Natalizumab improves ambulation in relapsing-remitting multiple sclerosis: results from the prospective TIMER study and a retrospective analysis of AFFIRM.

BACKGROUND AND PURPOSE: Impaired ambulation is a prominent disabling symptom of multiple sclerosis and can lead to reduced quality of life. Whether natalizumab, a monoclonal antibody shown to reduce disease activity in relapsing-remitting multiple sclerosis, could impact ambulation performance was examined. METHODS: A prospective open-label study, TIMER, was conducted in natalizumab-naive patients (n = 215). The timed 25-foot walk (T25FW) and timed 100-m walk (T100MW) were assessed at baseline and at weeks 24 and 48 of natalizumab therapy, together with Expanded Disability Status Scale scores. The effects of natalizumab on T25FW performance were also examined in a retrospective analysis of natalizumab-treated patients (n = 627) and placebo control patients (n = 315) from the AFFIRM study. RESULTS: In TIMER, a significant increase from baseline in T25FW speed was seen at week 24 (P = 0.0074) and in T100MW speed at weeks 24 and 48 (both P < 0.001). A greater proportion of patients showed clinically meaningful increases (≥20%) in walking speed on the T100MW (25%) than on the T25FW (13%) at week 48 (P = 0.032). In AFFIRM, natalizumab increased the proportion of patients with ≥20% confirmed improvement in T25FW speed at year 2 by 78% versus placebo (P = 0.0133). CONCLUSIONS: Natalizumab increased walking speed in patients with relapsing-remitting multiple sclerosis. The T100MW may be more sensitive to changes in ambulation capacity than the T25FW, and both tests appear to detect clinically meaningful improvements in ambulatory function.

Evaluation of the symbol digit modalities test (SDMT) and MS neuropsychological screening questionnaire (MSNQ) in natalizumab-treated MS patients over 48 weeks.

BACKGROUND AND OBJECTIVES: Brief cognitive tests to monitor cognitive impairment in patients with multiple sclerosis (MS) are needed. METHODS: Performance on monthly administrations of the Symbol Digit Modalities Test (SDMT) and the MS Neuropsychological Questionnaire (MSNQ) was assessed in 660 patients with MS in 21 countries (109 sites) for 48 weeks in an open-label, safety-extension study of natalizumab. RESULTS: At baseline, the cohort's mean age was 40.1 years, 67.6% were female and the median Expanded Disability Status Scale score was 2.5. Test-retest correlations were high for both SDMT (range 0.89 for weeks 0-4 to 0.96 for weeks 44-48) and MSNQ (0.82 for weeks 0-4 to 0.93 for weeks 44-48). There were no statistically significant effects of geographic region. While SDMT scores improved by 15 points over 48 weeks (p < 0.0001), incremental monthly changes were small (effect size d < 0.3). Similar results were obtained on the MSNQ except that scores moved downward, suggesting fewer cognitive complaints over 48 weeks (p < 0.0001), but again the incremental monthly changes were small (d <-0.2). CONCLUSIONS: These results replicate earlier work in a smaller cohort treated with conventional disease-modifying therapy, and support the reliability of the SDMT and MSNQ as potential screening for monitoring tools for cognition over time.

Development and evaluation of content of the mobile app Cinesia for patients with unilateral motor deficits after stroke / Desenvolvimento e avaliação do conteúdo do aplicativo móvel Cinesia para pacientes com déficits motores dimidiados após acidente vascular cerebral

