Analysing vaccine efficacy evaluated in phase 3 clinical trials carried out during outbreaks.

In this paper we examine several definitions of vaccine efficacy (VE) that we found in the literature, for diseases that express themselves in outbreaks, that is, when the force of infection grows in time, reaches a maximum and then vanishes. The fact that the disease occurs in outbreaks results in several problems that we analyse. We propose a mathematical model that allows the calculation of VE for several scenarios. Vaccine trials usually needs a large number of volunteers that must be enrolled. Ideally, all volunteers should be enrolled in approximately the same time, but this is generally impossible for logistic reasons and they are enrolled in a fashion that can be replaced by a continuous density function (for example, a Gaussian function). The outbreak can also be replaced by a continuous density function, and the use of these density functions simplifies the calculations. Assuming, for example Gaussian functions, one of the problems one can immediately notice is that the peak of the two curves do not occur at the same time. The model allows us to conclude: First, the calculated vaccine efficacy decreases when the force of infection increases; Second, the calculated vaccine efficacy decreases when the gap between the peak in the force of infection and the peak in the enrollment rate increases; Third, different trial protocols can be simulated with this model; different vaccine efficacy definitions can be calculated and in our simulations, all result are approximately the same. The final, and perhaps most important conclusion of our model, is that vaccine efficacy calculated during outbreaks must be carefully examined and the best way we can suggest to overcome this problem is to stratify the enrolled volunteer's in a cohort-by-cohort basis and do the survival analysis for each cohort, or apply the Cox proportional hazards model for each cohort.

Live, Attenuated, Tetravalent Butantan-Dengue Vaccine in Children and Adults.

BACKGROUND: Butantan-Dengue Vaccine (Butantan-DV) is an investigational, single-dose, live, attenuated, tetravalent vaccine against dengue disease, but data on its overall efficacy are needed. METHODS: In an ongoing phase 3, double-blind trial in Brazil, we randomly assigned participants to receive Butantan-DV or placebo, with stratification according to age (2 to 6 years, 7 to 17 years, and 18 to 59 years); 5 years of follow-up is planned. The objectives of the trial were to evaluate overall vaccine efficacy against symptomatic, virologically confirmed dengue of any serotype occurring more than 28 days after vaccination (the primary efficacy end point), regardless of serostatus at baseline, and to describe safety up to day 21 (the primary safety end point). Here, vaccine efficacy was assessed on the basis of 2 years of follow-up for each participant, and safety as solicited vaccine-related adverse events reported up to day 21 after injection. Key secondary objectives were to assess vaccine efficacy among participants according to dengue serostatus at baseline and according to the dengue viral serotype; efficacy according to age was also assessed. RESULTS: Over a 3-year enrollment period, 16,235 participants received either Butantan-DV (10,259 participants) or placebo (5976 participants). The overall 2-year vaccine efficacy was 79.6% (95% confidence interval [CI], 70.0 to 86.3) - 73.6% (95% CI, 57.6 to 83.7) among participants with no evidence of previous dengue exposure and 89.2% (95% CI, 77.6 to 95.6) among those with a history of exposure. Vaccine efficacy was 80.1% (95% CI, 66.0 to 88.4) among participants 2 to 6 years of age, 77.8% (95% CI, 55.6 to 89.6) among those 7 to 17 years of age, and 90.0% (95% CI, 68.2 to 97.5) among those 18 to 59 years of age. Efficacy against DENV-1 was 89.5% (95% CI, 78.7 to 95.0) and against DENV-2 was 69.6% (95% CI, 50.8 to 81.5). DENV-3 and DENV-4 were not detected during the follow-up period. Solicited systemic vaccine- or placebo-related adverse events within 21 days after injection were more common with Butantan-DV than with placebo (58.3% of participants, vs. 45.6%). CONCLUSIONS: A single dose of Butantan-DV prevented symptomatic DENV-1 and DENV-2, regardless of dengue serostatus at baseline, through 2 years of follow-up. (Funded by Instituto Butantan and others; DEN-03-IB ClinicalTrials.gov number, NCT02406729, and WHO ICTRP number, U1111-1168-8679.).

