Real-world use of the updated refractory epilepsy screening tool for Lennox-Gastaut syndrome.

OBJECTIVE: To evaluate the Refractory Epilepsy Screening Tool for Lennox-Gastaut Syndrome (REST-LGS) for real-world identification of LGS in adults and to develop a scoring system for the tool. METHODS: A retrospective chart review of adults with drug resistant epilepsy (DRE) and intellectual development disorder (IDD) was conducted by 2 primary care providers blinded to diagnosis. The REST-LGS was designed via the Modified Delphi Consensus and was previously validated. This tool consists of 8 criteria (4 major, 4 minor) considered indicative of LGS. To account for missing data in the earlier validation study and to evaluate applicability in a real-world setting, the REST-LGS was refined to include a scoring system in which major criteria were more heavily weighted than minor criteria, producing categories of "likely" (>11 points), "possible" (8-11 points), and "unlikely" (<8 points) LGS. Statistical analyses were descriptive. RESULTS: Of the 100 patients included in the analysis, data for slow spike-waves in electroencephalography and seizure onset age - both major REST-LGS criteria - were missing for 46% and 42% of patients, respectively. The majority of patients met 4 of the 8 REST-LGS criteria (cognitive impairment since childhood, 71%; persistent seizures despite a trial of ≥2 antiseizure medications, 65%; seizure onset before the age of 12 years, 57%; ≥2 seizure types, 56%). All 4 major criteria were met in 22 patients (22%). The percentages of patients considered "likely," "possible," or "unlikely" to have LGS were 26%, 30%, and 44%, respectively. Of the 74 patients without a previous LGS diagnosis, 42 (57%) were identified as "possible" or "likely" to have LGS using REST-LGS. SIGNIFICANCE: In this analysis, the validated REST-LGS was evaluated in a real-world setting. The majority of previously undiagnosed patients were identified via REST-LGS as "possible" or "likely" to have LGS. Extensive missing data highlights challenges of LGS diagnosis in adults. PLAIN LANGUAGE SUMMARY: There is a need to identify adult patients with Lennox-Gastaut syndrome (LGS) so they can receive appropriate treatment. The Refractory Epilepsy Screening Tool for LGS (REST-LGS) questionnaire was designed by experts to identify whether patients with seizures that are not controlled by medications may have LGS. In this study, 2 physicians completed the REST-LGS using charts for 100 patients who experience seizures not controlled by medications. Of the patients who were previously diagnosed as not having LGS, the majority were "likely" or "possible" to have LGS based on the REST-LGS; therefore, the REST-LGS can identify patients for further evaluation.

Ecotoxic effect in Allium cepa due to sphalerite weathering arising in calcareous conditions.

The ecotoxic effect of Zn species arising from the weathering of the marmatite-like sphalerite ((Fe, Zn)S) in Allium cepa systems was herein evaluated in calcareous soils and connected with its sulfide oxidation mechanism to determine the chemical speciation responsible of this outcome. Mineralogical analyses (X-ray diffraction patterns, Raman spectroscopy, scanning electron microscopy and atomic force microscopy), chemical study of leachates (total Fe, Zn, Cd, oxidation-reduction potential, pH, sulfates and total alkalinity) and electrochemical assessments (chronoamperometry, chronopotentiometry, cyclic voltammetry, and electrochemical impedance spectroscopy) were carried out using (Fe, Zn)S samples to elucidate interfacial mechanisms simulating calcareous soil conditions. Results indicate the formation of polysulfides (Sn2-), elemental sulfur (S0), siderite (FeCO3)-like, hematite (Fe2O3)-like with sorbed CO32- species, gunningite (ZnSO4·H2O)-like phase and smithsonite (ZnCO3)-like compounds in altered surface under calcareous conditions. However, the generation of gunningite (ZnSO4·H2O)-like phase was predominant bulk-solution system. Quantification of damage rates ranges from 75 to 90% of bulb cells under non-carbonated conditions after 15-30 days, while 50-75% of damage level is determined under neutral-alkaline carbonated conditions. Damage ratios are 70.08 and 30.26 at the highest level, respectively. These findings revealed lower ecotoxic damage due to ZnCO3-like precipitation, indicating the effect of carbonates on Zn compounds during vegetable up-taking (exposure). Other environmental suggestions of the (Fe, Zn)S weathering and ecotoxic effects under calcareous soil conditions are discussed.

Corrigendum: New insights into hypothalamic neurogenesis disruption after acute and intense stress: implications for microglia and inflammation.

[This corrects the article DOI: 10.3389/fnins.2023.1190418.].

Unveiling the Secrets of the Stressed Hippocampus: Exploring Proteomic Changes and Neurobiology of Posttraumatic Stress Disorder.

Intense stress, especially traumatic stress, can trigger disabling responses and in some cases even lead to the development of posttraumatic stress disorder (PTSD). PTSD is heterogeneous, accompanied by a range of distress symptoms and treatment-resistant disorders that may be associated with a number of other psychopathologies. PTSD is a very heterogeneous disorder with different subtypes that depend on, among other factors, the type of stressor that provokes it. However, the neurobiological mechanisms are poorly understood. The study of early stress responses may hint at the way PTSD develops and improve the understanding of the neurobiological mechanisms involved in its onset, opening the opportunity for possible preventive treatments. Proteomics is a promising strategy for characterizing these early mechanisms underlying the development of PTSD. The aim of the work was to understand how exposure to acute and intense stress using water immersion restraint stress (WIRS), which could be reminiscent of natural disaster, may induce several PTSD-associated symptoms and changes in the hippocampal proteomic profile. The results showed that exposure to WIRS induced behavioural symptoms and corticosterone levels reminiscent of PTSD. Moreover, the expression profiles of hippocampal proteins at 1 h and 24 h after stress were deregulated in favour of increased inflammation and reduced neuroplasticity, which was validated by histological studies and cytokine determination. Taken together, these results suggest that neuroplastic and inflammatory dysregulation may be a therapeutic target for the treatment of post-traumatic stress disorders.