Abstract Introduction The incidence of stroke in adults has increased in recent years, and individuals who survive often have one or more motor and cognitive deficits. In Brazil, the Unified Health System (SUS) faces difficulties in reabsorbing the entire population that needs physiotherapy after hospital discharge. In addition, the distance to rehabilitation units in Rio de Janeiro can be far, making it impossible for some patients to receive the treatment they need. Objective To create a complementary mobile application for adults with unilateral motor deficits and to evaluate its content through expert judges. Methods Applied research for the construction of a mobile app with the prototyping method by Pressman. Steps: 1) literature review; 2) development of the technological framework; 3) construction of the content; and 4) construction of a prototype. The app content was evaluated using the e-Delphi Method for peer review using a Likert-type questionnaire on the Google Forms platform. Results The application was developed and designed to run on the Android operating system. Three rounds were carried out to evaluate the app's content. The final average of the content validity index (CVI) of all content items was 0.85, reaching the minimum agreement of 0.80, suggested by authors. Conclusion The content of a mobile app for adults with unilateral post-stroke motor deficits was developed and approved, and its content was evaluated by expert judges. We believe that this app can contribute to the promotion of physical rehabilitation in people with unilateral motor deficits after hospital discharge.

Resumo Introdução A incidência do acidente vascular cerebral (AVC) em adultos tem aumentado nos últimos anos e os indivíduos sobreviventes apresentam frequentemente um ou mais déficits motores e cognitivos. O Sistema Único de Saúde enfrenta dificuldades em reabsorver toda a população que necessita de fisioterapia após a alta hospitalar. Além disso, a distância entre as unidades de reabilitação no Rio de Janeiro impossibilita que alguns pacientes realizem o tratamento necessário. Objetivo Criar um aplicativo móvel complementar para adultos com déficits motores dimidiados e avaliar seu conteúdo através de juízes-especialistas. Métodos Pesquisa aplicada para a construção de um aplicativo móvel com método de prototipação por Pressman. Etapas: 1) revisão da literatura; 2) desenvolvimento do arcabouço tecnológico; 3) construção do conteúdo; 4) construção de um protótipo. Avaliou-se o conteúdo do aplicativo pelo método e-Delphi para avaliação por pares através de um questionário do tipo Likert na plataforma Google Forms. Resultados O aplicativo foi desenvolvido e projetado para rodar no sistema operacional Android. Foram realizadas três rodadas para a avaliação do conteúdo do aplicativo. A média final do índice de validade de conteúdo (IVC) de todos os itens do conteúdo foi de 0,85, atingindo a concordância mínima de 0,80 sugerida por autores. Conclusão Foi desenvolvido e aprovado o conteúdo de um aplicativo móvel para adultos com déficits motores dimidiados pós-AVC e realizada a ava-liação de seu conteúdo através de juízes-especialistas. Espera-se que o aplicativo possa contribuir para a promoção da reabilitação física de pessoas com déficits motores dimidiados após alta hospitalar.

Gestão de Dados de Pesquisa: um desafio para os Programas de Pós-Graduação em Enfermagem / Research Data Management: a challenge for Graduate Nursing Programs

Introdução: A ciência aberta abre novos horizontes tanto para o pesquisador quanto para as atividades acadêmicas e científicas. Ela vem crescendo em todas as áreas do conhecimento e chega ao domínio da enfermagem como um grande desafio a ser enfrentado. Este artigo tem o objetivo de mostrar como os Programas de Pós-Graduação em Enfermagem, da Universidade Federal do Estado do Rio de Janeiro estão lidando com essa questão e a direção que vêm tomando para realizar a devida gestão dos dados gerados em suas pesquisas, no âmbito da ciência aberta. Revisão e Discussão: Para tal fim foi necessário; contextualizar o conceito de ciência aberta, enfatizando as práticas de gestão de dados; apresentar o ciclo de vida dos dados, os princípios FAIR e sua aplicação na rede GO FAIR Brasil Saúde - Enfermagem criada com a finalidade de elaborar estratégias para a implementação dos princípios FAIR no campo da enfermagem, visando o, compartilhamento e reuso desses dados em novas pesquisas. Considerações finais: A coordenação dos Programas de Pós-graduação em Enfermagem da UNIRIO e da Escola de Enfermagem Alfredo Pinto, da Rede GO FAIR Brasil Saúde - Enfermagem representa um exemplo de adoção de práticas da ciência aberta dentro de cursos de pós-graduação. Portanto, espera-se que por intermédio dos estudos e eventos que se iniciam no âmbito da Rede GO FAIR Brasil Saúde ­ Enfermagem, realizados em 2020 e programados para os anos seguintes, responder à pergunta feita na introdução deste artigo e contribuir para a promoção e implementação de estratégias de capacitação de aluno e profissionais da área da saúde, em geral, sobre a gestão de dados de pesquisa na área da enfermagem.

