A Descent Method for Equality and Inequality Constrained Multiobjective Optimization Problems

In this article we propose a descent method for equality and inequality constrained multiobjective optimization problems (MOPs) which generalizes the steepest descent method for unconstrained MOPs by Fliege and Svaiter to constrained problems by using two active set strategies. Under some regularity assumptions on the problem, we show that accumulation points of our descent method satisfy a necessary condition for local Pareto optimality. Finally, we show the typical behavior of our method in a numerical example

As funções terapêuticas da atividade: um estudo comparativo em terapia ocupacional

O propósito deste estudo foi verificar as alterações ocorridas em relação a assistência em terapia ocupacional na Unidade Psiquiátrica do Hospital São Paulo, vinculada ao Departamento de Psiquiatria e Psicologia Médica da Universidade Federal de São Paulo, através da análise da aplicação de um instrumento terapêutico da terapia ocupacional, a atividade. Este estudo baseou-se em pesquisa retrospectiva nos prontuários de pacientes internadas na Unidade Psiquiátrica. A pesquisa se propôs sistematizar o registro de procedimentos de terapeutas ocupacionais e de outros profissionais em relação a atividade, no sentido de dar uma contribuição universalização de alguns aspectos do discurso da Terapia Ocupacional, sistematizando-os em categorias. Pretendeu-se verificar a aplicabilidade do instrumento terapêutico pesquisado, através da comparação dos procedimentos encontrados em dois períodos. Os procedimentos metodológicos constaram de: a.- definição dos períodos a serem pesquisados: de 1/1/1988 a 31/12/1988 e de 1/1/1994 a 31/12/1994; b- coleta de dados: foram levantados em 257 prontuários de pacientes internadas na Unidade Psiquiátrica nos períodos acima definidos, os dados sócio demográficos e todos os registros encontrados nos prontuários, sobre uso de atividade e sobre terapia Ocupacional: c- categorização dos dados sobre atividade e terapia ocupacional segundo referências empíricas e funções da atividade e posteriormente em categorias empíricas em terapia ocupacional; d- análise dos dados: através do cotejamento do material encontrados nos dois períodos em relação As categorias criadas e A literatura. A análise dos dados demonstrou que não houve alterações no perfil sócio demográfico da clientela, não se alterando também a pouca atenção da equipe frente a dados relativos a origem, ocupação e perfil econômico. Em relação a idade média das pacientes e tempo de internação a distribuição dos mesmos difere, os indices mais altos encontrados relacionam-se ao segundo período. Quanto ao instrumento terapêutico, a atividade, o estudo comparativo, permitiu identificar modificações em relação a compreensão e uso do mesmo. No primeiro período, o recurso terapêutico, atividade, relaciona-se com a proposta de ambientoterapia, isto 6, toda a utilização da atividade insere-se num movimento mais amplo, grupal, com a participação efetiva de toda a equipe, voltado à experiências sociabilizantes, com raras abordagens especificas de terapeutas ocupacionais. No segundo período a utilização da atividade enquanto instrumento terapêutico, aproxima-se dos recursos teóricos e práticos da terapia ocupacional psicodinâmica, o que permitiu enfoques mais individualizados, introduziu a questão do processo terapêutico, a utilização deste recurso como uma aborgagem eletiva, ampliou o contato das terapeutas ocupacionais com a clientela em grupos específicos de terapia ocupacional e no ambulatório de egressos. Perdeu-se neste segundo período alguns procedimentos relativos a proposta da ambientoterapia e a uniformidade da equipe frente