New insights into hypothalamic neurogenesis disruption after acute and intense stress: implications for microglia and inflammation.

In recent years, the hypothalamus has emerged as a new neurogenic area, capable of generating new neurons after development. Neurogenesis-dependent neuroplasticity seems to be critical to continuously adapt to internal and environmental changes. Stress is a potent environmental factor that can produce potent and enduring effects on brain structure and function. Acute and chronic stress is known to cause alterations in neurogenesis and microglia in classical adult neurogenic regions such as the hippocampus. The hypothalamus is one of the major brain regions implicated in homeostatic stress and emotional stress systems, but little is known about the effect of stress on the hypothalamus. Here, we studied the impact of acute and intense stress (water immersion and restrain stress, WIRS), which may be considered as an inducer of an animal model of posttraumatic stress disorder, on neurogenesis and neuroinflammation in the hypothalamus of adult male mice, focusing on three nuclei: PVN, VMN and ARC, and also in the periventricular area. Our data revealed that a unique stressor was sufficient to provoke a significant impact on hypothalamic neurogenesis by inducing a reduction in the proliferation and number of immature neurons identified as DCX+ cells. These differences were accompanied by marked microglial activation in the VMN and ARC, together with a concomitant increase in IL-6 levels, indicating that WIRS induced an inflammatory response. To investigate the possible molecular mechanisms responsible for neuroplastic and inflammatory changes, we tried to identify proteomic changes. The data revealed that WIRS induced changes in the hypothalamic proteome, modifying the abundance of three and four proteins after 1 h or 24 h of stress application, respectively. These changes were also accompanied by slight changes in the weight and food intake of the animals. These results are the first to show that even a short-term environmental stimulus such as acute and intense stress can have neuroplastic, inflammatory, functional and metabolic consequences on the adult hypothalamus.

Arsenic: A Perspective on Its Effect on Pioglitazone Bioavailability.

Arsenic (As) is a common contaminant in drinking water in northeastern Mexico, which reduces the expression of cytochrome P450 (CYP 450). This enzyme group metabolizes numerous drugs, such as oral antidiabetic drugs such as pioglitazone (61% CYP 3A4, 49% CYP 2C8). When CYP 450's function is inadequate, it has decreased therapeutic activity in type 2 diabetes mellitus (T2DM). This study aimed to establish the effect of As on pioglitazone metabolism in patients with T2DM. METHODOLOGY: Urine, water, and plasma samples from a healthy population (n = 11) and a population with T2DM (n = 20) were obtained. Samples were analyzed by fluorescence spectroscopy/hydride generation (As) and HPLC (pioglitazone). Additionally, CYP 3A4 and CYP 2C8 were studied by density functional theory (DFT). RESULTS: The healthy and T2DM groups were exposed via drinking water to >0.010 ppm, Ka values with a factor of 4.7 higher, Cl 1.42 lower, and ABCt 1.26 times higher concerning the healthy group. In silico analysis (DFT) of CYP 3A4 and CYP 2C8 isoforms showed the substitution of the iron atom by As in the active sites of the enzymes. CONCLUSIONS: The results indicate that the substitution of Fe for As modifies the enzymatic function of CYP 3A4 and CYP 2C8 isoforms, altering the metabolic process of CYP 2D6 and CYP 3A4 in patients with T2DM. Consequently, the variation in metabolism alters the bioavailability of pioglitazone and the expected final effect.

Children's use of demonstrative words: spatial deictics beyond infancy.

Demonstrative words are one of the most important ways of establishing reference in conversation. This work describes Spanish-speaking children's demonstrative production between ages 2 to 10 using data from the CHILDES corpora. Results indicate that children feature all demonstratives in their lexicon - however, the distal term is scarce throughout development. Moreover, patterns of demonstrative use are not adult-like at age 10. We compare adult and child data to conclude that children's development of demonstrative production is largely protracted. Adult use of the distal demonstrative is higher than in young children, although both older children and adults use the medial term ese more than any other demonstratives. In contrast, younger children use proximals relatively more frequently than older children and adults. Suggestions for future research and theoretical implications for the Spanish demonstrative system are discussed.

Primary health care expenditure in the Americas: measuring what matters.

This special report compares the measurement of primary health care (PHC) expenditure proposed by the Organization for Economic Cooperation and Development (OECD) and by the World Health Organization (WHO), according to the global framework for reporting health expenditures (SHA 2011) in three countries in the Region of the Americas. There are conceptual differences: (1) operationalization as basic care, by OECD, versus first contact, by WHO; (2) a wider range of goods and services in the WHO definition (including medicines, administration, and collective preventive services); and (3) consideration only of services in outpatient providers by OECD. PHC expenditures as a percentage of current healthcare spending in 2017 for WHO and OECD: Mexico (43.6% vs. 15.1%); Dominican Republic (41.1% vs. 5.75%), and Costa Rica (31.4% vs. 5.7%). The broad WHO definition of PHC as first contact facilitates inclusion of services that reflect the way countries provide care to their populations. Even so, WHO could improve its category descriptions for the purposes of international comparison. Restricting PHC to outpatient providers (as the OECD does) greatly limits measurement and excludes interventions intrinsic to the concept of PHC, such as collective preventive services. As a transitional step, we recommend that countries should monitor PHC funding and should explain what they include in their definition. SHA 2011 makes it possible to identify and compare these differences.

