Serum Concentrations of Cholinesterase Inhibitors in Patients With Alzheimer's Dementia Are Frequently Below the Recommended Levels

Background: Acetylcholinesterase inhibitors (AChE-I) are recommended for the treatment of cognitive symptoms but also of behavioral and psychological symptoms in dementia. They are widely used not only in Alzheimer's disease, but also in other forms of dementia. Efficacy of treatment might depend on serum concentration of the respective AChE-I. Objective: In patients with mild to moderate Alzheimer's dementia, we measured serum concentrations of hepatically metabolized donepezil and renally excreted rivastigmine and investigated possible modifiers. Additionally, we looked at correlations between serum concentrations and efficacy for both drugs. Methods: Serum concentrations of donepezil and rivastigmine were measured by liquid chromatography – tandem mass spectrometry (LC-MS/MS). Real-time quantitative polymerase chain reaction (PCR). Allele specific PCR were performed to determine CYP2D6 genotype and gene dose. Clinical efficacy was assessed by changes of the subtest wordlist delayed recall of the Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery (CERAD-NAB). Results: Sixty-seven patients treated with a stable dosage of donepezil 10 mg (n=41) or rivastigmine 9.5 mg (n=26) were included. Mean serum concentration of donepezil and rivastigmine were 41.2 and 6.5 ng/ml, respectively. Serum concentrations were below the recommended range in 73% of the subjects in the donepezil group and in 65% of the participants in the rivastigmine group. When applying a dose-related reference, ranges 63% of patients in the donepezil group and 32% in the rivastigmine group had concentrations below the expected range. Gene dose, sex, and duration of treatment significantly predicted donepezil serum concentration (p=0.046, p=0.001, p=0.030 respectively). Only for rivastigmine did the serum concentration significantly contribute to the regression model predicting changes on the subtest word list delayed recall (β=0.472; p=0.019). Conclusions: Serum concentrations of about two thirds of the patients were below the recommended range. When not looking at absolute values but at the dose-related reference ranges, these numbers improved but still 32%, respectively 63% of patients had low serum concentrations. High serum concentrations of rivastigmine predicted clinical response to cognition. Therapeutic drug monitoring might help to identify the cause of poor clinical response to cognition and behavioral and psychological symptoms in patients with AChE-I treatment

