Patient, Family, Caregiver, and Community Engagement in Research: A Sensibility Evaluation of a Novel Infographic and Planning Guide.

Background: Engaging patients, families, caregivers, and the community (PFCCs) throughout the research cycle ensures that research is meaningful for the target population. Although tools have been developed to promote PFCC engagement, many are lengthy, complex, and lack recommended behaviours. This study evaluated the sensibility of an infographic and accompanying planning guide for facilitating engagement of PFCCs in research. Methods: Thirteen rehabilitation researchers reviewed the PFCC engagement tool and planning guide, participated in a semi-structured interview, and completed a 10-item sensibility questionnaire. Interviews were transcribed, imported into NVivo, and analyzed using direct content analysis. Median scores and proportions of responses for each of the 10 items in the questionnaire were calculated. Results: Median scores for all questionnaire items were ≥ 4 on a 7-point Likert Scale. Participants reported the tool was easy to navigate, contained relevant items to promote PFCC engagement, and followed a logical sequence. Suggested modifications of the tool related to formatting, design, and changing the title. Conclusions: The tool was deemed sensible for overt format, purpose and framework, face and content validity, and ease of usage and provides guidance to engage PFCCs across the research cycle. Further studies are recommended to assess the effectiveness of the tool to engage PFCCs in research.

Historique: la mobilisation des patients, des familles, des proches et de la communauté (PFPC) tout au long du cycle de la recherche permet de garantir que celle-ci soit significative pour la population ciblée. Même si des outils ont été mis au point pour promouvoir la mobilité des PFPC, bon nombre sont longs, complexes et dénués d'indications sur les comportements recommandés. La présente étude visait à évaluer la sensibilité d'une infographie et du guide de planification qui l'accompagne pour favoriser la mobilisation des PFPC en recherche. Méthodologie: au total, 13 chercheurs en réadaptation ont examiné l'outil de mobilisation des PFPC et le guide de planification, ont participé à une entrevue semi-structurée et ont rempli un questionnaire de sensibilité en dix points. Les entrevues ont été transcrites, importées dans NVivo et évaluées au moyen d'une analyse directe de contenu. Les scores médians et les proportions des réponses ont été calculés pour chacun des dix points du questionnaire. Résultats: les scores médians à tous les points du questionnaire étaient d'au moins 4 sur une échelle de Likert en sept points. Les participants ont indiqué que l'outil était facile à parcourir, contenait des points appropriés pour favoriser la mobilisation des PFPC et respectait une séquence logique. Les modifications proposées portaient sur le formatage, le graphisme et le changement de titre. Conclusions: l'outil était considéré comme sensible pour son caractère explicite, son objectif et sa structure, sa validité apparente et de contenu et sa facilité d'utilisation. De plus, il contenait des conseils pour mobiliser les PFPC tout au long du cycle de recherche. II est recommandé de réaliser d'autres études pour évaluer l'efficacité de l'outil à mobiliser les PFPC en recherche.

Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders.

Mitochondrial DNA (mtDNA) mutations frequently cause neurological diseases. Modeling of these defects has been difficult because of the challenges associated with engineering mtDNA. We show here that neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (iPSCs) retain the parental mtDNA profile and exhibit a metabolic switch toward oxidative phosphorylation. NPCs derived in this way from patients carrying a deleterious homoplasmic mutation in the mitochondrial gene MT-ATP6 (m.9185T>C) showed defective ATP production and abnormally high mitochondrial membrane potential (MMP), plus altered calcium homeostasis, which represents a potential cause of neural impairment. High-content screening of FDA-approved drugs using the MMP phenotype highlighted avanafil, which we found was able to partially rescue the calcium defect in patient NPCs and differentiated neurons. Overall, our results show that iPSC-derived NPCs provide an effective model for drug screening to target mtDNA disorders that affect the nervous system.

Expression of the human cytomegalovirus pentamer complex for vaccine use in a CHO system.

Human cytomegalovirus (HCMV) causes significant disease worldwide. Multiple HCMV vaccines have been tested in man but only partial protection has been achieved. The HCMV gH/gL/UL128/UL130/UL131A complex (Pentamer) is the main target of neutralizing antibodies in HCMV seropositive individuals and raises high titers of neutralizing antibodies in small animals and non-human primates (NHP). Thus, Pentamer is a promising candidate for an effective HCMV vaccine. Development of a Pentamer-based subunit vaccine requires expression of high amounts of a functional and stable complex. We describe here the development of a mammalian expression system for large scale Pentamer production. Several approaches comprising three different CHO-originated cell lines and multiple vector as well as selection strategies were tested. Stable cell pools expressed the HCMV Pentamer at a titer of approximately 60 mg/L at laboratory scale. A FACS-based single cell sorting approach allowed selection of a highly expressing clone producing Pentamer at the level of approximately 400 mg/L in a laboratory scale fed-batch culture. Expression in a 50 L bioreactor led to the production of HCMV Pentamer at comparable titers indicating the feasibility of further scale-up for manufacturing at commercial scale. The CHO-produced HCMV Pentamer bound to a panel of human neutralizing antibodies and raised potently neutralizing immune response in mice. Thus, we have generated an expression system for the large scale production of functional HCMV Pentamer at high titers suitable for future subunit vaccine production.

Acute stress enhances adult rat hippocampal neurogenesis and activation of newborn neurons via secreted astrocytic FGF2.

Stress is a potent modulator of the mammalian brain. The highly conserved stress hormone response influences many brain regions, particularly the hippocampus, a region important for memory function. The effect of acute stress on the unique population of adult neural stem/progenitor cells (NPCs) that resides in the adult hippocampus is unclear. We found that acute stress increased hippocampal cell proliferation and astrocytic fibroblast growth factor 2 (FGF2) expression. The effect of acute stress occurred independent of basolateral amygdala neural input and was mimicked by treating isolated NPCs with conditioned media from corticosterone-treated primary astrocytes. Neutralization of FGF2 revealed that astrocyte-secreted FGF2 mediated stress-hormone-induced NPC proliferation. 2 weeks, but not 2 days, after acute stress, rats also showed enhanced fear extinction memory coincident with enhanced activation of newborn neurons. Our findings suggest a beneficial role for brief stress on the hippocampus and improve understanding of the adaptive capacity of the brain. DOI:http://dx.doi.org/10.7554/eLife.00362.001.