En este informe especial se compara la medición del gasto en atención primaria en salud (APS) propuesta por la Organización para la Cooperación y el Desarrollo Económico (OCDE) y la Organización Mundial de la Salud (OMS) según el marco mundial para reportar gastos en salud (SHA 2011) en tres países de la región de las Américas. Hay divergencias conceptuales: 1) la operacionalización como atención básica, por OCDE, o primer contacto, por OMS; 2) la mayor amplitud de bienes y servicios en la definición de OMS (incluye medicamentos, administración y servicios preventivos colectivos); 3) la consideración únicamente de servicios en proveedores ambulatorios en OCDE. Los gastos en APS como el porcentaje del gasto corriente en salud (GCS) en 2017 para OMS y OCDE, serían: México (43,6% vs 15.1%); República Dominicana (41,1 vs 5,75%) y Costa Rica (31,4% vs 5,7%).La definición amplia de APS como primer contacto de OMS facilita la inclusión de servicios que reflejan la forma en que los países ofrecen atención a su población. Aun así, la OMS podría mejorar las descripciones de las categorías incluidas para fines de comparación internacional. Restringir la APS a proveedores ambulatorios como hace OCDE limita mucho la medición y excluye intervenciones intrínsecas al concepto de APS, como servicios colectivos de prevención. Como paso transitorio se recomienda a los países que monitoreen el financiamiento de la APS, explicitando qué incluyen en su definición. El SHA 2011 permite identificar y comparar estas diferencias.

Este informe especial apresenta uma comparação entre a medida do gasto em atenção primária à saúde (APS) conforme as propostas da Organização para a Cooperação e o Desenvolvimento Econômico (OCDE) e da Organização Mundial da Saúde (OMS), usando a metodologia mundialmente aceita para reportar gastos em saúde ­ o System of Health Accounts (SHA 2011) ­ em três países da Região das Américas. Observam-se divergências conceituais entre os métodos: 1) operacionalização do conceito como atenção básica pela OCDE ou primeiro contato pela OMS; 2) maior abrangência de bens e serviços de acordo com a definição da OMS (englobando medicamentos, administração e serviços de prevenção em âmbito coletivo) e 3) inclusão exclusivamente de serviços ambulatoriais de acordo com a OCDE. Os gastos em APS como percentual do gasto corrente em saúde (GCS) em 2017, de acordo com os métodos propostos pela OMS e pela OCDE, foram: 43,6% vs. 15,1% no México; 41,1 vs. 5,75% na República Dominicana; e 31,4% vs. 5,7% na Costa Rica. A definição ampla de APS como primeiro contato proposta pela OMS permite incluir os diferentes arranjos de atenção existentes nos países. No entanto, as categorias deveriam ser mais bem detalhadas para facilitar a comparação internacional. Por outro lado, a proposta da OECD restringe a APS aos prestadores de serviços ambulatoriais, o que limita muito a medição e exclui intervenções próprias do conceito de APS, como serviços de prevenção no âmbito coletivo. Numa etapa de transição, recomenda-se aos países monitorar o financiamento da APS, explicitando os itens incluídos na definição empregada. A metodologia SHA 2011 possibilita identificar e comparar essas diferenças.

[Primary health care expenditure in the Americas: measuring what mattersGasto en atención primaria en salud en las Américas: medir lo que importa]. / Gasto em atenção primária à saúde nas Américas: medir o que importa.

This special report compares the measurement of primary health care (PHC) expenditure proposed by the Organization for Economic Cooperation and Development (OECD) and by the World Health Organization (WHO), according to the global framework for reporting health expenditures (SHA 2011) in three countries in the Region of the Americas. There are conceptual differences: 1) operationalization as basic care, by OECD, versus first contact, by WHO; 2) a wider range of goods and services in the WHO definition (including medicines, administration, and collective preventive services); and 3) consideration only of services in outpatient providers by OECD. PHC expenditures as a percentage of current healthcare spending in 2017 for WHO and OECD: Mexico (43.6% vs. 15.1%); Dominican Republic (41.1% vs. 5.75%), and Costa Rica (31.4% vs. 5.7%). The broad WHO definition of PHC as first contact facilitates inclusion of services that reflect the way countries provide care to their populations. Even so, WHO could improve its category descriptions for the purposes of international comparison. Restricting PHC to outpatient providers (as the OECD does) greatly limits measurement and excludes interventions intrinsic to the concept of PHC, such as collective preventive services. As a transitional step, we recommend that countries should monitor PHC funding and should explain what they include in their definition. SHA 2011 makes it possible to identify and compare these differences.

En este informe especial se compara la medición del gasto en atención primaria en salud (APS) propuesta por la Organización para la Cooperación y el Desarrollo Económico (OCDE) y la Organización Mundial de la Salud (OMS) según el marco mundial para reportar gastos en salud (SHA 2011) en tres países de la región de las Américas. Hay divergencias conceptuales: 1) la operacionalización como atención básica, por OCDE, o primer contacto, por OMS; 2) la mayor amplitud de bienes y servicios en la definición de OMS (incluye medicamentos, administración y servicios preventivos colectivos); 3) la consideración únicamente de servicios en proveedores ambulatorios en OCDE. Los gastos en APS como el porcentaje del gasto corriente en salud (GCS) en 2017 para OMS y OCDE, serían: México (43,6% vs 15.1%); República Dominicana (41,1 vs 5,75%) y Costa Rica (31,4% vs 5,7%). La definición amplia de APS como primer contacto de OMS facilita la inclusión de servicios que reflejan la forma en que los países ofrecen atención a su población. Aun así, la OMS podría mejorar las descripciones de las categorías incluidas para fines de comparación internacional. Restringir la APS a proveedores ambulatorios como hace OCDE limita mucho la medición y excluye intervenciones intrínsecas al concepto de APS, como servicios colectivos de prevención. Como paso transitorio se recomienda a los países que monitoreen el financiamiento de la APS, explicitando qué incluyen en su definición. El SHA 2011 permite identificar y comparar estas diferencias.

