Prophylactic antibiotics or G(M)-CSF for the prevention of infections and improvement of survival in cancer patients receiving myelotoxic chemotherapy.

BACKGROUND Febrile neutropenia (FN) and other infectious complications are some of the most serious treatment-related toxicities of chemotherapy for cancer, with a mortality rate of 2% to 21%. The two main types of prophylactic regimens are granulocyte (macrophage) colony-stimulating factors (G(M)-CSF) and antibiotics, frequently quinolones or cotrimoxazole. Current guidelines recommend the use of colony-stimulating factors when the risk of febrile neutropenia is above 20%, but they do not mention the use of antibiotics. However, both regimens have been shown to reduce the incidence of infections. Since no systematic review has compared the two regimens, a systematic review was undertaken. OBJECTIVES To compare the efficacy and safety of G(M)-CSF compared to antibiotics in cancer patients receiving myelotoxic chemotherapy. SEARCH METHODS We searched The Cochrane Library, MEDLINE, EMBASE, databases of ongoing trials, and conference proceedings of the American Society of Clinical Oncology and the American Society of Hematology (1980 to December 2015). We planned to include both full-text and abstract publications. Two review authors independently screened search results. SELECTION CRITERIA We included randomised controlled trials (RCTs) comparing prophylaxis with G(M)-CSF versus antibiotics for the prevention of infection in cancer patients of all ages receiving chemotherapy. All study arms had to receive identical chemotherapy regimes and other supportive care. We included full-text, abstracts, and unpublished data if sufficient information on study design, participant characteristics, interventions and outcomes was available. We excluded cross-over trials, quasi-randomised trials and post-hoc retrospective trials. DATA COLLECTION AND ANALYSIS Two review authors independently screened the results of the search strategies, extracted data, assessed risk of bias, and analysed data according to standard Cochrane methods. We did final interpretation together with an experienced clinician. MAIN RESULTS In this updated review, we included no new randomised controlled trials. We included two trials in the review, one with 40 breast cancer patients receiving high-dose chemotherapy and G-CSF compared to antibiotics, a second one evaluating 155 patients with small-cell lung cancer receiving GM-CSF or antibiotics.We judge the overall risk of bias as high in the G-CSF trial, as neither patients nor physicians were blinded and not all included patients were analysed as randomised (7 out of 40 patients). We considered the overall risk of bias in the GM-CSF to be moderate, because of the risk of performance bias (neither patients nor personnel were blinded), but low risk of selection and attrition bias.For the trial comparing G-CSF to antibiotics, all cause mortality was not reported. There was no evidence of a difference for infection-related mortality, with zero events in each arm. Microbiologically or clinically documented infections, severe infections, quality of life, and adverse events were not reported. There was no evidence of a difference in frequency of febrile neutropenia (risk ratio (RR) 1.22; 95% confidence interval (CI) 0.53 to 2.84). The quality of the evidence for the two reported outcomes, infection-related mortality and frequency of febrile neutropenia, was very low, due to the low number of patients evaluated (high imprecision) and the high risk of bias.There was no evidence of a difference in terms of median survival time in the trial comparing GM-CSF and antibiotics. Two-year survival times were 6% (0 to 12%) in both arms (high imprecision, low quality of evidence). There were four toxic deaths in the GM-CSF arm and three in the antibiotics arm (3.8%), without evidence of a difference (RR 1.32; 95% CI 0.30 to 5.69; P = 0.71; low quality of evidence). There were 28% grade III or IV infections in the GM-CSF arm and 18% in the antibiotics arm, without any evidence of a difference (RR 1.55; 95% CI 0.86 to 2.80; P = 0.15, low quality of evidence). There were 5 episodes out of 360 cycles of grade IV infections in the GM-CSF arm and 3 episodes out of 334 cycles in the cotrimoxazole arm (0.8%), with no evidence of a difference (RR 1.55; 95% CI 0.37 to 6.42; P = 0.55; low quality of evidence). There was no significant difference between the two arms for non-haematological toxicities like diarrhoea, stomatitis, infections, neurologic, respiratory, or cardiac adverse events. Grade III and IV thrombopenia occurred significantly more frequently in the GM-CSF arm (60.8%) compared to the antibiotics arm (28.9%); (RR 2.10; 95% CI 1.41 to 3.12; P = 0.0002; low quality of evidence). Neither infection-related mortality, incidence of febrile neutropenia, nor quality of life were reported in this trial. AUTHORS' CONCLUSIONS As we only found two small trials with 195 patients altogether, no conclusion for clinical practice is possible. More trials are necessary to assess the benefits and harms of G(M)-CSF compared to antibiotics for infection prevention in cancer patients receiving chemotherapy.

