ESMO 2nd International Consensus Guidelines for Advanced Breast Cancer (ABC2). Simultaneous publication in.Breast. 2014; 23: 489-502Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar]. Although treatable, MBC remains virtually an incurable disease with a median overall survival (OS) of ∼3 years and a 5-year survival of only ∼25% [2.Cardoso F. Spence D. Mertz S. et al.Global analysis of advanced/metastatic breast cancer: decade report (2005–2015).Breast. 2018; 39: 131-138Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 3.N Howlader, AM Noone, M Krapcho et al (eds). SEER Cancer Statistics Review, 1975–2013. Bethesda, MD: National Cancer Institute. http://seer.cancer.gov/csr/1975_2013/, based on November 2015 SEER data submission, posted to the SEER web site, April 2016.Google Scholar]. The MBC Decade Report [2.Cardoso F. Spence D. Mertz S. et al.Global analysis of advanced/metastatic breast cancer: decade report (2005–2015).Breast. 2018; 39: 131-138Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar] shows that progress has been slow in terms of improved outcomes, quality of life (QoL), awareness and information regarding ABC. More recently, some studies seem to indicate an improvement in OS, mostly due to advances in human epidermal growth factor receptor 2 (HER2)-positive L. survival in metastatic breast cancer Full Text Full Text PDF PubMed Scopus Google Scholar, et of on the of with metastatic breast PubMed Scopus Google Scholar, et and overall survival of with advanced breast the Full Text Full Text PDF PubMed Scopus Google Scholar]. 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BACKGROUND: In an interim analysis of this phase 3 trial, the addition of pembrolizumab to chemotherapy resulted in longer progression-free survival than chemotherapy alone among patients with advanced triple-negative breast cancer whose tumors expressed programmed death ligand 1 (PD-L1) with a combined positive score (CPS; the number of PD-L1-staining tumor cells, lymphocytes, and macrophages, divided by the total number of viable tumor cells, multiplied by 100) of 10 or more. The results of the final analysis of overall survival have not been reported. METHODS: We randomly assigned patients with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer in a 2:1 ratio to receive pembrolizumab (200 mg) every 3 weeks plus the investigator's choice of chemotherapy (nanoparticle albumin-bound paclitaxel, paclitaxel, or gemcitabine-carboplatin) or placebo plus chemotherapy. The primary end points were progression-free survival (reported previously) and overall survival among patients whose tumors expressed PD-L1 with a CPS of 10 or more (the CPS-10 subgroup), among patients whose tumors expressed PD-L1 with a CPS of 1 or more (the CPS-1 subgroup), and in the intention-to-treat population. Safety was also assessed. RESULTS: A total of 847 patients underwent randomization: 566 were assigned to the pembrolizumab-chemotherapy group, and 281 to the placebo-chemotherapy group. The median follow-up was 44.1 months. In the CPS-10 subgroup, the median overall survival was 23.0 months in the pembrolizumab-chemotherapy group and 16.1 months in the placebo-chemotherapy group (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.55 to 0.95; two-sided P = 0.0185 [criterion for significance met]); in the CPS-1 subgroup, the median overall survival was 17.6 and 16.0 months in the two groups, respectively (hazard ratio, 0.86; 95% CI, 0.72 to 1.04; two-sided P = 0.1125 [not significant]); and in the intention-to-treat population, the median overall survival was 17.2 and 15.5 months, respectively (hazard ratio, 0.89; 95% CI, 0.76 to 1.05 [significance not tested]). Adverse events of grade 3, 4, or 5 that were related to the trial regimen occurred in 68.1% of the patients in the pembrolizumab-chemotherapy group and in 66.9% in the placebo-chemotherapy group, including death in 0.4% of the patients in the pembrolizumab-chemotherapy group and in no patients in the placebo-chemotherapy group. CONCLUSIONS: Among patients with advanced triple-negative breast cancer whose tumors expressed PD-L1 with a CPS of 10 or more, the addition of pembrolizumab to chemotherapy resulted in significantly longer overall survival than chemotherapy alone. (Funded by Merck Sharp and Dohme; KEYNOTE-355 ClinicalTrials.gov number, NCT02819518.).

Universidade Federal de Goiás

The goal of the present study was to apply deep learning algorithms to identify autism spectrum disorder (ASD) patients from large brain imaging dataset, based solely on the patients brain activation patterns. We investigated ASD patients brain imaging data from a world-wide multi-site database known as ABIDE (Autism Brain Imaging Data Exchange). ASD is a brain-based disorder characterized by social deficits and repetitive behaviors. According to recent Centers for Disease Control data, ASD affects one in 68 children in the United States. We investigated patterns of functional connectivity that objectively identify ASD participants from functional brain imaging data, and attempted to unveil the neural patterns that emerged from the classification. The results improved the state-of-the-art by achieving 70% accuracy in identification of ASD versus control patients in the dataset. The patterns that emerged from the classification show an anticorrelation of brain function between anterior and posterior areas of the brain; the anticorrelation corroborates current empirical evidence of anterior-posterior disruption in brain connectivity in ASD. We present the results and identify the areas of the brain that contributed most to differentiating ASD from typically developing controls as per our deep learning model.