A randomized double-blind comparison of ondansetron and metoclopramide in the prophylaxis of emesis induced by cyclophosphamide, fluorouracil, and doxorubicin or epirubicin chemotherapy.

Seventy-five breast cancer patients scheduled to receive a first course (in a new cycle) of cyclophosphamide, fluorouracil, and doxorubicin (FAC) or epirubicin (FEC) participated in a double-blind crossover study to compare the antiemetic efficacy and safety of ondansetron (GR38032), a 5-hydroxytryptamine3 (5-HT3) receptor antagonist, and metoclopramide. Ondansetron was given as an 8 mg loading dose (4 mg intravenously [IV] plus 4 mg orally) before chemotherapy followed by 8 mg every 8 hours orally for 3 to 5 days. Metoclopramide was given as an 80 mg loading dose (60 mg IV plus 20 mg orally) before chemotherapy followed by 20 mg every 8 hours orally for 3 to 5 days. A "period" interaction in the analysis of emetic response in the first 24 hours necessitated a parallel group analysis of first treatments only, 68 patients being assessable for this parameter. In the first 24 hours, complete or major control (zero to two emetic episodes) of emesis was achieved in 30 of 35 (86%) patients receiving ondansetron and in 14 of 33 (42%) patients receiving metoclopramide (P less than .001). Ondansetron was also more effective in reducing acute nausea. On days 2 to 3, the complete or major responses were significantly better with ondansetron (81% v 65%; P = .033), but there was no statistical difference in the control of nausea. There was a significant patient preference for ondansetron (63% v 26%; P = .001). Extrapyramidal reactions were observed in two metoclopramide treatments; both treatments were otherwise well tolerated. These results are consistent with serotonin (5-HT), being a significant neurotransmitter of cyclophosphamide/doxorubicin- or epirubicin/fluorouracil-induced emesis.

Prednisolone does not prevent hypersensitivity reactions in antiretroviral drug regimens containing abacavir with or without nevirapine.

OBJECTIVES: To determine the effect of adjuvant prednisolone use on the development of abacavir (ABC)- and nevirapine (NVP)-associated hypersensitivity reactions (HSR). METHODS: Randomized open-label study in antiretroviral-naive adult HIV-1 infected patients using a factorial design in which NVP and/or hydroxyurea (HU) and/or prednisolone are added to a regimen of ABC, zidovudine and lamivudine. Prednisolone (40 mg once daily) was added for the first 2 weeks of treatment. As it was difficult to distinguish ABC-associated HSR from NVP-associated HSR, these events were treated as a composite endpoint. The odds ratio (OR) of developing HSR for prednisolone-use was calculated with and without stratification by NVP and/or HU. Logistic regression was performed to identify risk factors for developing HSR. RESULTS: Of the 229 patients 115 were randomized to prednisolone and 114 to no-prednisolone; 19 (17%) and 11 (10%) patients, respectively, developed HSR. The expected prevention of HSR by prednisolone use was not observed. In fact use of prednisolone showed an increased risk for HSR although this did not reach statistical significance [OR, 1.82; 95% confidence interval (CI), 0.82-4.03]. There was a higher incidence of HSR in the NVP group than in the non-NVP group (20% versus 6%; P = 0.002). An additional risk factor identified in a multivariate logistic model was a high baseline CD4 cell count (OR, 1.26 per 100 x 10(6) cells/l increase; 95% CI, 1.06-1.51). CONCLUSIONS: The simultaneous start of ABC and NVP in first-line antiretroviral regimens should be avoided because of a high (20%) incidence of HSR. Short-term therapy with prednisolone did not prevent HSR in patients using ABC with or without NVP.

