Diagnostic and therapeutic approach to chronic meningitis in Brazil: a narrative review.

BACKGROUND: Chronic meningitis (CM) is characterized by neurological symptoms associated with the evidence of cerebrospinal fluid pleocytosis lasting > 4 weeks. Studies on the management of CM in Brazil are scarce. OBJECTIVE: To critically review the literature on CM and propose a rational approach in the Brazilian scenario. METHODS: Narrative literature review discussing the epidemiology, clinical evaluation, basic and advanced diagnostic testing, and empirical and targeted therapy for the most relevant causes of CM. The present review was contextualized with the local experience of the authors. In addition, we propose an algorithm for the management of CM in Brazil. RESULTS: In Brazil, tuberculosis and cryptococcosis are endemic and should always be considered in CM patients. In addition to these diseases, neurosyphilis and other endemic conditions should be included in the differential diagnosis, including neurocysticercosis, Baggio-Yoshinari syndrome, and endemic mycosis. After infectious etiologies, meningeal carcinomatosis and autoimmune diseases should be considered. Unbiased and targeted methods should be used based on availability and clinical and epidemiological data. CONCLUSION: We propose a rational approach to CM in Brazil, considering the epidemiological scenario, systematizing the etiological investigation, and evaluating the timely use of empirical therapies.

ANTECEDENTES: A meningite crônica (MC) é caracterizada por sintomas neurológicos associados à evidência de pleiocitose do líquido cefalorraquidiano por > 4 semanas. Os estudos sobre o manejo da MC no Brasil são escassos. OBJETIVO: Rever criticamente a literatura sobre MC e propor uma abordagem racional no cenário brasileiro. MéTODOS: Revisão da literatura narrativa discutindo a epidemiologia, avaliação clínica, testes diagnósticos básicos e avançados, além da terapia empírica e direcionada para as causas mais relevantes do MC. A presente revisão foi contextualizada com a experiência local dos autores. Além disso, propomos um algoritmo para o manejo da MC no Brasil. RESULTADOS: No Brasil, a tuberculose e a criptococose são endêmicas e devem ser sempre consideradas em pacientes com MC. Além destas doenças, a neurossífilis e outras condições endêmicas devem ser incluídas no diagnóstico diferencial, incluindo: neurocisticercose, síndrome de Baggio-Yoshinari e micoses endêmicas. Após etiologias infecciosas, devem ser consideradas a carcinomatose meningeal e doenças autoimunes sistêmicas. Métodos diagnósticos devem ser utilizados com base na disponibilidade, nos dados clínicos e nos dados epidemiológicos. CONCLUSãO: Propomos uma abordagem racional para a MC no Brasil, considerando o cenário epidemiológico, sistematizando a investigação etiológica e avaliando o uso oportuno de terapias empíricas.

Diagnostic and therapeutic approach to chronic meningitis in Brazil: a narrative review / Abordagem diagnóstica e terapêutica da meningite crônica no Brasil: uma revisão narrativa

Abstract Background Chronic meningitis (CM) is characterized by neurological symptoms associated with the evidence of cerebrospinal fluid pleocytosis lasting > 4 weeks. Studies on the management of CM in Brazil are scarce. Objective To critically review the literature on CM and propose a rational approach in the Brazilian scenario. Methods Narrative literature review discussing the epidemiology, clinical evaluation, basic and advanced diagnostic testing, and empirical and targeted therapy for the most relevant causes of CM. The present review was contextualized with the local experience of the authors. In addition, we propose an algorithm for the management of CM in Brazil. Results In Brazil, tuberculosis and cryptococcosis are endemic and should always be considered in CM patients. In addition to these diseases, neurosyphilis and other endemic conditions should be included in the differential diagnosis, including neurocysticercosis, Baggio-Yoshinari syndrome, and endemic mycosis. After infectious etiologies, meningeal carcinomatosis and autoimmune diseases should be considered. Unbiased and targeted methods should be used based on availability and clinical and epidemiological data. Conclusion We propose a rational approach to CM in Brazil, considering the epidemiological scenario, systematizing the etiological investigation, and evaluating the timely use of empirical therapies.