Peritonitis is a common and serious complication of peritoneal dialysis (PD). Although less than 5% of peritonitis episodes result in death, peritonitis is the direct or major contributing cause of death in around 16% of PD patients (1-6). In addition, severe or prolonged peritonitis leads to structural and functional alterations of the peritoneal membrane, eventually leading to membrane failure. Peritonitis is a major cause of PD technique failure and conversion to long-term hemodialysis (1,5,7,8). Recommendations under the auspices of the International Society for Peritoneal Dialysis (ISPD) were first published in 1983 and revised in 1993, 1996, 2000, 2005, and 2010 (9-14). The present recommendations are organized into 5 sections: 1. Peritonitis rate 2. Prevention of peritonitis 3. Initial presentation and management of peritonitis 4. Subsequent management of peritonitis 5

BACKGROUND: Whether vaccination during pregnancy could reduce the burden of respiratory syncytial virus (RSV)-associated lower respiratory tract illness in newborns and infants is uncertain. METHODS: In this phase 3, double-blind trial conducted in 18 countries, we randomly assigned, in a 1:1 ratio, pregnant women at 24 through 36 weeks' gestation to receive a single intramuscular injection of 120 μg of a bivalent RSV prefusion F protein-based (RSVpreF) vaccine or placebo. The two primary efficacy end points were medically attended severe RSV-associated lower respiratory tract illness and medically attended RSV-associated lower respiratory tract illness in infants within 90, 120, 150, and 180 days after birth. A lower boundary of the confidence interval for vaccine efficacy (99.5% confidence interval [CI] at 90 days; 97.58% CI at later intervals) greater than 20% was considered to meet the success criterion for vaccine efficacy with respect to the primary end points. RESULTS: At this prespecified interim analysis, the success criterion for vaccine efficacy was met with respect to one primary end point. Overall, 3682 maternal participants received vaccine and 3676 received placebo; 3570 and 3558 infants, respectively, were evaluated. Medically attended severe lower respiratory tract illness occurred within 90 days after birth in 6 infants of women in the vaccine group and 33 infants of women in the placebo group (vaccine efficacy, 81.8%; 99.5% CI, 40.6 to 96.3); 19 cases and 62 cases, respectively, occurred within 180 days after birth (vaccine efficacy, 69.4%; 97.58% CI, 44.3 to 84.1). Medically attended RSV-associated lower respiratory tract illness occurred within 90 days after birth in 24 infants of women in the vaccine group and 56 infants of women in the placebo group (vaccine efficacy, 57.1%; 99.5% CI, 14.7 to 79.8); these results did not meet the statistical success criterion. No safety signals were detected in maternal participants or in infants and toddlers up to 24 months of age. The incidences of adverse events reported within 1 month after injection or within 1 month after birth were similar in the vaccine group (13.8% of women and 37.1% of infants) and the placebo group (13.1% and 34.5%, respectively). CONCLUSIONS: RSVpreF vaccine administered during pregnancy was effective against medically attended severe RSV-associated lower respiratory tract illness in infants, and no safety concerns were identified. (Funded by Pfizer; MATISSE ClinicalTrials.gov number, NCT04424316.).

Polymyxins have re-emerged in clinical practice owing to the dry antibiotic development pipeline and worldwide increasing prevalence of nosocomial infections caused by multidrug-resistant (MDR) Gram-negative bacteria. Polymyxin B and colistin (polymyxin E) have been ultimately considered as the last-resort treatment of such infections. Microbiological, pharmacokinetic, pharmacodynamic and clinical data available for polymyxin B are reviewed in this paper. Polymyxin B has rapid in vitro bactericidal activity against major MDR Gram-negative bacteria, such as Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. Acquired resistance to this agent is still rare among these pathogens. However, optimized dosage regimens are not known yet. Good clinical outcomes have been observed in the majority of the patients treated with intravenous polymyxin B in recent studies. However, these studies failed to provide definitive conclusions due to limitations of study design and additional clinical trials are required. Although combination therapy may be an attractive option based on some currently available in vitro data, clinical data supporting such recommendations are lacking. Since polymyxins will be increasingly used for the treatment of infections caused by MDR bacteria, clinical pharmacokinetic, pharmacodynamic and toxicodynamic studies underpinning the optimal use of these drugs are urgently required.