High prevalence of hereditary thrombotic thrombocytopenic purpura in Central Norway: from clinical observation to evidence.

BACKGROUND Hereditary thrombotic thrombocytopenic purpura (TTP) caused by ADAMTS13 mutations is a rare, but serious condition. The prevalence is unknown, but seems to be high in Norway. OBJECTIVES To identify all patients with hereditary TTP in Central Norway and to investigate the prevalence of hereditary TTP and the population frequencies of two common ADAMTS13 mutations. Patients/Methods Patients were identified in a cross-sectional study within Central Norway Health Region by means of three different search strategies. Frequencies of ADAMTS13 mutations, c.4143_4144dupA and c.3178 C>T (p.R1060W) were investigated in a population-based cohort (500 alleles) and in healthy blood donors (2104 alleles) by taking advantage of the close neighbourhood of the ADAMTS13 and ABO blood group gene loci. The observed prevalence of hereditary TTP was compared to the rates of ADAMTS13 mutation carriers in different geographical regions. RESULTS We identified 11 families with hereditary TTP in Central Norway during the 10-year study period. The prevalence of hereditary TTP in Central Norway was 16.7 x 10(-6) . The most prevalent mutation was c.4143_4144dupA, accounting for two thirds of disease causing alleles among patients and having an allelic frequency of 0.33% in the Central, 0.10% in the Western, and 0.04% in the Southeastern Norwegian population. The allelic frequency of c.3178 C>T (p.R1060W) in the population was even higher (0.3-1%), but this mutation was infrequent among patients, with no homozygous cases. CONCLUSIONS We found a high prevalence of hereditary TTP in Central Norway and an apparently different penetrance of ADAMTS13 mutations. This article is protected by copyright. All rights reserved.

Modeling Techniques for the High-Resolution Interpretation of Cryo-Electron Microscopy Reconstructions