Pain in Patients With Type 2 Diabetes-Related Polyneuropathy Is Associated With Vascular Events and Mortality.

PURPOSE: Type 2 diabetes-related polyneuropathy (DPN) is associated with increased vascular events and mortality, but determinants and outcomes of pain in DPN are poorly understood. We sought to examine the effect of neuropathic pain on vascular events and mortality in patients without DPN, DPN with pain (DPN + P), and DPN without pain (DPN-P). METHODS: A retrospective cohort study was conducted within a large health system of adult patients with type 2 diabetes from January 1, 2009 through December 31, 2016. Using an electronic algorithm, patients were classified as no DPN, DPN + P, or DPN-P. Primary outcomes included number of vascular events and time to mortality. Independent associations with DPN + P were evaluated using multivariable negative binomial and Cox proportional hazards regression models, adjusting for demographics, socioeconomic characteristics, and comorbidities. RESULTS: Of 43 945 patients with type 2 diabetes (age 64.6 ±â€…14.0 years; 52.1% female), 13 910 (31.7%) had DPN: 9104 DPN + P (65.4%) vs 4806 DPN-P (34.6%). Vascular events occurred in 4538 (15.1%) of no DPN patients, 2401 (26.4%) DPN + P, and 1006 (20.9%) DPN-P. After adjustment, DPN + P remained a significant predictor of number of vascular events (incidence rate ratio [IRR] = 1.55, 95% CI, 1.29-1.85), whereas no DPN was protective (IRR = 0.70, 95% CI, 0.60-0.82), as compared to DPN-P. Compared to DPN-P, DPN + P was also a significant predictor of mortality (hazard ratio = 1.42, 95% CI, 1.25-1.61). CONCLUSIONS: Our study found a significant association between pain in DPN and an increased risk of vascular events and mortality. This observation warrants longitudinal study of the risk factors and natural history of pain in DPN.

A Review of Available Treatments, Clinical Evidence, and Guidelines for Diagnosis and Treatment of Pediatric Multiple Sclerosis in the United States.

Pediatric multiple sclerosis is associated with challenges in prompt diagnosis and uncertainty regarding optimal treatment. This review aimed to identify treatment guidelines or consensus statements for pediatric patients with multiple sclerosis, US Food and Drug Administration (FDA)-approved treatment options for pediatric multiple sclerosis, and any randomized controlled trials and observational studies examining available pharmacologic treatments in the pediatric multiple sclerosis population. Literature searches were performed in MEDLINE (1946-2016), EMBASE (1974-2016), and the Cochrane Central Register of Controlled Trials to identify treatment guidelines or consensus statements, pediatric multiple sclerosis treatment approvals, and randomized controlled trials and observation studies that examine the safety and effectiveness of available disease-modifying therapies. Only 3 consensus statements provided recommendations for pharmacologic treatments for children, all 3 published before the most recent revisions of the pediatric multiple sclerosis diagnostic guidelines. Despite the changes to the clinical landscape of pediatric multiple sclerosis with the introduction of diagnostic guidelines, fingolimod is the only FDA-approved treatment for pediatric multiple sclerosis in the United States. The effectiveness and safety of other disease-modifying therapies suggested by consensus statements have been reported in relatively small prospective and retrospective observational studies. Clinical evidence from a recently completed randomized controlled trial and future global registries can inform treatment decisions for the pediatric multiple sclerosis population.

Cost analysis of multiple sclerosis in Brazil: a cross-sectional multicenter study.