Primary health care expenditure in the Americas: measuring what matters

[ABSTRACT]. This special report compares the measurement of primary health care (PHC) expenditure proposed by the Organization for Economic Cooperation and Development (OECD) and by the World Health Organization (WHO), according to the global framework for reporting health expenditures (SHA 2011) in three countries in the Region of the Americas. There are conceptual differences: (1) operationalization as basic care, by OECD, versus first contact, by WHO; (2) a wider range of goods and services in the WHO definition (including medicines, administration, and collective preventive services); and (3) consideration only of services in outpatient providers by OECD. PHC expenditures as a percentage of current healthcare spending in 2017 for WHO and OECD: Mexico (43.6% vs. 15.1%); Dominican Republic (41.1% vs. 5.75%), and Costa Rica (31.4% vs. 5.7%). The broad WHO definition of PHC as first contact facilitates inclusion of services that reflect the way countries provide care to their populations. Even so, WHO could improve its category descriptions for the purposes of international comparison. Restricting PHC to outpatient providers (as the OECD does) greatly limits measurement and excludes interventions intrinsic to the concept of PHC, such as collective preventive services. As a transitional step, we recommend that countries should monitor PHC funding and should explain what they include in their definition. SHA 2011 makes it possible to identify and compare these differences.

Gasto em atenção primária à saúde nas Américas: medir o que importa

[RESUMO]. Este informe especial apresenta uma comparação entre a medida do gasto em atenção primária à saúde (APS) conforme as propostas da Organização para a Cooperação e o Desenvolvimento Econômico (OCDE) e da Organização Mundial da Saúde (OMS), usando a metodologia mundialmente aceita para reportar gastos em saúde – o System of Health Accounts (SHA 2011) – em três países da Região das Américas. Observam- -se divergências conceituais entre os métodos: 1) operacionalização do conceito como atenção básica pela OCDE ou primeiro contato pela OMS; 2) maior abrangência de bens e serviços de acordo com a definição da OMS (englobando medicamentos, administração e serviços de prevenção em âmbito coletivo) e 3) inclusão exclusivamente de serviços ambulatoriais de acordo com a OCDE. Os gastos em APS como percentual do gasto corrente em saúde (GCS) em 2017, de acordo com os métodos propostos pela OMS e pela OCDE, foram: 43,6% vs. 15,1% no México; 41,1 vs. 5,75% na República Dominicana; e 31,4% vs. 5,7% na Costa Rica. A definição ampla de APS como primeiro contato proposta pela OMS permite incluir os diferentes arranjos de atenção existentes nos países. No entanto, as categorias deveriam ser mais bem detalhadas para facilitar a comparação internacional. Por outro lado, a proposta da OECD restringe a APS aos prestadores de serviços ambulatoriais, o que limita muito a medição e exclui intervenções próprias do conceito de APS, como serviços de prevenção no âmbito coletivo. Numa etapa de transição, recomenda-se aos países monitorar o financiamento da APS, explicitando os itens incluídos na definição empregada. A metodologia SHA 2011 possibilita identificar e comparar essas diferenças.

Differential expression of HTR2A and MAOA genes in the prefrontal cortex and hypothalamus of suicide victims from Mexican population.

OBJECTIVE: The main aim of the current study was to investigate whether the expression levels of the HTR2A and MAOA genes are altered in the postmortem brain of suicide victims from Mexican population. METHODS: On the basis of a case- control study, we examined the expression levels of HTR2A and MAOA genes in the postmortem prefrontal cortex (Brodmann area 8/9) and hypothalamus (ventromedial nucleus) tissues from 20 suicide victims and 20 control subjects from a Mexican population. Gene-expression profile quantification was carried out by qPCR and determined by the 2-ΔΔCt method. RESULTS: In suicide victims, the expression levels of the HTR2A gene were significantly higher in the prefrontal cortex. In contrast, the expression of the MAOA gene in the hypothalamus of the suicide victims was significantly higher than in the control subjects. These results were consistent regardless of age, sex, postmortem interval, or pH of brain tissue. CONCLUSION: The evidence suggests that the pattern of differential expression of HTR2A and MAOA genes in the brain may be involved in suicide, providing a possible molecular basis for the brain abnormalities in suicide victims.

[Primary health care expenditure in the Americas: measuring what mattersGasto em atenção primária à saúde nas Américas: calcular o que importa]. / Gasto en atención primaria en salud en las Américas: medir lo que importa.

