Abstract Background Pupil reactivity and the Glasgow Coma Scale (CCS) score are the most clinically relevant information to predict the survival of traumatic brain injury (TBI) patients. Objective We evaluated the accuracy of the CCS-Pupil score (CCS-P) as a prognostic index to predict hospital mortality in Brazilian patients with severe TBI and compare it with a model combining CCS and pupil response with additional clinical and radiological prognostic factors. Methods Data from 1,066 patients with severe TBI from 5 prospective studies were analyzed. We determined the association between hospital mortality and the combination of CCS, pupil reactivity, age, glucose levels, cranial computed tomography (CT), or the CCS-P score by multivariate binary logistic regression. Results Eighty-five percent (n = 908) of patients were men. The mean age was 35 years old, and the overall hospital mortality was 32.8%. The area under the receiver operating characteristic curve (AUROC) was 0.73 (0.70–0.77) for the model using the CCS-P score and 0.80 (0.77–0.83) for the model including clinical and radiological variables. The CCS-P score showed similar accuracy in predicting the mortality reported for the patients with severe TBI derived from the International Mission for Prognosis and Clinical Trials in TBI (IMPACT) and the Corticosteroid Randomization After Significant Head Injury (CRASH) studies. Conclusion Our results support the external validation of the CCS-P to predict hospital mortality following a severe TBI. The predictive value of the CCS-P for long-term mortality, functional, and neuropsychiatric outcomes in Brazilian patients with mild, moderate, and severe TBI deserves further investigation.

Resumo Antecedentes A reatividade pupilar e o escore da Escala de Coma de Glasgow (ECC) representam as informações clínicas mais relevantes para predizer a sobrevivência de pacientes com traumatismo cranioencefálico (TCE). Objetivo Avaliar a acurácia da ECC com resposta pupilar (ECC-P) como índice prognóstico para predizer mortalidade hospitalar em pacientes brasileiros acometidos por TCE grave e compará-lo com um modelo combinando ECC e resposta pupilar com fatores prognósticos radiológicos. Métodos Foram analisados dados de 1.066 pacientes com TCE grave de 5 estudos prospectivos. Foi determinada a associação entre mortalidade hospitalar e a combinação de ECC, reatividade pupilar, idade, níveis glicêmicos, tomografia computadorizada (TC) de crânio ou o escore ECC-P por regressão logística binária multivariada. Resultados Oitenta e cinco por cento (n = 908) dos pacientes eram homens. A média de idade foi de 35 anos e a mortalidade hospitalar geral foi de 32,8%. A AUROC (em português, Curva Característica de Operação do Receptor) foi de 0,73 (0,70–0,77) para o modelo utilizando o escore ECC-P e de 0,80 (0,77–0,83) para o modelo incluindo variáveis clínicas e radiológicas. O escore ECC-P mostrou acurácia semelhante na previsão da mortalidade relatada para pacientes com TCE grave derivados dos estudos International Mission for Prognosis and Clinical Trials in TBI (IMPACT, na sigla em inglês) e Corticosteroid Randomization After Significant Head Injury (CRASH, na sigla em inglês). Conclusão Nossos resultados apoiam a validação externa da ECC-P para prever a mortalidade hospitalar após um TCE grave. O valor preditivo da ECC-P para mortalidade a longo prazo, resultados funcionais e neuropsiquiátricos em pacientes brasileiros com TCE leve, moderado e grave precisam ser investigados.

Objective: Parkinson’s disease (PD) is often accompanied by stigma, which could contribute to a worse prognosis. The objective of this study is to identify the variables associated with stigma in PD patients who are candidates for deep brain stimulation (DBS). Methods: We investigated sociodemographic and clinical variables associated with stigma in a sample of 54 PD patients indicated for DBS. The independent variables were motor symptoms assessed by the Movement Disorder Society‐sponsored revision of the Unified Parkinson Disease Rating Scale (MDS-UPDRS III), depressive symptoms measured by the Hospital Anxiety and Depression Scale, age, disease duration and the presence of a general medical condition. The Mobility, Activities of daily living and Emotional well-being domains of the 39-item Parkinson’s Disease Questionnaire (PDQ-39) were also investigated as independent variables, and the Stigma domain of the PDQ-39 scale was considered the outcome variable. Results: After multiple linear regression analysis, activities of daily living remained associated with the Stigma domain (B = 0.42 [95%CI 0.003-0.83], p = 0.048). The full model accounted for 15% of the variance in the Stigma domain (p = 0.03). Conclusions: Although causal assumptions are not appropriate for cross-sectional studies, the results suggest that ADL difficulties could contribute to greater stigma in PD patients with refractory motor symptoms who are candidates for DBS.