a esta questão. Percebeu-se que, a aplicabilidade deste recurso terapêutico, nos dois períodos, baseia-se nas possíveis funções da atividade, tomadas sempre como recursos estratégicos. Nos dois períodos foi possível verificar que a aplicabilidade deste instrumento terapêutico não se relacionou a categorias diagnósticas, podendo num sentido mais amplo, ter indicação a todos as pacientes.The purpose of this study was to verify the changes occurred within the Occupational Therapy assistance in the Psychiatric Unit of Hospital São Paulo, linked to the Psychiatry and Medical Psychology Department of Universidade Federal de Sao Paulo through the analysis of the use a therapeutic means of Occupational Therapy named the activity. The study was based on retrospective research of inpatients'clinical charts. The research purpose was to sistematyze the procedures of occupational therapists and of other professionals concerning the activity in order to contribute to the generalization of certains aspects of occupational therapy practices by arranging them into categories.Our intention was to verify the applicability of the therapeutic means under analysis through the comparison of procedures found in two distinct periods. The experimental methods consisted of: a. Definition of periods to be researched: from 01/01/1988 to 31/12/1988 and from 01/01/1994 to 31/12/1994. b.Data collection: Data were collected from 257 inpatineclinical charts during the above defined periods, specifically social demographics data and all the information found in charts concerning use of the activity and occupational therapy. c. data categorization about the activity and occupational therapy according to empirical references and functions of the activity and subsequently to empirical categories in occupational therapy d.data analyses: through comparison of the material found in both periods, through created categories and in reference to the existing literature. Data analyses showed that were no changes in patients social demographics profile, as well as in team members'poor charting of data relative to the source, occupation and economical profile of impatient. Concerning the age of the patients and hospitalization period, their distribution differed with higher levels found in the second period. As for the use of the therapeutic instrument, the activity, the comparison allowed the identification of due to its application.changes. In the first period, the activity relates to the millieu therapy proposal, that is, all the activity application inserts itself in a broader movement, with the effective participation of all the members focused on socialization with rare specif interventions of occupational therapists. In the secon period, the use of the activity as a therapeutic instrument follows the theoretical and practical resource of the psychodinamic occupational therapy; that allowed more specific approaches and introduced the subject of the therapeutic process in occupational therapy. The use of this resource as a choice approach enlarged the contact of occupational therapists with patients in Occupational Therapy groups and in the out patient follow-up treatment. During this second period some procedures relating to the millieu therapy project and the unity of the team concerning this subject were lost. We have noticed that the applicability of this therapeutic resource, the activity, during both periods is based on the possible functions of the activity, always taken as strategis resources. It was possible to verify, in both periods, that the applicability of this therapeutic instrument is not related to diagnostic categories, and it that can be beneficial to all the patients.BV UNIFESP: Teses e dissertaçõe

