A comprehensive integrative approach to investigate factors associated with preterm birth, related perinatal outcomes and its prediction using metabolomic markers

Orientador: José Guilherme CecattiTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: Introdução: O parto prematuro é uma das principais causas de morbimortalidade perinatal, neonatal e de crianças até 5 anos de idade e suas causas e fisiopatologia ainda são pouco conhecidas. Identificar quais são as mulheres de maior risco e desenvolver modelos de predição é ainda um grande desafio, potencialmente impactando nas medidas preventivas. Objetivo: Desenvolver uma abordagem abrangente com diferentes estudos e produtos relacionados aos fatores clínicos e epidemiológicos associados ao parto prematuro, seus preditores metabolômicos e respectivos desfechos perinatais. Métodos: Diferentes projetos de pesquisa e métodos foram utilizados, incluindo: duas análises secundárias de um estudo multicêntrico de corte transversal avaliando a associação do índice de massa corpórea (IMC), o ganho de peso gestacional por semana e fenótipos maternos com a ocorrência de prematuridade e desfechos maternos e perinatais; uma revisão narrativa sobre ciência ômica aplicada na área de saúde materna e perinatal, com enfoque na metabolômica; uma revisão sistemática e seu respectivo artigo de protocolo sobre a performance da metabolômica em predizer prematuridade espontânea em mulheres assintomáticas; dois artigos abordando o desenvolvimento do método e dos procedimentos técnicos para um estudo multicêntrico prospectivo para investigar parto prematuro; um estudo caso-controle aninhado a uma coorte multicêntrica internacional para identificar preditores clínicos e metabolômicos para prematuridade espontânea; dois artigos originais abordando a incidência, fatores clínicos e epidemiológicos e os desfechos maternos e perinatais associados ao parto prematuro em uma coorte multicêntrica no Brasil com gestantes nulíparas de baixo risco. Resultados: Nas análises secundárias do EMIP, observou-se que independente do IMC inicial, quanto maior o ganho de peso materno, maior a probabilidade para todos os subtipos de prematuridade, exceto para prematuridade espontânea em mulheres com IMC normal ou sobrepeso. Foram identificados três clusters de mulheres com parto prematuro, sendo um caracterizado principalmente por mulheres sem nenhuma das condições de risco, o segundo por mulheres com várias condições (cluster misto) e o terceiro por mulheres que tiveram pré-eclâmpsia, eclâmpsia, síndrome HELLP e/ou restrição de crescimento fetal. A revisão narrativa aborda os métodos e o embasamento teórico das ciências ômicas, como a genômica, transcriptômica, proteômica e metabolômica, dando enfoque especial à aplicação dessa última técnica na área de saúde materna e perinatal. A identificação e validação de marcadores pode auxiliar na predição e também no entendimento da fisiopatologia de doenças complexas como a prematuridade. A técnica de metabolômica identificou mais de 140 metabólitos nas amostras de soro de gestantes nulíparas e três destes foram significativamente associados com parto prematuro espontâneo nas amostras de Cork, Irlanda. Modelos preditores usando marcadores clínicos e metabolômicos mostraram uma área sob a curva ROC de 0,73 e 0,85 para parto prematuro abaixo de 37 e 34 semanas, respectivamente. Conclusão: O ganho de peso gestacional, um fator modificável, mostrou diferentes associações com a probabilidade de parto prematuro, a depender do IMC inicial. Possíveis investigações de risco e de prevenção devem considerar essa evidência. A utilização de critérios clínicos no rastreamento e predição do parto prematuro ainda mostra limitações. A análise por cluster, por exemplo, mostrou que um número considerável não possui nenhuma das condições pré-definidas como potencialmente associadas ao parto prematuro. A aplicação de estudos da ciência Ômica parece ser uma abordagem adequada para a identificação da etiologia e de marcadores para predição de complicações maternas e perinatais, embora ainda necessitem de sucessivas validações e evidência de reprodutibilidade. O desenvolvimento, implementação e coordenação de um estudo multicêntrico para estudar preditores e fatores associados ao parto prematuro requer recursos humanos qualificados, infraestrutura para pesquisa adequada, comprometimento institucional e envolvimento de agências de fomento e desenvolvimento de pesquisa. O modelo preditor para parto prematuro espontâneo em mulheres nulíparas mostra resultados de