Pharmacokinetic/pharmacodynamic target attainment of intravenous β-lactam regimens against Gram-negative bacteria isolated in a Brazilian teaching hospital

ABSTRACTINTRODUCTION: Monte Carlo simulations have been used for selecting optimal antibiotic regimens for treatment of bacterial infections. The aim of this study was to assess the pharmacokinetic and pharmacodynamic target attainment of intravenous β-lactam regimens commonly used to treat bloodstream infections (BSIs) caused by Gram-negative rod-shaped organisms in a Brazilian teaching hospital.METHODS: In total, 5,000 patients were included in the Monte Carlo simulations of distinct antimicrobial regimens to estimate the likelihood of achieving free drug concentrations above the minimum inhibitory concentration (MIC; fT > MIC) for the requisite periods to clear distinct target organisms. Microbiological data were obtained from blood culture isolates harvested in our hospital from 2008 to 2010.RESULTS: In total, 614 bacterial isolates, including Escherichia coli, Enterobacterspp., Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa, were analyzed Piperacillin/tazobactam failed to achieve a cumulative fraction of response (CFR) > 90% for any of the isolates. While standard dosing (short infusion) of β-lactams achieved target attainment for BSIs caused by E. coliand Enterobacterspp., pharmacodynamic target attainment against K. pneumoniaeisolates was only achieved with ceftazidime and meropenem (prolonged infusion). Lastly, only prolonged infusion of high-dose meropenem approached an ideal CFR against P. aeruginosa; however, no antimicrobial regimen achieved an ideal CFR against A. baumannii.CONCLUSIONS:These data reinforce the use of prolonged infusions of high-dose β-lactam antimicrobials as a reasonable strategy for the treatment of BSIs caused by multidrug resistant Gram-negative bacteria in Brazil.

Microsatellite instability in solitary and sporadic gastric cancer

Recently, the presence of microsatellite instability (MSI) has been reported in gastric cancer and associated with older age of presentation, distal tumor location, early disease staging, and better overall prognosis. Different characteristics in presentation and in tumor behavior may be explained by different genetic alterations during carcinogenesis of gastric cancer. Identification of specific genetic pathways in gastric cancer may have direct impact on prognosis and selection of treatment strategies. PATIENTS AND METHODS: All 24 patients were treated by radical surgery. Fragments of normal and tumor tissues were extracted from the specimen and stored at -80ºC before DNA purification and extraction. PCR amplification utilizing microsatellite markers was performed. Tumors presenting PCR products of abnormal sizes were considered positive for microsatellite instability (MSI+). RESULTS: Five patients (21%) had tumors that were MSI+ in at least 1 marker. In the group of patients with Lauren's intestinal-type gastric carcinoma, 3 had tumors that were MSI+ (23%), while in the group of diffuse-type gastric cancer, 2 patients had tumors that were MSI+ (19%). The mean age of presentation and the male:female ratio was similar in both groups. Tumors that were MSI+ were more frequently located in proximal portion of the stomach compared to microsatellite-stable (MSS) tumors (40% vs. 16%). Although there was a trend of patients with MSI+ tumors towards a proximal gastric tumor location, early staging, and negative lymph node metastasis, there was no statistical significance compared to those with MSS tumors (P >.1). Comparison of overall and disease-free survival between gastric tumors that were MSI+ and those that were MSS found no statistically significant differences (P >.1). CONCLUSIONS: Microsatellite instability is a frequent event in gastric carcinogenesis and shows a trend towards distinct clinical and pathological characteristics of gastric cancer.

NSP work project investment styles

This paper analyzes the Nova Student Portfolio (NSP) with the objective to understand performances of the fund. Each investment style has been analyzed (growth, value and momentum) in order to highlight what style allocation contributed positively and which had a negative impact. The results show that the team mainly invested in value stocks, which contributed positively but that its growth investments had a negative impact on the stock picking performance. The stock selection shows a major influence of the value investment style. A statistical approach shows that the market factor was the one explaining the most the NSP returns.

International partner selection Indian technical textile market

Due to a combination of a vast agricultural industry and a tremendously growing technical textile industry, Ludvig Svensson identified India as target market for possible expansion through domestic production and supply. However, Svensson needed additional information about the industry structure and key players. Therefore, this project focused on a detailed analysis of the technical textile market and its players by following the international partner selection process. Thereby, five key players were identified as potential partners, as well as the need for additional research to determine alternative entry modes, as the market does not currently seem to be receptive for Svensson products.

Triple negative breast cancer: nanosolutions for a big challenge

Triple negative breast cancer (TNBC) is a particular immunopathological subtype of breast cancer that lacks expression of estrogen and progesterone receptors (ER/PR) and amplification of the human epidermal growth factor receptor 2 (HER2) gene. Characterized by aggressive and metastatic phenotypes and high rates of relapse, TNBC is the only breast cancer subgroup still lacking effective therapeutic options, thus presenting the worst prognosis. The development of targeted therapies, as well as early diagnosis methods, is vital to ensure an adequate and timely therapeutic intervention in patients with TNBC. This review intends to discuss potentially emerging approaches for the diagnosis and treatment of TNBC patients, with a special focus on nano-based solutions that actively target these particular tumors.