Feasibility, drug safety, and effectiveness of etiological treatment programs for Chagas disease in Honduras, Guatemala, and Bolivia: 10-year experience of Médecins Sans Frontières

BACKGROUND: Chagas disease (American trypanosomiasis) is a zoonotic or anthropozoonotic disease caused by the parasite Trypanosoma cruzi. Predominantly affecting populations in poor areas of Latin America, medical care for this neglected disease is often lacking. Médecins Sans Frontières/Doctors Without Borders (MSF) has provided diagnostic and treatment services for Chagas disease since 1999. This report describes 10 years of field experience in four MSF programs in Honduras, Guatemala, and Bolivia, focusing on feasibility protocols, safety of drug therapy, and treatment effectiveness. METHODOLOGY: From 1999 to 2008, MSF provided free diagnosis, etiological treatment, and follow-up care for patients <18 years of age seropositive for T. cruzi in Yoro, Honduras (1999-2002); Olopa, Guatemala (2003-2006); Entre Ríos, Bolivia (2002-2006); and Sucre, Bolivia (2005-2008). Essential program components guaranteeing feasibility of implementation were information, education, and communication (IEC) at the community and family level; vector control; health staff training; screening and diagnosis; treatment and compliance, including family-based strategies for early detection of adverse events; and logistics. Chagas disease diagnosis was confirmed by testing blood samples using two different diagnostic tests. T. cruzi-positive patients were treated with benznidazole as first-line treatment, with appropriate counseling, consent, and active participation from parents or guardians for daily administration of the drug, early detection of adverse events, and treatment withdrawal, when necessary. Weekly follow-up was conducted, with adverse events recorded to assess drug safety. Evaluations of serological conversion were carried out to measure treatment effectiveness. Vector control, entomological surveillance, and health education activities were carried out in all projects with close interaction with national and regional programs. RESULTS: Total numbers of children and adolescents tested for T. cruzi in Yoro, Olopa, Entre Ríos, and Sucre were 24,471, 8,927, 7,613, and 19,400, respectively. Of these, 232 (0.9%), 124 (1.4%), 1,475 (19.4%), and 1,145 (5.9%) patients, respectively, were diagnosed as seropositive. Patients were treated with benznidazole, and early findings of seroconversion varied widely between the Central and South American programs: 87.1% and 58.1% at 18 months post-treatment in Yoro and Olopa, respectively; 5.4% by up to 60 months in Entre Ríos; and 0% at an average of 18 months in Sucre. Benznidazole-related adverse events were observed in 50.2% and 50.8% of all patients treated in Yoro and Olopa, respectively, and 25.6% and 37.9% of patients in Entre Ríos and Sucre, respectively. Most adverse events were mild and manageable. No deaths occurred in the treatment population. CONCLUSIONS: These results demonstrate the feasibility of implementing Chagas disease diagnosis and treatment programs in resource-limited settings, including remote rural areas, while addressing the limitations associated with drug-related adverse events. The variability in apparent treatment effectiveness may reflect differences in patient and parasite populations, and illustrates the limitations of current treatments and measures of efficacy. New treatments with improved safety profiles, pediatric formulations of existing and new drugs, and a faster, reliable test of cure are all urgently needed

An experimental study of executive function and social impairment in Cornelia de Lange syndrome

Background Extreme shyness and social anxiety is reported to be characteristic of adolescents and adults with Cornelia de Lange syndrome (CdLS); however, the nature of these characteristics is not well documented. In this study, we develop and apply an experimental assessment of social anxiety in a group of adolescents and adults with CdLS to determine the nature of the social difficulties and whether they are related to impairments in executive functioning. Methods A familiar and unfamiliar examiner separately engaged in socially demanding tasks comprising three experimental conditions with a group of individuals with CdLS (n = 25; % male = 44; mean age = 22.16; SD = 8.81) and a comparable group of individuals with Down syndrome (DS; n = 20; % male = 35; mean age = 24.35; SD = 5.97). Behaviours indicative of social anxiety were coded. The Behavior Rating Inventory of Executive Function-Preschool version, an informant measure of executive function, was completed by participants’ caregivers. Results Significantly less verbalisation was observed in the CdLS group than the DS group in conditions requiring the initiation of speech. In the CdLS group, impairments in verbalisation were not associated with a greater degree of intellectual disability but were significantly correlated with impairments in both planning and working memory. This association was not evident in the DS group. Conclusions Adolescents and adults with CdLS have a specific difficulty with the initiation of speech when social demands are placed upon them. This impairment in verbalisation may be underpinned by specific cognitive deficits, although further research is needed to investigate this fully

Performance deficits of NK1 receptor knockout mice in the 5 choice serial reaction time task: effects of d Amphetamine, stress and time of day.

