Search Dynamics on Multimodal Multiobjective Problems.

We continue recent work on the definition of multimodality in multiobjective optimization (MO) and the introduction of a test bed for multimodal MO problems. This goes beyond well-known diversity maintenance approaches but instead focuses on the landscape topology induced by the objective functions. More general multimodal MO problems are considered by allowing ellipsoid contours for single-objective subproblems. An experimental analysis compares two MO algorithms, one that explicitly relies on hypervolume gradient approximation, and one that is based on local search, both on a selection of generated example problems. We do not focus on performance but on the interaction induced by the problems and algorithms, which can be described by means of specific characteristics explicitly designed for the multimodal MO setting. Furthermore, we widen the scope of our analysis by additionally applying visualization techniques in the decision space. This strengthens and extends the foundations for Exploratory Landscape Analysis (ELA) in MO.

Analyzing the BBOB results by means of benchmarking concepts.

We present methods to answer two basic questions that arise when benchmarking optimization algorithms. The first one is: which algorithm is the "best" one? and the second one is: which algorithm should I use for my real-world problem? Both are connected and neither is easy to answer. We present a theoretical framework for designing and analyzing the raw data of such benchmark experiments. This represents a first step in answering the aforementioned questions. The 2009 and 2010 BBOB benchmark results are analyzed by means of this framework and we derive insight regarding the answers to the two questions. Furthermore, we discuss how to properly aggregate rankings from algorithm evaluations on individual problems into a consensus, its theoretical background and which common pitfalls should be avoided. Finally, we address the grouping of test problems into sets with similar optimizer rankings and investigate whether these are reflected by already proposed test problem characteristics, finding that this is not always the case.

Genomic and epigenomic co-evolution in follicular lymphomas.

Follicular lymphoma (FL) with a t(14;18) is a B-cell neoplasm clinically characterized by multiple recurrencies. In order to investigate the clonal evolution of this lymphoma, we studied paired primary and relapse tumor samples from 33 patients with recurrent non-transformed t(14;18)-positive FL. We reconstructed phylogenetic trees of the evolution by taking advantage of the activation-induced cytidine deaminase (AID)-mediated somatic hypermutation (SHM) active in the germinal center reaction using sequences of the clonal VHDHJH rearrangements of the immunoglobulin heavy chain (IGH) locus. Mutational analysis of the IGH locus showed evidence for ongoing somatic mutation and for counter-selection of mutations affecting the BCR conformation during tumor evolution. We further followed evolutionary divergence by targeted sequencing of gene loci affected by aberrant SHM as well as of known driver genes of lymphomagenesis, and by array-based genome-wide chromosomal imbalance and DNA methylation analysis. We observed a wide spectrum of evolutionary patterns ranging from almost no evolution to divergent evolution within recurrent non-transformed t(14;18) FL. Remarkably, we observed a correlation of the magnitude of evolutionary divergence across all genetic and epigenetic levels suggesting co-evolution. The distribution of coding mutations in driver genes and the correlation with SHM suggest CREBBP and AID to be potential modifiers of genetic and epigenetic co-evolution in FL.

Next-generation sequencing and real-time quantitative PCR for minimal residual disease detection in B-cell disorders.

In this study, we compared immunoglobulin heavy-chain-gene-based minimal residual disease (MRD) detection by real-time quantitative PCR (RQ-PCR) and next-generation sequencing (NGS) to assess whether NGS could overcome some limitations of RQ-PCR and further increase sensitivity, specificity, accuracy and reproducibility. In total, 378 samples from 55 patients with acute lymphoblastic leukemia (ALL), mantle cell lymphoma (MCL) or multiple myeloma (MM) were investigated for clonotype identification, clonotype identity and comparability of MRD results. Forty-five clonotypes were identified by RQ-PCR and 49 by NGS. Clonotypes identified by both tools were identical or >97% homologous in 96% of cases. Both tools were able to routinely reach a sensitivity level of 1 × E-05. A good correlation of MRD results was observed (R=0.791, P<0.001), with excellent concordance in 79.6% of cases. Few discordant cases were observed across all disease subtypes. NGS showed at least the same level of sensitivity as allele-specific oligonucleotides-PCR, without the need for patient-specific reagents. We conclude that NGS is an effective tool for MRD monitoring in ALL, MCL and MM. Prospective comparative analysis of unselected cases is required to validate the clinical impact of NGS-based MRD assessment.