This special report compares the measurement of primary health care (PHC) expenditure proposed by the Organization for Economic Cooperation and Development (OECD) and by the World Health Organization (WHO), according to the global framework for reporting health expenditures (SHA 2011) in three countries in the Region of the Americas. There are conceptual differences: 1) operationalization as basic care, by OECD, versus first contact, by WHO; 2) a wider range of goods and services in the WHO definition (including medicines, administration, and collective preventive services); and 3) consideration only of services in outpatient providers by OECD. PHC expenditures as a percentage of current healthcare spending in 2017 for WHO and OECD: Mexico (43.6% vs. 15.1%); Dominican Republic (41.1% vs. 5.75%), and Costa Rica (31.4% vs. 5.7%). The 30% target for current healthcare spending on PHC proposed by Compact 30-30-30 (Pan American Health Organization) would be surpassed by the WHO definition, but it would be far from achieved by the OECD definition. The broad WHO definition of PHC as first contact facilitates inclusion of services that reflect the way countries provide care to their populations. Even so, WHO could improve its category descriptions for the purposes of international comparison. Restricting PHC to outpatient providers (as the OECD does) greatly limits measurement and excludes interventions intrinsic to the concept of PHC, such as collective preventive services. As a transitional step, we recommend that countries should monitor PHC funding and should explain what they include in their definition. SHA 2011 makes it possible to identify and compare these differences.

Este informe especial apresenta uma comparação entre o cálculo do gasto em atenção primária à saúde (APS) conforme os métodos propostos pela Organização para a Cooperação e o Desenvolvimento Econômico (OCDE) e pela Organização Mundial da Saúde (OMS), segundo a metodologia System of Health Accounts (SHA 2011), em três países da Região das Américas. Observam-se divergências conceituais entre os métodos: 1) operacionalização do conceito como atenção básica pela OCDE ou primeiro contato pela OMS; 2) maior abrangência de bens e serviços de acordo com a definição da OMS (englobando medicamentos, administração e serviços de prevenção em âmbito coletivo) e 3) inclusão única de serviços ambulatoriais de acordo com a OCDE. Os gastos em APS como percentual do gasto corrente em saúde (GCS) em 2017, de acordo com os métodos propostos pela OMS e pela OCDE, foram: 43,6% vs. 15,1% no México; 41,1 vs. 5,75% na República Dominicana; e 31,4% vs. 5,7% na Costa Rica. Esses valores ultrapassam a meta de 30% do GCS em APS sugerida no Pacto 30.30.30 da Organização Pan-Americana da Saúde, com a definição proposta pela OMS, e essa meta estaria longe de ser alcançada com a definição proposta pela OCDE. A definição ampla de APS como primeiro contato que é proposta pela OMS permite incluir os diferentes serviços de atenção existentes nos países. No entanto, as categorias deveriam ser mais bem detalhadas para facilitar a comparação internacional. Por outro lado, a proposta da OECD restringe a APS aos prestadores de serviços ambulatoriais, o que limita muito o cálculo e exclui intervenções próprias do conceito de APS, como serviços de prevenção no âmbito coletivo. Numa etapa de transição, recomenda-se aos países monitorar o financiamento da APS, explicitando os itens incluídos na definição empregada. A metodologia SHA 2011 possibilita identificar e comparar essas diferenças.

Gasto en atención primaria en salud en las Américas: medir lo que importa

[RESUMEN]. En este informe especial se compara la medición del gasto en atención primaria en salud (APS) propuesta por la Organización para la Cooperación y el Desarrollo Económico (OCDE) y la Organización Mundial de la Salud (OMS) según el marco mundial para reportar gastos en salud (SHA 2011) en tres países de la región de las Américas. Hay divergencias conceptuales: 1) la operacionalización como atención básica, por OCDE, o primer contacto, por OMS; 2) la mayor amplitud de bienes y servicios en la definición de OMS (incluye medicamentos, administración y servicios preventivos colectivos); 3) la consideración únicamente de servicios en proveedores ambulatorios en OCDE. Los gastos en APS como el porcentaje del gasto corriente en salud (GCS) en 2017 para OMS y OCDE, serían: México (43,6% vs 15.1%); República Dominicana (41,1 vs 5,75%) y Costa Rica (31,4% vs 5,7%); superarían la meta del 30% del GCS en APS que propone el Pacto 30-30-30 de la Organización Panamericana de la Salud, con la definición de la OMS y estarían muy lejos de alcanzarla con la de la OCDE. La definición amplia de APS como primer contacto de OMS facilita la inclusión de servicios que reflejan la forma en que los países ofrecen atención a su población. Aun así, la OMS podría mejorar las descripciones de las categorías incluidas para fines de comparación internacional. Restringir la APS a proveedores ambulatorios como hace OCDE limita mucho la medición y excluye intervenciones intrínsecas al concepto de APS, como servicios colectivos de prevención. Como paso transitorio se recomienda a los países que monitoreen el financiamiento de la APS, explicitando qué incluyen en su definición. El SHA 2011 permite identificar y comparar estas diferencias.

GCKIII (Germinal Center Kinase III) Kinases STK24 and STK25 (Serine/Threonine Kinase 24 and 25) Inhibit Cavernoma Development.

BACKGROUND: Cavernous cerebral malformations can arise because of mutations in the CCM1, CCM2, or CCM3 genes, and lack of Cdc42 has also been reported to induce these malformations in mice. However, the role of the CCM3 (cerebral cavernous malformation 3)-associated kinases in cavernoma development is not known, and we, therefore, have investigated their role in the process. METHODS: We used a combination of an in vivo approach, using mice genetically modified to be deficient in the CCM3-associated kinases STK24 and STK25 (serine/threonine kinases 24 and 25), and the in vitro model of human endothelial cells in which expression of STK24 and STK25 was inhibited by RNA interference. RESULTS: Mice deficient for both Stk24 and Stk25, but not for either of them individually, developed aggressive vascular lesions with the characteristics of cavernomas at an early age. Stk25 deficiency also gave rise to vascular anomalies in the context of Stk24 heterozygosity. Human endothelial cells deficient for both kinases phenocopied several of the consequences of CCM3 loss, and single STK25 deficiency also induced KLF2 expression, Golgi dispersion, altered distribution of ß-catenin, and appearance of stress fibers. CONCLUSIONS: The CCM3-associated kinases STK24 and STK25 play a major role in the inhibition of cavernoma development.