Resumo Antecedentes A meningite crônica (MC) é caracterizada por sintomas neurológicos associados à evidência de pleiocitose do líquido cefalorraquidiano por > 4 semanas. Os estudos sobre o manejo da MC no Brasil são escassos. Objetivo Rever criticamente a literatura sobre MC e propor uma abordagem racional no cenário brasileiro. Métodos Revisão da literatura narrativa discutindo a epidemiologia, avaliação clínica, testes diagnósticos básicos e avançados, além da terapia empírica e direcionada para as causas mais relevantes do MC. A presente revisão foi contextualizada com a experiência local dos autores. Além disso, propomos um algoritmo para o manejo da MC no Brasil. Resultados No Brasil, a tuberculose e a criptococose são endêmicas e devem ser sempre consideradas em pacientes com MC. Além destas doenças, a neurossífilis e outras condições endêmicas devem ser incluídas no diagnóstico diferencial, incluindo: neurocisticercose, síndrome de Baggio-Yoshinari e micoses endêmicas. Após etiologias infecciosas, devem ser consideradas a carcinomatose meningeal e doenças autoimunes sistêmicas. Métodos diagnósticos devem ser utilizados com base na disponibilidade, nos dados clínicos e nos dados epidemiológicos. Conclusão Propomos uma abordagem racional para a MC no Brasil, considerando o cenário epidemiológico, sistematizando a investigação etiológica e avaliando o uso oportuno de terapias empíricas.

NeuroCOVID-19: a critical review.

BACKGROUND: The COVID-19 pandemic has challenged neurologists since its early days. Neurology consultation services were then overloaded by emergency department and intensive-care patients with acute neurological syndromes. These complications are better explained today, but the growing number of patients with reported longstanding neurological symptoms constitute an emerging, complex, and still poorly understood phenomenon. OBJECTIVE: This review summarizes data on relevant neurological manifestations of acute SARS-CoV-2 infection and lasting post-infectious disease, also known as Long COVID. The complex history of Long COVID is examined to illustrate the upsides and challenges imposed by the active participation of patient communities in the production of medical knowledge. METHODS: Narrative review. RESULTS: Infection with the severe acute respiratory syndrome coronavirus 2 is associated with encephalopathy/delirium, cerebrovascular disease, headache, and peripheral nervous system involvement. Long COVID is a living concept jointly defined by patient communities, physicians and scientists, including neurologists. CONCLUSION: Co-production of Long COVID knowledge between scientists and patients has initiated an era of patient-led research and evidence-based activism that acts as a two-edged sword - putting patient's suffering in the spotlight, but with a tradeoff in methodological consistency.

NeuroCOVID-19: a critical review / NeuroCOVID-19: uma revisão crítica

ABSTRACT Background: The COVID-19 pandemic has challenged neurologists since its early days. Neurology consultation services were then overloaded by emergency department and intensive-care patients with acute neurological syndromes. These complications are better explained today, but the growing number of patients with reported longstanding neurological symptoms constitute an emerging, complex, and still poorly understood phenomenon. Objective: This review summarizes data on relevant neurological manifestations of acute SARS-CoV-2 infection and lasting post-infectious disease, also known as Long COVID. The complex history of Long COVID is examined to illustrate the upsides and challenges imposed by the active participation of patient communities in the production of medical knowledge. Methods: Narrative review. Results: Infection with the severe acute respiratory syndrome coronavirus 2 is associated with encephalopathy/delirium, cerebrovascular disease, headache, and peripheral nervous system involvement. Long COVID is a living concept jointly defined by patient communities, physicians and scientists, including neurologists. Conclusion: Co-production of Long COVID knowledge between scientists and patients has initiated an era of patient-led research and evidence-based activism that acts as a two-edged sword - putting patient's suffering in the spotlight, but with a tradeoff in methodological consistency.

