Identification of Arhgef12 and Prkci as genetic modifiers of retinal dysplasia in the Crb1rd8 mouse model.

Mutations in the apicobasal polarity gene CRB1 lead to diverse retinal diseases, such as Leber congenital amaurosis, cone-rod dystrophy, retinitis pigmentosa (with and without Coats-like vasculopathy), foveal retinoschisis, macular dystrophy, and pigmented paravenous chorioretinal atrophy. Limited correlation between disease phenotypes and CRB1 alleles, and evidence that patients sharing the same alleles often present with different disease features, suggest that genetic modifiers contribute to clinical variation. Similarly, the retinal phenotype of mice bearing the Crb1 retinal degeneration 8 (rd8) allele varies with genetic background. Here, we initiated a sensitized chemical mutagenesis screen in B6.Cg-Crb1rd8/Pjn, a strain with a mild clinical presentation, to identify genetic modifiers that cause a more severe disease phenotype. Two models from this screen, Tvrm266 and Tvrm323, exhibited increased retinal dysplasia. Genetic mapping with high-throughput exome and candidate-gene sequencing identified causative mutations in Arhgef12 and Prkci, respectively. Epistasis analysis of both strains indicated that the increased dysplastic phenotype required homozygosity of the Crb1rd8 allele. Retinal dysplastic lesions in Tvrm266 mice were smaller and caused less photoreceptor degeneration than those in Tvrm323 mice, which developed an early, large diffuse lesion phenotype. At one month of age, Müller glia and microglia mislocalization at dysplastic lesions in both modifier strains was similar to that in B6.Cg-Crb1rd8/Pjn mice but photoreceptor cell mislocalization was more extensive. External limiting membrane disruption was comparable in Tvrm266 and B6.Cg-Crb1rd8/Pjn mice but milder in Tvrm323 mice. Immunohistological analysis of mice at postnatal day 0 indicated a normal distribution of mitotic cells in Tvrm266 and Tvrm323 mice, suggesting normal early development. Aberrant electroretinography responses were observed in both models but functional decline was significant only in Tvrm323 mice. These results identify Arhgef12 and Prkci as modifier genes that differentially shape Crb1-associated retinal disease, which may be relevant to understanding clinical variability and underlying disease mechanisms in humans.

Antiracism and Community-Based Participatory Research: Synergies, Challenges, and Opportunities.

Structural racism causes stark health inequities and operates at every level of society, including the academic and governmental entities that support health research and practice. We argue that health research institutions must invest in research that actively disrupts racial hierarchies, with leadership from racially marginalized communities and scholars. We highlight synergies between antiracist principles and community-based participatory research (CBPR), examine the potential for CBPR to promote antiracist research and praxis, illustrate structural barriers to antiracist CBPR praxis, and offer examples of CBPR actions taken to disrupt structural racism. We make recommendations for the next generation of antiracist CBPR, including modify health research funding to center the priorities of racially marginalized communities, support sustained commitments and accountability to those communities by funders and research institutions, distribute research funds equitably across community and academic institutions, amplify antiracist praxis through translation of research to policy, and adopt institutional practices that support reflection and adaptation of CBPR to align with emergent community priorities and antiracist practices. A critical application of CBPR principles offers pathways to transforming institutional practices that reproduce and reinforce racial inequities. (Am J Public Health. 2023;113(1):70-78. https://doi.org/10.2105/AJPH.2022.307114).

Current Views on Chr10q26 Contribution to Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is the leading cause of blindness in the global aging population. Familial aggregation and genome-wide association (GWA) studies have identified gene variants associated with AMD, implying a strong genetic contribution to AMD development. Two loci, on human Chr 1q31 and 10q26, respectively, represent the most influential of all genetic factors. While the role of CFH at Chr 1q31 is well established, uncertainty remains about the genes ARMS2 and HTRA1, at the Chr 10q26 locus. Since both genes are in strong linkage disequilibrium, assigning individual gene effects is difficult. In this chapter, we review current literature about ARMS2 and HTRA1 and their relevance to AMD risk. Future studies will be necessary to unravel the mechanisms by which they contribute to AMD.