A demonstration of the in vitro bacterial mutagenicity of procarbazine, using the microtitre fluctuation test and large concentrations of S9 fraction.

The anti-neoplastic agent procarbazine is genetically active in a variety of short term mutagenicity tests, and it also possesses carcinogenic and teratogenic potential. This compound has consistently yielded false negative results in in vitro microbial mutagenicity tests in the presence and absence of mammalian metabolic activation. In this study, procarbazine was not mutagenic in standard and preincubation Ames tests using large S9 concentrations and bacterial test strains devoid of the rfa mutation. The microtitre fluctuation test is a sensitive technique for the detection of bacterial mutagens. Using this assay, procarbazine proved to be a bacterial mutagen after in vitro metabolic activation at concentrations as low as 200 micrograms/ml. Activity was dependent upon liver S9-concentrations which were higher than those usually attained within agar assays, and was only observed when such fractions were derived from aroclor-treated or phenobarbitone plus beta-naphthoflavone treated rat livers. The excision-repair proficient strain E. coli WP2 was equally, if not more, sensitive than the repair deficient strain E. coli WP2 uvrA. Furthermore, the differential mutagenic effects obtained using S. typhimurium strains TA1535, TA1530 and his G46 indicated that the absence of an rfa mutation was essential for procarbazine mutagenesis. Procarbazine was also mutagenic for E. coli D494 in a forward mutation fluctuation assay measuring resistance to ampicillin. In this assay lower concentrations of S9-fraction were sufficient, reflecting the increased sensitivity of the test strain towards the mutagenic metabolites of the drug. In conclusion, the results suggest that rat liver S9-fraction contains only low levels of enzymes capable of activating procarbazine to a mutagen. This may be a result of rapid breakdown during storage, or due to intrinsically low levels in rat liver extracts. Inducing agents appear to increase these levels. The low concentrations of mutagenic species formed in vitro, may only be detectable using a highly sensitive assay such as the microtitre fluctuation test.

Implementação de um protocolo de extubação orotraqueal em pacientes neurocríticos em um hospital público do Rio de Janeiro / Implementation of an orotracheal extubation protocol in neurocritical patients in a public hospital in Rio de Janeiro

A falha de extubação em uma UTI neurocrítica é difícil de prever e está associada ao aumento da mortalidade, além de custos financeiros mais altos, devido à permanência prolongada nos hospitais. As diretrizes propostas para extubação orotraqueal são generalizadas e, em geral, não adaptadas especificamente para pacientes com doenças neurocríticas. O objetivo do estudo é descrever as etapas de implementação de um protocolo de extubação orotraqueal no setor de fisioterapia em pacientes neurocirúrgicos do Instituto Estadual do Cérebro Paulo Niemeyer, através de um estudo descritivo. As etapas de implementação foram: revisão bibliográfica sobre o tema; discussão e validação dos critérios com a equipe médica; criação de um Checklist de Aptidão para o TRE, composto por 14 itens, submetendo ao TRE os pacientes considerados aptos; estabelecimento de um TRE com PS 0, PEEP 0 e FiO2 <40% por 60 minutos; realização de quatro testes a cada 30 minutos do TRE: cuff leak test, IRRS, quatro comandos (fechar olhos, tossir, mexer os dedos do pé e mostrar dois dedos da mão) e reflexo faríngeo; treinamento da equipe de fisioterapia; registro dos dados em planilha específica para registro e monitoramento das atividades. Após a implementação do protocolo, os indicadores mostraram uma taxa média de 9,3% reintubações após extubação programada, equivalendo a uma redução de 31,9% em relação ao período sem implementação do protocolo. A implementação de um protocolo de extubação voltado aos pacientes neurocríticos demanda tempo e treinamento profissional, porém é viável e resultou em um melhor prognóstico aos pacientes submetidos ao protocolo

