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1.
N Engl J Med ; 387(5): 421-432, 2022 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-35921451

RESUMO

BACKGROUND: Aggregated α-synuclein plays an important role in the pathogenesis of Parkinson's disease. The monoclonal antibody prasinezumab, directed at aggregated α-synuclein, is being studied for its effect on Parkinson's disease. METHODS: In this phase 2 trial, we randomly assigned participants with early-stage Parkinson's disease in a 1:1:1 ratio to receive intravenous placebo or prasinezumab at a dose of 1500 mg or 4500 mg every 4 weeks for 52 weeks. The primary end point was the change from baseline to week 52 in the sum of scores on parts I, II, and III of the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 236, with higher scores indicating greater impairment). Secondary end points included the dopamine transporter levels in the putamen of the hemisphere ipsilateral to the clinically more affected side of the body, as measured by 123I-ioflupane single-photon-emission computed tomography (SPECT). RESULTS: A total of 316 participants were enrolled; 105 were assigned to receive placebo, 105 to receive 1500 mg of prasinezumab, and 106 to receive 4500 mg of prasinezumab. The baseline mean MDS-UPDRS scores were 32.0 in the placebo group, 31.5 in the 1500-mg group, and 30.8 in the 4500-mg group, and mean (±SE) changes from baseline to 52 weeks were 9.4±1.2 in the placebo group, 7.4±1.2 in the 1500-mg group (difference vs. placebo, -2.0; 80% confidence interval [CI], -4.2 to 0.2; P = 0.24), and 8.8±1.2 in the 4500-mg group (difference vs. placebo, -0.6; 80% CI, -2.8 to 1.6; P = 0.72). There was no substantial difference between the active-treatment groups and the placebo group in dopamine transporter levels on SPECT. The results for most clinical secondary end points were similar in the active-treatment groups and the placebo group. Serious adverse events occurred in 6.7% of the participants in the 1500-mg group and in 7.5% of those in the 4500-mg group; infusion reactions occurred in 19.0% and 34.0%, respectively. CONCLUSIONS: Prasinezumab therapy had no meaningful effect on global or imaging measures of Parkinson's disease progression as compared with placebo and was associated with infusion reactions. (Funded by F. Hoffmann-La Roche and Prothena Biosciences; PASADENA ClinicalTrials.gov number, NCT03100149.).


Assuntos
Anticorpos Monoclonais Humanizados , Antiparkinsonianos , Doença de Parkinson , alfa-Sinucleína , Anticorpos Monoclonais Humanizados/uso terapêutico , Antiparkinsonianos/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de Dopamina/uso terapêutico , Método Duplo-Cego , Humanos , Doença de Parkinson/tratamento farmacológico , Resultado do Tratamento , alfa-Sinucleína/antagonistas & inibidores
2.
J Transl Med ; 11: 247, 2013 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-24093459

RESUMO

HLA abnormalities on tumour cells for immune escape have been widely described. In addition, cellular components of the tumour microenvironment, in particular myeloid derived suppressor cells (MDSC) and alternatively activated M2 tumour-associated macrophages (TAMs), are involved in tumour promotion, progression, angiogenesis and suppression of anti-tumour immunity. However, the role of HLA in these activities is poorly understood. This review details MHC class I characteristics and describes MHC class I receptors functions. This analysis established the basis for a reflection about the crosstalk among the tumour cells, the TAMs and the cells mediating an immune response.The tumour cells and TAMs exploit MHC class I molecules to modulate the surrounding immune cells. HLA A, B, C and G molecules down-regulate the macrophage myeloid activation through the interaction with the inhibitory LILRB receptors. HLA A, B, C are able to engage inhibitory KIR receptors negatively regulating the Natural Killer and cytotoxic T lymphocytes function while HLA-G induces the secretion of pro-angiogenic cytokines and chemokine thanks to an activator KIR receptor expressed by a minority of peripheral NK cells. The open conformer of classical MHC-I is able to interact with LILRA receptors described as being associated to the Th2-type cytokine response, triggering a condition for the M2 like TAM polarization. In addition, HLA-E antigens on the surface of the TAMs bind the inhibitory receptor CD94/NKG2A expressed by a subset of NK cells and activated cytotoxic T lymphocytes protecting from the cytolysis.Furthermore MHC class II expression by antigen presenting cells is finely regulated by factors provided with immunological capacities. Tumour-associated macrophages show an epigenetically controlled down-regulation of the MHC class II expression induced by the decoy receptor DcR3, a member of the TNFR, which further enhances the M2-like polarization. BAT3, a positive regulator of MHC class II expression in normal macrophages, seems to be secreted by TAMs, consequently lacking its intracellular function, it looks like acting as an immunosuppressive factor.In conclusion HLA could cover a considerable role in tumour-development orchestrated by tumour-associated macrophages.