Modern felid species descend from relatively recent (<11 million years ago) divergence and speciation events that produced successful predatory carnivores worldwide but that have confounded taxonomic classifications. A highly resolved molecular phylogeny with divergence dates for all living cat species, derived from autosomal, X-linked, Y-linked, and mitochondrial gene segments (22,789 base pairs) and 16 fossil calibrations define eight principal lineages produced through at least 10 intercontinental migrations facilitated by sea-level fluctuations. A ghost lineage analysis indicates that available felid fossils underestimate (i.e., unrepresented basal branch length) first occurrence by an average of 76%, revealing a low representation of felid lineages in paleontological remains. The phylogenetic performance of distinct gene classes showed that Y-chromosome segments are appreciably more informative than mitochondrial DNA, X-linked, or autosomal genes in resolving the rapid Felidae species radiation.

Brain-derived neurotrophic factor (BDNF) is one of the most studied neurotrophins in the healthy and diseased brain. As a result, there is a large body of evidence that associates BDNF with neuronal maintenance, neuronal survival, plasticity, and neurotransmitter regulation. Patients with psychiatric and neurodegenerative disorders often have reduced BDNF concentrations in their blood and brain. A current hypothesis suggests that these abnormal BDNF levels might be due to the chronic inflammatory state of the brain in certain disorders, as neuroinflammation is known to affect several BDNF-related signaling pathways. Activation of glia cells can induce an increase in the levels of pro- and antiinflammatory cytokines and reactive oxygen species, which can lead to the modulation of neuronal function and neurotoxicity observed in several brain pathologies. Understanding how neuroinflammation is involved in disorders of the brain, especially in the disease onset and progression, can be crucial for the development of new strategies of treatment. Despite the increasing evidence for the involvement of BDNF and neuroinflammation in brain disorders, there is scarce evidence that addresses the interaction between the neurotrophin and neuroinflammation in psychiatric and neurodegenerative diseases. This review focuses on the effect of acute and chronic inflammation on BDNF levels in the most common psychiatric and neurodegenerative disorders and aims to shed some light on the possible biological mechanisms that may influence this effect. In addition, this review will address the effect of behavior and pharmacological interventions on BDNF levels in these disorders.

Abstract Diagenesis exerts a strong control on the quality and heterogeneity of most clastic reservoirs. Variations in the distribution of diagenetic alterations usually accentuate the variations in depositional porosity and permeability. Linking the types and distribution of diagenetic processes to the depositional facies and sequence-stratigraphic framework of clastic successions provides a powerful tool to predict the distribution of diagenetic alterations controlling quality and heterogeneity. The heterogeneity patterns of sandstone reservoirs, which determine the volumes, flow rates, and recovery of hydrocarbons, are controlled by geometry and internal structures of sand bodies, grain size, sorting, degree of bioturbation, provenance, and by the types, volumes, and distribution of diagenetic alterations. Variations in the pathways of diagenetic evolution are linked to (1) depositional facies, hence pore-water chemistry, depositional porosity and permeability, types and amounts of intrabasinal grains, and extent of bioturbation; (2) detrital sand composition; (3) rate of deposition (controlling residence time of sediments at specific near-surface, geochemical conditions); and (4) burial thermal history of the basin. The amounts and types of intrabasinal grains are also controlled by changes in the relative sea level and, therefore, can be predicted in the context of sequence stratigraphy, particularly in paralic and shallow marine environments. Changes in the relative sea level exert significant control on the types and extent of near-surface shallow burial diagenetic alterations, which in turn influence the pathways of burial diagenetic and reservoir quality evolution of clastic reservoirs. Carbonate cementation is more extensive in transgressive systems tract (TST) sandstones, particularly below parasequence boundaries, transgressive surface , and maximum flooding surface because of the abundance of carbonate bioclasts and organic matter, bioturbation, and prolonged residence time of the sediments at and immediately below the sea floor caused by low sedimentation rates, which also enhance the formation of glaucony. Eogenetic grain-coating berthierine, odinite, and smectite, formed mostly in TST and early highstand systems tract deltaic and estuarine sandstones, are transformed into ferrous chlorite during mesodiagenesis, helping preserve reservoir quality through the inhibition of quartz cementation. The infiltration of grain-coating smectitic clays is more extensive in braided than in meandering fluvial sandstones, forming flow barriers in braided amalgamated reservoirs, and may either help preserve porosity during burial because of quartz overgrowth inhibition or reduce it by enhancing intergranular pressure dissolution. Diagenetic modifications along sequence boundaries are characterized by considerable dissolution and kaolinization of feldspars, micas, and mud intraclasts under wet and warm climates, whereas a semiarid climate may lead to the formation of calcrete dolocrete cemented layers. Turbidite sandstones are typically cemented by carbonate along the contacts with interbedded mudrocks or carbonate mudstones and marls, as well as along layers of concentration of carbonate bioclasts and intraclasts. Commonly, hybrid carbonate turbidite arenites are pervasively cemented. Proximal, massive turbidites normally show only scattered spherical or ovoid carbonate concretions. Improved geologic models based on the connections among diagenesis, depositional facies, and sequence-stratigraphic surfaces and intervals may not only contribute to optimized production through the design of appropriate simulation models for improved or enhanced oil recovery strategies, as well as for CO2 geologic sequestration, but also support more effective hydrocarbon exploration through reservoir quality prediction.