Extubation failure in a neurocritical ICU is difficult to predict and is associated with increased mortality in addition to higher financial costs due to prolonged hospital stay. The guidelines proposed for orotracheal extubation are generalized and, in general, not adapted specifically for patients with neurocritical diseases. The goal of this study is to describe the steps of the implementation of an orotracheal extubation protocol in the physiotherapy sector in neurosurgical patients of the Instituto Estadual do Cérebro Paulo Niemeyer, through a descriptive study. The implementation stages were: bibliographic review on the theme; discussion and validation of the criteria with the medical team; Creation of a Fitness Checklist for the SBT, composed of 14 items, submitting to the SBT the patients considered fit; establishment of a SBT with PS 0, PEEP 0 and FiO 2 <40% for 60 minutes; performing four tests every 30 minutes of the SBT: cuff leak test, IRRS, four commands (close eyes, cough, wiggle toes and show two fingers of the hand) and pharyngeal reflex; physiotherapy team training; recording of data in a specific worksheet for recording and monitoring activities. After the implementation of the protocol, the indicators showed an average rate of 9.3% reintubations after scheduled extubation, equivalent to a reduction of 31.9% in relation to the period without protocol implementation. The implementation of an extubation protocol for neurocritical patients requires time and professional training, but it is doable and has resulted in a better prognosis for the patients submitted to the protocol

The effectiveness of a single intravenous dose of ondansetron.

This paper reviews data from 3 randomised, double-blind, parallel-group studies carried out in patients receiving high-dose cisplatin chemotherapy (50-120 mg/m2). These comparative trials show that a single intravenous dose of ondansetron (8-32 mg) is as effective as the continuous infusion and intermittent dose regimens used in previous clinical trials (8 mg i.v. followed by a 1 mg/h infusion for 24 h and 0.15 mg/kg i.v. x 3). One of the studies, carried out in Europe, demonstrated that a single 8 mg i.v. dose was as effective as 32 mg given either as an 8 mg loading dose followed by an infusion or as a single intravenous dose of 32 mg before chemotherapy. A similar study conducted in the United States showed that a 32 mg i.v. single dose was significantly more effective than both the 8 mg i.v. dose and the intermittent dose schedule. This study used a prospective stratification based on the dose of cisplatin (50-70 mg/m2 and greater than or equal to 100 mg/m2). In both strata the 32 mg dose was superior. These results emphasise the importance of selecting the dose of ondansetron (8-32 mg) based on factors that predispose patients to emesis, e.g., female gender, patients with a history of chemotherapy or motion sickness and the dose of cisplatin. The ondansetron dosing regimen for patients receiving a highly-emetogenic chemotherapy (8-32 mg i.v. followed by 8 mg orally twice daily) is both simple and flexible.

Investigations into the genotoxic potential of loxtidine, a long-acting H2-receptor antagonist.