The extended development of mapping spatial demonstratives onto space.

Spatial demonstratives (this and that in English) convey distance relative to speaker (within reach vs. out of reach) and object characteristics such as ownership. Previous studies indicate that object characteristics affect adult demonstrative choice, for example, greater use of this for owned objects. Here, production of spatial demonstratives was studied developmentally to identify when demonstrative production is sensitive to both distance and ownership. In two experiments, 7-year-olds, 11-year-olds, and adults completed an object location memory task, and a language task eliciting this or that to indicate an object. Results indicate that adult-like demonstrative production starts around 7 years of age and continues to develop beyond 11 years. Nonlinguistic spatial memory did not vary significantly across age groups. Spatial demonstratives encode both semantic and spatial object characteristics throughout development, revealing the fundamental importance of semantic factors for demonstrative production.

Gasto en atención primaria en salud en las Américas: medir lo que importa / Primary health care expenditure in the Americas: measuring what matters / Gasto em atenção primária à saúde nas Américas: calcular o que importa

RESUMEN En este informe especial se compara la medición del gasto en atención primaria en salud (APS) propuesta por la Organización para la Cooperación y el Desarrollo Económico (OCDE) y la Organización Mundial de la Salud (OMS) según el marco mundial para reportar gastos en salud (SHA 2011) en tres países de la región de las Américas. Hay divergencias conceptuales: 1) la operacionalización como atención básica, por OCDE, o primer contacto, por OMS; 2) la mayor amplitud de bienes y servicios en la definición de OMS (incluye medicamentos, administración y servicios preventivos colectivos); 3) la consideración únicamente de servicios en proveedores ambulatorios en OCDE. Los gastos en APS como el porcentaje del gasto corriente en salud (GCS) en 2017 para OMS y OCDE, serían: México (43,6% vs 15.1%); República Dominicana (41,1 vs 5,75%) y Costa Rica (31,4% vs 5,7%); superarían la meta del 30% del GCS en APS que propone el Pacto 30-30-30 de la Organización Panamericana de la Salud, con la definición de la OMS y estarían muy lejos de alcanzarla con la de la OCDE. La definición amplia de APS como primer contacto de OMS facilita la inclusión de servicios que reflejan la forma en que los países ofrecen atención a su población. Aun así, la OMS podría mejorar las descripciones de las categorías incluidas para fines de comparación internacional. Restringir la APS a proveedores ambulatorios como hace OCDE limita mucho la medición y excluye intervenciones intrínsecas al concepto de APS, como servicios colectivos de prevención. Como paso transitorio se recomienda a los países que monitoreen el financiamiento de la APS, explicitando qué incluyen en su definición. El SHA 2011 permite identificar y comparar estas diferencias.

ABSTRACT This special report compares the measurement of primary health care (PHC) expenditure proposed by the Organization for Economic Cooperation and Development (OECD) and by the World Health Organization (WHO), according to the global framework for reporting health expenditures (SHA 2011) in three countries in the Region of the Americas. There are conceptual differences: 1) operationalization as basic care, by OECD, versus first contact, by WHO; 2) a wider range of goods and services in the WHO definition (including medicines, administration, and collective preventive services); and 3) consideration only of services in outpatient providers by OECD. PHC expenditures as a percentage of current healthcare spending in 2017 for WHO and OECD: Mexico (43.6% vs. 15.1%); Dominican Republic (41.1% vs. 5.75%), and Costa Rica (31.4% vs. 5.7%). The 30% target for current healthcare spending on PHC proposed by Compact 30-30-30 (Pan American Health Organization) would be surpassed by the WHO definition, but it would be far from achieved by the OECD definition. The broad WHO definition of PHC as first contact facilitates inclusion of services that reflect the way countries provide care to their populations. Even so, WHO could improve its category descriptions for the purposes of international comparison. Restricting PHC to outpatient providers (as the OECD does) greatly limits measurement and excludes interventions intrinsic to the concept of PHC, such as collective preventive services. As a transitional step, we recommend that countries should monitor PHC funding and should explain what they include in their definition. SHA 2011 makes it possible to identify and compare these differences.

RESUMO Este informe especial apresenta uma comparação entre o cálculo do gasto em atenção primária à saúde (APS) conforme os métodos propostos pela Organização para a Cooperação e o Desenvolvimento Econômico (OCDE) e pela Organização Mundial da Saúde (OMS), segundo a metodologia System of Health Accounts (SHA 2011), em três países da Região das Américas. Observam-se divergências conceituais entre os métodos: 1) operacionalização do conceito como atenção básica pela OCDE ou primeiro contato pela OMS; 2) maior abrangência de bens e serviços de acordo com a definição da OMS (englobando medicamentos, administração e serviços de prevenção em âmbito coletivo) e 3) inclusão única de serviços ambulatoriais de acordo com a OCDE. Os gastos em APS como percentual do gasto corrente em saúde (GCS) em 2017, de acordo com os métodos propostos pela OMS e pela OCDE, foram: 43,6% vs. 15,1% no México; 41,1 vs. 5,75% na República Dominicana; e 31,4% vs. 5,7% na Costa Rica. Esses valores ultrapassam a meta de 30% do GCS em APS sugerida no Pacto 30.30.30 da Organização Pan-Americana da Saúde, com a definição proposta pela OMS, e essa meta estaria longe de ser alcançada com a definição proposta pela OCDE. A definição ampla de APS como primeiro contato que é proposta pela OMS permite incluir os diferentes serviços de atenção existentes nos países. No entanto, as categorias deveriam ser mais bem detalhadas para facilitar a comparação internacional. Por outro lado, a proposta da OECD restringe a APS aos prestadores de serviços ambulatoriais, o que limita muito o cálculo e exclui intervenções próprias do conceito de APS, como serviços de prevenção no âmbito coletivo. Numa etapa de transição, recomenda-se aos países monitorar o financiamento da APS, explicitando os itens incluídos na definição empregada. A metodologia SHA 2011 possibilita identificar e comparar essas diferenças.