Essential biological processes are governed by organized, dynamic interactions between multiple biomolecular systems. Complexes are thus formed to enable the biological function and get dissembled as the process is completed. Examples of such processes include the translation of the messenger RNA into protein by the ribosome, the folding of proteins by chaperonins or the entry of viruses in host cells. Understanding these fundamental processes by characterizing the molecular mechanisms that enable then, would allow the (better) design of therapies and drugs. Such molecular mechanisms may be revealed trough the structural elucidation of the biomolecular assemblies at the core of these processes. Various experimental techniques may be applied to investigate the molecular architecture of biomolecular assemblies. High-resolution techniques, such as X-ray crystallography, may solve the atomic structure of the system, but are typically constrained to biomolecules of reduced flexibility and dimensions. In particular, X-ray crystallography requires the sample to form a three dimensional (3D) crystal lattice which is technically di‑cult, if not impossible, to obtain, especially for large, dynamic systems. Often these techniques solve the structure of the different constituent components within the assembly, but encounter difficulties when investigating the entire system. On the other hand, imaging techniques, such as cryo-electron microscopy (cryo-EM), are able to depict large systems in near-native environment, without requiring the formation of crystals. The structures solved by cryo-EM cover a wide range of resolutions, from very low level of detail where only the overall shape of the system is visible, to high-resolution that approach, but not yet reach, atomic level of detail. In this dissertation, several modeling methods are introduced to either integrate cryo-EM datasets with structural data from X-ray crystallography, or to directly interpret the cryo-EM reconstruction. Such computational techniques were developed with the goal of creating an atomic model for the cryo-EM data. The low-resolution reconstructions lack the level of detail to permit a direct atomic interpretation, i.e. one cannot reliably locate the atoms or amino-acid residues within the structure obtained by cryo-EM. Thereby one needs to consider additional information, for example, structural data from other sources such as X-ray crystallography, in order to enable such a high-resolution interpretation. Modeling techniques are thus developed to integrate the structural data from the different biophysical sources, examples including the work described in the manuscript I and II of this dissertation. At intermediate and high-resolution, cryo-EM reconstructions depict consistent 3D folds such as tubular features which in general correspond to alpha-helices. Such features can be annotated and later on used to build the atomic model of the system, see manuscript III as alternative. Three manuscripts are presented as part of the PhD dissertation, each introducing a computational technique that facilitates the interpretation of cryo-EM reconstructions. The first manuscript is an application paper that describes a heuristics to generate the atomic model for the protein envelope of the Rift Valley fever virus. The second manuscript introduces the evolutionary tabu search strategies to enable the integration of multiple component atomic structures with the cryo-EM map of their assembly. Finally, the third manuscript develops further the latter technique and apply it to annotate consistent 3D patterns in intermediate-resolution cryo-EM reconstructions. The first manuscript, titled An assembly model for Rift Valley fever virus, was submitted for publication in the Journal of Molecular Biology. The cryo-EM structure of the Rift Valley fever virus was previously solved at 27Å-resolution by Dr. Freiberg and collaborators. Such reconstruction shows the overall shape of the virus envelope, yet the reduced level of detail prevents the direct atomic interpretation. High-resolution structures are not yet available for the entire virus nor for the two different component glycoproteins that form its envelope. However, homology models may be generated for these glycoproteins based on similar structures that are available at atomic resolutions. The manuscript presents the steps required to identify an atomic model of the entire virus envelope, based on the low-resolution cryo-EM map of the envelope and the homology models of the two glycoproteins. Starting with the results of the exhaustive search to place the two glycoproteins, the model is built iterative by running multiple multi-body refinements to hierarchically generate models for the different regions of the envelope. The generated atomic model is supported by prior knowledge regarding virus biology and contains valuable information about the molecular architecture of the system. It provides the basis for further investigations seeking to reveal different processes in which the virus is involved such as assembly or fusion. The second manuscript was recently published in the of Journal of Structural Biology (doi:10.1016/j.jsb.2009.12.028) under the title Evolutionary tabu search strategies for the simultaneous registration of multiple atomic structures in cryo-EM reconstructions. This manuscript introduces the evolutionary tabu search strategies applied to enable a multi-body registration. This technique is a hybrid approach that combines a genetic algorithm with a tabu search strategy to promote the proper exploration of the high-dimensional search space. Similar to the Rift Valley fever virus, it is common that the structure of a large multi-component assembly is available at low-resolution from cryo-EM, while high-resolution structures are solved for the different components but lack for the entire system. Evolutionary tabu search strategies enable the building of an atomic model for the entire system by considering simultaneously the different components. Such registration indirectly introduces spatial constrains as all components need to be placed within the assembly, enabling the proper docked in the low-resolution map of the entire assembly. Along with the method description, the manuscript covers the validation, presenting the benefit of the technique in both synthetic and experimental test cases. Such approach successfully docked multiple components up to resolutions of 40Å. The third manuscript is entitled Evolutionary Bidirectional Expansion for the Annotation of Alpha Helices in Electron Cryo-Microscopy Reconstructions and was submitted for publication in the Journal of Structural Biology. The modeling approach described in this manuscript applies the evolutionary tabu search strategies in combination with the bidirectional expansion to annotate secondary structure elements in intermediate resolution cryo-EM reconstructions. In particular, secondary structure elements such as alpha helices show consistent patterns in cryo-EM data, and are visible as rod-like patterns of high density. The evolutionary tabu search strategy is applied to identify the placement of the different alpha helices, while the bidirectional expansion characterizes their length and curvature. The manuscript presents the validation of the approach at resolutions ranging between 6 and 14Å, a level of detail where alpha helices are visible. Up to resolution of 12 Å, the method measures sensitivities between 70-100% as estimated in experimental test cases, i.e. 70-100% of the alpha-helices were correctly predicted in an automatic manner in the experimental data. The three manuscripts presented in this PhD dissertation cover different computation methods for the integration and interpretation of cryo-EM reconstructions. The methods were developed in the molecular modeling software Sculptor (http://sculptor.biomachina.org) and are available for the scientific community interested in the multi-resolution modeling of cryo-EM data. The work spans a wide range of resolution covering multi-body refinement and registration at low-resolution along with annotation of consistent patterns at high-resolution. Such methods are essential for the modeling of cryo-EM data, and may be applied in other fields where similar spatial problems are encountered, such as medical imaging.

