Spontaneous intracerebral hemorrhage, the non-traumatic rupture of cerebral blood vessels, is the most devastating form of stroke. The disease is dynamic, unpredictable, and patients can worsen acutely within the first 24 hours secondary to hematoma expansion: re-bleeding of a baseline hemorrhage. Hematoma expansion is a major predictor of mortality and poor long-term outcome. This secondary analysis thesis proposes to advance the current understanding of this phenomenon through three separate research endeavors: 1) a scoping review of hematoma expansion prediction scores, 2) an independent validation of a non-contrast prediction score, and 3) an assessment and revision of the dichotomous definition of hematoma expansion used in clinical trials. These three projects will offer different contributions that will advance the science of intracerebral hemorrhage, a field where treatment options, outcome measures, and basic definitions, are all under active debate.

Submitted by KELLEN CRISTIANE DO VALE LUCIO LUCIO (kellen.lucio@gmail.com) on 2017-03-03T19:39:59Z No. of bitstreams: 1 Dissertação final kellen.pdf: 3714896 bytes, checksum: 1f584543e024419a56cafffd8ec295b7 (MD5) / Approved for entry into archive by LUIZA DE MENEZES ROMANETTO (luizamenezes@reitoria.unesp.br) on 2017-03-08T20:28:01Z (GMT) No. of bitstreams: 1 lucio_kcv_me_bot.pdf: 3714896 bytes, checksum: 1f584543e024419a56cafffd8ec295b7 (MD5) / Made available in DSpace on 2017-03-08T20:28:01Z (GMT). No. of bitstreams: 1 lucio_kcv_me_bot.pdf: 3714896 bytes, checksum: 1f584543e024419a56cafffd8ec295b7 (MD5) Previous issue date: 2017-02-03 / Introdução e Objetivo: A Retinopatia da prematuridade (ROP) é a principal causa de deficiência visual permanente na infância. A identificação precoce da forma grave da ROP pode prevenir a cegueira. O ROPScore é um sistema de pontuação desenvolvido para otimizar a triagem e calcular o risco de ROP em neonatos pré-termo. Este estudo objetivou avaliar a acurácia deste algoritmo como preditor de ROP em uma coorte brasileira. Métodos: Realizou-se um estudo coorte prospectivo de 220 neonatos pré-temo com PN ≤1500 g e / ou IG ≤ 32 semanas. O ROPScore foi aplicado na 6ª semana de vida nas 181 crianças que sobreviveram até a 45ª semana de idade gestacional corrigida. Cada criança foi classificada como Sem-ROP, ROP em qualquer estágio ou ROP grave. Curvas ROC foram utilizadas para determinar os melhores valores de sensibilidade e especificidade do escore na população estudada. Resultados: A média de PN foi de 1271,6g ± 354,6 e a IG média foi de 29,2 ± 2,26 semanas. Dos 181 prematuros estudados, 32 (17,6%) desenvolveram ROP. O melhor ponto de corte do ROPscore para sensibilidade e especificidade foi 16,0 para ROP em qualquer estágio e 16,6 para ROP grave. A área sob a curva ROC para prever ROP em qualquer estágio foi 0,937 (IC 95%: 0,888-0,986; P <0,0001), e para prever ROP grave, 0,962 (IC 95% 0,931-0,993; P <0,0001). A sensibilidade para ROP em qualquer estágio foi 87,5% e para ROP grave foi 95,4%. Utilizando o ROPscore, 130 pré-termos não precisariam ser avaliados com a mesma frequência, diminuindo em 71,8% o número total de exames necessários para detectar ROP. Conclusão: O ROPScore foi um método auxiliar útil para a triagem de ROP, otimizou os exames e teve precisão para identificar ROP grave. / Background and Objective: Retinopathy of prematurity (ROP) is the leading cause of childhood permanent visual impairment. Early identification of severe form of ROP can prevent blindness. The ROPScore is a scoring system, developed to optimize the screening and calculate risk of ROP in preterm infants. This study aimed to evaluate the accuracy of this algorithm as predictor of ROP in a Brazilian cohort. Methods: A prospective