Background The neurochemical status and hyperactivity of mice lacking functional substance P-preferring NK1 receptors (NK1R-/-) resemble abnormalities in Attention Deficit Hyperactivity Disorder (ADHD). Here we tested whether NK1R-/- mice express other core features of ADHD (impulsivity and inattentiveness) and, if so, whether they are diminished by d-amphetamine, as in ADHD. Prompted by evidence that circadian rhythms are disrupted in ADHD, we also compared the performance of mice that were trained and tested in the morning or afternoon. Methods and Results The 5-Choice Serial Reaction-Time Task (5-CSRTT) was used to evaluate the cognitive performance of NK1R-/- mice and their wildtypes. After training, animals were tested using a long (LITI) and a variable (VITI) inter-trial interval: these tests were carried out with, and without, d-amphetamine pretreatment (0.3 or 1 mg/kg i.p.). NK1R-/- mice expressed greater omissions (inattentiveness), perseveration and premature responses (impulsivity) in the 5-CSRTT. In NK1R-/- mice, perseveration in the LITI was increased by injection-stress but reduced by d-amphetamine. Omissions by NK1R-/- mice in the VITI were unaffected by d-amphetamine, but premature responses were exacerbated by this psychostimulant. Omissions in the VITI were higher, overall, in the morning than the afternoon but, in the LITI, premature responses of NK1R-/- mice were higher in the afternoon than the morning. Conclusion In addition to locomotor hyperactivity, NK1R-/- mice express inattentiveness, perseveration and impulsivity in the 5-CSRTT, thereby matching core criteria for a model of ADHD. Because d-amphetamine reduced perseveration in NK1R-/- mice, this action does not require functional NK1R. However, the lack of any improvement of omissions and premature responses in NK1R-/- mice given d-amphetamine suggests that beneficial effects of this psychostimulant in other rodent models, and ADHD patients, need functional NK1R. Finally, our results reveal experimental variables (stimulus parameters, stress and time of day) that could influence translational studies

Sexual selection protects against extinction

Reproduction through sex carries substantial costs, mainly because only half of sexual adults produce offspring. It has been theorised that these costs could be countered if sex allows sexual selection to clear the universal fitness constraint of mutation load. Under sexual selection, competition between (usually) males, and mate choice by (usually) females create important intraspecific filters for reproductive success, so that only a subset of males gains paternity. If reproductive success under sexual selection is dependent on individual condition, which depends on mutation load, then sexually selected filtering through ‘genic capture’ could offset the costs of sex because it provides genetic benefits to populations. Here, we test this theory experimentally by comparing whether populations with histories of strong versus weak sexual selection purge mutation load and resist extinction differently. After evolving replicate populations of the flour beetle Tribolium castaneum for ~7 years under conditions that differed solely in the strengths of sexual selection, we revealed mutation load using inbreeding. Lineages from populations that had previously experienced strong sexual selection were resilient to extinction and maintained fitness under inbreeding, with some families continuing to survive after 20 generations of sib × sib mating. By contrast, lineages derived from populations that experienced weak or non-existent sexual selection showed rapid fitness declines under inbreeding, and all were extinct after generation 10. Multiple mutations across the genome with individually small effects can be difficult to clear, yet sum to a significant fitness load; our findings reveal that sexual selection reduces this load, improving population viability in the face of genetic stress

Extracellular Hsp72 concentration relates to a minimum endogenous criteria during acute exercise-heat exposure

Extracellular heat-shock protein 72 (eHsp72) concentration increases during exercise-heat stress when conditions elicit physiological strain. Differences in severity of environmental and exercise stimuli have elicited varied response to stress. The present study aimed to quantify the extent of increased eHsp72 with increased exogenous heat stress, and determine related endogenous markers of strain in an exercise-heat model. Ten males cycled for 90 min at 50% O2peak in three conditions (TEMP, 20°C/63% RH; HOT, 30.2°C/51%RH; VHOT, 40.0°C/37%RH). Plasma was analysed for eHsp72 pre, immediately post and 24-h post each trial utilising a commercially available ELISA. Increased eHsp72 concentration was observed post VHOT trial (+172.4%) (P<0.05), but not TEMP (-1.9%) or HOT (+25.7%) conditions. eHsp72 returned to baseline values within 24hrs in all conditions. Changes were observed in rectal temperature (Trec), rate of Trec increase, area under the curve for Trec of 38.5°C and 39.0°C, duration Trec ≥ 38.5°C and ≥ 39.0°C, and change in muscle temperature, between VHOT, and TEMP and HOT, but not between TEMP and HOT. Each condition also elicited significantly increasing physiological strain, described by sweat rate, heart rate, physiological strain index, rating of perceived exertion and thermal sensation. Stepwise multiple regression reported rate of Trec increase and change in Trec to be predictors of increased eHsp72 concentration. Data suggests eHsp72 concentration increases once systemic temperature and sympathetic activity exceeds a minimum endogenous criteria elicited during VHOT conditions and is likely to be modulated by large, rapid changes in core temperature

