Developing relevant assessments of community-engaged research partnerships: A community-based participatory approach to evaluating clinical and health research study teams.

Background/Objective: In 2017, the Michigan Institute for Clinical and Health Research (MICHR) and community partners in Flint, Michigan collaborated to launch a research funding program and evaluate the dynamics of those research partnerships receiving funding. While validated assessments for community-engaged research (CEnR) partnerships were available, the study team found none sufficiently relevant to conducting CEnR in the context of the work. MICHR faculty and staff along with community partners living and working in Flint used a community-based participatory research (CBPR) approach to develop and administer a locally relevant assessment of CEnR partnerships that were active in Flint in 2019 and 2021. Methods: Surveys were administered each year to over a dozen partnerships funded by MICHR to evaluate how community and academic partners assessed the dynamics and impact of their study teams over time. Results: The results suggest that partners believed that their partnerships were engaging and highly impactful. Although many substantive differences between community and academic partners' perceptions over time were identified, the most notable regarded the financial management of the partnerships. Conclusion: This work contributes to the field of translational science by evaluating how the financial management of community-engaged health research partnerships in a locally relevant context of Flint can be associated with these teams' scientific productivity and impact with national implications for CEnR. This work presents evaluation methods which can be used by clinical and translational research centers that strive to implement and measure their use of CBPR approaches.

Brain Serotonin Release Is Reduced in Patients With Depression: A [11C]Cimbi-36 Positron Emission Tomography Study With a d-Amphetamine Challenge.

BACKGROUND: The serotonin hypothesis of depression proposes that diminished serotonergic (5-HT) neurotransmission is causal in the pathophysiology of the disorder. Although the hypothesis is over 50 years old, there is no firm in vivo evidence for diminished 5-HT neurotransmission. We recently demonstrated that the 5-HT2A receptor agonist positron emission tomography (PET) radioligand [11C]Cimbi-36 is sensitive to increases in extracellular 5-HT induced by an acute d-amphetamine challenge. Here we applied [11C]Cimbi-36 PET to compare brain 5-HT release capacity in patients experiencing a major depressive episode (MDE) to that of healthy control subjects (HCs) without depression. METHODS: Seventeen antidepressant-free patients with MDE (3 female/14 male, mean age 44 ± 13 years, Hamilton Depression Rating Scale score 21 ± 4 [range 16-30]) and 20 HCs (3 female/17 male, mean age 32 ± 9 years) underwent 90-minute dynamic [11C]Cimbi-36 PET before and 3 hours after a 0.5-mg/kg oral dose of d-amphetamine. Frontal cortex (main region of interest) 5-HT2A receptor nondisplaceable binding was calculated from kinetic analysis using the multilinear analysis-1 approach with the cerebellum as the reference region. RESULTS: Following d-amphetamine administration, frontal nondisplaceable binding potential (BPND) was significantly reduced in the HC group (1.04 ± 0.31 vs. 0.87 ± 0.24, p < .001) but not in the MDE group (0.97 ± 0.25 vs. 0.92 ± 0.22, not significant). ΔBPND of the MDE group was significantly lower than that of the HC group (HC: 15% ± 14% vs. MDE: 6.5% ± 20%, p = .041). CONCLUSIONS: This first direct assessment of 5-HT release capacity in people with depression provides clear evidence for dysfunctional serotonergic neurotransmission in depression by demonstrating reduced 5-HT release capacity in patients experiencing an MDE.

Improving cardiovascular health with the patient-centered, integrated primary care HEARTS model in Trinidad and Tobago.

This article describes the introduction of the Pan American Health Organization's HEARTS in the Americas program in Trinidad and Tobago and the successful experiences and challenges encountered in introducing and scaling it up as a strategy for strengthening the health system's response to cardiovascular diseases. Evidence about implementation of the HEARTS program in the World Health Organization's Region of the Americas was reviewed to identify the progress made, barriers, success factors and lessons learned. In 2019, the Ministry of Health commenced implementation of the program in 5 (4.9%) of the 102 primary health care centers, and by the end of 2021, it had been scaled up to 46 (45.0%) centers. The HEARTS program ensures that patients' cardiovascular health is managed in a comprehensive way through providing counseling about a healthy lifestyle, using evidence-based treatment protocols, ensuring access to essential medicines and technologies, and using a risk-based team approach, a monitoring and evaluation system and also a team-based approach to care delivery. The barriers encountered during implementation included the fragmentation of the existing health care system, the paternalistic role assumed by health care professionals, the resistance of some health care workers to change and a lack of team-based approaches to providing care. Successful implementation of the program was enabled through ensuring high-level political commitment, establishing the national HEARTS Oversight Committee, ensuring stakeholder involvement throughout all phases and implementing standardized approaches to care. When implemented in the context of existing primary health care settings, the HEARTS program provides an exceptionally well integrated and comprehensive model of care that embodies the principles of universal health care while ensuring the health of both populations and individuals. Thus, it enables and promotes a strengthened primary health care system and services that are responsive and resilient.