Compositions of branched glycerol dialkyl glycerol tetraethers (GDGTs) in sediment samples from Bullenmoor peat bog, Northern Germany

Two types of intact branched glycerol dialkyl glycerol tetraethers (GDGTs) were detected in peat bog samples from Bullenmoor, Northern Germany. Glucuronosyl and glucosyl branched GDGTs comprise on average ca. 4% of the microbial intact polar lipids in the anoxic, acidic peat layer ca. 20 cm below the surface of the bog, suggesting an important ecological role for the source microorganisms. No corresponding phospholipids were detected. Notably, glycosidic branched GDGTs are 5-10 times less abundant than their intact isoprenoid counterparts derived from Archaea, while branched GDGT core lipids exceed their isoprenoid analogues by about an order of magnitude. These contrasting relationships may reflect lower standing stocks of the biomass of producers of branched GDGTs, combined with higher population growth rates relative to soil Archaea. Search strategies for the microbial producers of these conspicuous orphan lipids should benefit from the discovery of their intact polar precursors.

Seasonal migration and micro-credit in the lean period : evidence from northwest Bangladesh

This paper investigates the relationship between access to micro-credit and temporary seasonal migration, an issue which is largely ignored in the standard rural-urban migration literature. Seasonal migration due to agricultural downturns is a common phenomenon in developing countries. Using primary data from a cross-sectional household survey from the northwest part of Bangladesh, this study quantifies the factors that influence such migration decisions. Among other results, we find that network effects play a significant role in influencing the migration decision, with the presence of kinsmen at the place of destination having considerable impact. Seasonal migration is a natural choice for individual suffering periodic hardship; however the strict weekly loan repayment rules of Micro-credit Institutes can have an adverse effect on this process, reducing the ability of borrowers to react to a shock. Our result suggests that poor individuals prefer the option of not accessing the micro-credit and opt for temporal seasonal migration during the lean period. The results have numerous potential policy implications, including the design of typical micro-credit schemes.

Heterogenous match efficiency

In this paper, we show a model with one-sided endogenous match efficiency. It is assumed that schooling can enhance match efficiency, and people will choose the schooling level optimally to balance its costs and benefits of enhanced match efficiency. Assuming a financial market imperfection which limits individuals to borrow, we showed that, in equilibrium, when educational achievements can be characterised by dicohotomy (secondary vs. tertiary), tertiary education gives higher wages even it only has pure match efficiency (signalling) value with no human capital value. We also showed that relative match efficiency vis-a-vis its mean matters in wage levels.

The role of a firm's absorptive capacity and the technology transfer process in clusters: How effective are technology centres in low-tech clusters?