boa performance, entretanto requer futuras validações antes de qualquer uso clínico. É provável que os metabólitos que compõem o modelo não sejam identificados da mesma forma em outras populaçõesAbstract: Introduction: Preterm birth is the leading cause of perinatal, neonatal and under-5 year¿s morbidity and mortality. Identifying women at higher risk and developing prediction models remains a great challenge, potentially affecting preventive interventions. Objectives: To develop a comprehensive approach including diverse study designs to investigate clinical and epidemiological risk factors associated with preterm birth, its metabolomics predictors and respective perinatal outcomes. Methods: Different projects and methods were applied in this thesis, including: two secondary analysis of a multicentre cross-sectional with a nested case-control study addressing the association of maternal body mass index (BMI), gestational weight gain per week and phenotypes with the occurrence of preterm birth and maternal and perinatal outcomes; an integrative review about omics sciences applied to maternal and perinatal health, focusing on metabolomics; a systematic review and respective protocol investigating the performance of metabolomics to predict spontaneous preterm birth (sPTB) in asymptomatic women; two articles describing the methods, clinical protocol, technical procedures for the development and implementation of a multicentre prospective cohort study to investigate preterm birth and other maternal and perinatal complications; a nested case-control from a multicentre international cohort to identify clinical and metabolomics predictors for sPTB; two articles addressing incidence, clinical and epidemiological risk factors and maternal and perinatal outcomes associated with sPTB in a Brazilian multicentre cohort of low-risk nulliparous pregnant women. Results: According to the EMIP secondary analyses, the greater the rate of weight gain, the higher the predicted probability for all preterm birth subtypes regardless the initial BMI, except in normal BMI or overweight women and sPTB. Three clusters of women with preterm birth were identified; cluster one of women without any pre-defined conditions, cluster two with mixed conditions and cluster three with women who had preeclampsia, eclampsia, HELLP syndrome and/or fetal growth restriction. Maternal and perinatal outcomes did not differ between clusters. An integrative review addressed Omis Science's methods and theoretical background, as genomics, transcriptomics, proteomics and metabolomics, focusing on the application on maternal and perinatal health. Metabolomics approach has been applied to better understand the pathophysiology and to identify and validate predictors for complex diseases as preterm birth. Metabolomics technique identified more than 140 metabolites in serum samples of nulliparous pregnant women and three of them were significantly associated with sPTB in samples from Cork, Ireland. Predictive models associating metabolites and clinical markers showed an area under ROC curve of 0.73 and 0.85 for sPTB below 37 and 34 weeks, respectively. Conclusion: Gestational weight gain, a modifiable factor, showed to have different associations with the predicted probability for preterm birth, depending on the initial BMI. The use of clinical criteria in the screening of preterm birth still shows limited performance. Cluster analysis, for instance, showed that a substantial number of women does not present the predefined potential conditions associated with preterm birth. Omics science studies might be a reasonable approach to investigate the aetiology and predictive markers for maternal and perinatal complications. Metabolomic studies addressing the prediction for sPTB, preeclampsia, gestational diabetes mellitus and fetal growth restriction show promising findings, although they still require repeated validations and reproducibility. The development, implementation and management of a multicenter study to investigate factors associated with sPTB requires qualified human resources, adequate infrastructure, institutional commitment and the involvement of funding and research agencies. The predictive model for sPTB in nulliparous women showed a good performance, although further validation is required before clinical application. Possibly, reproducibility of the predictive model is limited, once metabolites comprising the model were only identified in one of the subsetDoutoradoSaúde Materna e PerinatalDoutor em Ciências da SaúdeCAPE