En este artículo se describe la introducción del programa HEARTS en las Américas de la Organización Panamericana de la Salud en Trinidad y Tabago y las experiencias satisfactorias y los desafíos encontrados con su ejecución y ampliación como estrategia para fortalecer la respuesta del sistema de salud a las enfermedades cardiovasculares. Se reunieron datos sobre la ejecución del programa HEARTS en la Región de las Américas de la Organización Mundial de la Salud con el fin de determinar cuáles han sido los avances, los obstáculos, los factores de éxito y las enseñanzas extraídas. En el año 2019, el Ministerio de Salud inició la ejecución del programa en cinco (4,9%) de los 102 centros de atención primaria de salud, y para fines del 2021, se había ampliado a 46 (45,0%). El programa HEARTS garantiza el manejo integral de la salud cardiovascular de los pacientes mediante la prestación de asesoramiento sobre hábitos saludables, la aplicación de protocolos de tratamiento basados en la evidencia, la garantía de acceso a medicamentos y tecnologías esenciales, así como el uso de un enfoque de trabajo en equipo basado en el riesgo, un sistema de monitoreo y evaluación, y un enfoque basado en el equipo para abordar la prestación de la atención. Entre los obstáculos para su ejecución se encontraron la fragmentación del sistema de atención médica, el papel paternalista asumido por los profesionales de la salud, la resistencia al cambio de algunos trabajadores de salud y la falta de enfoques de trabajo en equipo para la prestación de la atención. La ejecución satisfactoria del programa fue posible gracias a un compromiso político de alto nivel, la creación de un comité nacional de supervisión de HEARTS, la participación de las partes interesadas en todas las fases del programa y la aplicación de enfoques estandarizados para la atención. En su ejecución en el contexto de los entornos de atención primaria de salud existentes, el programa HEARTS proporciona un modelo de atención excepcionalmente bien integrado y exhaustivo que encarna los principios de acceso universal a la atención de salud al tiempo que garantiza la salud individual y poblacional. De este modo, este modelo fomenta un sistema de atención primaria de salud fortalecido y unos servicios receptivos y resilientes.

Este artigo descreve a introdução do programa HEARTS nas Américas da Organização Pan-Americana da Saúde em Trinidad e Tobago e as experiências bem-sucedidas e os desafios encontrados durante a introdução e expansão do programa como estratégia para fortalecer a resposta do sistema de saúde às doenças cardiovasculares. Analisaram-se evidências sobre a implementação do programa HEARTS na Região das Américas da Organização Mundial da Saúde para identificar os avanços obtidos, os obstáculos, os fatores de sucesso e as lições aprendidas. Em 2019, o Ministério da Saúde iniciou a implementação do programa em 5 (4,9%) dos 102 centros de atenção primária à saúde; no final de 2021, o programa havia sido ampliado para 46 (45,0%) centros. O programa HEARTS assegura que a saúde cardiovascular dos pacientes seja manejada de uma forma abrangente por meio de aconselhamento sobre estilo de vida saudável, uso de protocolos de tratamento baseados em evidências, garantia de acesso a medicamentos e tecnologias essenciais e utilização de uma estratégia de equipe baseada no risco, de um sistema de monitoramento e avaliação e de uma abordagem de atendimento baseado em equipe. Os obstáculos encontrados durante a implementação incluíam a fragmentação do sistema de saúde existente, o papel paternalista assumido pelos profissionais de saúde, a resistência de alguns profissionais de saúde a mudanças e a falta de abordagens baseadas em equipe na prestação do atendimento. Para permitir que a implementação do programa fosse bem-sucedida, obteve-se compromisso político de alto nível, criou-se o Comitê de Supervisão do HEARTS nacional, assegurou-se o envolvimento de interessados diretos em todas as fases e implementaram-se abordagens padronizadas de atendimento. Quando implementado no contexto dos ambientes existentes de atenção primária à saúde, o programa HEARTS oferece um modelo de atenção excepcionalmente bem integrado e abrangente que incorpora os princípios de atenção universal à saúde, ao mesmo tempo em que garante a saúde das populações e dos indivíduos. Dessa forma, viabiliza e promove um sistema de atenção primária à saúde fortalecido e serviços responsivos e resilientes.