Interaction paradigms versus age-related user profiles: an evaluation on content selection

Novel input modalities such as touch, tangibles or gestures try to exploit human's innate skills rather than imposing new learning processes. However, despite the recent boom of different natural interaction paradigms, it hasn't been systematically evaluated how these interfaces influence a user's performance or whether each interface could be more or less appropriate when it comes to: 1) different age groups; and 2) different basic operations, as data selection, insertion or manipulation. This work presents the first step of an exploratory evaluation about whether or not the users' performance is indeed influenced by the different interfaces. The key point is to understand how different interaction paradigms affect specific target-audiences (children, adults and older adults) when dealing with a selection task. 60 participants took part in this study to assess how different interfaces may influence the interaction of specific groups of users with regard to their age. Four input modalities were used to perform a selection task and the methodology was based on usability testing (speed, accuracy and user preference). The study suggests a statistically significant difference between mean selection times for each group of users, and also raises new issues regarding the “old” mouse input versus the “new” input modalities.

Evidence for inter- and intra-species biofilm formation variability among a small group of coagulase-negative staphylococci

Coagulase-negative staphylococci (CoNS) are common bacterial colonisers of the human skin. They are often involved in nosocomial infections due to biofilm formation in indwelling medical devices. While biofilm formation has been extensively studied in Staphylococcus epidermidis, little is known regarding other CoNS species. Here, biofilms from six different CoNS species were characterised in terms of biofilm composition and architecture. Interestingly, the ability to form a thick biofilm was not associated with any particular species, and high variability on biofilm accumulation was found within the same species. Cell viability assays also revealed different proportions of live and dead cells within biofilms formed by different species, although this parameter was particularly similar at the intra-species level. On the other hand, biofilm disruption assays demonstrated important inter- and intra-species differences regarding extracellular matrix composition. Lastly, confocal laser scanning microscopy (CLSM) experiments confirmed this variability, highlighting important differences and common features of CoNS biofilms. We hypothesised that the biofilm formation heterogeneity observed was rather associated with biofilm matrix composition than with cells themselves. Additionally, our results indicate that polysaccharides, DNA and proteins are fundamental pieces in the process of CoNS biofilm formation.

Attachment style impacts behavior and early oculomotor response to positive, but not negative, pictures

The present study investigated whether oculomotor behavior is influenced by attachment styles. The Relationship Scales Questionnaire was used to assess attachment styles of forty-eight voluntary university students and to classify them into attachment groups (secure, preoccupied, fearful, and dismissing). Eye-tracking was recorded while participants engaged in a 3-seconds free visual exploration of stimuli presenting either a positive or a negative picture together with a neutral picture, all depicting social interactions. The task consisted in identifying whether the two pictures depicted the same emotion. Results showed that the processing of negative pictures was impermeable to attachment style, while the processing of positive pictures was significantly influenced by individual differences in insecure attachment. The groups highly avoidant regarding to attachment (dismissing and fearful) showed reduced accuracy, suggesting a higher threshold for recognizing positive emotions compared to the secure group. The groups with higher attachment anxiety (preoccupied and fearful) showed differences in automatic capture of attention, in particular an increased delay preceding the first fixation to a picture of positive emotional valence. Despite lenient statistical thresholds induced by the limited sample size of some groups (p < 0.05 uncorrected for multiple comparisons), the current findings suggest that the processing of positive emotions is affected by attachment styles. These results are discussed within a broader evolutionary framework.

Rapid assessment of fruit-color selection by birds using artificial fruits at local scale in Central Amazonia

Modeling clays have been used in several ecological experiments and have proved to be an important tool to variables control. The objective of our study was to determine if fruit color in isolated and grouped displays influences the fruit selection by birds in the field using artificial fruits. Data were collected in six plots distributed homogeneously in 3 km long trails with a minimum distance of 0.5 km. We used a paired experimental design to establish our experiments, so that all treatments were available to the local bird community in each plot. Overall, red was more pecked than brown and white. Isolated red and brown displays were significantly more pecked than others display. Even though our study was conducted in small spatial scales, artificial fruits appeared to be efficient in register fruit consumption attempts by bird. Although inconclusive about selective forces that sharp the dynamics of fruit color polymorphisms and choice by frugivorous birds, our findings corroborate recent studies wherein birds showed preferences by high- over low-contrast fruit signals.

Analysis and selection of indicators for a sustainability assessment method for school buildings based on SBTool ‐ PT

Nowadays, the sustainability of buildings has an extreme importance. This concept goes towards the European aims of the Program Horizon 2020, which concerns about the reduction of the environmental impacts through such aspects as the energy efficiency and renewable technologies, among others. Sustainability is an extremely broad concept but, in this work, it is intended to include the concept of sustainability in buildings. Within the concept that aims the integration of environmental, social and economic levels towards the preservation of the planet and the integrity of the users, there are, currently, several types of tools of environmental certification that are applicable to the construction industry (LEED, BREEAM, DGNB, SBTool, among others). Within this context, it is highlighted the tool SBTool (Sustainable Building Tool) that is employed in several countries and can be subject to review in institutions of basic education, which are the base for the formation of the critical masses and for the development of a country. The main aim of this research is to select indicators that can be used in a methodology for sustainability assessment (SBTool) of school buildings in Portugal and in Brazil. In order to achieve it, it will also be analyzed other methodologies that already incorporate parameters directly related with the schools environment, such as BREEAM or LEED.

