Genetics of Schizophrenia and Smoking: An Approach to Studying their Comorbidity Based on Epidemiological Findings

The association between schizophrenia and tobacco smoking has been described in more than 1,000 articles, many with inadequate methodology. The studies on this association can focus on: (1) current smoking, ever smoking or smoking cessation; (2) non-psychiatric controls or controls with severe mental illness (e.g., bipolar disorder); and (3) higher smoking frequency or greater usage in smokers. The association with the most potential for genetic studies is that between ever daily smoking and schizophrenia; it may reflect a shared genetic vulnerability. To reduce the number of false-positive genes, we propose a three-stage approach derived from epidemiological knowledge. In the first stage, only genetic variations associated with ever daily smoking that are simultaneously significant within the non-psychiatric controls, the bipolar disorder controls and the schizophrenia cases will be selected. Only those genetic variations that are simultaneously significant in the three hypothesis tests will be tested in the second stage, where the prevalence of the genes must be significantly higher in schizophrenia than in bipolar disorder, and significantly higher in bipolar disorder than in controls. The genes simultaneously significant in the second stage will be included in a third stage where the gene variations must be significantly more frequent in schizophrenia patients who did not start smoking daily until their 20s (late start) versus those who had an early start. Any genetic approach to psychiatric disorders may fail if attention is not given to comorbidity and epidemiological studies that suggest which comorbidities are likely to be explained by genetics and which are not. Our approach, which examines the results of epidemiological studies on comorbidities and then looks for genes that simultaneously satisfy epidemiologically suggested sets of hypotheses, may also apply to the study of other major illnesses

Clobazam Therapeutic Drug Monitoring: A Comprehensive Review of the Literature With Proposals to Improve Future Studies

Background: Clobazam was recently approved for Lennox–Gastaut syndrome in the United States. There is no published review article focused on clobazam therapeutic drug monitoring (TDM) in English. Methods: More than 200 clobazam articles identified by a PubMed search were carefully reviewed for information on clobazam pharmacokinetics. Clobazam is mainly metabolized by a cytochrome P450 (CYP) isoenzyme, CYP3A4, to its active metabolite, N-desmethylclobazam. Then, N-desmethylclobazam is mainly metabolized by CYP2C19 unless the individual has no CYP2C19 activity [poor metabolizer (PM)]. Results: Using a mechanistic approach to reinterpret the published findings of steady-state TDM and single-dosing pharmacokinetic studies, 4 different serum clobazam concentration ratios were studied. The available limited steady-state TDM data suggest that the serum N-desmethylclobazam/clobazam ratio can be useful for clinicians, including identifying CYP2C19 PMs (ratio \u3e25 in the absence of inhibitors). There are 3 possible concentration/dose (C/D) ratios. The clobazam C/D ratio has the potential to measure the contribution of CYP3A4 activity to the clearance of clobazam from the body. The N-desmethylclobazam C/D ratio does not seem to be a good measure of clobazam clearance and should be substituted with the total (clobazam + N-desmethylclobazam) C/D ratio. Conclusions: Future clobazam TDM studies need to use trough concentrations after steady state has been reached (\u3e3 weeks in normal individuals and several months in CYP2C19 PMs). These future studies need to explore the potential of clobazam and total C/D ratios. Better studies on the relative potency of N-desmethylclobazam compared with the parent compound are needed to provide weighted total serum concentrations that correct for the possible lower N-desmethylclobazam pharmacodynamic activity. Standardization and more studies of C/D ratios from clobazam and other drugs can be helpful to move TDM forward

Por los doct.res Bernardo de Olea... [et al.] y canonigos de la Santa Iglesia de Leon con el Cabildo de Canonigos de la misma Catedral y con el Dean de la propia... Iglesia... sobre que las dignidades deben presidir y dirigir al Capitulo, asi en el Coro como en los Cabildos y demas Juntas particulares... y otros puntos de residencia, disciplina y culto.