Improving cardiovascular health with the patient-centered, integrated primary care HEARTS model in Trinidad and Tobago

[ABSTRACT]. This article describes the introduction of the Pan American Health Organization’s HEARTS in the Americas program in Trinidad and Tobago and the successful experiences and challenges encountered in introducing and scaling it up as a strategy for strengthening the health system’s response to cardiovascular diseases. Evidence about implementation of the HEARTS program in the World Health Organization’s Region of the Americas was reviewed to identify the progress made, barriers, success factors and lessons learned. In 2019, the Ministry of Health commenced implementation of the program in 5 (4.9%) of the 102 primary health care centers, and by the end of 2021, it had been scaled up to 46 (45.0%) centers. The HEARTS program ensures that patients’ cardiovascular health is managed in a comprehensive way through providing counseling about a healthy lifestyle, using evidence-based treatment protocols, ensuring access to essential medicines and technologies, and using a risk-based team approach, a monitoring and evaluation system and also a teambased approach to care delivery. The barriers encountered during implementation included the fragmentation of the existing health care system, the paternalistic role assumed by health care professionals, the resistance of some health care workers to change and a lack of team-based approaches to providing care. Successful implementation of the program was enabled through ensuring high-level political commitment, establishing the national HEARTS Oversight Committee, ensuring stakeholder involvement throughout all phases and implementing standardized approaches to care. When implemented in the context of existing primary health care settings, the HEARTS program provides an exceptionally well integrated and comprehensive model of care that embodies the principles of universal health care while ensuring the health of both populations and individuals. Thus, it enables and promotes a strengthened primary health care system and services that are responsive and resilient.

[RESUMEN]. En este artículo se describe la introducción del programa HEARTS en las Américas de la Organización Panamericana de la Salud en Trinidad y Tabago y las experiencias satisfactorias y los desafíos encontrados con su ejecución y ampliación como estrategia para fortalecer la respuesta del sistema de salud a las enfermedades cardiovasculares. Se reunieron datos sobre la ejecución del programa HEARTS en la Región de las Américas de la Organización Mundial de la Salud con el fin de determinar cuáles han sido los avances, los obstáculos, los factores de éxito y las enseñanzas extraídas. En el año 2019, el Ministerio de Salud inició la ejecución del programa en cinco (4,9%) de los 102 centros de atención primaria de salud, y para fines del 2021, se había ampliado a 46 (45,0%). El programa HEARTS garantiza el manejo integral de la salud cardiovascular de los pacientes mediante la prestación de asesoramiento sobre hábitos saludables, la aplicación de protocolos de tratamiento basados en la evidencia, la garantía de acceso a medicamentos y tecnologías esenciales, así como el uso de un enfoque de trabajo en equipo basado en el riesgo, un sistema de monitoreo y evaluación, y un enfoque basado en el equipo para abordar la prestación de la atención. Entre los obstáculos para su ejecución se encontraron la fragmentación del sistema de atención médica, el papel paternalista asumido por los profesionales de la salud, la resistencia al cambio de algunos trabajadores de salud y la falta de enfoques de trabajo en equipo para la prestación de la atención. La ejecución satisfactoria del programa fue posible gracias a un compromiso político de alto nivel, la creación de un comité nacional de supervisión de HEARTS, la participación de las partes interesadas en todas las fases del programa y la aplicación de enfoques estandarizados para la atención. En su ejecución en el contexto de los entornos de atención primaria de salud existentes, el programa HEARTS proporciona un modelo de atención excepcionalmente bien integrado y exhaustivo que encarna los principios de acceso universal a la atención de salud al tiempo que garantiza la salud individual y poblacional. De este modo, este modelo fomenta un sistema de atención primaria de salud fortalecido y unos servicios receptivos y resilientes.

[RESUMO]. Este artigo descreve a introdução do programa HEARTS nas Américas da Organização Pan-Americana da Saúde em Trinidad e Tobago e as experiências bem-sucedidas e os desafios encontrados durante a introdução e expansão do programa como estratégia para fortalecer a resposta do sistema de saúde às doenças cardiovasculares. Analisaram-se evidências sobre a implementação do programa HEARTS na Região das Américas da Organização Mundial da Saúde para identificar os avanços obtidos, os obstáculos, os fatores de sucesso e as lições aprendidas. Em 2019, o Ministério da Saúde iniciou a implementação do programa em 5 (4,9%) dos 102 centros de atenção primária à saúde; no final de 2021, o programa havia sido ampliado para 46 (45,0%) centros. O programa HEARTS assegura que a saúde cardiovascular dos pacientes seja manejada de uma forma abrangente por meio de aconselhamento sobre estilo de vida saudável, uso de protocolos de tratamento baseados em evidências, garantia de acesso a medicamentos e tecnologias essenciais e utilização de uma estratégia de equipe baseada no risco, de um sistema de monitoramento e avaliação e de uma abordagem de atendimento baseado em equipe. Os obstáculos encontrados durante a implementação incluíam a fragmentação do sistema de saúde existente, o papel paternalista assumido pelos profissionais de saúde, a resistência de alguns profissionais de saúde a mudanças e a falta de abordagens baseadas em equipe na prestação do atendimento. Para permitir que a implementação do programa fosse bem-sucedida, obteve-se compromisso político de alto nível, criou-se o Comitê de Supervisão do HEARTS nacional, assegurou-se o envolvimento de interessados diretos em todas as fases e implementaram-se abordagens padronizadas de atendimento. Quando implementado no contexto dos ambientes existentes de atenção primária à saúde, o programa HEARTS oferece um modelo de atenção excepcionalmente bem integrado e abrangente que incorpora os princípios de atenção universal à saúde, ao mesmo tempo em que garante a saúde das populações e dos indivíduos. Dessa forma, viabiliza e promove um sistema de atenção primária à saúde fortalecido e serviços responsivos e resilientes.

Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimer's disease.

Cell stress and impaired oxidative phosphorylation are central to mechanisms of synaptic loss and neurodegeneration in the cellular pathology of Alzheimer's disease (AD). In this study, we quantified the in vivo expression of the endoplasmic reticulum stress marker, sigma 1 receptor (S1R), using [11C]SA4503 positron emission tomography (PET), the mitochondrial complex I (MC1) with [18F]BCPP-EF, and the presynaptic vesicular protein SV2A with [11C]UCB-J in 12 patients with early AD and in 16 cognitively normal controls. We integrated these molecular measures with assessments of regional brain volumes and cerebral blood flow (CBF) measured with magnetic resonance imaging arterial spin labeling. Eight patients with AD were followed longitudinally to estimate the rate of change of the physiological and structural pathology markers with disease progression. The patients showed widespread increases in S1R (≤ 27%) and regional reduction in MC1 (≥ -28%) and SV2A (≥ -25%) radioligand binding, brain volume (≥ -23%), and CBF (≥ -26%). [18F]BCPP-EF PET MC1 binding (≥ -12%) and brain volumes (≥ -5%) showed progressive reductions over 12 to 18 months, suggesting that they both could be used as pharmacodynamic indicators in early-stage therapeutics trials. Associations of reduced MC1 and SV2A and increased S1R radioligand binding with reduced cognitive performance in AD, although exploratory, suggested a loss of metabolic functional reserve with disease. Our study thus provides in vivo evidence for widespread, clinically relevant cellular stress and bioenergetic abnormalities in early AD.

Pharmacokinetics and brain σ1 receptor occupancy of MR309, a selective σ1 receptor antagonist.

AIMS: Preclinical studies of MR309, a selective sigma-1 receptor (σ1R) antagonist, support a potential role in treating neuropathic pain. We report 2 studies that provide insight into the pharmacokinetics (PK) and brain σ1R binding of MR309. METHODS: Steady-state PK of MR309 (400 mg once daily and 200 mg twice-daily [BID] for 10 days; EudraCT 2015-001818-99 [PK study]) and the relationship between MR309 plasma exposure and brain σ1R occupancy (EudraCT 2017-000670-11 [positron emission tomography study]) were investigated in healthy volunteers. Positron emission tomography using the σ1R ligand [11 C]SA4503 was conducted at baseline, and 2 and 8 hours after a single dose of MR309 (200-800 mg). The relationship between brain σ1R occupancy and MR309 exposure was explored using data-driven model fitting. RESULTS: MR309 was well tolerated, brain σ1R occupancy ranged between 30.5 and 74.9% following single-dose MR309 (n = 7). MR309 BID provided a plasma PK profile with less fluctuation than once daily dosing (n = 16). MR309 200 mg BID yielded average steady state plasma concentrations between 2000 and 4000 ng/mL in the PK study, which corresponded to an estimated brain σ1R occupancy of 59-74%. CONCLUSION: MR309 200 mg BID dose was below the 75% σ1R occupancy threshold expected to elicit maximal antinociceptive effect as observed in neuropathic pain models. Further investigations of MR309 for neuropathic pain will require higher brain σ1R occupancy, and establish the optimal dose by elucidating the clinical impact of a broad range of brain σ1R occupancy across different neuropathic pain indications.

Endogenous dopamine release in the human brain as a pharmacodynamic biomarker: evaluation of the new GPR139 agonist TAK-041 with [11C]PHNO PET.

The use of positron emission tomography (PET) in early-phase development of novel drugs targeting the central nervous system, is well established for the evaluation of brain penetration and target engagement. However, when novel targets are involved a suitable PET ligand is not always available. We demonstrate an alternative approach that evaluates the attenuation of amphetamine-induced synaptic dopamine release by a novel agonist of the orphan G-protein-coupled receptor GPR139 (TAK-041). GPR139 agonism is a novel candidate mechanism for the treatment of schizophrenia and other disorders associated with social and cognitive dysfunction. Ten healthy volunteers underwent [11C]PHNO PET at baseline, and twice after receiving an oral dose of d-amphetamine (0.5 mg/kg). One of the post-d-amphetamine scans for each subject was preceded by a single oral dose of TAK-041 (20 mg in five; 40 mg in the other five participants). D-amphetamine induced a significant decrease in [11C]PHNO binding potential relative to the non-displaceable component (BPND) in all regions examined (16-28%), consistent with increased synaptic dopamine release. Pre-treatment with TAK-041 significantly attenuated the d-amphetamine-induced reduction in BPND in the a priori defined regions (putamen and ventral striatum: 26% and 18%, respectively). The reduction in BPND was generally higher after the 40 mg than the 20 mg TAK-041 dose, with the difference between doses reaching statistical significance in the putamen. Our findings suggest that TAK-041 enters the human brain and interacts with GPR139 to affect endogenous dopamine release. [11C]PHNO PET is a practical method to detect the effects of novel drugs on the brain dopaminergic system in healthy volunteers, in the early stages of drug development.