RATIONALE: Bronchial thermoplasty (BT) is a bronchoscopic procedure in which controlled thermal energy is applied to the airway wall to decrease smooth muscle. OBJECTIVES: To evaluate the effectiveness and safety of BT versus a sham procedure in subjects with severe asthma who remain symptomatic despite treatment with high-dose inhaled corticosteroids and long-acting beta(2)-agonists. METHODS: A total of 288 adult subjects (Intent-to-Treat [ITT]) randomized to BT or sham control underwent three bronchoscopy procedures. Primary outcome was the difference in Asthma Quality of Life Questionnaire (AQLQ) scores from baseline to average of 6, 9, and 12 months (integrated AQLQ). Adverse events and health care use were collected to assess safety. Statistical design and analysis of the primary endpoint was Bayesian. Target posterior probability of superiority (PPS) of BT over sham was 95%, except for the primary endpoint (96.4%). MEASUREMENTS AND MAIN RESULTS: The improvement from baseline in the integrated AQLQ score was superior in the BT group compared with sham (BT, 1.35 +/- 1.10; sham, 1.16 +/- 1.23 [PPS, 96.0% ITT and 97.9% per protocol]). Seventy-nine percent of BT and 64% of sham subjects achieved changes in AQLQ of 0.5 or greater (PPS, 99.6%). Six percent more BT subjects were hospitalized in the treatment period (up to 6 wk after BT). In the posttreatment period (6-52 wk after BT), the BT group experienced fewer severe exacerbations, emergency department (ED) visits, and days missed from work/school compared with the sham group (PPS, 95.5, 99.9, and 99.3%, respectively). CONCLUSIONS: BT in subjects with severe asthma improves asthma-specific quality of life with a reduction in severe exacerbations and healthcare use in the posttreatment period. Clinical trial registered with www.clinialtrials.gov (NCT00231114).

The freshwater and marine fish faunas of South America are the most diverse on Earth, with current species richness estimates standing above 9100 species. In addition, over the last decade at least 100 species were described every year. There are currently about 5160 freshwater fish species, and the estimate for the freshwater fish fauna alone points to a final diversity between 8000 and 9000 species. South America also has c. 4000 species of marine fishes. The mega-diverse fish faunas of South America evolved over a period of >100 million years, with most lineages tracing origins to Gondwana and the adjacent Tethys Sea. This high diversity was in part maintained by escaping the mass extinctions and biotic turnovers associated with Cenozoic climate cooling, the formation of boreal and temperate zones at high latitudes and aridification in many places at equatorial latitudes. The fresh waters of the continent are divided into 13 basin complexes, large basins consolidated as a single unit plus historically connected adjacent coastal drainages, and smaller coastal basins grouped together on the basis of biogeographic criteria. Species diversity, endemism, noteworthy groups and state of knowledge of each basin complex are described. Marine habitats around South America, both coastal and oceanic, are also described in terms of fish diversity, endemism and state of knowledge. Because of extensive land use changes, hydroelectric damming, water divergence for irrigation, urbanization, sedimentation and overfishing 4-10% of all fish species in South America face some degree of extinction risk, mainly due to habitat loss and degradation. These figures suggest that the conservation status of South American freshwater fish faunas is better than in most other regions of the world, but the marine fishes are as threatened as elsewhere. Conserving the remarkable aquatic habitats and fishes of South America is a growing challenge in face of the rapid anthropogenic changes of the 21st century, and deserves attention from conservationists and policy makers.

Persistence is a characteristic attribute of long-term memories (LTMs). However, little is known about the molecular mechanisms that mediate this process. We recently showed that persistence of LTM requires a late protein synthesis- and BDNF-dependent phase in the hippocampus. Here, we show that intrahippocampal delivery of BDNF reverses the deficit in memory persistence caused by inhibition of hippocampal protein synthesis. Importantly, we demonstrate that BDNF induces memory persistence by itself, transforming a nonlasting LTM trace into a persistent one in an ERK-dependent manner. Thus, BDNF is not only necessary, but sufficient to induce a late postacquisition phase in the hippocampus essential for persistence of LTM storage.