Texto firmado por Francisco Rodriguez Maqueda.Precede al tít.: Jesus, Maria y Josef.Marca tip. en port.Sign.: []1, A-N2.Copia digital : Diputación de Málaga. Biblioteca Canovas del Castillo, 201

Sermon predicado en Seuilla dia del inclito martyr Rey San Hermenegildo, patron de la ciudad

Copia digital. Madrid : Ministerio de Cultura. Subdirección General de Coordinación Bibliotecaria, 2008Sign. : A-C\p4\

Análise do impacto da pandemia de COVID-19 sobre a atenção a mulheres em situação de aborto na América Latina e Caribe

Objective: to understand the influence of the COVID-19 pandemic on aspects of quality of care provided to women in abortion situations in sentinel centers of the CLAP MUSA-Network (a multicenter network with international cooperation with the aim of encouraging good practices in Latin America and the Caribbean). Methods: cross-sectional study between January/2017 and December/2021 with women of any age admitted for abortion or miscarriage. We analyzed the total number of cases and the proportion of legal abortions. The dependent variables were complications and use of contraceptives after abortion. The independent variables were COVID-19 pandemic, clinical and sociodemographic data. Statistical analysis was carried out using linear regression, multiple Poisson regression, Cochran-Armitage, chi-square, Mann-Whitney and Cohen tests. Results: we analyzed data from 93689 women assisted in 12 sentinel centers of the CLAP MUSA-Network, 64.55% in the pre-pandemic period (NP) and 35.45% in the pandemic period (PP) (22.73% received post-abortion care and 77.27% legal abortion). We found no differences in the number of cases over the period, regardless of the legal context. We observed a significant increase in the proportion of legal abortions in liberal and moderate contexts. In NP, 46.46% of women underwent medical abortion, while 62.18% of women underwent medical abortion in PP (h-Cohen 0.32). We found no increase in the number of complications during PP. In NP, 79.12% started contraceptives after abortion, while in PP, 70.39% started contraceptives after abortion (h-Cohen 0.20). Conclusion: the COVID-19 pandemic was not associated with a decrease in the number of cases, a decrease in the proportion of legal interruptions, or an increase in complications in sentinel centers of the CLAP MUSA-Network. Submission: 30/04/23|Review: 08/11/23|Approval: 09/11/23Objetivo: comprender la influencia de la pandemia de COVID-19 en aspectos de la calidad de la atención brindada a las mujeres en situación de aborto en los centros centinela de la Red CLAP-MUSA (una red multicéntrica de cooperación internacional con el objetivo de fomentar buenas prácticas en América Latina y el Caribe). Metodología: estudio transversal entre enero/2017 y diciembre/2021 con mujeres de cualquier edad ingresadas para abortos espontáneos o inducidos. Se analizó el número total de casos y la proporción de abortos legales. Las variables dependientes fueron las complicaciones y el uso de anticonceptivos después del aborto. Las variables independientes fueron pandemia de COVID-19, datos clínicos y sociodemográficos. El análisis estadístico se realizó mediante regresión lineal, regresión múltiple de Poisson, pruebas de Cochran-Armitage, chi-cuadrado, Mann-Whitney y Cohen. Resultados: se analizaron datos de 93689 mujeres atendidas en 12 centros centinela de la Red CLAP-MUSA, 64,55% en el período prepandemia (NP) y 35,45% en el período pandemia (PP) (22,73% recibieron atención postaborto y 77,27% aborto legal). No encontramos diferencias en el número de casos durante el período, independientemente del contexto legal. Observamos un aumento significativo en la proporción de abortos legales en contextos liberales y moderados. En NP, el 46,46% de las mujeres se sometieron al aborto con medicamentos, mientras que el 62,18% de las mujeres se sometieron al aborto con medicamentos en PP (h-Cohen 0,32). No encontramos aumento en el número de complicaciones durante el PP. En NP, 79,12% inició anticonceptivos después del aborto, mientras que en PP, 70,39% inició anticonceptivos después del aborto (h-Cohen 0,20). Conclusión: la pandemia de COVID-19 no se asoció con una disminución en el número de casos, una disminución en la proporción de interrupciones legales o un aumento en las complicaciones en los centros centinela de la Red CLAP-MUSA. Acceptación: 30/04/23|Revisión: 08/11/23|Aprobación: 09/11/23Objetivo: compreender a influência da pandemia de COVID-19 nos aspectos da qualidade da assistência prestada às mulheres em situação de abortamento nos centros sentinela da Rede CLAP-MUSA, uma rede multicêntrica com cooperação internacional visando encorajar boas práticas na América Latina e no Caribe. Metodologia: estudo transversal entre janeiro/2017 e dezembro/2021 com mulheres de qualquer idade admitidas por abortamentos espontâneos ou induzidos. Analisamos o número total de casos e a proporção de abortos legais. As variáveis dependentes foram complicações e uso de anticoncepcionais após o aborto. As variáveis independentes foram a pandemia de COVID-19, dados clínicos e sociodemográficos. A análise estatística foi realizada por meio de regressão linear, regressão múltipla de Poisson, testes de Cochran-Armitage, qui-quadrado, Mann-Whitney e Cohen. Resultados: foram analisados dados de 93.689 mulheres, atendidas em 12 centros sentinelas da Rede CLAP-MUSA, 64,55% no período pré-pandêmico (NP) e 35,45% no período pandêmico (PP) (22,73% receberam atendimento pós-aborto e 77,27%, aborto legal). Não encontramos diferenças no número de casos ao longo do período, independentemente do contexto legal. Observamos um aumento significativo na proporção de abortos legais em contextos liberais e moderados. No NP, 46,46% das mulheres realizaram aborto medicamentoso, enquanto 62,18% das mulheres realizaram aborto medicamentoso no PP (h-Cohen 0,32). Não encontramos aumento no número de complicações durante o PP. No NP, 79,12% iniciaram anticoncepcionais após o aborto, enquanto no PP, 70,39% iniciaram anticoncepcionais após o aborto (h-Cohen 0,20). Conclusão: a pandemia de COVID-19 não se associou à diminuição do número de casos, à diminuição da proporção de interrupções legais ou ao aumento de complicações nos centros sentinelas da Rede CLAP-MUSA. Submissão: 30/04/23|Revisão: 08/11/23|Aprovação: 09/11/2