Loxtidine, a potent, non-competitive histamine H2-receptor antagonist was evaluated for genotoxic potential using a range of short-term mutagenicity assays. Unequivocally negative results were obtained in a Salmonella/plate incorporation assay and a liquid pre-incubation assay (using S. typhimurium strains TA1535, TA100, TA1537, TA1538 and TA98), a fluctuation assay [using Escherichia coli strains WP2, WP2 uvrA (R46) and 343/113 lys60 (R46)], a gene conversion assay (using Saccharomyces cerevisiae JD1) and a human peripheral lymphocyte cytogenetic assay. All of these in vitro tests were carried out in the presence and absence of rat liver S9 mix. In addition, the major metabolites of loxtidine in the rat were also negative in the same range of microbial mutagenicity assays. Loxtidine was inactive in the mouse micronucleus test after oral administration. The potential nitrosatability of loxtidine was investigated using an expanded version of the WHO Nitrosation Assay Procedure, and detectable quantities of mutagenic nitroso-species were not formed. The subsequent appearance of carcinoid tumours within the gastric fundus of rodents treated orally with loxtidine for most of their natural lifespan, led to additional assays being carried out on this compound to determine whether the tumorigenic effects were due to alternative mutagenic mechanisms. Negative results were obtained in an in vitro unscheduled DNA synthesis assay using primary rat hepatocytes, and an assay for spindle damaging agents using Muntjac skin fibroblasts. It can be concluded from these results that loxtidine is unlikely to be a genotoxic carcinogen. The increase in carcinoid tumour incidence observed in rats and mice after loxtidine treatment was probably related to the prolonged achlorhydria produced by this potent unsurmountable histamine H2-receptor antagonist.

Comparison of the 5-hydroxytryptamine3 (serotonin) antagonist ondansetron (GR 38032F) with high-dose metoclopramide in the control of cisplatin-induced emesis.

To compare ondansetron (GR 38032F), a 5-hydroxytryptamine3-receptor antagonist, with metoclopramide in the prophylaxis of acute cisplatin-induced emesis, we conducted a double-blind crossover study in 97 patients scheduled to receive cisplatin (80 to 100 mg per square meter of body-surface area) for treatment of cancer. None had received chemotherapy before this trial. Among the 76 patients who satisfactorily completed both parts of the study, complete or nearly complete control of emesis (i.e., no episodes of emesis occurred, or only one or two) was achieved in 57 of 76 treatments (75 percent) with ondansetron and in 32 of 76 treatments (42 percent) with metoclopramide (P less than 0.001). Ondansetron was also more effective in controlling acute nausea, as assessed with a visual-analogue scale (P = 0.019) or a graded scale (P = 0.024). There was a significant preference among patients for ondansetron (55 vs. 26 percent; P = 0.006). Dystonic reactions were observed during three treatments with metoclopramide; both agents were otherwise well tolerated. We conclude that ondansetron is more effective than metoclopramide in the control of cisplatin-induced nausea and vomiting, and that this suggests that serotonin is an important mediator of this side effect.

Comparison of the anti-emetic efficacy of different doses of ondansetron, given as either a continuous infusion or a single intravenous dose, in acute cisplatin-induced emesis. A multicentre, double-blind, randomised, parallel group study. Ondansetron Study Group.

A total of 535 chemotherapy naive, hospitalised patients (263 male/272 female) scheduled to receive cisplatin (50-120 mg m-2)-containing regimens participated in a randomised, double-blind, parallel group study to evaluate the efficacy and safety of three intravenous dose schedules of ondansetron in the prophylaxis of acute nausea and emesis. One hundred and eighty two patients received a loading dose of 8 mg of ondansetron followed by a 24 h infusion of 1 mg h-1 (group 1); 180 and 173 patients received single doses of 32 mg (group II) and 8 mg (group III) respectively, followed by a 24 h placebo infusion. Complete and major control (less than or equal to 2 emetic episodes) of acute emesis was achieved in 74% of patients in group I, 78% in group II and 74% in group III. Seventy seven per cent of the patients in group I, and 75% of patients in groups II and III respectively experienced no or mild nausea during the 24 h observation period. A retrospective stratification of the efficacy data on the basis of patient gender showed the response rate in females to be significant lower (43% vs 67%; less than 0.001). Ondanestron was well tolerated; mild headache was the most commonly reported adverse event (11% of patients) with a similar incidence in the three groups of patients. In conclusion, a single intravenous dose of 8 mg of ondansetron given prior to chemotherapy is as effective as a 32 mg daily dose given as either a single dose of a continuous infusion in the prophylaxis of acute cisplatin-induced emesis.