Phenobarbital for neonatal seizures:response rate and predictors of refractoriness

Background : Phenobarbital is the first-line choice for neonatal seizures treatment, despite a response rate of approximately 45%. Failure to respond to acute anticonvulsants is associated with poor neurodevelopmental outcome, but knowledge on predictors of refractoriness is limited. Objective : To quantify response rate to phenobarbital and to establish variables predictive of its lack of efficacy. Methods : We retrospectively evaluated newborns with electrographically confirmed neonatal seizures admitted between January 1999 and December 2012 to the neonatal intensive care unit of Parma University Hospital (Italy), excluding neonates with status epilepticus. Response was categorized as complete (cessation of clinical and electrographic seizures after phenobarbital administration), partial (reduction but not cessation of electrographic seizures with the first bolus, response to the second bolus), or absent (no response after the second bolus). Multivariate analysis was used to identify independent predictors of refractoriness. Results : Out of 91 newborns receiving phenobarbital, 57 (62.6%) responded completely, 15 (16.5%) partially, and 19 (20.9%) did not respond. Seizure type (p = 0.02), background electroencephalogram (EEG; p ≤ 0.005), and neurologic examination (p ≤ 0.005) correlated with response to phenobarbital. However, EEG (p ≤ 0.02) and seizure type (p ≤ 0.001) were the only independent predictors. Conclusion : Our results suggest a prominent role of neurophysiological variables (background EEG and electrographic-only seizure type) in predicting the absence of response to phenobarbital in high-risk newborns.

More Than Words, Brand Destruction in the Online Sphere

The focus of this paper is brand destruction, however in a slightly different sense than the traditional marketing literature depicts it. The concept of brand destruction basically tends to be discussed either (1) as an accidental, counter-productive event in a campaign which leads to the ruining of the brand, or (2) an intentional act by competitors in the market, which results the same breakdown mentioned above. As this paper shows, there are other ways to consider as well, when speaking about brand destruction. An often overlooked type of brand destruction is a rather new phenomenon: destroying the brand by customers or business partners. The adequate scene for this case is the internet itself, especially different social media platforms, e. g. Facebook, Twitter, Tumblr, Instagram, etc. Also popular weblogs can play an important role in brand destruction made by customers or business partners (general cases related to social media are depicted in Lipsman – Mud – Rich – Bruich, 2012). This paper presents a couple of cases in the online field and focuses basically on online communicative activities, in which a brand’s negative properties come to discussion. Both Hungarian and foreign examples are easy to find and they all demonstrate the growing power of consumers. This observation led marketing experts to start talking about the ‘smooth seizure of power by consumers’. Whilst the critic of this concept is considered to be relevant, this paper describes the elements and methods of the ‘seizure’ – from an online social point of view. The key of handling brand destruction cases efficiently lies in the role of social media users. They are not only consumers, but the opportunity for producing online contents is in their hands as well – this fact results in the idea of ‘prosumers’. Thus customers on social media platforms must be handled as a ‘critical mass’: as civic warriors with strong weapons in their armoury. No companies are allowed to feel safe, as the slightest error may well be punished by the crowd.

Subdural electroencephalogram analysis for extracting discriminating measures in epileptogenic data

This dissertation introduces an integrated algorithm for a new application dedicated at discriminating between electrodes leading to a seizure onset and those that do not, using interictal subdural EEG data. The significance of this study is in determining among all of these channels, all containing interictal spikes, why some electrodes eventually lead to seizure while others do not. A first finding in the development process of the algorithm is that these interictal spikes had to be asynchronous and should be located in different regions of the brain, before any consequential interpretations of EEG behavioral patterns are possible. A singular merit of the proposed approach is that even when the EEG data is randomly selected (independent of the onset of seizure), we are able to classify those channels that lead to seizure from those that do not. It is also revealed that the region of ictal activity does not necessarily evolve from the tissue located at the channels that present interictal activity, as commonly believed.^ The study is also significant in terms of correlating clinical features of EEG with the patient's source of ictal activity, which is coming from a specific subset of channels that present interictal activity. The contributions of this dissertation emanate from (a) the choice made on the discriminating parameters used in the implementation, (b) the unique feature space that was used to optimize the delineation process of these two type of electrodes, (c) the development of back-propagation neural network that automated the decision making process, and (d) the establishment of mathematical functions that elicited the reasons for this delineation process. ^