BACKGROUND: Multiple sclerosis (MS) is a central nervous system disease associated with irreversible progression of disability, which imposes a substantial socioeconomic onus. The objective of this study was to determine the economic impact of multiple sclerosis from the Brazilian household and healthcare system perspectives. Secondary objectives were to assess the impact of fatigue on daily living and health-related quality of life (HRQL) of MS patients. METHODS: This is a cross-sectional study in which Brazilian eligible patients attending eight major MS specialized sites answered an interview capturing data on demographics, disease characteristics and severity, comorbidities, resource utilization, fatigue, utilities and health-related quality of life from November/2011 to May/2012 . Costs were assessed considering a prevalence-based approach within 1 year of resource consumption and were estimated by multiplying the amount used by the corresponding unit cost. Patients were classified as having mild, moderate or severe disability according to the Expanded Disability Status Scale (EDSS). RESULTS: In total, 210 patients who met eligibility criteria were included, 40 % had mild, 43 % moderate and 16 % severe disability; disability level was missing for 1 %. The average total direct cost per year was USD 19,012.32 (SD = 10,465.96), and no statistically significant differences were not observed according to MS disability level (p = 0.398). The use of disease modifying therapies (DMTs) corresponded to the majority of direct expenditures, especially among those patients with lower levels of disability, representing around 90 % of total costs for mild and moderate MS patients. It was also observed that expenses with medical (except DMTs) and non-medical resources are higher among patients with more severe disease. Worsening disability also had an important influence on health-related quality of life and self-perceived impact of fatigue on daily living. CONCLUSION: Our data demonstrates the significant economic impact of MS on both Brazilian household and health system, in terms of DMTs and other disease management costs. When patients move upwards on the disease severity scale, costs with health resources other than drugs are significantly increased.

The profile of patients followed at the Neuroimmunology Clinic at UNIFESP: 20 years analysis.

OBJECTIVE: To describe the clinical activities at the Neuroimmunology Clinic of the Universidade Federal de São Paulo (UNIFESP) from 1994 to 2013. METHOD: The final diagnosis of all patients that attended the center was reviewed and established upon specific guidelines for each disease. The number of total appointments and extra clinical activities (reports and prescriptions) were also analyzed, as are part of routine activities. RESULTS: 1,599 patients attended the Clinic from 1994 to 2013: 816 with multiple sclerosis (MS), 172 with clinical isolated syndromes, 178 with neuromyelitis optica (NMO), 216 with other demyelinating disease, 20 with metabolic disorder, 42 with a vascular disease and 155 with other or undetermined diagnosis. A mean 219 outpatient visits and 65 extra clinical activities were performed monthly. CONCLUSION: We identified that 15% of patients seen have NMO. As patients with NMO have a more severe disease than MS, this data may be important for planning local health care policies.

The profile of patients followed at the Neuroimmunology Clinic at UNIFESP: 20 years analysis / O perfil de pacientes atendidos no setor de Neuroimunologia da UNIFESP: análise de 20 anos

Objective To describe the clinical activities at the Neuroimmunology Clinic of the Universidade Federal de São Paulo (UNIFESP) from 1994 to 2013. Method The final diagnosis of all patients that attended the center was reviewed and established upon specific guidelines for each disease. The number of total appointments and extra clinical activities (reports and prescriptions) were also analyzed, as are part of routine activities. Results 1,599 patients attended the Clinic from 1994 to 2013: 816 with multiple sclerosis (MS), 172 with clinical isolated syndromes, 178 with neuromyelitis optica (NMO), 216 with other demyelinating disease, 20 with metabolic disorder, 42 with a vascular disease and 155 with other or undetermined diagnosis. A mean 219 outpatient visits and 65 extra clinical activities were performed monthly. Conclusion We identified that 15% of patients seen have NMO. As patients with NMO have a more severe disease than MS, this data may be important for planning local health care policies. .