Local non-negative initial data scalar characterization of the Kerr solution

For any vacuum initial data set, we define a local, non-negative scalar quantity which vanishes at every point of the data hypersurface if and only if the data are Kerr initial data. Our scalar quantity only depends on the quantities used to construct the vacuum initial data set which are the Riemannian metric defined on the initial data hypersurface and a symmetric tensor which plays the role of the second fundamental form of the embedded initial data hypersurface. The dependency is algorithmic in the sense that given the initial data one can compute the scalar quantity by algebraic and differential manipulations, being thus suitable for an implementation in a numerical code. The scalar could also be useful in studies of the non-linear stability of the Kerr solution because it serves to measure the deviation of a vacuum initial data set from the Kerr initial data in a local and algorithmic way.

Human and murine clonal CD8+ T cell expansions arise during tuberculosis because of TCR selection

The immune system can recognize virtually any antigen, yet T cell responses against several pathogens, including Mycobacterium tuberculosis, are restricted to a limited number of immunodominant epitopes. The host factors that affect immunodominance are incompletely understood. Whether immunodominant epitopes elicit protective CD8+ T cell responses or instead act as decoys to subvert immunity and allow pathogens to establish chronic infection is unknown. Here we show that anatomically distinct human granulomas contain clonally expanded CD8+ T cells with overlapping T cell receptor (TCR) repertoires. Similarly, the murine CD8+ T cell response against M. tuberculosis is dominated by TB10.44-11-specific T cells with extreme TCRß bias. Using a retro genic model of TB10.44-11-specific CD8+ Tcells, we show that TCR dominance can arise because of competition between clonotypes driven by differences in affinity. Finally, we demonstrate that TB10.4-specific CD8+ T cells mediate protection against tuberculosis, which requires interferon-? production and TAP1-dependent antigen presentation in vivo. Our study of how immunodominance, biased TCR repertoires, and protection are inter-related, provides a new way to measure the quality of T cell immunity, which if applied to vaccine evaluation, could enhance our understanding of how to elicit protective T cell immunity.

Monovarietal extra-virgin olive oil classification: a fusion of human sensory attributes and an electronic tongue

Olive oil quality grading is traditionally assessed by human sensory evaluation of positive and negative attributes (olfactory, gustatory, and final olfactorygustatory sensations). However, it is not guaranteed that trained panelist can correctly classify monovarietal extra-virgin olive oils according to olive cultivar. In this work, the potential application of human (sensory panelists) and artificial (electronic tongue) sensory evaluation of olive oils was studied aiming to discriminate eight single-cultivar extra-virgin olive oils. Linear discriminant, partial least square discriminant, and sparse partial least square discriminant analyses were evaluated. The best predictive classification was obtained using linear discriminant analysis with simulated annealing selection algorithm. A low-level data fusion approach (18 electronic tongue signals and nine sensory attributes) enabled 100 % leave-one-out cross-validation correct classification, improving the discrimination capability of the individual use of sensor profiles or sensory attributes (70 and 57 % leave-one-out correct classifications, respectively). So, human sensory evaluation and electronic tongue analysis may be used as complementary tools allowing successful monovarietal olive oil discrimination.

Fine time scaling of purifying selection on human nonsynonymous mtDNA mutations based on the worldwide population tree and mother-child pairs

A high-resolution mtDNA phylogenetic tree allowed us to look backward in time to investigate purifying selection. Purifying selection was very strong in the last 2,500 years, continuously eliminating pathogenic mutations back until the end of the Younger Dryas (∼11,000 years ago), when a large population expansion likely relaxed selection pressure. This was preceded by a phase of stable selection until another relaxation occurred in the out-of-Africa migration. Demography and selection are closely related: expansions led to relaxation of selection and higher pathogenicity mutations significantly decreased the growth of descendants. The only detectible positive selection was the recurrence of highly pathogenic nonsynonymous mutations (m.3394T>C-m.3397A>G-m.3398T>C) at interior branches of the tree, preventing the formation of a dinucleotide STR (TATATA) in the MT-ND1 gene. At the most recent time scale in 124 mother-children transmissions, purifying selection was detectable through the loss of mtDNA variants with high predicted pathogenicity. A few haplogroup-defining sites were also heteroplasmic, agreeing with a significant propensity in 349 positions in the phylogenetic tree to revert back to the ancestral variant. This nonrandom mutation property explains the observation of heteroplasmic mutations at some haplogroup-defining sites in sequencing datasets, which may not indicate poor quality as has been claimed.

Avaliação do impacto na circulação e risco de acidente em estradas em obras

Dissertação de mestrado integrado em Engenharia Civil