cohort of 220 preterm infants with BW ≤1500 g and/or GA ≤32 weeks was conducted. The ROPScore was applied in the 6th week of life in 181 infants that survived who survived until the 45th week of corrected gestational age. Each infant was categorized as having no-ROP, any stage ROP or severe ROP. Receivers operating characteristic (ROC) curves were used to determine the best sensitivity and specificity values of the score in the population studied. Results: Mean BW was 1271,6 g ± 354.6 and the mean GA was 29,2 ± 2,2 weeks. Of 181 studied preterm, 32 (17,6%) developed ROP. The best cutoff point for sensitivity and specificity was established as 16.0 for any stage ROP and 16.6 for severe ROP. The area under the ROC curve to predict ROP at any stage was 0,937 (95% CI: 0,888 to 0,986; P <0,0001), and to predict severe ROP, 0,962 (95% CI 0,931 to 0,993; P <0,0001). The sensitivity for any stage ROP was 87,5% and for severe ROP was 95,4%. Using ROPscore, 130 pre-terms did not need to be evaluated at the same frequency, reducing the total number of examinations required to detect ROP by 71,8%. Conclusion: The ROPScore was a useful adjunct screening tool for ROP, optimized the examinations and had accuracy for identify severe ROP.

Orientador: Eliane Chaves Jorge / Resumo: Introdução: A retinopatia da prematuridade (ROP) é uma doença vaso proliferativa multifatorial e uma das principais causas de cegueira infantil no mundo. O exame oftalmológico seriado identifica a forma grave da doença, porém pode causar estresse e instabilidade cardiorrespiratória nos neonatos prematuros. O algoritmo ROPScore, aferido na sexta semana de vida é efetivo em predizer o risco de ROP e diminuir o número de exames necessários para o diagnóstico. No entanto, nos casos em que a doença grave é precoce ou se desenvolve em neonatos mais maduros, o ROPScore seria mais efetivo se aferido antes da sexta semana de vida. Objetivo: avaliar a acurácia do ROPScore aferido na segunda semana de vida quando comparada com a da sexta semana. Métodos: Realizou-se um estudo coorte prospectivo de neonatos pré-termos com peso ao nascimento (PN) ≤1500 g e / ou idade gestacional (IG) ≤ 32 semanas. O ROPScore foi aplicado na 2ª e na 6ª semanas de vida. Curvas ROC foram utilizadas para determinar os melhores valores de sensibilidade, especificidade e seus valores preditivos positivos (VPP) e negativos (VPN) para o desenvolvimento de ROP em qualquer estágio (RQE) e ROP grave (RG). Resultados: Dos 282 RNPT, 40 (14,2%) desenvolveram ROP e 27 (9,5%) a sua forma grave. A sensibilidade do ROPScore na 2ª semana para prever ROP em qualquer estadiamento foi de 92,5% e de 92,8% na ROP grave. Na 6ª semana foi de 90% e 92,6% respectivamente. O VPN foi alto tanto na 2ª (99%) como na 6ª (98%) semanas, pa... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Background: Retinopathy of prematurity (ROP) is a multifactorial proliferative vessel disease and one of the leading causes of childhood blindness in the world. Serial ophthalmic examination identifies the severe form of the disease but may cause cardiorespiratory stress and instability in preterm infants. The ROPScore algorithm, measured in the sixth week of life, is effective in predicting ROP risk and decreasing the number of tests required for diagnosis. However, in cases where the severe disease is early or develops in more mature neonates, ROPScore would be more effective if measured before the sixth week of life. Objective: to evaluate the accuracy of ROPScore measured in the second week of life when compared to the sixth week. Methods: A prospective cohort study of preterm newborns with birth weight (BW) ≤1500 g and/or gestational age (GA) ≤ 32 weeks was performed. ROPScore was applied in the 2nd and 6th weeks