EQUIPAMENTOS PÚBLICOS COMUNITÁRIOS DE SAÚDE: UMA ANÁLISE DA ABRANGÊNCIA NO PERÍMETRO URBANO DA CIDADE DE IJUÍ/RS

Public Health Equipment (PHE) has a crucial function within Brazilian municipalities, as they are responsible for controlling the quality of life of the population, whose duty is to guarantee access to all equally. Given the sanitary situation that has been faced in the last three years, due to Covid-19, these spaces reaffirm their importance of comprehensiveness and quality in care to the population. In this sense, the objective of the research is to conduct a quantitative survey of structures designed to care for the population of the municipality of Ijuí, located in the Northwest of the State of Rio Grande do Sul, verifying the perimeter covered by each structure, which are called public/community health urban equipment so that, later, an analysis was made based on the collected data. Regarding the methodological procedures, a qualitative research was carried out, which was aggregated from an EPS survey, using the AutoCAD software, and the Google Maps and Street View platforms, allowing a mapping of the equipment found, admitting a data analysis as the next step. It is noted that, although there is a coherent distribution of health centers in the municipality, health centers do not follow the same uniform relationship. It was possible to observe which areas of the city are vulnerable to the lack of basic health units (UBS) and family health strategy units (ESF), thus overloading the city's health centers and hospitals.Los Equipos de Salud Pública (PHE) tienen una función crucial dentro de los municipios brasileños, ya que son responsables de controlar la calidad de vida de la población, cuyo deber es garantizar el acceso a todos por igual. Dada la situación sanitaria que se ha enfrentado en los últimos tres años, debido al Covid-19, estos espacios reafirman su importancia de integralidad y calidad en la atención a la población. En este sentido, el objetivo de la investigación es realizar un levantamiento cuantitativo de las estructuras diseñadas para atender a la población del municipio de Ijuí, ubicado en el Noroeste del Estado de Rio Grande do Sul, verificando el perímetro cubierto por cada estructura, que se denominan equipamiento urbano de salud pública/comunitaria para que, posteriormente, se realice un análisis basado en los datos recolectados. En cuanto a los procedimientos metodológicos, se realizó una investigación cualitativa, que se agregó a partir de una encuesta EPS, utilizando el software AutoCAD, y las plataformas Google Maps y Street View, permitiendo un mapeo de los equipos encontrados, admitiendo un análisis de datos como siguiente paso. Se observa que, aunque existe una distribución coherente de los centros de salud en el municipio, los centros de salud no siguen la misma relación uniforme. Fue posible observar qué áreas de la ciudad son vulnerables a la falta de unidades básicas de salud (UBS) y unidades de estrategia de salud de la familia (ESF), sobrecargando así los centros de salud y hospitales de la ciudad.Os Equipamentos Públicos de Saúde (EPS) possuem função crucial dentro dos municípios brasileiros, pois são responsáveis pelo controle da qualidade de vida da população, cujo dever é garantir acesso a todos de forma igualitária. Diante da situação sanitária que tem sido enfrentada nos últimos três anos, em decorrência da Covid-19, esses espaços reafirmam sua importância de abrangência e qualidade em atendimento à população. Nesse sentido, o objetivo da pesquisa é realizar um levantamento quantitativo de estruturas destinadas ao atendimento da população do município de Ijuí, localizado no Noroeste do Estado do Rio Grande do Sul, verificando o perímetro abrangido por cada estrutura, as quais são designadas equipamentos urbanos públicos/comunitários de saúde para que, posteriormente, fosse confeccionada uma análise com base nos dados coletados. Quanto aos procedimentos metodológicos, foi realizada uma pesquisa qualitativa, que foi agregada de um levantamento de EPS, utilizando o software AutoCAD, e as plataformas Google Maps e Street View, permitindo realizar um mapeamento dos equipamentos encontrados, admitindo uma análise de dados como etapa seguinte. Nota-se que, apesar de haver uma distribuição coerente de centros de saúde no município, os postos de saúde não seguem a mesma relação uniforme. Foi possível observar quais áreas da cidade estão vulneráveis à falta de unidades básicas de saúde (UBS), e unidades de estratégia da saúde da família (ESF), sobrecarregando assim os centros de saúde e hospitais da cidade.Os Equipamentos Públicos de Saúde (EPS) possuem função crucial dentro dos municípios brasileiros, pois são responsáveis pelo controle da qualidade de vida da população, cujo dever é garantir acesso a todos de forma igualitária. Diante da situação sanitária que tem sido enfrentada nos últimos três anos, em decorrência da Covid-19, esses espaços reafirmam sua importância de abrangência e qualidade em atendimento à população. Nesse sentido, o objetivo da pesquisa é realizar um levantamento quantitativo de estruturas destinadas ao atendimento da população do município de Ijuí, localizado no Noroeste do Estado do Rio Grande do Sul, verificando o perímetro abrangido por cada estrutura, as quais são designadas equipamentos urbanos públicos/comunitários de saúde para que, posteriormente, fosse confeccionada uma análise com base nos dados coletados. Quanto aos procedimentos metodológicos, foi realizada uma pesquisa qualitativa, que foi agregada de um levantamento de EPS, utilizando o software AutoCAD, e as plataformas Google Maps e Street View, permitindo realizar um mapeamento dos equipamentos encontrados, admitindo uma análise de dados como etapa seguinte. Nota-se que, apesar de haver uma distribuição coerente de centros de saúde no município, os postos de saúde não seguem a mesma relação uniforme. Foi possível observar quais áreas da cidade estão vulneráveis à falta de unidades básicas de saúde (UBS), e unidades de estratégia da saúde da família (ESF), sobrecarregando assim os centros de saúde e hospitais da cidade

Suicidal Ideations and Behavior in Patients With Young and Late Onset Dementia.