Assuntos
Antígenos HLA/imunologia , Macrófagos/imunologia , Macrófagos/patologia , Neoplasias/imunologia , Neoplasias/patologia , Humanos , Receptores Imunológicos/metabolismo , Transdução de Sinais
3.
Front Neurol ; 12: 705407, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34659081

RESUMO

Background: Currently available treatments for Parkinson's disease (PD) do not slow clinical progression nor target alpha-synuclein, a key protein associated with the disease. Objective: The study objective was to evaluate the efficacy and safety of prasinezumab, a humanized monoclonal antibody that binds aggregated alpha-synuclein, in individuals with early PD. Methods: The PASADENA study is a multicenter, randomized, double-blind, placebo-controlled treatment study. Individuals with early PD, recruited across the US and Europe, received monthly intravenous doses of prasinezumab (1,500 or 4,500 mg) or placebo for a 52-week period (Part 1), followed by a 52-week extension (Part 2) in which all participants received active treatment. Key inclusion criteria were: aged 40-80 years; Hoehn & Yahr (H&Y) Stage I or II; time from diagnosis ≤2 years; having bradykinesia plus one other cardinal sign of PD (e.g., resting tremor, rigidity); DAT-SPECT imaging consistent with PD; and either treatment naïve or on a stable monoamine oxidase B (MAO-B) inhibitor dose. Study design assumptions for sample size and study duration were built using a patient cohort from the Parkinson's Progression Marker Initiative (PPMI). In this report, baseline characteristics are compared between the treatment-naïve and MAO-B inhibitor-treated PASADENA cohorts and between the PASADENA and PPMI populations. Results: Of the 443 patients screened, 316 were enrolled into the PASADENA study between June 2017 and November 2018, with an average age of 59.9 years and 67.4% being male. Mean time from diagnosis at baseline was 10.11 months, with 75.3% in H&Y Stage II. Baseline motor and non-motor symptoms (assessed using Movement Disorder Society-Unified Parkinson's Disease Rating Scale [MDS-UPDRS]) were similar in severity between the MAO-B inhibitor-treated and treatment-naïve PASADENA cohorts (MDS-UPDRS sum of Parts I + II + III [standard deviation (SD)]; 30.21 [11.96], 32.10 [13.20], respectively). The overall PASADENA population (63.6% treatment naïve and 36.4% on MAO-B inhibitor) showed a similar severity in MDS-UPDRS scores (e.g., MDS-UPDRS sum of Parts I + II + III [SD]; 31.41 [12.78], 32.63 [13.04], respectively) to the PPMI cohort (all treatment naïve). Conclusions: The PASADENA study population is suitable to investigate the potential of prasinezumab to slow disease progression in individuals with early PD. Trial Registration: NCT03100149.