A research platform for artificial neural networks with applications in pediatric epilepsy

This dissertation established a state-of-the-art programming tool for designing and training artificial neural networks (ANNs) and showed its applicability to brain research. The developed tool, called NeuralStudio, allows users without programming skills to conduct studies based on ANNs in a powerful and very user friendly interface. A series of unique features has been implemented in NeuralStudio, such as ROC analysis, cross-validation, network averaging, topology optimization, and optimization of the activation function’s slopes. It also included a Support Vector Machines module for comparison purposes. Once the tool was fully developed, it was applied to two studies in brain research. In the first study, the goal was to create and train an ANN to detect epileptic seizures from subdural EEG. This analysis involved extracting features from the spectral power in the gamma frequencies. In the second application, a unique method was devised to link EEG recordings to epileptic and nonepileptic subjects. The contribution of this method consisted of developing a descriptor matrix that can be used to represent any EEG file regarding its duration and the number of electrodes. The first study showed that the inter-electrode mean of the spectral power in the gamma frequencies and its duration above a specific threshold performs better than the other frequencies in seizure detection, exhibiting an accuracy of 95.90%, a sensitivity of 92.59%, and a specificity of 96.84%. The second study yielded that Hjorth’s parameter activity is sufficient to accurately relate EEG to epileptic and non-epileptic subjects. After testing, accuracy, sensitivity and specificity of the classifier were all above 0.9667. Statistical tests measured the superiority of activity at over 99.99 % certainty. It was demonstrated that (1) the spectral power in the gamma frequencies is highly effective in locating seizures from EEG and (2) activity can be used to link EEG recordings to epileptic and non-epileptic subjects. These two studies required high computational load and could be addressed thanks to NeuralStudio. From a medical perspective, both methods proved the merits of NeuralStudio in brain research applications. For its outstanding features, NeuralStudio has been recently awarded a patent (US patent No. 7502763).

Rapid inline derivatization of primary and secondary amine containing drugs by capillary electrophoresis with laser-induced fluorescence

Despite the ongoing "war on drugs" the seizure rates for phenethylamines and their analogues have been steadily increasing over the years. The illicit manufacture of these compounds has become big business all over the world making it all the more attractive to the inexperienced "cook". However, as a result, the samples produced are more susceptible to contamination with reactionary byproducts and leftover reagents. These impurities are useful in the analysis of seized drugs as their identities can help to determine the synthetic pathway used to make these drugs and thus, the provenance of these analytes. In the present work two fluorescent dyes, 4-fluoro-7-nitrobenzofurazan and 5-(4,6-dichlorotriazinyl)aminofluorescein, were used to label several phenethylamine analogues for electrophoretic separation with laser-induced fluorescence detection. The large scale to which law enforcement is encountering these compounds has the potential to create a tremendous backlog. In order to combat this, a rapid, sensitive method capable of full automation is required. Through the utilization of the inline derivatization method developed whereby analytes are labeled within the capillary efficiently in a minimum span of time, this can be achieved. The derivatization and separation parameters were optimized on the basis of a variety of experimentally determined factors in order to give highly resolved peaks in the fluorescence spectrum with limits of detection in the low µg/mL range.

A Research Platform for Artificial Neural Networks with Applications in Pediatric Epilepsy