RESUMO A sonolência e o comprometimento cognitivo são queixas comuns na epilepsia. Investigamos se a sonolência relatada pelo paciente está associada ao desempenho cognitivo na epilepsia do lobo temporal mesial refratária com esclerose do hipocampo (ELTM-EH). 71 pacientes com ELTM-EH foram avaliados pela Escala de Sonolência de Stanford (ESS) antes da avaliação neuropsicológica. A média na ESS foi comparada com a de controles. Cada teste foi comparado entre os pacientes com sonolência (ESS ≥ 3) ou sem sonolência (ESS <3). Diferenças foram controladas por regressão logística múltipla. Os pacientes relataram uma sonolência maior do que os controles (p <0,0001). Após a regressão, a sonolência relatada pelos pacientes mostrou-se associada a apenas um teste (RAVLT total). Os pacientes com ELTM-EH referem mais sonolência do que os controles, mas esta não foi associada com a cognição. Se confirmado em outras populações, nossos resultados implicarão na tomada de decisão sobre o impacto da sonolência no contexto neuropsicológico.

ABSTRACT Sleepiness and cognitive impairment are common symptoms observed in patients with epilepsy. We investigate whether self-reported sleepiness is associated with cognitive performance in patients with refractory mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). Seventy-one consecutive patients with MTLE-HS were evaluated with the Stanford Sleepiness Scale (SSS) before neuropsychological evaluation. Their mean SSS scores were compared with controls. Each cognitive test was compared between patients with (SSS ≥ 3) or without sleepiness (SSS < 3). Imbalances were controlled by regression analysis. Patients reported a significantly higher degree of sleepiness than controls (p < 0.0001). After multiple linear regression analysis, only one test (RAVLT total) remained associated with self-reported sleepiness. Conclusion: Self-reported sleepiness was significantly higher in MTLE-HS patients than controls, but did not affect their cognitive performance. If confirmed in other populations, our results may have implications for decision making about sleepiness screening in neuropsychological settings.

RESUMOObjetivo Realizar a adaptação transcultural do questionário “Scales of Cognitive Ability for Traumatic Brain Injury”(SCATBI) para avaliação das habilidades linguístico-cognitivas após traumatismo cranioencefálico (TCE).Método Após as fases de tradução e retrotradução do instrumento, uma equipe multidisciplinar julgou as versões obtidas quanto à manutenção do conceito original, compreensibilidade e clareza para a população brasileira. A versão final foi testada em 55 indivíduos saudáveis.Resultados Os indivíduos possuíam média de idade de 41,75 anos (18-81), escolaridade de 12,96 anos, e 69% eram mulheres. Escores mais altos no SCATBI foram positivamente correlacionados com a escolaridade (p < 0,001) e status sócio-econômico (p = 0,001), enquanto indivíduos mais velhos tiveram pior desempenho (p = 0,001). Na comparação dos gêneros houve diferença estatisticamente significativa apenas no domínio Organização (p = 0,02).Conclusão Por ser uma bateria cognitiva abrangente, que avalia indivíduos em extensa faixa de idade, a versão brasileira do SCATBI é um instrumento sensível para diagnóstico e acompanhamento das alterações cognitivas comumente prejudicadas após um TCE.

ABSTRACTObjective To perform the cross-cultural adaptation of the “Scales of Cognitive Ability for Traumatic Brain Injury” (SCATBI).Method After the translation and back-translation phases, a multidisciplinary committee judged and elaborated versions in order to maintain its conceptual equivalence, content, comprehensibility and contextual adjustment for Brazilian population. The final version was tested on 55 healthy subjects.Results The individuals’ mean age was 41.75 ± 17.40 years (range = 18-81), 69% were women and they had a mean schooling of 12.96 ± 4.55 years. Higher total scores were positively correlated with years of schooling (p < 0.001) and social-economic status (p = 0.001), while older aged individuals performed worse than younger ones (p = 0.001). Both genders performed similarly on all domains of the instrument, except for “organization” ability, where women performed significantly better than men (p = 0.02).Conclusion The Brazilian version of SCATBI is a useful tool for the diagnosis and monitoring of cognitive impairments after a traumatic brain injury.