RESUMO Antecedentes: A pandemia de COVID-19 trouxe desafios aos neurologistas desde seus primeiros dias. Os serviços de interconsulta neurológica foram inicialmente sobrecarregados pelo volume de atendimentos a síndromes neurológicas agudas em departamentos de emergência e unidades de terapia intensiva. Essas complicações são bem conhecidas hoje, mas o verdadeiro desafio está no número crescente de pacientes com sintomas atribuídos a "Long COVID"/COVID Longa, um problema novo, complexo e ainda pouco compreendido. Objetivo: Esta revisão resume literatura sobre manifestações neurológicas da infecção aguda por SARS-CoV-2 e COVID longa. A complexa história de COVID longa é examinada para ilustrar os ganhos e as dificuldades impostos pela participação ativa das comunidades de pacientes na produção de conhecimento médico. Métodos: Revisão narrativa. Resultados: A infecção pelo SARS-CoV-2 está associada a encefalopatia/delirium, doença cerebrovascular, cefaléia e neuropatias periféricas. COVID Longa é um conceito ainda plástico, definido em conjunto por comunidades de pacientes, médicos e cientistas, incluindo neurologistas. Conclusão: A co-produção do conhecimento sobre COVID longa, unindo cientistas, médicos (incluindo neurologistas), e pacientes, iniciou uma nova era de pesquisa conduzida por pacientes e "ativismo baseado em evidências". Este atua como uma faca de dois gumes, alinhando os rumos da pesquisa às demandas e sofrimentos dos pacientes, ao custo de problemas metodológicos.

Post-acute sequelae of SARS-CoV-2 infection (PASC): a protocol for a multidisciplinary prospective observational evaluation of a cohort of patients surviving hospitalisation in Sao Paulo, Brazil.

INTRODUCTION: COVID-19 may lead to persistent and potentially incapacitating clinical manifestations (post-acute sequelae of SARS-CoV-2 infection (PASC)). Using easy-to-apply questionnaires and scales (often by telephone interviewing), several studies evaluated samples of COVID-19 inpatients from 4 weeks to several months after discharge. However, studies conducting systematic multidisciplinary assessments of PASC manifestations are scarce, with thorough in-person objective evaluations restricted to modestly sized subsamples presenting greatest disease severity. METHODS AND ANALYSES: We will conduct a prospective observational study of surviving individuals (above 18 years of age) from a cohort of over 3000 subjects with laboratory-confirmed COVID-19 who were treated as inpatients at the largest academic health centre in Sao Paulo, Brazil (Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo). All eligible subjects will be consecutively invited to undergo a 1-2-day series of multidisciplinary assessments at 2 time-points, respectively, at 6-9 months and 12-15 months after discharge. Assessment schedules will include detailed multidomain questionnaires applied by medical research staff, self-report scales, objective evaluations of cardiopulmonary functioning, physical functionality and olfactory status, standardised neurological, psychiatric and cognitive examinations, as well as diagnostic laboratory, muscle ultrasound and chest imaging exams. Remaining material from blood tests will be incorporated by a local biobank for use in future investigations on inflammatory markers, genomics, transcriptomics, peptidomics and metabolomics. ETHICS AND DISSEMINATION: All components of this programme have been approved by local research ethics committees. We aim to provide insights into the frequency and severity of chronic/post-COVID multiorgan symptoms, as well as their interrelationships and associations with acute disease features, sociodemographic variables and environmental exposures. Findings will be disseminated in peer-reviewed journals and at scientific meetings. Additionally, we aim to provide a data repository to allow future pathophysiological investigations relating clinical PASC features to biomarker data extracted from blood samples. TRIAL REGISTRATION NUMBER: RBR-8z7v5wc; Pre-results.

Potential autoimmune encephalitis following yellow fever vaccination: A report of three cases.

Meningoencephalitis following yellow fever vaccination is considered a viral neuroinvasive disease. We describe three patients with typical autoimmune encephalitis syndromes that developed 1-27 days following yellow fever vaccination. Anti-N-methyl-d-aspartate-r antibodies were identified in the CSF and serum of two patients and the other case was associated with anti-neurexin-3 antibodies. One case was confirmed as vaccine-associated neurotropic disease due to reactive CSF yellow fever IgM, which suggested an infectious-autoimmune overlap mechanism. Two aditional cases of Anti-N-methyl-d-aspartate-r encephalitis were identified in the literature review. Antibody-positive autoimmune encephalitis should be included in the differential diagnosis of neurologic adverse events following yellow fever vaccination.

Neurological consultations and diagnoses in a large, dedicated COVID-19 university hospital.