Three Patients Needing High Doses of Valproic Acid to Get Therapeutic Concentrations

Valproic acid (VPA) can autoinduce its own metabolism. Cases requiring VPA doses \u3e4000 mg/day to obtain therapeutic plasma concentrations, such as these 3 cases, have never been published. Case 1 received VPA for seizures and schizophrenia and had \u3e50 VPA concentrations in 4 years. A high dose of 5,250 mg/day of VPA concentrate was prescribed for years but this dose led to an intoxication when switched to the enterocoated divalproex sodium formulation, requiring a normal dose of 2000 mg/day. VPA metabolic capacity was significantly higher (t = -9.6; df = 6.3, p \u3c 0.001) during the VPA concentrate therapy, possibly due to autoinduction in that formulation. Case 2 had VPA for schizoaffective psychosis with 10 VPA concentrations during an 8-week admission. To maintain a VPA level ≥50 μg/mL, VPA doses increased from 1500 to 4000 mg/day. Case 3 had tuberous sclerosis and epilepsy and was followed up for \u3e4 years with 137 VPA concentrations. To maintain VPA concentrations ≥50 μg/mL, VPA doses increased from 3,375 to 10,500 mg/day. In Cases 2 and 3, the duration of admission and the VPA dose were strongly correlated (r around 0.90; p \u3c 0.001) with almost no change after controlling for VPA concentrations, indicating progressive autoinduction that increased with time