Improving cardiovascular health with the patient-centered, integrated primary care HEARTS model in Trinidad and Tobago / Mejorar la salud cardiovascular con HEARTS, un modelo integrado de atención primaria centrado en el paciente, en Trinidad y Tabago / Melhoria da saúde cardiovascular com o modelo HEARTS de atenção primária integrada e centrada no paciente em Trinidad e Tobago

ABSTRACT This article describes the introduction of the Pan American Health Organization's HEARTS in the Americas program in Trinidad and Tobago and the successful experiences and challenges encountered in introducing and scaling it up as a strategy for strengthening the health system's response to cardiovascular diseases. Evidence about implementation of the HEARTS program in the World Health Organization's Region of the Americas was reviewed to identify the progress made, barriers, success factors and lessons learned. In 2019, the Ministry of Health commenced implementation of the program in 5 (4.9%) of the 102 primary health care centers, and by the end of 2021, it had been scaled up to 46 (45.0%) centers. The HEARTS program ensures that patients' cardiovascular health is managed in a comprehensive way through providing counseling about a healthy lifestyle, using evidence-based treatment protocols, ensuring access to essential medicines and technologies, and using a risk-based team approach, a monitoring and evaluation system and also a team-based approach to care delivery. The barriers encountered during implementation included the fragmentation of the existing health care system, the paternalistic role assumed by health care professionals, the resistance of some health care workers to change and a lack of team-based approaches to providing care. Successful implementation of the program was enabled through ensuring high-level political commitment, establishing the national HEARTS Oversight Committee, ensuring stakeholder involvement throughout all phases and implementing standardized approaches to care. When implemented in the context of existing primary health care settings, the HEARTS program provides an exceptionally well integrated and comprehensive model of care that embodies the principles of universal health care while ensuring the health of both populations and individuals. Thus, it enables and promotes a strengthened primary health care system and services that are responsive and resilient.

RESUMEN En este artículo se describe la introducción del programa HEARTS en las Américas de la Organización Panamericana de la Salud en Trinidad y Tabago y las experiencias satisfactorias y los desafíos encontrados con su ejecución y ampliación como estrategia para fortalecer la respuesta del sistema de salud a las enfermedades cardiovasculares. Se reunieron datos sobre la ejecución del programa HEARTS en la Región de las Américas de la Organización Mundial de la Salud con el fin de determinar cuáles han sido los avances, los obstáculos, los factores de éxito y las enseñanzas extraídas. En el año 2019, el Ministerio de Salud inició la ejecución del programa en cinco (4,9%) de los 102 centros de atención primaria de salud, y para fines del 2021, se había ampliado a 46 (45,0%). El programa HEARTS garantiza el manejo integral de la salud cardiovascular de los pacientes mediante la prestación de asesoramiento sobre hábitos saludables, la aplicación de protocolos de tratamiento basados en la evidencia, la garantía de acceso a medicamentos y tecnologías esenciales, así como el uso de un enfoque de trabajo en equipo basado en el riesgo, un sistema de monitoreo y evaluación, y un enfoque basado en el equipo para abordar la prestación de la atención. Entre los obstáculos para su ejecución se encontraron la fragmentación del sistema de atención médica, el papel paternalista asumido por los profesionales de la salud, la resistencia al cambio de algunos trabajadores de salud y la falta de enfoques de trabajo en equipo para la prestación de la atención. La ejecución satisfactoria del programa fue posible gracias a un compromiso político de alto nivel, la creación de un comité nacional de supervisión de HEARTS, la participación de las partes interesadas en todas las fases del programa y la aplicación de enfoques estandarizados para la atención. En su ejecución en el contexto de los entornos de atención primaria de salud existentes, el programa HEARTS proporciona un modelo de atención excepcionalmente bien integrado y exhaustivo que encarna los principios de acceso universal a la atención de salud al tiempo que garantiza la salud individual y poblacional. De este modo, este modelo fomenta un sistema de atención primaria de salud fortalecido y unos servicios receptivos y resilientes.