This dissertation established a state-of-the-art programming tool for designing and training artificial neural networks (ANNs) and showed its applicability to brain research. The developed tool, called NeuralStudio, allows users without programming skills to conduct studies based on ANNs in a powerful and very user friendly interface. A series of unique features has been implemented in NeuralStudio, such as ROC analysis, cross-validation, network averaging, topology optimization, and optimization of the activation function’s slopes. It also included a Support Vector Machines module for comparison purposes. Once the tool was fully developed, it was applied to two studies in brain research. In the first study, the goal was to create and train an ANN to detect epileptic seizures from subdural EEG. This analysis involved extracting features from the spectral power in the gamma frequencies. In the second application, a unique method was devised to link EEG recordings to epileptic and non-epileptic subjects. The contribution of this method consisted of developing a descriptor matrix that can be used to represent any EEG file regarding its duration and the number of electrodes. The first study showed that the inter-electrode mean of the spectral power in the gamma frequencies and its duration above a specific threshold performs better than the other frequencies in seizure detection, exhibiting an accuracy of 95.90%, a sensitivity of 92.59%, and a specificity of 96.84%. The second study yielded that Hjorth’s parameter activity is sufficient to accurately relate EEG to epileptic and non-epileptic subjects. After testing, accuracy, sensitivity and specificity of the classifier were all above 0.9667. Statistical tests measured the superiority of activity at over 99.99 % certainty. It was demonstrated that 1) the spectral power in the gamma frequencies is highly effective in locating seizures from EEG and 2) activity can be used to link EEG recordings to epileptic and non-epileptic subjects. These two studies required high computational load and could be addressed thanks to NeuralStudio. From a medical perspective, both methods proved the merits of NeuralStudio in brain research applications. For its outstanding features, NeuralStudio has been recently awarded a patent (US patent No. 7502763).

A saúde do trabalhador na atenção básica: concepções e práticas dos enfermeiros

This study aims to analyze concepts and practices developed by nurses in occupational health in primary care, and it is justified by the need to expand knowledge of this thematic area. This is an analytical qualitative study carried out in primary care units of health districts of the city of Natal-RN, in one health unit in each neighborhood. Data collection was held from August to October 2014, through semistructured interviews, in the following order: Selection of respondents and scheduling of interview; interviews and application of data collection instrument in order to trace socio-demographic profile of the target population; transcription of interviews; categorization of information and analysis in light of hermeneutic-dialectic. The concept of Occupational Health reported by subjects investigated, although simplified with respect to specificities of workers, was revealed with a wide dimension, with perspective of workers’ approach in their physical, mental and social context, suggesting a good seizure according to the expanded concept of health. Furthermore, it was possible to affirm the recognition of an incipient performance of primary care nurses on Occupational Health, whose performance was appointed as defective. In general, some specific actions of Occupational Health, carried out in health facilities, were cited. Other activities showed up to be routine, being held by a minority of professionals aware of the importance and need to reach these users, in order to engage them in the routine of the health unit. Most professionals reported not having approached Occupational Health during undergraduate nursing, highlighting a lack in theoretical and practical aspects of the area

Pediatric CNS pathophysiology

Research in pediatric central nervous system pathophysiology is focused around three primary goals: identification of neurodevelopmental disorders, understanding the differences in brain development which underlie these disorders, and improving treatment for these young children. Autism spectrum disorders (ASDs) are a complex set of disorders which are characterized by difficulties in language and social interactions. These behavioral measures are highly variable and a number of underlying causes can generate similar behavioral effects. Therefore, it is important to identify neurophysiological markers to better identify and characterize these disorders. Recent ASD findings using MEG show atypical latency and amplitude responses and poor cortical connectivity in children with ASDs across the cognitive spectrum from basic auditory processing, multisensory integration, to face and semantic processing. These results further support the view that ASDs are a complex neurologically-based disorder. On the other hand, the cause of Down syndrome is well understood as originating from a partial or full replication of chromosome 21. However, the cognitive and neurological consequences of this chromosomal abnormality are not yet well understood. Using a simple observation and motor execution task, poor functional connectivity in sensory-motor areas, particularly in the gamma band range, has been identified in children with Down syndrome and is consistent with behavioral deficits in the sensory-motor realm. Additional studies are needed to better understand whether targeted identification of these abnormalities can facilitate treatment in this disorder. Finally, while epilepsy can be reliably diagnosed, seizure control is still limited in many cases where the seizure onset zone is not readily apparent. Advances in pre-surgical evaluation and intra-operative co-registration will be described. These studies describing pediatric CNS pathophysiology will be discussed. © Springer-Verlag 2010.