Poeira continental soprada pelo vento como combustível para paleoprodutividade ao longo do sudoeste do Oceano Atlântico durante o último período glacial

Glaciogenic dust has a strong relationship with global climate and ocean biogeochemical processes especially during glacial periods, being a major source of nutrients, mainly iron, that increase marine productivity. Different studies have attributed higher marine paleoproductivity along the southwestern Atlantic during the last glacial period to fluvial inputs and upwelling, but the possible influence of continental dust on that process is still unknown. This paper presents evidence suggesting that eolian-sourced glaciogenic dust favored higher ocean productivity during the last glacial, recorded in three sediment cores obtained on the lower continental slope off southern Brazil (~29°-30°S, ~47°W) at water depths between 1,514 and 2,091 m. The sampled sediments are silt-dominated terrigenous siliciclastics, but higher proportions of sand-sized biogenic carbonate (mostly foraminifer tests) at intervals corresponding to the stadials MIS 4 and 2 and parts of the interstadial MIS 3 point to intervals of increased productivity, correlated with pulses of higher deflation of dust from southern South America as recorded in the EPICA Dome C ice core in Antarctica. It is proposed that glacial climate-driven increased eolian processes transported iron-bearing dust produced by the expanded Patagonian ice sheet up to the southwestern Atlantic, fueling higher phytoplankton productivity and thus favoring the proliferation of planktonic and benthic foraminifera recorded in the cores. Eventual anthropogenically-driven reduction of tropical-sourced summer rainfall reaching southern South America, driven by equatorial ocean warming and deforestation in the Amazon region, may increase dust deflation and thus affect ocean productivity along the southwestern Atlantic in the future.A poeira glaciogênica tem forte relação com o clima global e os processos biogeoquímicos oceânicos, principalmente durante os períodos glaciais, sendo uma importante fonte de nutrientes, como o ferro, que aumentam a produtividade marinha. Diferentes estudos tenham atribuído a maior paleoprodutividade marinha ao longo do Atlântico sudoeste durante o último período glacial a aportes fluviais e ressurgência, mas a possível influência da poeira continental nesse processo ainda é desconhecida. Este artigo apresenta evidências sugerindo que a poeira glaciogênica de origem eólica favoreceu maior produtividade oceânica durante a última glaciação, registrada em três testemunhos sedimentares obtidos no talude continental inferior no sul do Brasil (~29°-30°S, ~47°W) em profundidades da lâmina d'água entre 1.514 e 2.091 m. Os sedimentos amostrados são siliciclásticos terrígenos dominados por silte, mas maiores proporções de carbonato biogênico de tamanho areia (principalmente testes de foraminíferos) em intervalos correspondentes aos estadiais MIS 4 e 2 e partes do interestadial MIS 3 indicam intervalos de maior produtividade, correlacionados com pulsos de maior deflação de poeira do sul da América do Sul, conforme registrado no testemunho de gelo antártico obtido no EPICA Domo C. Propõe-se que os processos eólicos intensificados devido ao clima glacial transportaram para o Atlântico sudoeste poeira contendo ferro produzida pela expansão do manto de gelo da Patagônia, alimentando uma maior produtividade do fitoplâncton eassim favorecendo a proliferação de foraminíferos planctônicos e bentônicos registrados nos testemunhos. A eventual redução antrópica das chuvas de verão de origem tropical que atingem o sul da América do Sul, impulsionada pelo aquecimento do oceano equatorial e pelo desmatamento na região amazônica, pode aumentar a deflação de poeira, assim afetar a produtividade do oceano ao longo do Atlântico sudoeste no futuro

Mental health treatment outcomes in a humanitarian emergency: a pilot model for the integration of mental health into primary care in Habilla, Darfur

BACKGROUND: There is no description of outcomes for patients receiving treatment for mental illnesses in humanitarian emergencies. MSF has developed a model for integration of mental health into primary care in a humanitarian emergency setting based on the capacity of community health workers, clinical officers and health counsellors under the supervision of a psychiatrist trainer. Our study aims to describe the characteristics of patients first attending mental health services and their outcomes on functionality after treatment. METHODS: A total of 114 patients received mental health care and 81 adult patients were evaluated with a simplified functionality assessment instrument at baseline, one month and 3 months after initiation of treatment. RESULTS: Most patients were diagnosed with epilepsy (47%) and psychosis (31%) and had never received treatment. In terms of follow up, 58% came for consultations at 1 month and 48% at 3 months. When comparing disability levels at baseline versus 1 month, mean disability score decreased from 9.1 (95%CI 8.1-10.2) to 7.1 (95%CI 5.9-8.2) p = 0.0001. At 1 month versus 3 months, mean score further decreased to 5.8 (95%CI 4.6-7.0) p < 0.0001. CONCLUSION: The findings suggest that there is potential to integrate mental health into primary care in humanitarian emergency contexts. Patients with severe mental illness and epilepsy are in particular need of mental health care. Different strategies for integration of mental health into primary care in humanitarian emergency settings need to be compared in terms of simplicity and feasibility