Resampling methods for meta-model validation with recommendations for evolutionary computation.

Meta-modeling has become a crucial tool in solving expensive optimization problems. Much of the work in the past has focused on finding a good regression method to model the fitness function. Examples include classical linear regression, splines, neural networks, Kriging and support vector regression. This paper specifically draws attention to the fact that assessing model accuracy is a crucial aspect in the meta-modeling framework. Resampling strategies such as cross-validation, subsampling, bootstrapping, and nested resampling are prominent methods for model validation and are systematically discussed with respect to possible pitfalls, shortcomings, and specific features. A survey of meta-modeling techniques within evolutionary optimization is provided. In addition, practical examples illustrating some of the pitfalls associated with model selection and performance assessment are presented. Finally, recommendations are given for choosing a model validation technique for a particular setting.

Statistical methods for convergence detection of multi-objective evolutionary algorithms.

In this paper, two approaches for estimating the generation in which a multi-objective evolutionary algorithm (MOEA) shows statistically significant signs of convergence are introduced. A set-based perspective is taken where convergence is measured by performance indicators. The proposed techniques fulfill the requirements of proper statistical assessment on the one hand and efficient optimisation for real-world problems on the other hand. The first approach accounts for the stochastic nature of the MOEA by repeating the optimisation runs for increasing generation numbers and analysing the performance indicators using statistical tools. This technique results in a very robust offline procedure. Moreover, an online convergence detection method is introduced as well. This method automatically stops the MOEA when either the variance of the performance indicators falls below a specified threshold or a stagnation of their overall trend is detected. Both methods are analysed and compared for two MOEA and on different classes of benchmark functions. It is shown that the methods successfully operate on all stated problems needing less function evaluations while preserving good approximation quality at the same time.

Mutation of an IKK phosphorylation site within the transactivation domain of REL in two patients with B-cell lymphoma enhances REL's in vitro transforming activity.

The human c-rel proto-oncogene (REL) encodes a subunit of the nuclear factor-kappaB (NF-kappaB) transcription factor. In this report, we have identified an identical point mutation in two human B-cell lymphomas (follicular (FL) and mediastinal) that changes serine (Ser)525 (TCA) to proline (Pro) (CCA) within the REL transactivation domain. This mutation was not identified in a similarly sized cohort of healthy individuals. In the mediastinal B-cell lymphoma, the mutation in REL is of germ-line origin. In both tumors, the S525P mutant allele is over-represented. REL-S525P shows enhanced in vitro transforming activity in chicken spleen cells. REL-S525P has a reduced ability to activate the human manganese superoxide dismutase (MnSOD) promoter in A293 cells; however, the MnSOD protein shows increased expression in REL-S525P-transformed chicken spleen cells as compared to wild-type REL-transformed cells. Ser525 is a site for phosphorylation by IkappaB kinase (IKK) in vitro. The S525P mutation reduces IKKalpha- and tumor necrosis factor (TNF)alpha-stimulated transactivation by a GAL4-REL protein. Furthermore, REL-S525P-transformed chicken spleen cells are more resistant to TNFalpha-induced cell death than cells transformed by wild-type REL. These results suggest that the S525P mutation contributes to the development of human B-cell lymphomas by affecting an IKKalpha-regulated transactivation activity of REL.

Production of recombinant proteins in Chinese hamster ovary cells using a protein-free cell culture medium.

The growth-factor prototrophic Chinese hamster ovary (CHO) SSF3 cell line was previously adapted for growth in serum-free media. Here we present a newly designed medium which allows these cells to grow in the absence of any exogenously added growth factors. To investigate the capacity of CHO SSF3 cells for the efficient production of recombinant proteins in protein-free media, expression plasmids containing either a human single chain urokinase-type plasminogen activator (uPA)-encoding cDNA or a humanized immunoglobulin G (IgG) kappa light chain cDNA were introduced by transfection. The tryptophan synthase (trpB) gene of Escherichia coli was used as a dominantly acting selection marker allowing the cells to survive in a medium containing indole in place of tryptophan. Some of the clones obtained exhibited a stable uPA expression over a period of several months under selective conditions and the yields were up to 74 mg of uPA/l in a bioreactor and the productivity was around 40 mg/day per 10(9) cells. The yields of IgG light chains were up to 118 mg/l and the productivity was in the order of 56 mg/day per 10(9) cells in a bioreactor. These results demonstrate the potential of CHO SSF3 cells for the efficient production of recombinant proteins under protein-free conditions.