Functional Evaluation of Causal Mutations Identified in Human Genetic Studies

Human genetics has been experiencing a wave of genetic discoveries thanks to the development of several technologies, such as genome-wide association studies (GWAS), whole-exome sequencing, and whole genome sequencing. Despite the massive genetic discoveries of new variants associated with human diseases, several key challenges emerge following the genetic discovery. GWAS is known to be good at identifying the locus associated with the patient phenotype. However, the actually causal variants responsible for the phenotype are often elusive. Another challenge in human genetics is that even the causal mutations are already known, the underlying biological effect might remain largely ambiguous. Functional evaluation plays a key role to solve these key challenges in human genetics both to identify causal variants responsible for the phenotype, and to further develop the biological insights from the disease-causing mutations.

We adopted various methods to characterize the effects of variants identified in human genetic studies, including patient genetic and phenotypic data, RNA chemistry, molecular biology, virology, and multi-electrode array and primary neuronal culture systems. Chapter 1 is a broader introduction for the motivation and challenges for functional evaluation in human genetic studies, and the background of several genetics discoveries, such as hepatitis C treatment response, in which we performed functional characterization.

Chapter 2 focuses on the characterization of causal variants following the GWAS study for hepatitis C treatment response. We characterized a non-coding SNP (rs4803217) of IL28B (IFNL3) in high linkage disequilibrium (LD) with the discovery SNP identified in the GWAS. In this chapter, we used inter-disciplinary approaches to characterize rs4803217 on RNA structure, disease association, and protein translation.

Chapter 3 describes another avenue of functional characterization following GWAS focusing on the novel transcripts and proteins identified near the IL28B (IFNL3) locus. It has been recently speculated that this novel protein, which was named IFNL4, may affect the HCV treatment response and clearance. In this chapter, we used molecular biology, virology, and patient genetic and phenotypic data to further characterize and understand the biology of IFNL4. The efforts in chapter 2 and 3 provided new insights to the candidate causal variant(s) responsible for the GWAS for HCV treatment response, however, more evidence is still required to make claims for the exact causal roles of these variants for the GWAS association.

Chapter 4 aims to characterize a mutation already known to cause a disease (seizure) in a mouse model. We demonstrate the potential use of multi-electrode array (MEA) system for the functional characterization and drug testing on mutations found in neurological diseases, such as seizure. Functional characterization in neurological diseases is relatively challenging and available systematic tools are relatively limited. This chapter shows an exploratory research and example to establish a system for the broader use for functional characterization and translational opportunities for mutations found in neurological diseases.

Overall, this dissertation spans a range of challenges of functional evaluations in human genetics. It is expected that the functional characterization to understand human mutations will become more central in human genetics, because there are still many biological questions remaining to be answered after the explosion of human genetic discoveries. The recent advance in several technologies, including genome editing and pluripotent stem cells, is also expected to make new tools available for functional studies in human diseases.

Impurity profiling and synthesis of precursors to the hallucinogenic amphetamine DOB

DOB (4‐bromo‐2,5‐dimethoxyamphetamine) is a newly emerging hallucinogenic amphetamine that sparked serious health warnings in Ireland, following its first seizure back in 2003. Known more commonly as “snowball”, this drug is highly potent and may be used as a substitute to ecstasy (MDMA) and lysergic acid diethylamide (LSD). To date, the work carried out on the impurity profiling of DOB is limited in comparison to amphetamine, methamphetamine and MDMA. In this work, the impurity profile of 4‐bromo‐2,5‐dimethoxyphenyl‐2‐propanone (4‐Br‐2,5‐P2P) is explored. This ketone is a direct precursor to DOB. Its more versatile non‐bromo analogue, 2,5‐ dimethoxyphenyl‐2‐propanone (2,5‐P2P) is also examined, as in addition to DOB, it may be used in the synthesis of a range of several other hallucinogenic amphetamines. A number of different routes to both 2,5‐P2P and 4‐Br‐2,5‐P2P were investigated. For each of these routes, the impurities produced were carefully isolated. Following isolation, the impurities were fully characterised (by 1H‐NMR/13C‐NMR spectroscopy, IR, MS), in order to aid structure elucidation. Compounds not easily resolved by flash column chromatography were analysed by LC‐MS and/or independently synthesised for the purpose of attaining reference standards. Adaptation of the well‐known ‘phenylacetic acid route’ to synthesis of both 2,5‐P2P and 4‐Br‐2,5‐P2P, was found to provide low yields of the expected ketone products. Four impurities were isolated during the preparation of both ketones. The yield of one of these impurities (possessing a dibenzylketone core), was greatly influenced by the amount of acetic anhydride reagent used during the reaction. Having carried out the reaction with several different equivalents of acetic anhydride, it was found that formation of the ‘dibenzylketone’ could not be eliminated. This may increase its likelihood of being detected in the final drug product. The ‘Darzens route’, having very recently emerged as a synthetic route to amphetamine and MDMA precursors, was discovered to be a viable route for manufacture of 2,5‐P2P and 4‐Br‐2,5‐P2P. Despite execution of the reaction being more tedious, the route provides superior yields (≈50–60%) to those achieved using the ‘phenylacetic acid route’ (≈35–38%). Incorporation of a bromine atom (at the aromatic 4‐position) is required at some stage during synthesis of DOB. The bromination of many intermediates/starting materials was therefore also examined in detail. Bromination of the acid starting material 2,5‐dimethoxyphenylacetic acid (2,5‐PAA) was found to be clean and high yielding. This was in stark contrast to the bromination of the benzaldehyde starting material, the ketone precursor 2,5‐P2P and the dibenzylketone‐based impurity. Numerous brominated products were isolated from each of these reactions, many of which were novel compounds, and previously unreported as impurities in the literature. The unpredictable/nondescript nature of these brominations is likely to have a significant impact on the impurity profile of illicitly produced DOB.