Phase-space reconstruction of an atomic chaotic system

We consider the dynamics of a single atom submitted to periodic pulses of a far-detuned standing wave generated by a high-finesse optical cavity, which is an atomic version of the well-known ``kicked rotor''. We show that the classical phase-space map can be ``reconstructed'' by monitoring the transmission of the cavity. We also studied the effect of spontaneous emission on the reconstruction, and put limits to the maximum acceptable spontaneous emission rate.Comment: 5 figures, submitted to PR

New combinations and synonymies for Neotropical species of Diaphorinae (Diptera: Dolichopodidae).

Anhand von Untersuchungen an Material von Dolichopodidae (Diptera) der Senckenberg Naturhistorischen Sammlung in Dresden werden acht neotropische Arten der Gattung Diaphorus Meigen in die Gattung Chrysotus Meigen übertragen: C. amicus (Parent), comb. n.; C. ciliatus (Becker), comb. n. (= C. superbiens (Parent), comb. n. et syn. n.); C. hamatus (Parent), comb. n.; C. vicinus (Becker), comb. n., nec Parent; C. luteipalpus (Parent), comb. n.; C. mediotinctus (Becker), comb. n.; C. propinquus (Becker), comb. n. Zusätzlich wird C. kallweiti Capellari & Amorim, nom. n. als Ersatzname für C. vicinus Parent, nec C. vicinus (Becker), comb. n. vorgeschlagen. C. diligens Parent ist ein Junior-Synonym von C. viridis Becker. Für Arten, die Syntypen in ihren Typenserien enthalten, werden Lectotyp und Paralectotypen festgelegt. Die mediotinctus-Gruppe, darunter fünf südamerikanische Arten, wird als kleiner Zweig innerhalb von Chrysotus angesehen. Ein Bestimmungsschlüssel zu diesen Arten ist vorhanden.StichwörterDiaphorus, Chrysotus, Dubius, Staatliches Museum für Tierkunde DresdenNomenklatorische Handlungenamicus (Parent, 1931) (Chrysotus), comb. n. hitherto Diaphorus amicus Parent, 1931ciliatus (Becker, 1922) (Chrysotus), comb. n. hitherto Diaphorus ciliatus Becker, 1922diligens Parent, 1931 (Chrysotus), LT; syn. n. of Chrysotus viridis Becker, 1922hamatus (Parent, 1931) (Chrysotus), comb. n. hitherto Diaphorus hamatus Parent, 1931luteipalpus (Parent, 1929) (Chrysotus), comb. n. hitherto Diaphorus luteipalpus Parent, 1929mediotinctus (Becker, 1922) (Chrysotus), LT; comb. n. hitherto Diaphorus mediotinctus Becker, 1922propinquus (Becker, 1922) (Chrysotus), LT; comb. n. hitherto Diaphorus propinquus Becker, 1922vicinus (Becker, 1922) (Chrysotus), LT; comb. n. hitherto Diaphorus propinquus Becker, 1922superbiens Parent, 1931 (Diaphorus), syn. n. of Chrysotus ciliatus (Becker, 1922)Based on examination of the Dolichopodidae (Diptera) material in the Senckenberg Naturhistorische Sammlung Dresden, eight Neotropical species of Diaphorus Meigen are herein transferred to the genus Chrysotus Meigen: C. amicus (Parent), comb. n.; C. ciliatus (Becker), comb. n. (= C. superbiens (Parent), comb. n. et syn. n.); C. hamatus (Parent), comb. n.; C. vicinus (Becker), comb. n., nec Parent; C. luteipalpus (Parent), comb. n.; C. mediotinctus (Becker), comb. n.; C. propinquus (Becker), comb. n. Additionally, C. kallweiti Capellari & Amorim, nom. n. is proposed as a replacement name for C. vicinus Parent, nec C. vicinus (Becker), comb. n., and C. diligens Parent is found to be a junior-synonym of C. viridis Becker. Lectotype and paralectotypes are designated for species with syntypes in their type-series. The mediotinctus-group is proposed within Chrysotus for a small clade including five South American species, and an identification key to the species of the group is provided.KeywordsDiaphorus, Chrysotus, Dubius, Staatliches Museum für Tierkunde DresdenNomenclatural Actsamicus (Parent, 1931) (Chrysotus), comb. n. hitherto Diaphorus amicus Parent, 1931ciliatus (Becker, 1922) (Chrysotus), comb. n. hitherto Diaphorus ciliatus Becker, 1922diligens Parent, 1931 (Chrysotus), LT; syn. n. of Chrysotus viridis Becker, 1922hamatus (Parent, 1931) (Chrysotus), comb. n. hitherto Diaphorus hamatus Parent, 1931luteipalpus (Parent, 1929) (Chrysotus), comb. n. hitherto Diaphorus luteipalpus Parent, 1929mediotinctus (Becker, 1922) (Chrysotus), LT; comb. n. hitherto Diaphorus mediotinctus Becker, 1922propinquus (Becker, 1922) (Chrysotus), LT; comb. n. hitherto Diaphorus propinquus Becker, 1922vicinus (Becker, 1922) (Chrysotus), LT; comb. n. hitherto Diaphorus propinquus Becker, 1922superbiens Parent, 1931 (Diaphorus), syn. n. of Chrysotus ciliatus (Becker, 1922