Primary health care expenditure in the Americas: measuring what matters / Gasto en atención primaria en salud en las Américas: medir lo que importa / Gasto em atenção primária à saúde nas Américas: medir o que importa

ABSTRACT This special report compares the measurement of primary health care (PHC) expenditure proposed by the Organization for Economic Cooperation and Development (OECD) and by the World Health Organization (WHO), according to the global framework for reporting health expenditures (SHA 2011) in three countries in the Region of the Americas. There are conceptual differences: (1) operationalization as basic care, by OECD, versus first contact, by WHO; (2) a wider range of goods and services in the WHO definition (including medicines, administration, and collective preventive services); and (3) consideration only of services in outpatient providers by OECD. PHC expenditures as a percentage of current healthcare spending in 2017 for WHO and OECD: Mexico (43.6% vs. 15.1%); Dominican Republic (41.1% vs. 5.75%), and Costa Rica (31.4% vs. 5.7%). The broad WHO definition of PHC as first contact facilitates inclusion of services that reflect the way countries provide care to their populations. Even so, WHO could improve its category descriptions for the purposes of international comparison. Restricting PHC to outpatient providers (as the OECD does) greatly limits measurement and excludes interventions intrinsic to the concept of PHC, such as collective preventive services. As a transitional step, we recommend that countries should monitor PHC funding and should explain what they include in their definition. SHA 2011 makes it possible to identify and compare these differences.

RESUMEN En este informe especial se compara la medición del gasto en atención primaria en salud (APS) propuesta por la Organización para la Cooperación y el Desarrollo Económico (OCDE) y la Organización Mundial de la Salud (OMS) según el marco mundial para reportar gastos en salud (SHA 2011) en tres países de la región de las Américas. Hay divergencias conceptuales: 1) la operacionalización como atención básica, por OCDE, o primer contacto, por OMS; 2) la mayor amplitud de bienes y servicios en la definición de OMS (incluye medicamentos, administración y servicios preventivos colectivos); 3) la consideración únicamente de servicios en proveedores ambulatorios en OCDE. Los gastos en APS como el porcentaje del gasto corriente en salud (GCS) en 2017 para OMS y OCDE, serían: México (43,6% vs 15.1%); República Dominicana (41,1 vs 5,75%) y Costa Rica (31,4% vs 5,7%).La definición amplia de APS como primer contacto de OMS facilita la inclusión de servicios que reflejan la forma en que los países ofrecen atención a su población. Aun así, la OMS podría mejorar las descripciones de las categorías incluidas para fines de comparación internacional. Restringir la APS a proveedores ambulatorios como hace OCDE limita mucho la medición y excluye intervenciones intrínsecas al concepto de APS, como servicios colectivos de prevención. Como paso transitorio se recomienda a los países que monitoreen el financiamiento de la APS, explicitando qué incluyen en su definición. El SHA 2011 permite identificar y comparar estas diferencias.

RESUMO Este informe especial apresenta uma comparação entre a medida do gasto em atenção primária à saúde (APS) conforme as propostas da Organização para a Cooperação e o Desenvolvimento Econômico (OCDE) e da Organização Mundial da Saúde (OMS), usando a metodologia mundialmente aceita para reportar gastos em saúde - o System of Health Accounts (SHA 2011) - em três países da Região das Américas. Observam-se divergências conceituais entre os métodos: 1) operacionalização do conceito como atenção básica pela OCDE ou primeiro contato pela OMS; 2) maior abrangência de bens e serviços de acordo com a definição da OMS (englobando medicamentos, administração e serviços de prevenção em âmbito coletivo) e 3) inclusão exclusivamente de serviços ambulatoriais de acordo com a OCDE. Os gastos em APS como percentual do gasto corrente em saúde (GCS) em 2017, de acordo com os métodos propostos pela OMS e pela OCDE, foram: 43,6% vs. 15,1% no México; 41,1 vs. 5,75% na República Dominicana; e 31,4% vs. 5,7% na Costa Rica. A definição ampla de APS como primeiro contato proposta pela OMS permite incluir os diferentes arranjos de atenção existentes nos países. No entanto, as categorias deveriam ser mais bem detalhadas para facilitar a comparação internacional. Por outro lado, a proposta da OECD restringe a APS aos prestadores de serviços ambulatoriais, o que limita muito a medição e exclui intervenções próprias do conceito de APS, como serviços de prevenção no âmbito coletivo. Numa etapa de transição, recomenda-se aos países monitorar o financiamento da APS, explicitando os itens incluídos na definição empregada. A metodologia SHA 2011 possibilita identificar e comparar essas diferenças.