of life. ROC curves were used to determine the best values of sensitivity, specificity and positive predictive values (PPV) and negative predictive value (NPV) for the development of ROP at any stage (RQE) and severe ROP (RG). Results: Of the 282 preterms, 40 (14.2%) developed ROP and 27 (9.5%) developed their severe form. The sensitivity of ROPScore at 2nd week to predict ROP at any stage was 92.5% and 92.8% at ROP. In the 6th week, it was 90% and 92.6% respectively. The NPV was high in both the second (99%) and the sixth (98%) weeks, for ROP in any stage and s... (Complete abstract click electronic access below) / Mestre

Submitted by HEITOR DO AMARAL SIMOES (heitor.simoes@unesp.br) on 2018-09-13T01:17:04Z No. of bitstreams: 1 MEPAREM - Heitor do Amaral Simoes - Avaliação do ROPScore como preditor de retinopatia da prematuridade em neonatos prematuros. Estudo Comparativo.pdf: 1887030 bytes, checksum: 2e9cfdf0558f9a8d0105c14a99fd67ad (MD5) / Rejected by ROSANGELA APARECIDA LOBO null (rosangelalobo@btu.unesp.br), reason: Solicitamos que realize uma nova submissão seguindo as orientações abaixo: problema 1: Númeração das folhas As folhas pré-textuais são contadas mas não numeradas. A inclusão da numeração é a partir da Introdução. problema 2: folha em branco Há uma folha em branco logo após o Abstract. Assim que tiver efetuado a correção submeta o arquivo, em formato PDF, novamente. Agradecemos a compreensão. on 2018-09-14T12:56:03Z (GMT) / Submitted by HEITOR DO AMARAL SIMOES (heitor.simoes@unesp.br) on 2018-09-28T22:22:28Z No. of bitstreams: 1 MEPAREM - Heitor do Amaral Simoes - Avaliação do ROPScore como preditor de retinopatia da prematuridade em neonatos prematuros. Estudo Comparativo.pdf: 1885675 bytes, checksum: a64bed9e84aad34bc646de4d1e0bd75c (MD5) / Approved for entry into archive by ROSANGELA APARECIDA LOBO null (rosangelalobo@btu.unesp.br) on 2018-10-02T12:31:30Z (GMT) No. of bitstreams: 1 simoes_ha_me_bot.pdf: 1885675 bytes, checksum: a64bed9e84aad34bc646de4d1e0bd75c (MD5) / Made available in DSpace on 2018-10-02T12:31:31Z (GMT). No. of bitstreams: 1 simoes_ha_me_bot.pdf: 1885675 bytes, checksum: a64bed9e84aad34bc646de4d1e0bd75c (MD5) Previous issue date: 2018-07-25 / Introdução: A retinopatia da prematuridade (ROP) é uma doença vaso proliferativa multifatorial e uma das principais causas de cegueira infantil no mundo. O exame oftalmológico seriado identifica a forma grave da doença, porém pode causar estresse e instabilidade cardiorrespiratória nos neonatos prematuros. O algoritmo ROPScore, aferido na sexta semana de vida é efetivo em predizer o risco de ROP e diminuir o número de exames necessários para o diagnóstico. No entanto, nos casos em que a doença grave é precoce ou se desenvolve em neonatos mais maduros, o ROPScore seria mais efetivo se aferido antes da sexta semana de vida. Objetivo: avaliar a acurácia do ROPScore aferido na segunda semana de vida quando comparada com a da sexta semana. Métodos: Realizou-se um estudo coorte prospectivo de neonatos pré-termos com peso ao nascimento (PN) ≤1500 g e / ou idade gestacional (IG) ≤ 32 semanas. O ROPScore foi aplicado na 2ª e na 6ª semanas de vida. Curvas ROC foram utilizadas para determinar os melhores valores de sensibilidade, especificidade e seus valores preditivos positivos (VPP) e negativos (VPN) para o desenvolvimento de ROP em qualquer estágio (RQE) e ROP grave (RG). Resultados: Dos 282 RNPT, 40 (14,2%) desenvolveram ROP e 27 (9,5%) a sua forma grave. A sensibilidade do ROPScore na 2ª semana para prever ROP em qualquer estadiamento foi de 92,5% e de 92,8% na ROP grave. Na 6ª semana foi de 90% e 92,6% respectivamente. O VPN foi alto tanto na 2ª (99%) como na 6ª (98%) semanas, para ROP em qualquer estadiamento e ROP grave (98,4% e 