BACKGROUND: More than one-third of COVID-19 patients present neurological symptoms ranging from anosmia to stroke and encephalopathy. Furthermore, pre-existing neurological conditions may require special treatment and may be associated with worse outcomes. Notwithstanding, the role of neurologists in COVID-19 is probably underrecognized. OBJECTIVE: The aim of this study was to report the reasons for requesting neurological consultations by internists and intensivists in a COVID-19-dedicated hospital. METHODS: This retrospective study was carried out at Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil, a 900-bed COVID-19 dedicated center (including 300 intensive care unit beds). COVID-19 diagnosis was confirmed by SARS-CoV-2-RT-PCR in nasal swabs. All inpatient neurology consultations between March 23rd and May 23rd, 2020 were analyzed. Neurologists performed the neurological exam, assessed all available data to diagnose the neurological condition, and requested additional tests deemed necessary. Difficult diagnoses were established in consensus meetings. After diagnosis, neurologists were involved in the treatment. RESULTS: Neurological consultations were requested for 89 out of 1,208 (7.4%) inpatient COVID admissions during that period. Main neurological diagnoses included: encephalopathy (44.4%), stroke (16.7%), previous neurological diseases (9.0%), seizures (9.0%), neuromuscular disorders (5.6%), other acute brain lesions (3.4%), and other mild nonspecific symptoms (11.2%). CONCLUSIONS: Most neurological consultations in a COVID-19-dedicated hospital were requested for severe conditions that could have an impact on the outcome. First-line doctors should be able to recognize neurological symptoms; neurologists are important members of the medical team in COVID-19 hospital care.

Neurological consultations and diagnoses in a large, dedicated COVID-19 university hospital / Consultas neurológicas e diagnósticos em um grande hospital universitário dedicado a COVID-19

ABSTRACT Background: More than one-third of COVID-19 patients present neurological symptoms ranging from anosmia to stroke and encephalopathy. Furthermore, pre-existing neurological conditions may require special treatment and may be associated with worse outcomes. Notwithstanding, the role of neurologists in COVID-19 is probably underrecognized. Objective: The aim of this study was to report the reasons for requesting neurological consultations by internists and intensivists in a COVID-19-dedicated hospital. Methods: This retrospective study was carried out at Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil, a 900-bed COVID-19 dedicated center (including 300 intensive care unit beds). COVID-19 diagnosis was confirmed by SARS-CoV-2-RT-PCR in nasal swabs. All inpatient neurology consultations between March 23rd and May 23rd, 2020 were analyzed. Neurologists performed the neurological exam, assessed all available data to diagnose the neurological condition, and requested additional tests deemed necessary. Difficult diagnoses were established in consensus meetings. After diagnosis, neurologists were involved in the treatment. Results: Neurological consultations were requested for 89 out of 1,208 (7.4%) inpatient COVID admissions during that period. Main neurological diagnoses included: encephalopathy (44.4%), stroke (16.7%), previous neurological diseases (9.0%), seizures (9.0%), neuromuscular disorders (5.6%), other acute brain lesions (3.4%), and other mild nonspecific symptoms (11.2%). Conclusions: Most neurological consultations in a COVID-19-dedicated hospital were requested for severe conditions that could have an impact on the outcome. First-line doctors should be able to recognize neurological symptoms; neurologists are important members of the medical team in COVID-19 hospital care.

RESUMO Introdução: Mais de um terço dos pacientes com COVID-19 apresentam sintomas neurológicos que variam de anosmia a AVC e encefalopatia. Além disso, doenças neurológicas prévias podem exigir tratamento especial e estar associadas a piores desfechos. Não obstante, o papel dos neurologistas na COVID-19 é provavelmente pouco reconhecido. Objetivo: O objetivo deste estudo foi relatar os motivos para solicitar consultas neurológicas por clínicos e intensivistas em um hospital dedicado à COVID-19. Métodos: Estudo retrospectivo realizado no Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brasil, um centro dedicado à COVID-19 com 900 leitos (incluindo 300 leitos para unidades de terapia intensiva). O diagnóstico de COVID-19 foi confirmado por SARS-CoV-2-RT-PCR em swabs nasais. Todas as interconsultas de neurologia hospitalar entre 23 de março e 23 de maio de 2020 foram analisadas. Os neurologistas realizaram o exame neurológico, avaliaram todos os dados disponíveis para diagnosticar a patologia neurológica e solicitaram exames adicionais conforme necessidade. Diagnósticos difíceis foram estabelecidos em reuniões de consenso. Após o diagnóstico, os neurologistas participaram da condução dos casos. Resultados: Foram solicitadas consultas neurológicas para 89 de 1.208 (7,4%) em pacientes internados por COVID-19 durante o período. Os principais diagnósticos neurológicos incluíram: encefalopatia (44,4%), acidente vascular cerebral (16,7%), doenças neurológicas prévias (9,0%), crises epilépticas (9,0%), transtornos neuromusculares (5,6%), outras lesões encefálicas agudas (3,4%) e outros sintomas leves inespecíficos (11,2%). Conclusões: A maioria das consultas neurológicas em um hospital dedicado à COVID-19 foi solicitada para condições graves que poderiam afetar o desfecho clínico. Os médicos na linha de frente devem ser capazes de reconhecer sintomas neurológicos. Os neurologistas são membros importantes da equipe médica no atendimento hospitalar à COVID-19.