Dynamic classifiers for neonatal brain monitoring

Brain injury due to lack of oxygen or impaired blood flow around the time of birth, may cause long term neurological dysfunction or death in severe cases. The treatments need to be initiated as soon as possible and tailored according to the nature of the injury to achieve best outcomes. The Electroencephalogram (EEG) currently provides the best insight into neurological activities. However, its interpretation presents formidable challenge for the neurophsiologists. Moreover, such expertise is not widely available particularly around the clock in a typical busy Neonatal Intensive Care Unit (NICU). Therefore, an automated computerized system for detecting and grading the severity of brain injuries could be of great help for medical staff to diagnose and then initiate on-time treatments. In this study, automated systems for detection of neonatal seizures and grading the severity of Hypoxic-Ischemic Encephalopathy (HIE) using EEG and Heart Rate (HR) signals are presented. It is well known that there is a lot of contextual and temporal information present in the EEG and HR signals if examined at longer time scale. The systems developed in the past, exploited this information either at very early stage of the system without any intelligent block or at very later stage where presence of such information is much reduced. This work has particularly focused on the development of a system that can incorporate the contextual information at the middle (classifier) level. This is achieved by using dynamic classifiers that are able to process the sequences of feature vectors rather than only one feature vector at a time.

A dinâmica do campo organizacional e a adoção de estratégias na carcinicultura do RN

This study aimed to understand the relations inside the organizational Structuring of the shrimp Field - the shrimp agribusiness placed in Rio Grande do Norte State and the strategies adopted by its players. In order to achieve that, semi-structured interviews were conducted with samples of various organizations that act in the field, like cooperatives, associations, enterprises of different links in the chain, universities and state agencies. The interviews built up a large collection of secondary data. As expected, it was found that Field and strategies are related in a recursive way: the configuration of the field, a result from his own biography, has decisively influenced the strategies adopted by its actors, who, as evolved, eventually caused further changes in the Field and outlines the plot of this area of interaction. It was found, for example, that after thirty-five years of its genesis, the Field of shrimp RN still has a low level of institutionalization, which helps to understand the difficulty of its actors in establish strategies based on partnerships and cooperation; Those actions are so necessary to alleviate the effects of the crisis that devastated the industry since 2004. It was noticed, however, that this level of institutionalization is a result, beside other factors, the very strategies that field actors are embracing along its trajectory. Thus, this study hopes to have contributed both to the necessary revival of the agency to institutional phenomenon, cited by Oliver (1991), and to meet the need for more contextualized approaches to organizational strategies (MINTZBERG, 1987; CLEGG, 2004; WHITTINGTON, 2004; 2006; SARAIVA and CARRIERI, 2007). It is an exploratory study that needs further investigation in order to get deep in this research. In this sense, others methodologies and theoretical perspectives need to be used, especially those relating to the seizure of the disputes and discursive aspects of power, as salient in the field investigated. Moreover, in terms of "practical actions", it is suggested that, as soon as possible, the main actors of the field (cooperatives, companies, and state entities in class) can be able of agglutinate efforts to support the shrimp field in RN State and make sustainable actions, which can promote the development of activity in a global view. On the apse of shrimp activities everybody wanted to be the "father of the child," Now, someone has to "stay in the goal."