Objective: To evaluate predictors of non-return to work (nRTW) among social, demographic, clinical, and psychiatric variables after severe traumatic brain injury (TBI) in a cohort of Brazilian patients. Methods: Prospective study. Forty-three community-dwelling individuals treated at a Level I trauma center at the time of TBI were evaluated 18 months after trauma. Measures included DSM-IV-TR criteria for personality changes after TBI and Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) to assess psychiatric diagnosis. Hospitalization variables included Glasgow Coma Scale scores, pupil examination findings, associated limb trauma, Marshall computed tomography classification, and blood glucose levels. Results: After multiple logistic regression analysis, only the diagnosis of personality changes was found to be independently associated with nRTW, with an adjusted odds ratio of 10.92 (p = 0.02, 95% confidence interval 1.41-84.28). Conclusions: In this study, personality changes were an independent predictor of nRTW after severe TBI. Ways to predict risk factors associated with personality changes after severe brain injury could aid in identification of early and effective interventions that might ease the burden associated with this condition.

Objective: To evaluate the validity and utility of the Hamilton Rating Scale for Depression (HAM-D), Beck Depression Inventory (BDI), and Hospital Anxiety and Depression Scale (HADS) as screening tools for depression after severe traumatic brain injury (TBI). Methods: Forty-six consecutive survivors of severe TBI were evaluated at a median of 15 months after injury. Receiver operating characteristic (ROC) analysis was performed using HAM-D, BDI, and HADS as predictors, and the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) as gold standard. Results: The area under the curve (AUC) for HAM-D was 0.89, and the optimal cutoff point was 7 (sensitivity 92.9%, specificity 78.1%); for the BDI, the AUC was 0.946 and the optimal cutoff point was 14 (sensitivity 92.3%, specificity 96.7%); for the HADS, the AUC was 0.947 and the optimal cutoff point was 9 (sensitivity 100%, specificity 80.7%); and for the HADS depression subscale, the AUC was 0.937 and the optimal cutoff point was 6 (sensitivity 92.9%, specificity 83.9%). There were no statistically significant differences among the AUCs. Conclusion: Our findings support a high validity and utility for the HAM-D, BDI, and HADS as screening tools for depression in patients with severe TBI, without major changes in standard cutoff points.

INTRODUÇÃO: A epilepsia é uma doença neurológica prevalente que pode causar fracasso escolar devido a fatores como severidade das crises, pouca informação sobre a doença e estigma. Este estudo teve como objetivo avaliar a percepção do estigma e conhecimento em epilepsia pelos profissionais de educação, fornecer informações corretas sobre epilepsia e reduzir o estigma através de um curso de curta duração. METODOLOGIA: Os dados sociodemográficos e o grau de estigma foram obtidos através da Escala de Estigma em Epilepsia. O grau de conhecimento em epilepsia foi obtido através da adaptação do Questionário Sobre Epilepsia. O teste de correlação de Pearson ou Spearman foi utilizado para análise das variáveis numéricas contínuas paramétricas ou não-paramétricas. O valor de p<0,05 foi considerado significante. RESULTADOS: Duzentos e vinte e cinco sujeitos foram entrevistados em três cidades do Sul do Brasil. Aproximadamente 65% deles abriria a boca do estudante durante uma crise e o grau do estigma avaliado com a Escala de Estigma em Epilepsia pré-curso foi de 45.4±16.61. CONCLUSÃO: Os dados indicam que os profissionais da educação têm um conhecimento pacial sobre epilepsia e que um curso de curta duração foi capaz de aumentar o conhecimento e reduzir o estigma na população estudada.