4.
Tumori ; 96(6): 918-25, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-21388052

RESUMO

AIMS AND BACKGROUND: To assess feasibility and toxicity of intraperitoneal administration of cisplatin and paclitaxel, followed by intravenous chemotherapy in pretreated patients with suboptimal ovarian cancer (residuum >1 cm) or primary peritoneal tumor, and suffering from ascites and/or intestinal obstruction. METHODS: Fourteen relapsed ovarian cancer patients, 5 of whom were platinum sensitive (platinum-free interval >6 mo), 7 platinum-resistant (platinum-free interval <6 mo), and 2 platinum-refractory, received one cycle of intraperitoneal cisplatin, 100 mg/m2 on day 1, and two cycles of intraperitoneal paclitaxel, 120 mg/m2 on days 8 and 14. Intravenous chemotherapy was administrated 4 weeks following the last intraperitoneal paclitaxel instillation. Blood and peritoneal fluid samples were harvested at 0, 1, 4 and 24 h after ending paclitaxel delivery to guarantee proper tumor exposure and patient safety. RESULTS: Intraperitoneal cisplatin determined 6 cases of vomiting grade 1-2 (40% of the morbidity). Intraperitoneal paclitaxel was associated with 6 events of grade 1-2 abdominal pain; the only grade 4 toxicity was one case of neutropenia and one of mucositis. Ascites decreased in 11 patients: the median time to first need for paracentesis was 5 months, compared to a median baseline paracentesis of 4 weeks. Three intestinal normalizations were obtained. The median overall survival was 10 months for our cohort of patients. Intraperitoneal paclitaxel clearance was significantly higher in patients with suboptimal tumor and symptomatic disease than in patients with smaller residual masses and without ascites (P = 0.004). CONCLUSIONS: Intraperitoneal treatment was feasible, and enhanced response to the following intravenous chemotherapy was seen in these patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasia Residual/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ascite/etiologia , Carcinoma Papilar/tratamento farmacológico , Cistadenoma Seroso/tratamento farmacológico , Estudos de Viabilidade , Feminino , Humanos , Infusões Intravenosas , Infusões Parenterais , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasia Residual/complicações , Neoplasias Ovarianas/complicações , Paclitaxel/administração & dosagem , Neoplasias Peritoneais/complicações , Compostos de Platina/administração & dosagem , Estudos Retrospectivos , Terapia de Salvação , Análise de Sobrevida , Resultado do Tratamento
5.
Ital J Pediatr ; 46(1): 123, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32887637

RESUMO

BACKGROUND: Anticipatory guidance for parents is commonly used to improve parenting skills. The objective of this pre/post-intervention controlled study was to evaluate the effectiveness of a periodic newsletter with advice on childcare and development in improving parenting self-efficacy. METHODS: This was a non-randomized pre/post-intervention controlled study. All the parents of children born between September 2014 and December 2015 resident in the S. Ilario d'Enza municipality (Italy) received eight Baby Newsletters. Parents resident in other municipalities of the same Health District were the control. Parents with linguistic barriers or with preterm or hospitalized children were excluded. Improvement in parenting self-efficacy was measured through the TOPSE (Tool to Measure Parenting Self-Efficacy) questionnaire during the first week (t0) after delivery and at 5 (t1) and 12 months (t2) of life at two vaccination appointments. A score ranging from 0 to 60 was computed for each of the eight domains investigated by the TOPSE. Variations of each TOPSE score between delivery and 12 months in the two groups were compared, adjusting for parity, education, age of parents, and child's sex, and stratifying by parity and education. RESULTS /FINDINGS: One hundred thirty-six families accepted to participate in the study. Scores at 12 months were higher than 1 week after delivery in both groups for all TOPSE domains. The improvement was slightly stronger in the Newsletter group for almost all the skills except learning and knowledge [difference in the mean of variation: -0.48 (95% CI: - 3.17; 2.21)]; the difference was significant only for play and enjoyment [2.18 (95% CI: 0.12; 4.25)]. The increase in scores in almost all domains was more pronounced for parents with high education level at first child. CONCLUSIONS: The intervention was effective in improving parents' ability to play. However, it risks worsening existing differences between parents with high and with low education levels. TRIAL REGISTRATION: Clinical trial registration: NCT03268408 .