Impact of self-reported cognitive dysfunction on the alternative model of personality disorders among older adults.

METHOD: Older adults (N = 202) completed the Levels of Personality Functioning Scale-Self-Report, Personality Inventory for DSM-5, and Coolidge Axis II Inventory with its six self-report cognitive dysfunction scales. RESULTS: Results suggested high correlational overlap between subjective cognitive problems with personality functioning and pathological personality, as measured by the AMPD. Hierarchical regressions revealed that subjective measures of executive functions, perceptual motor, and language difficulties were most strongly related to the AMPD's constructs. Results are discussed in the context of prior research on objective cognitive impairment among individuals with PDs. CONCLUSION: The degree of overlap found within the current older adult sample suggested an age-related problem or potential age-bias, with older adults being at-risk of (a) having their subjective cognitive problems being incorrectly interpreted as personality pathology under the AMPD or (b) having personality pathology being overlooked under the AMPD, with symptoms instead attributed to subjective cognitive issues. This study suggested that subjective cognitive dysfunction may be one mechanism that contributes to differential performance of the AMPD among older adults.

Genetic Interaction between Mfrp and Adipor1 Mutations Affect Retinal Disease Phenotypes.

Adipor1tm1Dgen and Mfrprd6 mutant mice share similar eye disease characteristics. Previously, studies established a functional relationship of ADIPOR1 and MFRP proteins in maintaining retinal lipidome homeostasis and visual function. However, the independent and/or interactive contribution of both genes to similar disease phenotypes, including fundus spots, decreased axial length, and photoreceptor degeneration has yet to be examined. We performed a gene-interaction study where homozygous Adipor1tm1Dgen and Mfrprd6 mice were bred together and the resulting doubly heterozygous F1 offspring were intercrossed to produce 210 F2 progeny. Four-month-old mice from all nine genotypic combinations obtained in the F2 generation were assessed for white spots by fundus photo documentation, for axial length by caliper measurements, and for photoreceptor degeneration by histology. Two-way factorial ANOVA was performed to study individual as well as gene interaction effects on each phenotype. Here, we report the first observation of reduced axial length in Adipor1tmlDgen homozygotes. We show that while Adipor1 and Mfrp interact to affect spotting and degeneration, they act independently to control axial length, highlighting the complex functional association between these two genes. Further examination of the molecular basis of this interaction may help in uncovering mechanisms by which these genes perturb ocular homeostasis.

A Dpagt1 Missense Variant Causes Degenerative Retinopathy without Myasthenic Syndrome in Mice.

Congenital disorders of glycosylation (CDG) are a heterogenous group of primarily autosomal recessive mendelian diseases caused by disruptions in the synthesis of lipid-linked oligosaccharides and their transfer to proteins. CDGs usually affect multiple organ systems and vary in presentation, even within families. There is currently no cure, and treatment is aimed at ameliorating symptoms and improving quality of life. Here, we describe a chemically induced mouse mutant, tvrm76, with early-onset photoreceptor degeneration. The recessive mutation was mapped to Chromosome 9 and associated with a missense mutation in the Dpagt1 gene encoding UDP-N-acetyl-D-glucosamine:dolichyl-phosphate N-acetyl-D-glucosaminephosphotransferase (EC 2.7.8.15). The mutation is predicted to cause a substitution of aspartic acid with glycine at residue 166 of DPAGT1. This represents the first viable animal model of a Dpagt1 mutation and a novel phenotype for a CDG. The increased expression of Ddit3, and elevated levels of HSPA5 (BiP) suggest the presence of early-onset endoplasmic reticulum (ER) stress. These changes were associated with the induction of photoreceptor apoptosis in tvrm76 retinas. Mutations in human DPAGT1 cause myasthenic syndrome-13 and severe forms of a congenital disorder of glycosylation Type Ij. In contrast, Dpagt1tvrm76 homozygous mice present with congenital photoreceptor degeneration without overt muscle or muscular junction involvement. Our results suggest the possibility of DPAGT1 mutations in human patients that present primarily with retinitis pigmentosa, with little or no muscle disease. Variants in DPAGT1 should be considered when evaluating cases of non-syndromic retinal degeneration.