Background and Objectives: Data on suicidal ideation, behavior and the risk factors in patients with dementia is scarce. To evaluate the prevalence of death wishes, suicidal ideation, and suicidal behavior of young (YOD) and late onset dementia (LOD) and to identify risk factors for suicidal ideation and behavior. Methods: We interviewed 157 family caregivers of patients with advanced dementia using questions from the Columbia-Suicide Severity Rating Scale to gather information about suicidal ideation and behavior before the onset of symptoms of dementia, after the onset of dementia and within 30 days prior to the interview. At the time of the interview, we also assessed disease severity, cognitive function, and other psychological, behavioral and physical symptoms of the patients as well as the caregivers' psychological well-being. Results: Forty four (28%) of the patients expressed suicidal ideation or behavior at some time after the onset of symptoms, and 14 (9%) of these within the month prior to the assessment. Two patients had attempted suicide after the onset of dementia. There were no statistically significant differences between patients with and without suicidal ideations or behavior with regards to demographics or age at onset of dementia. In patients with advanced dementia, Alzheimer's disease (rather than frontotemporal lobar degeneration), better cognitive function, more severe psychological, behavioral, and physical symptoms, and a reduced quality of life were associated with the expression of suicidal ideation. Conclusions: According to caregivers' reports, majority of patients with dementia did not express suicidal ideation or show suicidal behavior. Patients who expressed suicidal ideation during early stages of dementia often stopped expressing them in advanced stages. It remains unclear if this was due to reduced communication abilities, a reduction of disease awareness, and/ or an adjustment to their situation

Correction: The landscape of epilepsy-related GATOR1 variants

International audienceThe original version of this article contained an error in the spelling of the author Erik H. Niks, which was incorrectly given as Erik Niks. This has now been corrected in both the PDF and HTML versions of the article

The landscape of epilepsy-related GATOR1 variants

Purpose: To define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway Methods: We analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants. Results: The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%). Infantile spasms were reported in 10% of the probands. Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families. Novel classification framework of all 140 epilepsy-related GATOR1 variants (including the variants of this study) revealed that 68% are loss-of-function pathogenic, 14% are likely pathogenic, 15% are variants of uncertain significance and 3% are likely benign. Conclusion: Our data emphasize the increasingly important role of GATOR1 genes in the pathogenesis of focal epilepsies (>180 probands to date). The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and SUDEP

Natalizumab plus interferon beta-1a for relapsing multiple sclerosis.

Item does not contain fulltextBACKGROUND: Interferon beta is used to modify the course of relapsing multiple sclerosis. Despite interferon beta therapy, many patients have relapses. Natalizumab, an alpha4 integrin antagonist, appeared to be safe and effective alone and when added to interferon beta-1a in preliminary studies. METHODS: We randomly assigned 1171 patients who, despite interferon beta-1a therapy, had had at least one relapse during the 12-month period before randomization to receive continued interferon beta-1a in combination with 300 mg of natalizumab (589 patients) or placebo (582 patients) intravenously every 4 weeks for up to 116 weeks. The primary end points were the rate of clinical relapse at 1 year and the cumulative probability of disability progression sustained for 12 weeks, as measured by the Expanded Disability Status Scale, at 2 years. RESULTS: Combination therapy resulted in a 24 percent reduction in the relative risk of sustained disability progression (hazard ratio, 0.76; 95 percent confidence interval, 0.61 to 0.96; P=0.02). Kaplan-Meier estimates of the cumulative probability of progression at two years were 23 percent with combination therapy and 29 percent with interferon beta-1a alone. Combination therapy was associated with a lower annualized rate of relapse over a two-year period than was interferon beta-1a alone (0.34 vs. 0.75, P<0.001) and with fewer new or enlarging lesions on T(2)-weighted magnetic resonance imaging (0.9 vs. 5.4, P<0.001). Adverse events associated with combination therapy were anxiety, pharyngitis, sinus congestion, and peripheral edema. Two cases of progressive multifocal leukoencephalopathy, one of which was fatal, were diagnosed in natalizumab-treated patients. CONCLUSIONS: Natalizumab added to interferon beta-1a was significantly more effective than interferon beta-1a alone in patients with relapsing multiple sclerosis. Additional research is needed to elucidate the benefits and risks of this combination treatment. (ClinicalTrials.gov number, NCT00030966.)