Neurological consultations and diagnoses in a large, dedicated COVID-19 university hospital / Consultas neurológicas e diagnósticos em um grande hospital universitário dedicado a COVID-19

Background: More than one-third of COVID-19 patients present neurological symptomsranging from anosmia to stroke and encephalopathy. Furthermore, pre-existingneurological conditions may require special treatment and may be associated with worseoutcomes. Notwithstanding, the role of neurologists in COVID-19 is probablyunderrecognized. Objective: The aim of this study was to report the reasons forrequesting neurological consultations by internists and intensivists in a COVID-19-dedicated hospital. Methods: This retrospective study was carried out at Hospital dasClínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil, a 900-bedCOVID-19 dedicated center (including 300 intensive care unit beds). COVID-19 diagnosiswas confirmed by SARS-CoV-2-RT-PCR in nasal swabs. All inpatient neurologyconsultations between March 23rd and May 23rd, 2020 were analyzed. Neurologistsperformed the neurological exam, assessed all available data to diagnose theneurological condition, and requested additional tests deemed necessary. Difficultdiagnoses were established in consensus meetings. After diagnosis, neurologists wereinvolved in the treatment. Results: Neurological consultations were requested for 89 outof 1,208 (7.4%) inpatient COVID admissions during that period. Main neurologicaldiagnoses included: encephalopathy (44.4%), stroke (16.7%), previous neurologicaldiseases (9.0%), seizures (9.0%), neuromuscular disorders (5.6%), other acute brainlesions (3.4%), and other mild nonspecific symptoms (11.2%). Conclusions: Mostneurological consultations in a COVID-19-dedicated hospital were requested for severeconditions that could have an impact on the outcome. First-line doctors should be able torecognize neurological symptoms; neurologists are important members of the medicalteam in COVID-19 hospital care.

Introdução: Mais de um terço dos pacientes com COVID-19 apresentam sintomasneurológicos que variam de anosmia a AVC e encefalopatia. Além disso, doençasneurológicas prévias podem exigir tratamento especial e estar associadas a pioresdesfechos. Não obstante, o papel dos neurologistas na COVID-19 é provavelmentepouco reconhecido. Objetivo: O objetivo deste estudo foi relatar os motivos para solicitarconsultas neurológicas por clínicos e intensivistas em um hospital dedicado à COVID-19. Métodos: Estudo retrospectivo realizado no Hospital das Clínicas da Faculdade deMedicina da Universidade de São Paulo, Brasil, um centro dedicado à COVID-19 com900 leitos (incluindo 300 leitos para unidades de terapia intensiva). O diagnóstico deCOVID-19 foi confirmado por SARS-CoV-2-RT-PCR em swabs nasais. Todas asinterconsultas de neurologia hospitalar entre 23 de março e 23 de maio de 2020 foramanalisadas. Os neurologistas realizaram o exame neurológico, avaliaram todos os dadosdisponíveis para diagnosticar a patologia neurológica e solicitaram exames adicionaisconforme necessidade. Diagnósticos difíceis foram estabelecidos em reuniões deconsenso. Após o diagnóstico, os neurologistas participaram da condução dos casos.Resultados: Foram solicitadas consultas neurológicas para 89 de 1.208 (7,4%) empacientes internados por COVID-19 durante o período. Os principais diagnósticosneurológicos incluíram: encefalopatia (44,4%), acidente vascular cerebral (16,7%),doenças neurológicas prévias (9,0%), crises epilépticas (9,0%), transtornosneuromusculares (5,6%), outras lesões encefálicas agudas (3,4%) e outros sintomasleves inespecíficos (11,2%). Conclusões: A maioria das consultas neurológicas em umhospital dedicado à COVID-19 foi solicitada para condições graves que poderiam afetaro desfecho clínico. Os médicos na linha de frente devem ser capazes de reconhecersintomas neurológicos. Os neurologistas são membros importantes da equipe médica noatendimento hospitalar à COVID-19.