This paper analyses how the internal resources of small- and medium-sized enterprises determine access (learning processes) to technology centres (TCs) or industrial research institutes (innovation infrastructure) in traditional low-tech clusters. These interactions basically represent traded (market-based) transactions, which constitute important sources of knowledge in clusters. The paper addresses the role of TCs in low-tech clusters, and uses semi-structured interviews with 80 firms in a manufacturing cluster. The results point out that producer–user interactions are the most frequent; thus, the higher the sector knowledge-intensive base, the more likely the utilization of the available research infrastructure becomes. Conversely, the sectors with less knowledge-intensive structures, i.e. less absorptive capacity (AC), present weak linkages to TCs, as they frequently prefer to interact with suppliers, who act as transceivers of knowledge. Therefore, not all the firms in a cluster can fully exploit the available research infrastructure, and their AC moderates this engagement. In addition, the existence of TCs is not sufficient since the active role of a firm's search strategies to undertake interactions and conduct openness to available sources of knowledge is also needed. The study has implications for policymakers and academia.

The anatomy of urban social networks and its implications in the searchability problem

The appearance of large geolocated communication datasets has recently increased our understanding of how social networks relate to their physical space. However, many recurrently reported properties, such as the spatial clustering of network communities, have not yet been systematically tested at different scales. In this work we analyze the social network structure of over 25 million phone users from three countries at three different scales: country, provinces and cities. We consistently find that this last urban scenario presents significant differences to common knowledge about social networks. First, the emergence of a giant component in the network seems to be controlled by whether or not the network spans over the entire urban border, almost independently of the population or geographic extension of the city. Second, urban communities are much less geographically clustered than expected. These two findings shed new light on the widely-studied searchability in self-organized networks. By exhaustive simulation of decentralized search strategies we conclude that urban networks are searchable not through geographical proximity as their country-wide counterparts, but through an homophily-driven community structure.

Migration and Integration. Common Challenges and Responses from Europe and Asia

With the signing of the ASEAN Framework Agreement for the Integration of Priority Sectors (FA) in 2004, migration and integration issues gained significance on the agenda. Primarily concerned with increasing economic growth, this framework excludes the integration of low and unskilled migrant workers; instead, ASEAN efforts to address migration and integration issues have been limited to Mutual Recognition Agreements for skilled labour and professionals. After an analysis of migration policy in the region, we highlight specific barriers to the integration of labour migrants in two priority sectors – nursing, which is highly regulated by the state, and Information, Communications and Technology (ICT), which is typically selfregulated and privately run. Despite a MRA for nursing allowing registered nurses to practice in another ASEAN country under supervision of local nurses without registering with the host country’s nursing regulatory authority, in practice, there are major barriers to the free movement of nurses within ASEAN in terms of skills recognition, licensure requirements and other protectionist measures. Although regulations governing the inflow of ICT professionals are not as stringent as those for healthcare professionals, private costs associated with job search and gaining foreign employment are higher in the ICT sector, largely due to limited information on international mobility within the industry. Three sets of barriers to greater integration are discussed. First, the economic and political diversity within ASEAN makes integration more problematic than in the European Union. Second, the primary concern with value-adding economic growth means that regional agreements are focused on skilled and professional labour migration only. Third, the “ASEAN way” of doing things – via a strong emphasis on consensus and non-interference with domestic policies – often means that the FA provision for the free movement of labour is usually trumped by domestic policies that do not reflect the same desire for labour integration.

Do chimpanzees (Pan troglodytes) understand single invisible displacement?

Previous research suggests that chimpanzees understand single invisible displacement. However, this Piagetian task may be solvable through the use of simple search strategies rather than through mentally representing the past trajectory of an object. Four control conditions were thus administered to two chimpanzees in order to separate associative search strategies from performance based on mental representation. Strategies involving experimenter cue-use, search at the last or first box visited by the displacement device, and search at boxes adjacent to the displacement device were systematically controlled for. Chimpanzees showed no indications of utilizing these simple strategies, suggesting that their capacity to mentally represent single invisible displacements is comparable to that of 18-24-month-old children.

Cautionary tales in the interpretation of systematic reviews of therapy trials

This is the second in a series of articles emphasizing the cautions in the interpretation of health-care studies. Systematic reviews are presented as comprehensive, unbiased summaries of evidence and are often referred to by clinicians, guideline developers and health policy-makers. Their strengths and limitations, and how their results can be subject to bias and misinterpretation, are discussed.