99%). Utilizando o ROPScore na 2ª semana, 191 RNPT não precisariam ser avaliados, diminuindo em 67,30% o número total de exames necessários para detectar ROP. Na 6ª semana, 199 não precisariam ser avaliados com a mesma frequência, diminuindo em 70,56% o número total de exames. Conclusão: O ROPScore foi uma ferramenta útil para detecção de ROP e da sua forma grave, mantendo a acurácia quando aferido na segunda semana de vida. / Background: Retinopathy of prematurity (ROP) is a multifactorial proliferative vessel disease and one of the leading causes of childhood blindness in the world. Serial ophthalmic examination identifies the severe form of the disease but may cause cardiorespiratory stress and instability in preterm infants. The ROPScore algorithm, measured in the sixth week of life, is effective in predicting ROP risk and decreasing the number of tests required for diagnosis. However, in cases where the severe disease is early or develops in more mature neonates, ROPScore would be more effective if measured before the sixth week of life. Objective: to evaluate the accuracy of ROPScore measured in the second week of life when compared to the sixth week. Methods: A prospective cohort study of preterm newborns with birth weight (BW) ≤1500 g and/or gestational age (GA) ≤ 32 weeks was performed. ROPScore was applied in the 2nd and 6th weeks of life. ROC curves were used to determine the best values of sensitivity, specificity and positive predictive values (PPV) and negative predictive value (NPV) for the development of ROP at any stage (RQE) and severe ROP (RG). Results: Of the 282 preterms, 40 (14.2%) developed ROP and 27 (9.5%) developed their severe form. The sensitivity of ROPScore at 2nd week to predict ROP at any stage was 92.5% and 92.8% at ROP. In the 6th week, it was 90% and 92.6% respectively. The NPV was high in both the second (99%) and the sixth (98%) weeks, for ROP in any stage and severe ROP (98.4% and 99%). Using ROPScore at week 2, 191 newborns would not need to be evaluated, decreasing the total number of exams needed to detect ROP by 67.30%. At week 6, 199 did not need to be evaluated at the same frequency, decreasing the total number of exams by 70.56%. Conclusion: ROPScore was a useful tool for detecting ROP and its severe form, maintaining accuracy when measured in the second week of life.

Orientador: Eliane Chaves Jorge / Resumo: Introdução e Objetivo: A Retinopatia da prematuridade (ROP) é a principal causa de deficiência visual permanente na infância. A identificação precoce da forma grave da ROP pode prevenir a cegueira. O ROPScore é um sistema de pontuação desenvolvido para otimizar a triagem e calcular o risco de ROP em neonatos pré-termo. Este estudo objetivou avaliar a acurácia deste algoritmo como preditor de ROP em uma coorte brasileira. Métodos: Realizou-se um estudo coorte prospectivo de 220 neonatos pré-temo com PN ≤1500 g e / ou IG ≤ 32 semanas. O ROPScore foi aplicado na 6ª semana de vida nas 181 crianças que sobreviveram até a 45ª semana de idade gestacional corrigida. Cada criança foi classificada como Sem-ROP, ROP em qualquer estágio ou ROP grave. Curvas ROC foram utilizadas para determinar os melhores valores de sensibilidade e especificidade do escore na população estudada. Resultados: A média de PN foi de 1271,6g ± 354,6 e a IG média foi de 29,2 ± 2,26 semanas. Dos 181 prematuros estudados, 32 (17,6%) desenvolveram ROP. O melhor ponto de corte do ROPscore para sensibilidade e especificidade foi 16,0 para ROP em qualquer estágio e 16,6 para ROP grave. A área sob a curva ROC para prever ROP em qualquer estágio foi 0,937 (IC 95%: 0,888-0,986; P <0,0001), e para prever ROP grave, 0,962 (IC 95% 0,931-0,993; P <0,0001). A sensibilidade para ROP em qualquer estágio foi 87,5% e para ROP grave foi 95,4%. Utilizando o ROPscore, 130 pré-termos não precisariam ser avaliados com a mesma frequên... (Resumo completo, clicar acesso eletrônico abaixo) / Mestre