INTRODUCTION: Epilepsy is a prevalent neurological disorder that may cause school failure due to several factors such as seizure severity, lack of information about the condition and stigma. This study aimed to evaluate the degree of perceived stigma and knowledge towards epilepsy among education professionals, and additionally, provide them correct information about epilepsy to reduce stigma through a training course. METHODS: Social and demographic data, as well as the degree of stigma were obtained through the Stigma Scale of Epilepsy. To estimate the level of educational professionals' knowledge about epilepsy we used the Questionnaire about Epilepsy. Statistical analysis consisted of Pearson's or Spearman's correlation tests for numerical parametric or non-parametric variables were used to determine potential significant associations. A p <0.05 was considered significant. RESULTS: Two hundred and twenty-five education professionals were interviewed in three different cities in Southern Brazil. Approximately 65% of subjects would attempt to open the mouth of a student during a seizure and the stigma measured by Stigma Scale of Epilepsy before the course was 45.4±16.61. CONCLUSION: The data indicate that education professionals have partial knowledge about epilepsy and a short duration course would be able to improve it and reduce its stigma in this population.

OBJETIVO: Avaliar a função hipofisária-gonadal nos pacientes vítimas de TCE graves ocorridos na Grande Florianópolis, entre 2000 e 2004. MÉTODOS: Foram estudados 30 pacientes, sendo 22 homens e 8 mulheres, submetidos à avaliação clínica e laboratorial em seguimento médio de 4 anos após a data do traumatismo. RESULTADOS: Os homens possuíam em média 38 anos no ano da avaliação, enquanto as mulheres, 42 anos. A maioria dos traumatismos está relacionada aos acidentes de trânsito (63,3%). Três pacientes (10%) estavam com valores de FSH abaixo do normal e apenas 1 paciente (3,3%) apresentou LH alterado. Nas mulheres avaliadas, os níveis de estradiol foram normais. Na população masculina, foi evidenciado nível de testosterona baixo em 2 pacientes (9,1%). Todos os pacientes apresentavam normoprolactinemia. CONCLUSÃO: Dois casos de hipogonadismo masculino (9,1%) foram diagnosticados neste estudo. Isso indica a necessidade de atenção aos pacientes sobreviventes de TCE grave para realizar diagnóstico precoce de hipogonadismo.

OBJECTIVE: The purpose of this study is to evaluate pituitary function impairment in order to verify the prevalence of sex hormone deficiency and to analyze the profile of TBI population. METHODS: Thirty patients were studied, 22 were male and 8 were female. All patients had their gonadal function assessed and they were evaluated at a median of 4 years post-trauma. RESULTS: The average age of the men was 38 years at the time of the evaluation, while the mean age of women was 42 years. The majority of TBI was related to traffic accidents (63.3%). Three patients (10%) had low FSH and only 1 patient (3.3%) had low LH. There was no biochemical evidence of hypogonadism in women. Two male patients presented low testosterone (9.1%) and were diagnosed with hypogonadism. Prolactin levels were normal in all patients. CONCLUSION: Two cases of hypogonadism (9.1%) were diagnosed among men in this study. It is therefore necessary that medical professionals involved in the management of TBI patients are aware of hypogonadism as a complication of TBI, in order to diagnose it early.

O traumatismo cranioencefálico (TCE) é a causa mais comum de morte e incapacidade em adultos jovens. Desordens neuroendócrinas pós-TCE vêm sendo reconhecidas cada vez mais nos últimos anos devido à sua potencial contribuição para a morbidade e, possivelmente, mortalidade após trauma. Alterações acentuadas do eixo hipotálamo-hipófise foram documentadas nas fases aguda e crônica pós-TCE. Estudos prospectivos e longitudinais têm mostrado que algumas anormalidades são transitórias. Por outro lado, existe uma elevada frequência de deficiências hormonais hipofisárias a longo prazo entre os sobreviventes de TCE, que varia de 15% a 68%. Hipogonadismo pós-TCE é um achado comum a longo prazo e estima-se que, em média, 16% dos sobreviventes sejam afetados. Hipogonadismo pós-TCE tem sido associado a resultados adversos tanto na fase aguda quanto na fase crônica após a lesão. Esses dados reforçam a necessidade da identificação e adequado tratamento das deficiências hormonais, para otimizar a recuperação do paciente, melhorar a qualidade de vida e evitar as consequências negativas a longo prazo do hipogonadismo não tratado.