Assuntos
Educação não Profissionalizante , Poder Familiar , Pais/educação , Pais/psicologia , Autoeficácia , Adulto , Estudos Controlados Antes e Depois , Feminino , Humanos , Itália , Masculino , Jornais como Assunto , Jogos e Brinquedos , Inquéritos e Questionários
6.
Haematologica ; 91(2): 255-7, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16461314

RESUMO

We investigated the efficacy of dexamethasone plus diclofenac eye drops as prophylaxis for conjunctivitis induced by high-dose (HD) cytarabine (Ara-C). Sixty patients were randomized to receive either dexamethasone (group A, n=29) or dexamethasone plus diclofenac (group B, n=31). Conjunctivitis was experienced by 13/29 (45%) patients in group A, and 4/31 (13%) patients in group B (p

Assuntos
Conjuntivite/prevenção & controle , Citarabina/efeitos adversos , Dexametasona/administração & dosagem , Pré-Medicação , Administração Tópica , Adulto , Idoso , Anti-Inflamatórios/administração & dosagem , Conjuntivite/induzido quimicamente , Conjuntivite/tratamento farmacológico , Diclofenaco/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
7.
Pediatr Med Chir ; 38(2): 113, 2016 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-27345601

RESUMO

Infantile hemangiomas (IH) complicated by ulceration, disfigurement, functional impairment or life-threatening conditions need early, safe and effective treatment. This study explores the impact of propranolol on complicated IH. We report our experience of 62 patients treated with oral propranolol for complicated IH. The effect of propranolol was assessed using a score on a visual analogue scale integrated with echo, magnetic resonance or endoscopic findings. The average age at the beginning of the treatment was seven months [standard deviation (SD)±8.9], with a median of four months (range 1-53 months). The average age at the end of the treatment was 15 months (SD±8.4), with a median of 13 months (range 7-59 months). The mean treatment length was eight months (SD±3.2). Oral propranolol was successful in 95.2% of the patients in reducing the volume, the intensity of color and the elevation of IH. Statistically significant improvement of IH volume was observed in the first two months of therapy (P≤0.001), and between the second month and the end of the treatment (P<0.05). No significant bradycardia or hypotension occurred. Severe hypoglycemia occurred in one patient. Mild adverse effects were observed in seven patients. Our study demonstrates that propranolol administered orally at 2 to 3 mg/kg/day has a rapid therapeutic effect leading to remarkable shortening of the natural course of IH and it is safe in the majority of patients.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Hemangioma/tratamento farmacológico , Propranolol/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Administração Oral , Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas Adrenérgicos beta/efeitos adversos , Pré-Escolar , Feminino , Hemangioma/patologia , Humanos , Lactente , Masculino , Propranolol/administração & dosagem , Propranolol/efeitos adversos , Neoplasias Cutâneas/patologia , Fatores de Tempo , Resultado do Tratamento
8.
Methods Mol Biol ; 1102: 353-66, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24258987

RESUMO

The major histocompatibility complex (MHC) comprises a set of genes that are essential to immunity and surveillance against neoplastic transformation. MHC antigens not only regulate antitumor immune responses in experimental animal models but also directly correlate with survival and prognosis of patients with various types of cancers. Effective recognition of tumor cells by effector T cells may be affected by the genotype and the extent of expression of human leukocyte antigen (HLA)-peptide complexes. Therefore, MHC antigens may serve as potential biomarkers for prognosis and allow selection of cancer patients for specific therapy. We describe PCR-based method to determine the HLA genotype in healthy individuals and patients using blood and tumor tissue as DNA source.