O valor do empreendedorismo na Universidade

O objeto central deste estudo são os significados que os alunos do curso de Administração atribuem aos valores do ensino do Empreendedorismo em sua formação acadêmica, delineado à luz dos pressupostos teórico-metodológicos da psicologia de Vygotsky e alicerçado com a pesquisa efetuada durante o ano de 2015, com um cariz qualitativo. A proposta metodológica da pesquisa contempla a triangulação de procedimentos, a saber: questionários, entrevistas e grupo focal. Participaram do trabalho de entrevista e grupo focal um total de 14 alunos somados aos 109 que integraram o procedimento metodológico em forma de questionário. Todos os alunos participantes cursavam, no momento da pesquisa, o sexto e sétimos períodos do curso de administração. Como ponto de partida dos núcleos de significação deste trabalho, procurou-se verificar as possíveis formas de apreensão do conhecimento acadêmico com vistas à ação empreendedora dos sujeitos pesquisados, buscando estudá-los nas seguintes dimensões: quem são os alunos universitários; como é a sua vida acadêmica; de que maneira os estudantes constroem e significam a importância do conhecimento empreendedor para a construção de seu caminho na busca de seus objetivos e sonhos. O estudo permite defender a seguinte tese central: os significados atribuídos pelos alunos do Curso de Administração à sua formação empreendedora. A apreensão do conhecimento é significada com responsabilidade, compromisso, persistência e confiança em si mesmos. São pessoas que possuem esperança de ter um futuro promissor, de realizar seus objetivos, coroados de fortes sentimentos advindos de suas vivências, compreendendo o Empreendedorismo como forma de desenvolvimento social. A partir dessa tese central, outra se destacou por ter sido considerada a base de todo o processo empreendedor delineado pelos sujeitos pesquisados: a família. Esta instituição central declarou-se ser a base geradora para a sua motivação na construção de seus caminhos, rumo à conquista dos sonhos e anseios desejados. É ponto de destaque e elo firme em suprir uma das características do empreendedor, que é ter um “modelo”, aquele que o inspira, que o influencia para seguir em frente em sua meta. Outra tese que emergiu neste estudo foi o distanciamento da instituição de ensino das empresas, fato uníssono nas falas dos sujeitos pesquisados. A carência da prática no curso de administração foi sentida e evocada como um óbice a ser resolvido.

Medidas cautelares de embargo de bienes estatales en procesos ejecutivos ante la jurisdicción contencioso-administrativa

A partir del principio general de inembargabilidad de bienes del Estado, el contenido de este documento incursiona en el tema de las excepciones al mismo legalmente contempladas, a efectos de verificar la aplicabilidad de la medida cautelar de embargo sobre tales bienes en los casos procedentes, cuando los particulares adelantan procesos ejecutivos ante la jurisdicción contenciosoadministrativa, en procura de defender sus intereses y del pago de dineros a cargo del Estado como consecuencia de contratos, sentencias, acreencias laborales, laudos arbitrales u otro tipo de documento eficaz. El propósito fue establecer claramente la normatividad aplicable en este tipo de eventos, aportando de este modo respuesta objetiva y confiable frente a la problemática generada tanto por las distintas posiciones en torno al tema adoptadas por el legislador, como igualmente por dificultades para clasificar los bienes y rentas estatales en orden a determinar su carácter y la posibilidad real de su embargo. Todo ello, además, con el referente de pronunciamientos jurisprudenciales adoptados como soporte conceptual básico puesto que desde esta perspectiva dan cuenta de una línea coincidente de pensamiento por parte de los altos organismos pertinentes.

A história da ciência como subsídio para a construção do conhecimento do conceito da dupla hélice

Acompanha: Dupla-hélice: a construção de um conhecimento