Information retrieval system using Multiwords Expressions (MWE) as descriptors

This paper aims to propose an alternative method for retrieving documents using Multiwords Expressions (MWE) extracted from a document base to be used as descriptors in search of an Information Retrieval System (IRS). In this sense, unlike methods that consider the text as a set of words, bag of words, we propose a method that takes into account the characteristics of the physical structure of the document in the extraction process of MWE. From this set of terms comparing pre-processed using an exhaustive algorithmic technique proposed by the authors with the results obtained for thirteen different measures of association statistics generated by the software Ngram Statistics Package (NSP). To perform this experiment was set up with a corpus of documents in digital format

Renal Tubular Dysfunction Linked to Tenofovir in Antiretroviral Therapy in HIV-Infected Patients

Introduction: tenofovir disoproxil fumarate (TDF) has low general toxicity and can lead to moderate reduction in glomerular filtration rate (GFR) and a larger prevalence of renal tubular dysfunction (RTD). The mechanism of RTD has been attributed to the mitocondrial lesion in the proximal tubule cells caused by the increase of the intracelular TDF concentration. Aditionaly, host´s genetic polymorphisms have been considered one of the TDF concentration increasing causes. RTD can be characterized by the deficiency in the solutes reabsorption as bicarbonate, uric acid, phosphate, glucose and low weight molecular proteins. &nbsp;Objectives: verify the prevalence of renal tubular dysfunction &nbsp;in the people living with HIV (PLWH) on TDF treatment, identify the risk factors associated and compare the 24-hours urine findings with the serum creatinine and its calculated clearance for the RTD identification. Methods: prospective case control study, performed between january 2011 to december 2015. Results: 163 patients were included in the study, in which 106 (68.4%) didn't use TDF and 57 (31.6%) used TDF. RTD occured in 8 patients that used TDF, a prevalence of 14%. The patients age was identified as significant risk factor for the development of RTD. Proteinuria and the phosphaturia were significant for the diagnosis of RTD. Conclusions: age was determined as risk factor for RTD, mainly in patients over 60 years-old. Phosphaturia and proteinuria showed the greatest diagnosis sensitivity for RTD. The serum creatinine and phosphorus concentration, the creatinine clearance and the stand alone hyperproteinuria should not be used as diagnosis predictors for RTD