Objetivo Descrever a casuística de pacientes atendidos no setor de Neuroimunologia da Universidade Federal de São Paulo (UNIFESP) de 1994 a 2013. Método Analisamos o diagnóstico final de todos os pacientes atendidos de 1999 a 2013, sendo o diagnóstico revisado na última consulta e estabelecido de acordo com os critérios específicos para cada doença. O volume de atendimentos clínicos e não clínicos (relatórios e receitas) foram contabilizados para avaliar a carga de trabalho da equipe. Resultados 1.599 pacientes foram avaliados: 816 com esclerose múltipla (EM), 172 com síndromes clínicas isoladas, 178 com neuromielite óptica (NMO), 216 com outras doenças desmielinizantes, 20 com doenças metabólicas, 42 com doenças vasculares e 155 com outros diagnósticos ou diagnósticos indefinidos. Identificamos uma média de 219 consultas e 65 solicitações de relatórios por mês. Conclusão Identificamos que 15% dos pacientes atendidos tem NMO. Por ser uma doença mais incapacitante que a EM estes dados podem ser importantes para o planejamento de políticas de saúde locais. .

Disease perceptions of Brazilian fibromyalgia patients: do they resemble perceptions from other countries?

The purpose of this study was to discover how Brazilian fibromyalgia patients perceive their disease. Fifteen women who fulfilled the American College of Rheumatology Classification Criteria for Fibromyalgia were given an individual semi-structured interview about their perception of fibromyalgia. There was a marked uniformity in the description of clinical symptoms, with diffuse pain and fatigue being considered the most important symptoms. Pain descriptions were imprecise as to the main localization but insidious pain of moderate intensity was frequently described. Other referred symptoms were: sleep disturbances, anxiety and memory and concentration difficulties. The following points were considered to be trigger events for pain: intense physical efforts, physical trauma, climate variation and genetic heritage. The reported modulating factors were: stressful events, emotional disturbances, climate variation and period of the day. Most patients reported being unable to control the symptoms of fibromyalgia. Religious support, reduction of tasks, physical exercises and short resting periods during the day were the main coping strategies mentioned by the interviewed patients. Their main concern was an eventual evolution to total physical incapacity and loss of independence in self-care. The clinical characteristics and patient perceptions in these Brazilian patients are very similar to those described in international studies.

Estudo qualitativo da percepção das pacientes sobre a fibromialgia / Qualitative study of patient’s perception of fibromyalgia

O conhecimento da percepção das pacientes sobre a fibromialgia pode ser utilizado para elaborar estratégias educativas. Essa abordagem pode reduzir a ansiedade gerada pelas incertezas decorrentes da falta de informações. OBJETIVO: conhecer a percepção das pacientes sobre a sua doença. MÉTODOS: estudou-se 15 mulheres que preencheram os Critérios de Classificação para Fibromialgia do Colégio Americano de Reumatologia. Realizou-se estudo qualitativo por meio de entrevistas semi-estruturadas sobre sua percepção da doença, dúvidas, preocupações e qualidade de vida. As informações foram gravadas e classificadas em categorias de relevância para os objetivos propostos. RESULTADOS: observa-se uma uniformidade nas descrições dos quadros clínicos. Dor e fadiga são os sintomas referidos como mais freqüentes e importantes. A dor é de difícil descrição, início insidioso e de intensidade moderada e severa. Registra-se a presença de fatores desencadeantes e moduladores. Outros sintomas descritos como relevantes são distúrbios do sono, ansiedade ou angústia e dificuldade de memória e/ou concentração. Os pacientes descrevem como eventos desencadeantes esforço físico exagerado, atividade ocupacional, trauma físico, variação climática brusca e herança genética. Foi referido pela maioria das pacientes incapacidade total de controlar a intensidade da sintomatologia. Tentativas como apoio religioso, redução na velocidade de execução de tarefas, exercícios físicos leves e períodos curtos de repouso durante o dia foram adotadas pelas pacientes. Quanto ao prognóstico, há uma incerteza para a maioria das pacientes. A principal preocupação é com a evolução para a incapacidade física definitiva. Em relação ao atendimento médico, queixam-se do desconhecimento dos médicos em geral sobre a fibromialgia e indiferença quanto ao seu sofrimento. As principais dúvidas referem-se à natureza da doença e ao prognóstico. CONCLUSÕES: os principais sintomas da fibromialgia são dor e fadiga; a ansiedade é uma característica importante. A incerteza quanto ao prognóstico e medo de incapacidade funcional definitiva é constante.