Intracranial germinoma causing cerebral haemiatrophy and hypopituitarism.

A young woman presented with primary amenorrhoea, progressive haemiparesis, visual disturbance, dementia and focal motor seizures. Investigations showed hypopituitarism, unilateral cerebral atrophy and inflamed cerebrospinal fluid. A trans-sphenoidal biopsy gave a unifying diagnosis of a pituitary germinoma.

Psychosis and concurrent impulse control disorder in Parkinson's disease: A review based on a case report / Psicose e transtorno de impulsividade concomitantes na Doença de Parkinson: revisão baseada em um relato de caso

ABSTRACT Psychosis, impulse control disorders (e.g., pathological gambling and hypersexuality) and repetitive behaviors such as punding are known psychiatric complications of Parkinson's disease (PD). Impulsive, compulsive and repetitive behaviors are strongly associated with dopamine-replacement therapy. We present the case of a 58-year-old man with PD and a myriad of psychiatric symptoms. Concurrent psychosis, punding and pathological gambling developed more than six years after the introduction of pramipexole and ceased shortly after the addition of quetiapine and discontinuation of pramipexole. This report emphasizes the importance of monitoring for a wide array of psychiatric symptoms in patients on dopamine replacement therapy.

RESUMO Psicose, transtornos do impulso (como jogo patológico e hipersexualidade) e comportamentos repetitivos como punding são complicações psiquiátricas conhecidas da doença de Parkinson. Comportamentos repetitivos, impulsivos e compulsivos são fortemente associados a terapia de reposição dopaminérgica. Nós apresentamos o caso de um homem de 58 anos com doença de Parkinson de início precoce e múltiplos sintomas psiquiátricos. Psicose, punding e jogo patológico surgiram mais de seis anos após a introdução de pramipexol e cessaram pouco após sua descontinuação e introdução de quetiapina. Nosso relato enfatiza a importância do monitoramento para uma ampla gama de sintomas psiquiatricos em pacientes com doença de parkinson em uso de terapia de reposição dopaminérgica.

Psychosis and concurrent impulse control disorder in Parkinson's disease: A review based on a case report.

Psychosis, impulse control disorders (e.g., pathological gambling and hypersexuality) and repetitive behaviors such as punding are known psychiatric complications of Parkinson's disease (PD). Impulsive, compulsive and repetitive behaviors are strongly associated with dopamine-replacement therapy. We present the case of a 58-year-old man with PD and a myriad of psychiatric symptoms. Concurrent psychosis, punding and pathological gambling developed more than six years after the introduction of pramipexole and ceased shortly after the addition of quetiapine and discontinuation of pramipexole. This report emphasizes the importance of monitoring for a wide array of psychiatric symptoms in patients on dopamine replacement therapy.

Psicose, transtornos do impulso (como jogo patológico e hipersexualidade) e comportamentos repetitivos como punding são complicações psiquiátricas conhecidas da doença de Parkinson. Comportamentos repetitivos, impulsivos e compulsivos são fortemente associados a terapia de reposição dopaminérgica. Nós apresentamos o caso de um homem de 58 anos com doença de Parkinson de início precoce e múltiplos sintomas psiquiátricos. Psicose, punding e jogo patológico surgiram mais de seis anos após a introdução de pramipexol e cessaram pouco após sua descontinuação e introdução de quetiapina. Nosso relato enfatiza a importância do monitoramento para uma ampla gama de sintomas psiquiatricos em pacientes com doença de parkinson em uso de terapia de reposição dopaminérgica.