RESUMO Este artigo descreve a introdução do programa HEARTS nas Américas da Organização Pan-Americana da Saúde em Trinidad e Tobago e as experiências bem-sucedidas e os desafios encontrados durante a introdução e expansão do programa como estratégia para fortalecer a resposta do sistema de saúde às doenças cardiovasculares. Analisaram-se evidências sobre a implementação do programa HEARTS na Região das Américas da Organização Mundial da Saúde para identificar os avanços obtidos, os obstáculos, os fatores de sucesso e as lições aprendidas. Em 2019, o Ministério da Saúde iniciou a implementação do programa em 5 (4,9%) dos 102 centros de atenção primária à saúde; no final de 2021, o programa havia sido ampliado para 46 (45,0%) centros. O programa HEARTS assegura que a saúde cardiovascular dos pacientes seja manejada de uma forma abrangente por meio de aconselhamento sobre estilo de vida saudável, uso de protocolos de tratamento baseados em evidências, garantia de acesso a medicamentos e tecnologias essenciais e utilização de uma estratégia de equipe baseada no risco, de um sistema de monitoramento e avaliação e de uma abordagem de atendimento baseado em equipe. Os obstáculos encontrados durante a implementação incluíam a fragmentação do sistema de saúde existente, o papel paternalista assumido pelos profissionais de saúde, a resistência de alguns profissionais de saúde a mudanças e a falta de abordagens baseadas em equipe na prestação do atendimento. Para permitir que a implementação do programa fosse bem-sucedida, obteve-se compromisso político de alto nível, criou-se o Comitê de Supervisão do HEARTS nacional, assegurou-se o envolvimento de interessados diretos em todas as fases e implementaram-se abordagens padronizadas de atendimento. Quando implementado no contexto dos ambientes existentes de atenção primária à saúde, o programa HEARTS oferece um modelo de atenção excepcionalmente bem integrado e abrangente que incorpora os princípios de atenção universal à saúde, ao mesmo tempo em que garante a saúde das populações e dos indivíduos. Dessa forma, viabiliza e promove um sistema de atenção primária à saúde fortalecido e serviços responsivos e resilientes.

Test-retest variability and reference region-based quantification of 18F-BCPP-EF for imaging mitochondrial complex I in the human brain.

Mitochondrial complex I (MC-I) is an essential regulator of brain bioenergetics and can be quantified in the brain using PET radioligand 18F-BCPP-EF. Here we evaluate the test-retest reproducibility of 18F-BCPP-EF in humans, and assess the use of a non-invasive quantification method (standardised uptake value ratio - SUVR). Thirty healthy volunteers had a 90-min dynamic 18F-BCPP-EF scan with arterial blood sampling, five of which received a second scan to be included in the test-retest analysis. Time-activity curves (TAC) were analysed using multilinear analysis 1 (MA1) and the two-tissue compartment model (2TC) to estimate volumes of distribution (VT). Regional SUVR-1 values were calculated from the 70 to 90-min TAC data using the centrum semiovale as a pseudo reference region, and compared to kinetic analysis-derived outcome measures. The mean absolute test-retest variability of VT ranged from 12% to 18% across regions. Both DVR-1and SUVR-1 had improved test-retest variability in the range 2%-7%. SUVR-1 was highly correlated with DVR-1 (r2 = 0.97, n = 30). In conclusion, 18F-BCPP-EF has suitable test-retest reproducibility and can be used to quantify MC-I in clinical studies.

Characterization of 3 PET Tracers for Quantification of Mitochondrial and Synaptic Function in Healthy Human Brain: 18F-BCPP-EF, 11C-SA-4503, and 11C-UCB-J.

Mitochondrial complex 1 is involved in maintaining brain bioenergetics; σ-1 receptor responds to neuronal stress; and synaptic vesicle protein 2A reflects synaptic integrity. Expression of each of these proteins is altered in neurodegenerative diseases. Here, we characterize the kinetic behavior of 3 PET radioligands-18F-BCPP-EF, 11C-SA-4503, and 11C-UCB-J-for the measurement of mitochondrial complex 1, σ-1 receptor, and synaptic vesicle protein 2A, respectively, and determine appropriate analysis workflows for their application in future studies of the in vivo molecular pathology of these diseases. Methods: Twelve human subjects underwent dynamic PET scans with each radioligand, including associated arterial blood sampling. A range of kinetic models was investigated to identify an optimal kinetic analysis method for each radioligand and a suitable acquisition duration. Results: All 3 radioligands readily entered the brain and yielded heterogeneous uptake consistent with the known distribution of the targets. The optimal models determined for the regional estimates of volume of distribution were multilinear analysis 1 (MA1) and the 2-tissue-compartment model for 18F-BCPP-EF, MA1 for 11C-SA-4503, and both MA1 and the 1-tissue-compartment model for 11C-UCB-J. Acquisition times of 70, 80, and 60 min for 18F-BCPP-EF, 11C-SA-4503, 11C-UCB-J, respectively, provided good estimates of regional volume of distribution values. An effect of age was observed on 18F-BCPP-EF and 11C-UCB-J signal in the caudate. Conclusion: These ligands can be assessed for their potential to stratify patients or monitor the progression of molecular neuropathology in neurodegenerative diseases.