Traumatic brain injury (TBI) is the most common cause of death and disability in young adults. Post-TBI neuroendocrine disorders have been increasingly acknowledged in recent years due to their potential contribution to morbidity and, probably, to mortality after trauma. Marked alterations of the hypothalamic-pituitary axis during the post-TBI acute and chronic phases have been reported. Prospective and longitudinal studies have shown that some abnormalities are transitory. On the other hand, there is a high frequency (15% to 68%) of pituitary hormone deficiency among TBI survivors in a long term setting. Post-TBI hypogonadism is a common finding after cranial trauma, and it is predicted to develop in 16% of the survivors in the long term. Post-TBI hypogonadism has been associated with adverse results in the acute and chronic phases after injury. These data reinforce the need for identification of hormonal deficiencies and their proper treatment, in order to optimize patient recovery, improve their life quality, and avoid the negative consequences of non-treated hypogonadism in the long term.

OBJETIVO: Comparar os tratamentos para hipogonadismo masculino disponíveis no Brasil. MÉTODOS: Foram selecionados 32 homens com hipogonadismo tardio ("andropausa") no Hospital de Guarnição de Florianópolis. O diagnóstico foi feito por meio do questionário AMS (acima de 27 pontos) e dos níveis diminuídos de testosterona total dosada (abaixo de 300 ng/dL) e/ou testosterona livre calculada (abaixo de 6,5 ng/dL). Os pacientes foram divididos em três grupos de tratamento parenteral (Deposteron® - 11 pacientes; Durateston® - 11 pacientes; Nebido® - 10 pacientes). RESULTADOS: Clinicamente, o tratamento com Nebido® mostrou-se superior ao tratamento com Deposteron® (média do percentual de melhora; p = 0,03) e ao Durateston® (média do questionário AMS pós-tratamento; p = 0,03). Laboratorialmente, o tratamento com Nebido® mostrou níveis de testosterona superiores ao Deposteron® e Durateston® (p < 0,001). CONCLUSÕES: As três formulações de testosterona parenteral existentes no mercado brasileiro são eficientes em elevar os níveis de testosterona e melhorar clinicamente pacientes hipogonádicos, sendo o Nebido® mais efetivo clínica e laboratorialmente.

OBJECTIVE: To compare the modalities of treatment for male hypogonadism available in Brazil. METHODS: Thirty-two men with late-onset hypogonadism ("andropause") were followed-up in the Hospital de Guarnição de Florianópolis, in Florianópolis, south Brazil. Clinical diagnosis was established according to AMS questionnaire (positive if equal to or higher than 27 points), and laboratorial diagnosis was made through low values of total testosterone (under 300 ng/dL) and/or free calculated testosterone (under 6.5 ng/dL). Patients were randomized to three non-enteral treatment groups (Deposteron® - 11 patients; Durateston® - 11 patients; and Nebido® - 10 patients). RESULTS: Clinically, Nebido® seemed to be superior when compared to Deposteron® (mean value of improvement percentage; p = 0.03) and when compared to Durateston® (post-treatment average AMS score; p = 0.03). According to laboratorial analysis, Nebido® showed higher testosterone levels than Deposteron® and Durateston® (p < 0.001). CONCLUSIONS: All non-enteral testosterone formulas available in the Brazilian market are efficient in raising testosterone levels and in clinical improvement of hypogonadal patients. Nebido® showed both a better clinical and laboratorial effectiveness.

Introdução: Um dos objetivos da avaliação pré-cirúrgica de pacientes com epilepsia do lobo temporal é detectar pacientes com mau prognóstico cirúrgico para o controle das crises epilépticas. Teoricamente, testes neuropsicológicos poderiam ser empregados com tal finalidade. Objetivo: Avaliar se testes de memória verbal e visual podem ser utilizados como preditores isolados de resultado cirúrgico do controle de crises em pacientes com epilepsia do lobo temporal mesial associada a esclerose hipocampal refratária ao tratamento farmacológico. Métodos: Em um estudo de coorte retrospectivo, usando como endpoint o controle de crises epilépticas, nós avaliamos 187 pacientes, correlacionando aspectos clínicos, avaliação cognitiva, dados de neuroimagem, dados demográficos e achados eletrofisiológicos com o resultado do controle de crises após a lobectomia nesses pacientes. Resultados: Um prognóstico desfavorável no período pós-operatório foi observado apenas em associação com baixos escores de reprodução visual (memória visual). Contudo, após uma correção de Bonferroni, necessária para reduzir a chance de erro tipo I, esse resultado mostrou-se espúrio. Conclusão: Nós concluímos que os testes neuropsicológicos de memória verbal e visual, tais como utilizados na avaliação pré-cirúrgica de rotina dos nossos pacientes com epilepsia do lobo temporal, não são bons preditores isolados de resultado cirúrgico.