Assuntos
Biomarcadores Tumorais/metabolismo , Técnicas de Genotipagem/métodos , Antígenos HLA/genética , Haplótipos/genética , Neoplasias/genética , Neoplasias/imunologia , Reação em Cadeia da Polimerase/métodos , Alelos , DNA de Neoplasias/isolamento & purificação , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfócitos/metabolismo , Inclusão em Parafina , Prognóstico , Reprodutibilidade dos Testes , Fixação de Tecidos
9.
Acta Biomed ; 85(3): 236-42, 2014 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-25567460

RESUMO

We tested the possibility to prepare a hyperproteic and hyperenergetic supplementary food for malnutrition rehabilitation in children starting from available ingredients in popular markets in Sierra Leone. Twelve residents in Paediatrics from University of Parma, Italy, prepared in a hospital near the capital Freetown with modest technology a mixture of peanut flour, palm oil, milk powder, sugar and vitamins to which they gave the name of "Parma pap". Three hundred and thirty-two malnourished children (mean age 14±6.3 months) who were receiving Feeding Program Supplementations (FPS), were enrolled in the study: 177 participants received randomly FSP portions only (Group 1), and 159 participants were treated with FSP regimen plus a supplement of "Parma pap" (Group 2). Outcomes of the study were computed as WHZ-score increment (Δ value) by subtracting the discharge WHZ-score from the admission WHZ-score. The best Δ-WHZ-scores (>+4) were recorded among participants of Group 2 (64%) rather than in Group 1 (21%; p=0.040). The children receiving FSP portions plus "Parma pap" recovered faster (5.54 week on average) than those treated with FSP regimen only (8.16 on average). The percentage of children who did not recover was higher in Group 1 (25.3%) than in Group 2 (; 13%; p=0.05). A slight positive correlation has been found between WHZ-scores at admission and at the end of the study (r=0.19; p=0.045). During the experience in Sierra Leone we have had the chance to give "Parma pap" to twenty one malnourished children admitted to Xaverian Mission in Makeni, northern Sierra Leone, not taking other supplementary food. Sixteen of these children recovered in 4.9 week on average and five in 6 to 8 weeks. Mean Δ-WHZ-scores ranged between + 1 and + 5. The data from the present study suggest that "Parma pap" could be an effective additional food to FPS regimen in malnutrition recovering. Further researches are needed on the contrary to prove if "Parma pap" could be defined as a veritable ready to use therapeutic food, although this characteristic seems already to result from the experience in Makeni Mission.


Assuntos
Suplementos Nutricionais/estatística & dados numéricos , Alimentos Fortificados , Desnutrição/dietoterapia , Aumento de Peso/fisiologia , Pré-Escolar , Feminino , Seguimentos , Humanos , Incidência , Lactente , Itália/epidemiologia , Masculino , Desnutrição/epidemiologia , Desnutrição/fisiopatologia , Estudos Retrospectivos , Resultado do Tratamento
10.
PLoS One ; 7(8): e43379, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22927961

RESUMO

BACKGROUND AND AIM: Colon crypts are characterized by a hierarchy of cells distributed along the crypt axis. Aim of this paper was to develop an in vitro system for separation of epithelial cell subsets in different maturation stages from normal human colon. METHODOLOGY AND MAJOR FINDINGS: Dissociated colonic epithelial cells were stained with PKH26, which allows identification of distinct populations based on their proliferation rate, and cultured in vitro in the absence of serum. The cytofluorimetric expression of CK20, Msi-1 and Lgr5 was studied. The mRNA levels of several stemness-associated genes were also compared in cultured cell populations and in three colon crypt populations isolated by microdissection. A PKH(pos) population survived in culture and formed spheroids; this population included subsets with slow (PKH(high)) and rapid (PKH(low)) replicative rates. Molecular analysis revealed higher mRNA levels of both Msi-1 and Lgr-5 in PKH(high) cells; by cytofluorimetric analysis, Msi-1(+)/Lgr5(+) cells were only found within PKH(high) cells, whereas Msi-1(+)/Lgr5(-) cells were also observed in the PKH(low) population. As judged by qRT-PCR analysis, the expression of several stemness-associated markers (Bmi-1, EphB2, EpCAM, ALDH1) was highly enriched in Msi-1(+)/Lgr5(+) cells. While CK20 expression was mainly found in PKH(low) and PKH(neg) cells, a small PKH(high) subset co-expressed both CK20 and Msi-1, but not Lgr5; cells with these properties also expressed Mucin, and could be identified in vivo in colon crypts. These results mirrored those found in cells isolated from different crypt portions by microdissection, and based on proliferation rates and marker expression they allowed to define several subsets at different maturation stages: PKH(high)/Lgr5(+)/Msi-1(+)/CK20(-), PKH(high)/Lgr5(-)/Msi-1(+)/CK20(+), PKH(low)/Lgr5(-)/Msi-1(+)/Ck20(-), and PKH(low)/Lgr5(-)/Msi-1(-)/CK20(+) cells. CONCLUSIONS: Our data show the possibility of deriving in vitro, without any selection strategy, several distinct cell subsets of human colon epithelial cells, which recapitulate the phenotypic and molecular profile of cells in a discrete crypt location.