Serotonin release measured in the human brain: a PET study with [11C]CIMBI-36 and d-amphetamine challenge.

Positron emission tomography (PET) enables non-invasive estimation of neurotransmitter fluctuations in the living human brain. While these methods have been applied to dopamine and some other transmitters, estimation of 5-hydroxytryptamine (5-HT; Serotonin) release has proved to be challenging. Here we demonstrate the utility of the novel 5-HT2A receptor agonist radioligand, [11C]CIMBI-36, and a d-amphetamine challenge to evaluate synaptic 5-HT changes in the living human brain. Seventeen healthy male volunteers received [11C]CIMBI-36 PET scans before and 3 h after an oral dose of d-amphetamine (0.5 mg/kg). Dynamic PET data were acquired over 90 min, and the total volume of distribution (VT) in the frontal cortex and the cerebellum derived from a kinetic analysis using MA1. The frontal cortex binding potential (BPNDfrontal) was calculated as (VTfrontal/VTcerebellum) - 1. ∆BPNDfrontal = 1 - (BPNDfrontal post-dose/BPNDfrontal baseline) was used as an index of 5-HT release. Statistical inference was tested by means of a paired Students t-test evaluating a reduction in post-amphetamine [11C]CIMBI-36 BPNDfrontal. Following d-amphetamine administration, [11C]CIMBI-36 BPNDfrontal was reduced by 14 ± 13% (p = 0.002). Similar effects were observed in other cortical regions examined in an exploratory analysis. [11C]CIMBI-36 binding is sensitive to synaptic serotonin release in the human brain, and when combined with a d-amphetamine challenge, the evaluation of the human brain serotonin system in neuropsychiatric disorders, such as major depression and Parkinson's disease is enabled.

A study of the focal adhesion kinase inhibitor GSK2256098 in patients with recurrent glioblastoma with evaluation of tumor penetration of [11C]GSK2256098.

Background: GSK2256098 is a novel oral focal adhesion kinase (FAK) inhibitor. Preclinical studies demonstrate growth inhibition in glioblastoma cell lines. However, rodent studies indicate limited blood-brain barrier (BBB) penetration. In this expansion cohort within a phase I study, the safety, tolerability, pharmacokinetics (PK), and clinical activity of GSK2256098 were evaluated in patients with recurrent glioblastoma. Biodistribution and kinetics of [11C]GSK2256098 were assessed in a substudy using positron-emission tomography (PET). Methods: Patients were treated with GSK2256098 until disease progression or withdrawal due to adverse events (AEs). Serial PK samples were collected on day 1. On a single day between days 9 and 20, patients received a microdose of intravenous [11C]GSK2256098 and were scanned with PET over 90 minutes with parallel PK sample collection. Response was assessed by MRI every 6 weeks. Results: Thirteen patients were treated in 3 dose cohorts (1000 mg, 750 mg, 500 mg; all dosed twice daily). The maximum tolerated dose was 1000 mg twice daily. Dose-limiting toxicities were related to cerebral edema. Treatment-related AEs (>25%) were diarrhea, fatigue, and nausea. Eight patients participated in the PET substudy, with [11C]GSK2256098 VT (volume of distribution) estimates of 0.9 in tumor tissue, 0.5 in surrounding T2 enhancing areas, and 0.4 in normal brain. Best response of stable disease was observed in 3 patients, including 1 patient on treatment for 11.3 months. Conclusions: GSK2256098 was tolerable in patients with relapsed glioblastoma. GSK2256098 crossed the BBB at low levels into normal brain, but at markedly higher levels into tumor, consistent with tumor-associated BBB disruption. Additional clinical trials of GSK2256098 are ongoing.

Investigation of the Brain Biodistribution of the Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitor [18F]GSK2647544 in Healthy Male Subjects.