Gasto em atenção primária à saúde nas Américas: medir o que importa / Primary health care expenditure in the Americas: measuring what matters / Gasto en atención primaria en salud en las Américas: medir lo que importa

RESUMO Este informe especial apresenta uma comparação entre a medida do gasto em atenção primária à saúde (APS) conforme as propostas da Organização para a Cooperação e o Desenvolvimento Econômico (OCDE) e da Organização Mundial da Saúde (OMS), usando a metodologia mundialmente aceita para reportar gastos em saúde - o System of Health Accounts (SHA 2011) - em três países da Região das Américas. Observam-se divergências conceituais entre os métodos: 1) operacionalização do conceito como atenção básica pela OCDE ou primeiro contato pela OMS; 2) maior abrangência de bens e serviços de acordo com a definição da OMS (englobando medicamentos, administração e serviços de prevenção em âmbito coletivo) e 3) inclusão exclusivamente de serviços ambulatoriais de acordo com a OCDE. Os gastos em APS como percentual do gasto corrente em saúde (GCS) em 2017, de acordo com os métodos propostos pela OMS e pela OCDE, foram: 43,6% vs. 15,1% no México; 41,1 vs. 5,75% na República Dominicana; e 31,4% vs. 5,7% na Costa Rica. A definição ampla de APS como primeiro contato proposta pela OMS permite incluir os diferentes arranjos de atenção existentes nos países. No entanto, as categorias deveriam ser mais bem detalhadas para facilitar a comparação internacional. Por outro lado, a proposta da OECD restringe a APS aos prestadores de serviços ambulatoriais, o que limita muito a medição e exclui intervenções próprias do conceito de APS, como serviços de prevenção no âmbito coletivo. Numa etapa de transição, recomenda-se aos países monitorar o financiamento da APS, explicitando os itens incluídos na definição empregada. A metodologia SHA 2011 possibilita identificar e comparar essas diferenças.

ABSTRACT This special report compares the measurement of primary health care (PHC) expenditure proposed by the Organization for Economic Cooperation and Development (OECD) and by the World Health Organization (WHO), according to the global framework for reporting health expenditures (SHA 2011) in three countries in the Region of the Americas. There are conceptual differences: 1) operationalization as basic care, by OECD, versus first contact, by WHO; 2) a wider range of goods and services in the WHO definition (including medicines, administration, and collective preventive services); and 3) consideration only of services in outpatient providers by OECD. PHC expenditures as a percentage of current healthcare spending in 2017 for WHO and OECD: Mexico (43.6% vs. 15.1%); Dominican Republic (41.1% vs. 5.75%), and Costa Rica (31.4% vs. 5.7%). The broad WHO definition of PHC as first contact facilitates inclusion of services that reflect the way countries provide care to their populations. Even so, WHO could improve its category descriptions for the purposes of international comparison. Restricting PHC to outpatient providers (as the OECD does) greatly limits measurement and excludes interventions intrinsic to the concept of PHC, such as collective preventive services. As a transitional step, we recommend that countries should monitor PHC funding and should explain what they include in their definition. SHA 2011 makes it possible to identify and compare these differences.

RESUMEN En este informe especial se compara la medición del gasto en atención primaria en salud (APS) propuesta por la Organización para la Cooperación y el Desarrollo Económico (OCDE) y la Organización Mundial de la Salud (OMS) según el marco mundial para reportar gastos en salud (SHA 2011) en tres países de la región de las Américas. Hay divergencias conceptuales: 1) la operacionalización como atención básica, por OCDE, o primer contacto, por OMS; 2) la mayor amplitud de bienes y servicios en la definición de OMS (incluye medicamentos, administración y servicios preventivos colectivos); 3) la consideración únicamente de servicios en proveedores ambulatorios en OCDE. Los gastos en APS como el porcentaje del gasto corriente en salud (GCS) en 2017 para OMS y OCDE, serían: México (43,6% vs 15.1%); República Dominicana (41,1 vs 5,75%) y Costa Rica (31,4% vs 5,7%). La definición amplia de APS como primer contacto de OMS facilita la inclusión de servicios que reflejan la forma en que los países ofrecen atención a su población. Aun así, la OMS podría mejorar las descripciones de las categorías incluidas para fines de comparación internacional. Restringir la APS a proveedores ambulatorios como hace OCDE limita mucho la medición y excluye intervenciones intrínsecas al concepto de APS, como servicios colectivos de prevención. Como paso transitorio se recomienda a los países que monitoreen el financiamiento de la APS, explicitando qué incluyen en su definición. El SHA 2011 permite identificar y comparar estas diferencias.

Do changes in microglial status underlie neurogenesis impairments and depressive-like behaviours induced by psychological stress? A systematic review in animal models.

Stress may have a negative effect on mental health and is the primary environmental risk factor in the aetiology of depression. Nevertheless, the neurobiological mechanisms underlying this mood disorder remain poorly characterized. The hippocampus is a target structure of the adverse effects of stress, and hippocampal neurogenesis plays a crucial role. However, we do not know the mechanisms by which stress impacts neurogenesis. Recent studies indicate that changes in neuroinflammation, primarily via microglial cells, may play an essential role in this process. However, the relationship between stress, microglial changes, and alterations in neurogenesis and their involvement in the development of depression is poorly characterized. For this reason, this systematic review aims to synthesise and evaluate current studies that have investigated the relationship between these variables. Taken together, the revised data, although not entirely conclusive, seem to suggest that microglial changes induced by psychological stress regulate neurogenesis and in turn may be responsible for the development of depressive-like behaviours, but other factors that influence these stressful experiences should not be dismissed.