La Neurofibromatose 1 (NF1) est une maladie autosomique dominante dont l’évolutivité est inconnue. En effet, ni le type de mutation du gène, la gravité d’éventuels cas familiaux, ni une première complication ne permettent de prédire le pronostic de la maladie. L’objectif général de ce travail de thèse était de cibler les malades les plus à risque de morbi-mortalité au cours de la NF1. Méthode. Les différents travaux se sont appuyés sur les données phénotypiques de patients NF1 suivis dans le Réseau NF-France labellisé par le ministère de la Santé. Il s’agit d’une filière nationale monothématique ayant pour mission la prise en charge des malades atteints de NF1. Une cohorte d’environ 2500 malades est actuellement suivie dans ce réseau. Résultats. La mortalité des patients NF1 a tout d’abord été comparée à celle de la population générale française par l’estimation du rapport de mortalité standardisée (SMR). Entre 1980 et 2006, 1 895 patients NF1 ont été rétrospectivement inclus dans la cohorte. Un excès de mortalité était observé chez les [10-20[ ans (SMR=5.2, IC95% : 2.6 – 9.3, p<10-4) et les [20-40[ ans (SMR=4.1, IC95% : 2.8 – 5.8, p<10-4). Les principales causes de décès étaient la transformation de neurofibromes internes en tumeurs malignes des gaines nerveuses (TMGN). Une étude cas témoins portant sur 208 patients NF1 a permis d’expliquer le risque de mortalité accru chez les patients présentant des neurofibromes sous cutanés (SC-NF) en confirmant en IRM la présence chez ces patients de neurofibromes internes à fort risque de transformation en TMGN (OR=4.3, IC95% : 2.2 – 8.2). Cet effet était d’autant plus marqué que le nombre de SC-NF était important et notamment au-delà d’un seuil de 10 (OR=82, IC95% : 10.4 – 647.9) et que les neurofibromes internes étaient diffus (OR=14.7, IC95% : 3.8 – 57.3) et de taille ≥ 3 cm (OR=6.3, IC95% : 2.3 – 17.4). Les patients présentant des SC-NF représentent 20 à 30% de la population NF1. Afin d’identifier les patients à risque de développer une TMGN, nous avons élaboré un score prédictif de la présence des neurofibromes internes à partir des caractéristiques phénotypiques des patients. La présence de SC-NF (OR=4.7, IC95% : 2.1 – 10.5), l’absence de neurofibromes cutanés (OR=2.6, IC95% : 0.9 – 7.5), un âge inférieur ou égal à 30 ans (OR=3.1, IC95% : 1.4 – 6.8) et moins de 6 tâches café au lait (OR=2, IC95% : 0.9 – 4.6) étaient les variables qui constituaient le NF1Score. Le NF1Score = 10*(âge ≤ 30 ans) + 10*(absence de neurofibromes cutanés) + 5*(moins de 6 tâches café-au-lait) + 15*(plus de 2 neurofibrome sous cutanés) avait une excellente adéquation (test C de Hosmer-Lemeshow=4,53 avec 7ddl, p>0,50) et une capacité discriminante satisfaisante (aire sous la courbe ROC non paramétrique = 0,75 [0,68-0,82]). Enfin, l’expression phénotypique variant au cours du temps chez un même patient nous avons réalisé une étude spécifique chez l’enfant. Ainsi, l’âge (OR=1.1, IC95% : 1.0 – 1.2), la présence de xanthogranulomes (OR=4.5, IC95% : 0.9 – 21.7), celle de neurofibromes sous cutanés et plexiformes (OR=5.0, IC95% : 1.8 – 13.6) étaient indépendamment associés à celle des neurofibromes internes chez l’enfant NF1 de moins de 17 ans. Dans cette dernière étude, les neurofibromes internes se développaient de façon exponentielle pendant l’adolescence et plus précocement chez les femmes en accord avec les données de la littérature. Conclusion. La période à risque de développer des neurofibromes internes semblent donc sesituer entre l’adolescence et l’âge de 30 ans. Les recommandations de suivi