The arithmetic of receiver scheduling for electronic support

In Electronic Support, it is well known that periodic search strategies for swept-frequency superheterodyne receivers (SHRs) can cause synchronisation with the radar it seeks to detect. Synchronisation occurs when the periods governing the search strategies of the SHR and radar are commensurate. The result may be that the radar is never detected. This paper considers the synchronisation problem in depth. We find that there are usually a finite number of synchronisation ratios between the radar’s scan period and the SHR’s sweep period. We develop three geometric constructions by which these ratios can be found and we relate them to the Farey series. The ratios may be used to determine the intercept time for any combination of scan and sweep period. This theory can assist the operator of an SHR in selecting a sweep period that minimises the intercept time against a number of radars in a threat emitter list.

TRANSMISSÃO GERACIONAL E A PRESENÇA DA ESCOLA NA FORMAÇÃO DA CONSCIÊNCIA AMBIENTAL Estudo exploratório de famílias que convivem em áreas de proteção aos mananciais

Este projeto de pesquisa trata sobre a influência de processos educacionais e de conscientização junto a dois grupos de famílias, em três gerações, que convivem em áreas de proteção dos mananciais da represa Billings, reservas de produção hídrica de alta importância estratégica para gestão de um ambiente e seus ecossistemas frágeis com uma acentuada necessidade preservacionista e estrutural para a manutenção de sua qualidade para as atuais e futuras gerações. A importância dos resultados obtidos pela pesquisa sobre o longo processo de conscientização destas comunidades são fundamentais para perceber o status em que se encontram, seja a partir das condições e de seu status quanto as relações da escola na formação da consciência ambiental através de observações das condições de vida no próprio habitat, pela questão da terra, da relação fundiária conquistada quanto à propriedade em que residem, pelo esgotamento sanitário, incluindo condição e destino dos dejetos e águas residuárias, origem da água para dessedentação e da gestão sobre as doenças. Além destas questões este trabalho buscou importantes relações quanto às condições das fontes hídricas e seus usos múltiplos pela comunidade local, seja para lazer e consumo de bens naturais, tipos de tratamento da poluição e contaminação ambiental, infra-estrutura e equipamentos públicos existentes como suporte sustentável a qualidade de vida dos cidadãos locais.

Managing Interval Resources in Automated Planning

In this paper RDPPLan, a model for planning with quantitative resources specified as numerical intervals, is presented. Nearly all existing models of planning with resources require to specify exact values for updating resources modified by actions execution. In other words these models cannot deal with more realistic situations in which the resources quantities are not completely known but are bounded by intervals. The RDPPlan model allow to manage domains more tailored to real world, where preconditions and effects over quantitative resources can be specified by intervals of values, in addition mixed logical/quantitative and pure numerical goals can be posed. RDPPlan is based on non directional search over a planning graph, like DPPlan, from which it derives, it uses propagation rules which have been appropriately extended to the management of resource intervals. The propagation rules extended with resources must verify invariant properties over the planning graph which have been proven by the authors and guarantee the correctness of the approach. An implementation of the RDPPlan model is described with search strategies specifically developed for interval resources.

An Adaptive Genetic Algorithm with Dynamic Population Size for Optimizing Join Queries

The problem of finding the optimal join ordering executing a query to a relational database management system is a combinatorial optimization problem, which makes deterministic exhaustive solution search unacceptable for queries with a great number of joined relations. In this work an adaptive genetic algorithm with dynamic population size is proposed for optimizing large join queries. The performance of the algorithm is compared with that of several classical non-deterministic optimization algorithms. Experiments have been performed optimizing several random queries against a randomly generated data dictionary. The proposed adaptive genetic algorithm with probabilistic selection operator outperforms in a number of test runs the canonical genetic algorithm with Elitist selection as well as two common random search strategies and proves to be a viable alternative to existing non-deterministic optimization approaches.