PURPOSE: GSK2647544 is a potent and specific inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2), which was in development as a potential treatment for Alzheimer's disease (AD). In order to refine therapeutic dose predictions and confirm brain penetration, a radiolabelled form of the inhibitor, [18F]GSK2647544, was manufactured for use in a positron emission tomography (PET) biodistribution study. PROCEDURES: [18F]GSK2647544 was produced using a novel, copper iodide (Cu(I)) mediated, [18F]trifluoromethylation methodology. Healthy male subjects (n = 4, age range 34-42) received an oral dose of unlabelled GSK2647544 (100 mg) and after 2 h an intravenous (iv) injection of [18F]GSK2647544 (average injected activity and mass were 106 ± 47 MBq and 179 ± 55 µg, respectively) followed by dynamic PET scans for 120 min. Defined regions of interest (ROI) throughout the brain were used to obtain regional time-activity curves (TACs) and compartmental modelling analysis used to estimate the primary outcome measure, whole brain volume of distribution (VT). Secondary PK and safety endpoints were also recorded. RESULTS: PET dynamic data were successfully obtained from all four subjects and there were no clinically significant variations of the safety endpoints. Inspection of the TACs indicated a relatively homogenous uptake of [18F]GSK2647544 across all the ROIs examined. The mean whole brain VT was 0.56 (95 % CI, 0.41-0.72). Secondary PK parameters, Cmax (geometric mean) and Tmax (median), were 354 ng/ml and 1.4 h, respectively. Metabolism of GSK2647544 was relatively consistent across subjects, with 20-40 % of the parent compound [18F]GSK2647544 present after 120 min. CONCLUSIONS: The study provides evidence that GSK2647544 is able to cross the blood brain barrier in healthy male subjects leading to a measurable brain exposure. The administered doses of GSK2647544 were well tolerated. Exploratory modelling suggested that a twice-daily dose of 102 mg, at steady state, would provide ~80 % trough inhibition of brain Lp-PLA2 activity. TRIAL REGISTRATION: Clintrials.gov: NCT01924858.

Determination of [(11)C]PBR28 binding potential in vivo: a first human TSPO blocking study.

Positron emission tomography (PET) targeting the 18 kDa translocator protein (TSPO) is used to quantify neuroinflammation. Translocator protein is expressed throughout the brain, and therefore a classical reference region approach cannot be used to estimate binding potential (BPND). Here, we used blockade of the TSPO radioligand [(11)C]PBR28 with the TSPO ligand XBD173, to determine the non-displaceable volume of distribution (VND), and hence estimate the BPND. A total of 26 healthy volunteers, 16 high-affinity binders (HABs) and 10 mixed affinity binders (MABs) underwent a [(11)C]PBR28 PET scan with arterial sampling. Six of the HABs received oral XBD173 (10 to 90 mg), 2 hours before a repeat scan. In XBD173-dosed subjects, VND was estimated via the occupancy plot. Values of BPND for all subjects were calculated using this VND estimate. Total volume of distribution (VT) of MABs (2.94±0.31) was lower than VT of HABs (4.33±0.29) (P<0.005). There was dose-dependent occupancy of TSPO by XBD173 (ED50=0.34±0.13 mg/kg). The occupancy plot provided a VND estimate of 1.98 (1.69, 2.26). Based on these VND estimates, BPND for HABs is approximately twice that of MABs, consistent with predictions from in vitro data. Our estimates of [(11)C]PBR28 VND and hence BPND in the healthy human brain are consistent with in vitro predictions. XBD173 blockade provides a practical means of estimating VND for TSPO targeting radioligands.

Integrating women's human rights into global health research: an action framework.

This article uses Scale of Change theory as a framework to guide global health researchers to synergistically target women's health outcomes in the context of improving their right to freedom, equity, and equality of opportunities. We hypothesize that health researchers can do so through six action strategies. These strategies include (1) becoming fully informed of women's human rights directives to integrate them into research, (2) mainstreaming gender in the research, (3) using the expertise of grass roots women's organizations in the setting, (4) showcasing women's equity and equality in the organizational infrastructure, (5) disseminating research findings to policymakers in the study locale to influence health priorities, and (6) publicizing the social conditions that are linked to women's diseases. We explore conceptual and logistical dilemmas in transforming a study using these principles and also provide a case study of obstetric fistula reduction in Nigeria to illustrate how these strategies can be operationalized. Our intent is to offer a feasible approach to health researchers who, conceptually, may link women's health to social and cultural conditions but are looking for practical implementation strategies to examine a women's health issue through the lens of their human rights.

Mapping a message for faith leaders: encouraging community health promotion with local health data.

This study reports the use of a community-based health survey to share local health information with faith leaders. Geographical information systems software identified survey respondents within 2 km (1.25 miles) of places of worship. Results were tabulated for the community surrounding each place of worship and were compared with city- and county-level data. Faith leaders were presented with community-specific reports describing the health attributes of residents who lived in the surrounding area, in order to assist with the identification issues of concern and opportunities to develop health ministries to address these issues. Faith leaders were encouraged to share this information with members of their faith community and develop means of obtaining additional information on the people of interest. We believe that engaging faith leaders with neighborhood-specific health information will be critical in providing an understanding of the importance of their voice in improving health outcomes of their faith community, the surrounding neighborhood, and the community at large. Our goal is to empower faith leaders to understand personal and community health issues and to act as a conduit for health-related information and health promotion at a local level. Church health teams developed an HIV and sexually transmitted infection prevention program for African American adolescents and young adults.