FLORA: a novel method to predict protein function from structure in diverse superfamilies

Predicting protein function from structure remains an active area of interest, particularly for the structural genomics initiatives where a substantial number of structures are initially solved with little or no functional characterisation. Although global structure comparison methods can be used to transfer functional annotations, the relationship between fold and function is complex, particularly in functionally diverse superfamilies that have evolved through different secondary structure embellishments to a common structural core. The majority of prediction algorithms employ local templates built on known or predicted functional residues. Here, we present a novel method (FLORA) that automatically generates structural motifs associated with different functional sub-families (FSGs) within functionally diverse domain superfamilies. Templates are created purely on the basis of their specificity for a given FSG, and the method makes no prior prediction of functional sites, nor assumes specific physico-chemical properties of residues. FLORA is able to accurately discriminate between homologous domains with different functions and substantially outperforms (a 2–3 fold increase in coverage at low error rates) popular structure comparison methods and a leading function prediction method. We benchmark FLORA on a large data set of enzyme superfamilies from all three major protein classes (α, β, αβ) and demonstrate the functional relevance of the motifs it identifies. We also provide novel predictions of enzymatic activity for a large number of structures solved by the Protein Structure Initiative. Overall, we show that FLORA is able to effectively detect functionally similar protein domain structures by purely using patterns of structural conservation of all residues

Clonal hematopoiesis and therapy-related myeloid neoplasms following neuroblastoma treatment.

Therapy-related myeloid neoplasms (TMN) constitute one of the most challengingcomplications of cancer treatment.1 Whilst understanding of TMN pathogenesis remains fragmentary, genomic studies in adults have thus far refuted the notion that TMN simply result from cytotoxin-induced DNA damage.2–4 Analysis of the preclinical evolution of a limited number of adult TMN have retraced the majority of cases to clonal haematopoiesis (CH) that predates cytotoxic treatment and lacks the mutational footprint of genotoxic therapies.2–6 Balanced translocations, generally attributed to treatment with topoisomerase II inhibitors, are implicated in a minority of TMN.1 TMN is a leading cause of premature death in childhood cancer survivors, and affects 7-11% of children treated for high-risk neuroblastoma and sarcoma.7,8 However, the origin of pediatric TMN remains unclear. Targeted sequencing of known cancer genes detects CH in ~4% of children following cytotoxic treatment,6,9 whereas CH is vanishingly rare in young individuals in the general population.10,11 Moreover, to our knowledge, no cases of childhood TMN have been retraced to pretreatment CH. In light of these observations, we asked whether a broader driver landscape had eluded targeted CH screens in pediatric cancer patients and/or whether therapy-induced mutagenesis may be an under-recognised catalyst of CH and TMN in this patient group

Evidence for Pervasive Adaptive Protein Evolution in Wild Mice

The relative contributions of neutral and adaptive substitutions to molecular evolution has been one of the most controversial issues in evolutionary biology for more than 40 years. The analysis of within-species nucleotide polymorphism and between-species divergence data supports a widespread role for adaptive protein evolution in certain taxa. For example, estimates of the proportion of adaptive amino acid substitutions (alpha) are 50% or more in enteric bacteria and Drosophila. In contrast, recent estimates of alpha for hominids have been at most 13%. Here, we estimate alpha for protein sequences of murid rodents based on nucleotide polymorphism data from multiple genes in a population of the house mouse subspecies Mus musculus castaneus, which inhabits the ancestral range of the Mus species complex and nucleotide divergence between M. m. castaneus and M. famulus or the rat. We estimate that 57% of amino acid substitutions in murids have been driven by positive selection. Hominids, therefore, are exceptional in having low apparent levels of adaptive protein evolution. The high frequency of adaptive amino acid substitutions in wild mice is consistent with their large effective population size, leading to effective natural selection at the molecular level. Effective natural selection also manifests itself as a paucity of effectively neutral nonsynonymous mutations in M. m. castaneus compared to humans