A novel approach to the specification of in-vitro dissolution boundaries based on regulatory requirements for bioequivalence.

Although bioequivalence between products has gained considerable importance over the last few years, the concept has not yet been transferred to "within product bioequivalence", i.e. "batch-to-batch bioequivalence". Two different formulations of an active substance are considered bioequivalent if they differ by not more than 20% in rate and extent of absorption. This regulatory requirement should also be satisfied for two different batches of the same formulation ("within product bioequivalence"). Euphylong pellets appear to be the first sustained-release theophylline formulation for which data on the "within product bioequivalence" can be presented. The upper and lower limits of the in-vitro dissolution were specified so that even the most extreme batches within these specifications, which normally do not occur among production batches, are bioequivalent. This novel procedure requires that the in-vitro method used is suitable to detect in-vivo differences. Furthermore, it should be able to predict the in-vivo absorption kinetics on the basis of in-vitro data, at least insofar as a discriminatory ranking is concerned. It has been shown how this approach has lead to the in-vitro specifications of Euphylong pellets and how specially manufactured experimental batches representing the upper and lower specification limits were tested for bioequivalence. Finally, it is shown that a typical production batch conforms well with the specification limits and does not reach the extremes of the experimental batches which were specially manufactured for the purpose of this study.

Theophylline therapeutic drug monitoring in the case of a new sustained-release pellet formulation for once-daily evening administration.

In view of the large interindividual differences in theophylline clearance and the narrow therapeutic range it is essential to individualize the theophylline dose. In order to do so, estimation of minimum and maximum serum theophylline concentrations during one dosing interval from one or two blood samples is desirable, particularly in the case of once-daily administration. Whereas the minimum (trough) concentration can be readily estimated from the pre-dose level, the maximum (peak) concentration occurs at night. For Euphylong, a new sustained-release theophylline pellet formulation, administered once-daily in the evening, for example between 7 p.m. and 8 p.m., the nocturnal maximum concentration can be calculated as 110-120% of the serum theophylline concentration determined from a blood sample taken in the early morning, for example between 7 a.m. and 8 a.m. This procedure works not only for mean data but also on an individual basis. The procedure is based on the extended nocturnal plateau profile of Euphylong with its high reproducibility and cannot be transferred to other formulations.

Theophylline steady-state pharmacokinetics: recent concepts and their application in chronotherapy of reactive airway diseases.

With the introduction of sustained-release theophylline formulations for once-daily dosing or for unequally divided twice-daily dosing, comparison with conventional equally divided twice-daily dosing has been focused on nocturnal serum theophylline concentrations (STCs), plateau properties and peak-trough fluctuation. The merits of various steady-state characteristics such as nocturnal excess, plateau time, residual concentration, peak-trough fluctuation, swing and AUC fluctuation are illustrated by 15 data sets from 7 multiple-dose studies, each including either 10-12 healthy volunteers or 12-20 COPD-patients. In all of the studies, STCs were determined at least every 2 hr over a 24-hr period in steady-state. Included in the studies were 7 sustained-release theophylline formulations which were administered either once daily (in the morning or in the evening), or twice daily (either equally divided, or unequally divided with one-third of the dose being given in the morning and two-thirds in the evening.

Complicaciones quirurgicas de la fiebre tifoidea y paratifus A y B en el nino. / Surgical complications of typhoid fever and paratyphoid A and B in children

Se analizan 52 casos de complicaciones estimadas quirurgicas en 1.044 casos de fiebre tifoidea egresados del Hospital M. Arriaran entre 1970 y 1979. Fueran operados solo 13 ninos. Las complicaciones mas frecuentes fueron: la hemorragia digestiva con 21 casos y colecistitis tifica con 13 casos. La hemorragia digestiva tifica se presento entre la segunda y tercera semana de evolucion; en algunos casos fue severa, requiriendo varias transfusiones. No fue necesaria la cirugia para su curacion. La colecistitis tifica se presento habitualmente en la segunda semana, cedio generalmente con el tratamiento medico, algunas veces fue intervenida de urgencia sin sospechar una fiebre tifoidea.No existio mortalidad en nuestra casuistica, pese el agravamiento del cuadro tifico que significo la complicacion