Introduction: One of the objectives of pre-surgical evaluation in mesial temporal epilepsy associated to hippoocampal sclerosis is the identification of patients with bad surgical prognosis for seizure control. At least theoretically, neuropsychological tests could be used in this venue. Objective: To evaluate whether verbal and visual memory tests can be used as isolate predictors of the post-surgical seizure outcome in patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis refractory to pharmacological treatment. Methods: In a retrospective cohort study using the control of epileptic seizures as end-point, we evaluated 187 patients and calculated the correlation of clinical variables, cognitive evaluation, neuroimaging data, demographic data and electrophysiological findings with the result of seizure control after lobectomy in these patients. Results: An unfavorable prognosis during the postoperative period was observed only in association with low visual reproduction scores (visual memory). However, after Bonferroni correction, which was necessary to reduce the chance of type I error, this result was found to be spurious. Conclusion: We conclude that neuropsychological tests of verbal and visual memory such as those used in the routine presurgical evaluation of our patients with temporal lobe epilepsy are not good isolated predictors of surgical outcome.

A epilepsia é uma das causas mais comuns de incapacidade funcional. Comorbidades psiquiátricas, como as psicoses, estão freqüentemente associadas à epilepsia. Psicoses na epilepsia (PNE) requerem tratamento farmacológico mais cuidadoso, levando-se em conta a propensão dos antipsicóticos (AP) em provocar crises convulsivas e o risco de interação farmacocinética com as drogas antiepilépticas (DAE). Após uma breve descrição da classificação e das principais características clínicas das PNE, foram discutidos alguns aspectos gerais do tratamento farmacológico das PNE e o uso de AP típicos e atípicos, destacando seu potencial para diminuir o limiar epileptogênico (LE), bem como possíveis interações AP/DAE. Os AP atípicos, à exceção da clozapina, demonstraram exercer menor influência sobre o LE. Quanto às interações farmacocinéticas, as principais DAE estiveram relacionadas com um aumento importante do metabolismo dos AP. Portanto, apesar do risco para convulsões por AP ser dose-dependente, doses mais elevadas de AP podem ser necessárias no tratamento das PNE.

Epilepsy is one of the main causes of functional disability, and it is usually associated to psychiatric comorbidity, such as psychosis of epilepsy (POE). POE requires more careful pharmacological treatment, considering the propensity of the antipsychotics (AP) to provoke seizures and the risk of pharmacokinetic interaction with anti-epileptic drugs (AEDs). We discussed the classification and the main types of POE, as well as some characteristics of AP typical and atypical, its potential to decrease the epileptogenic threshold (ET) and possible interactions between AP and AED. Atypical AP, except clozapine, disclosed smaller influence on ET than typical AP. Regarding pharmacokinetic interactions, AEDs are related with a significant increase of the AP metabolism. Therefore, in spite of the risk for AP induced convulsions be dose-dependent, higher doses of AP can be necessary in the treatment of POE.

Since William James (1890) first distinguished primary from secondary memory, equivalent to short- and long-term memory, respectively, it has been assumed that short-term memory processes are in charge of cognition while long-term memory is being consolidated. From those days a major question has been whether short-term memory is merely a initial phase of long-term memory, or a separate phenomena. Recent experiments have shown that many treatments with specific molecular actions given into the hippocampus and related brain areas after one-trial avoidance learning can effectively cancel short-term memory without affecting long-term memory formation. This shows that short-term memory and long-term memory involve separate mechanisms and are independently processed. Other treatments, however, influence both memory types similarly, suggesting links between both at the receptor and at the post-receptor level, which should not be surprising as they both deal with nearly the same sensorimotor representations. This review examines recent advances in short- and long-term memory mechanisms based on the effect of intra-hippocampal infusion of drugs acting upon neurotransmitter and signal transduction systems on both memory types.