pourraient prendre en compte le phénotype à risque, mais également la période de survenue de ces complications en réévaluant l’intérêt dans ce contexte d’investigations complémentaires / Neurofibromatosis-1 (NF1) is a common autosomal dominant condition which is a source of various multisystemic manifestations related either to the accumulation of neurofibromas or to specific developmental abnormalities. There are no obvious factors that predict disease progression. Thus, the aim of our project was to characterize the phenotype of NF1 patients with a severe prognosis. Patients were identified among adults with NF-1 followed up in the Réseau NF-France. The Réseau NF-France is a French medical network devoted to neurofibromatosis 1. It has elaborated recommendations for the management of the disease and recommended a coordinated follow-up in specialized multidisciplinary centres. About 2 500 patients were enrolled. We first evaluated the mortality in a large retrospective cohort of NF1 patients. The standardized mortality ratio (SMR) with its 95% confidence interval (CI) was calculated as the ratio of observed over expected numbers of deaths. Between 1980 and 2006, 1895 NF1 patients were seen. The excess mortality occurred among patients aged 10 to 20 years (SMR=5.2; CI, 2.6-9.3; P<10-4) and 20 to 40 years (SMR, 4.1; 2.8-5.8; P<10-4). The main cause of death was the malignant tumors of the nerve sheath (MPNSTs) developing from preexisting internal neurofibromas. Then, a case-control study including 208 patients with NF1 allowed us to explain the increased risk of mortality among NF1 patients harboring subcutaneous neurofibromas (SC-NF) by the presence of internal neurofibromas (NF) at risk of MPNSTs systematically investigated with imaging (MRI) (OR=4.3, IC95% : 2.2 – 8.2). The association with SC-NF was stronger for patients with ten or more SC-NFs (OR=82, IC95% : 10.4 – 647.9) and for diffuse (OR=14.7, IC95% : 3.8 – 57.3), and ≥ 3 cm (OR=6.3, IC95% : 2.3 – 17.4) internal neurofibromas. Patients with SC-NF constituted 20 to 30% of the NF1 population. So, to characterize patients at risk of developping MPNSTs, we developped and validated a clinical score for predicting internal neurofibromas in adults. Four variables were independently associated with internal neurofibromas: at least two subcutaneous neurofibromas (OR=4.7, IC95% : 2.1 – 10.5), age ≤30 years (OR=3.1, IC95% : 1.4 – 6.8), absence of cutaneous neurofibromas (OR=2.6, IC95% : 0.9 – 7.5), and fewer than six café-au-lait spots (OR=2, IC95% : 0.9 – 4.6). The NF1Score was computed as 10 . [age ≤30 years] + 10 • [absence of cutaneous neurofibromas] + 15 • [≥2 subcutaneous neurofibromas] + 5 • [<6 café-au-lait spots]). Calibration was excellent (Hosmer-Lemeshow statistic=4.53; degrees of freedom=7; P>0.5) and discrimination was good (AUC-ROC= 0.75; 95%CI, 0.7-0.8). Finally clinical expressivity is variable and manifestations of NF1 change at different times in an individual’s life. Consequently, a specific study was needed in pediatric patients. We identified easily recognizable clinical characteristics associated with internal neurofibromas in children with NF1. By multivariate analysis, age (OR=1.1, IC95% : 1.0 – 1.2), xanthogranulomas (OR=4.5, IC95% : 0.9 – 21.7), and presence of both subcutaneous and plexiform neurofibromas (OR=5.0, IC95% : 1.8 – 13.6) were independently associated with internal neurofibromas. Moreover internal neurofibromas increased during adolescence. Excess risk of developing internal neurofibromas seems to occur between the adolescence and the age of to 30 in NF1 patients. These clinical features in adults and children would define a new population at risk for complications that may need closer clinical and imaging follow-up