Assuntos
Separação Celular/métodos , Colo/citologia , Mucosa Intestinal/citologia , Compostos Orgânicos/metabolismo , Biomarcadores/metabolismo , Diferenciação Celular , Proliferação de Células , Regulação da Expressão Gênica , Humanos , Mucosa Intestinal/metabolismo , Esferoides Celulares/citologia , Esferoides Celulares/metabolismo , Coloração e Rotulagem
11.
Eur J Endocrinol ; 165(2): 307-14, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21646284

RESUMO

OBJECTIVE: Premature pubarche (PP) is the most frequent sign of nonclassic congenital adrenal hyperplasia (NCCAH) due to 21-hydroxylase deficiency in childhood. The aim of this study was to assess the relationship between the CYP21A2 genotype and baseline and ACTH-stimulated 17-hydroxyprogesterone (17-OHP) and cortisol serum levels in patients presenting with PP. PATIENTS AND METHODS: A total of 152 Italian children with PP were studied. Baseline and ACTH-stimulated 17-OHP and cortisol serum levels were measured and CYP21A2 gene was genotyped in all subjects. RESULTS: Baseline and ACTH-stimulated serum 17-OHP levels were significantly higher in NCCAH patients than in both heterozygotes and children with idiopathic PP (IPP). Of the patient population, four NCCAH patients (7.3%) exhibited baseline 17-OHP values <2 ng/ml (6 nmol/l). An ACTH-stimulated 17-OHP cutoff level of 14 ng/ml (42 nmol/l) identified by the receiver-operating characteristics curves showed the best sensitivity (90.9%) and specificity (100%) in distinguishing NCCAH patients. This value, while correctly identifying all unaffected children, missed 9% of affected individuals. Cortisol response to ACTH stimulation was <18.2 µg/dl (500 nmol/l) in 14 NCCAH patients (28%) and none of the heterozygotes or IPP children. Among the 55 NCCAH patients, 54.5% were homozygous for mild CYP21A2 mutations, 41.8% were compound heterozygotes for one mild and one severe CYP21A2 gene mutations, and 3.6% had two severe CYP21A2 gene mutations. CONCLUSION: In children with PP, baseline 17-OHP levels are not useful to rule out the diagnosis of NCCAH, which is accomplished by means of ACTH testing only. The different percentages of severe and mild CYP21A2 gene mutations found in PP children compared with adult NCCAH patients is an indirect evidence that the enzyme defect is under-diagnosed in childhood, and it might not lead to the development of hyperandrogenic symptoms in adulthood. Stress-dose glucocorticoids should be considered in patients with suboptimal cortisol response to ACTH stimulation.


Assuntos
17-alfa-Hidroxiprogesterona/sangue , Hidrocortisona/sangue , Puberdade Precoce/sangue , Puberdade Precoce/genética , Esteroide 21-Hidroxilase/genética , Hiperplasia Suprarrenal Congênita/sangue , Hiperplasia Suprarrenal Congênita/genética , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , Lactente , Itália , Masculino , Polimorfismo de Nucleotídeo Único/fisiologia , Estudos Retrospectivos
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