Social Ecology of Hypertension Management Among Latinos Living in the U.S.-Mexico Border Region.

INTRODUCTION: While a growing body of research examines individual factors affecting the prevalence and management of hypertension among Latinos, less is known about how socioecological factors operate to determine health and affect implementation of interventions in rural communities. METHOD: We conducted eight focus groups to assess perceived risks and protective factors associated with managing hypertension among Latino adults and their family members living in two rural/frontier counties in the U.S.-Mexico border region. This analysis is part of a larger study, Corazon por la Vida (Heart for Life), which involved multiple data collection strategies to evaluate the effectiveness of a primary care and a promotora de salud intervention to manage hypertension. RESULTS: Of the 49 focus group participants, 70% were female and 30% were male, 39% were Spanish-only speakers, and 84% had hypertension. Participants' ages ranged between 18 and 75 years, and 63% reported annual incomes below $30,000. Drawing from a social-ecological framework to analyze focus group data, four major themes and subthemes emerged as factors facilitating or inhibiting disease management: (1) individual (emotional burdens, coping mechanisms), (2) social relationships (family as a source of support, family as a source of stress), (3) health system (trust/mistrust, patient-provider communication), and (4) environment (lack of access to safe exercise environment, lack of affordable food). CONCLUSION: Our findings are relevant to public health practitioners, researchers, and policymakers seeking to shift from individual level or single interventions aimed at improving treatment-modality adherence to multilevel or multiple interventions for rural Latino communities.

Relationships between pathological narcissism and maladaptive personality traits among older adults.

Objectives: The Pathological Narcissism Inventory (PNI) is a measure of narcissism, with two domains of Vulnerability and Grandiosity, that has limited evidence of validity among older adults. Subsequently, the objective of the present study was to examine relationships between the PNI and measures of diverse pathological personality features.Method: Participants consisted of 125 community-dwelling older adults (M age = 71.8 years) who completed the PNI, the Personality Inventory for DSM-5 (PID-5), and the Coolidge Axis II Inventory (CATI).Results: Total Narcissism, Vulnerability, and Grandiosity were significantly correlated with every PD scale, with the exception of Grandiosity with Schizotypal PD. Regression analyses revealed that Narcissistic and Avoidant PDs had the strongest relationships with the PNI. Total Narcissism was also significantly correlated with all five PID-5 domains, with regression indicating Negative Affect and Antagonism as the strongest predictors.Conclusions: Findings generally support the convergent validity of the PNI for use among older adults and suggest that pathological narcissism may be related to general personality pathology in later life.

An Empirical Evaluation of the DSM-5 Alternative Model of Personality Disorders in Later Life.

Personality disorders (PDs) in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) are conceptualized as distinct clinical syndromes. However, debate persists about the clinical utility of this categorical model, with many researchers supporting a dimensional model that focuses on pathological personality traits and personality dysfunction. This model was published in Section III of DSM-5 and named the Alternative Model of Personality Disorders (AMPD). This study evaluated the AMPD by examining relationships between traits and dysfunction with traditional categorical PD constructs among older adults. Older adults (N = 202) completed the Personality Inventory for DSM-5, Levels of Personality Functioning Scale-Self-Report, and Coolidge Axis II Inventory. Results indicated that pathological personality traits do not relate to categorical PDs in directions predicted by the AMPD. Personality functioning related to categorical PDs in expected theoretical patterns according to the AMPD but lacked incremental validity above pathological personality traits. An implication of these findings is that the AMPD does not fully resolve the age-related issues with the traditional categorical PD model.

An FRMD4B variant suppresses dysplastic photoreceptor lesions in models of enhanced S-cone syndrome and of Nrl deficiency.

Photoreceptor dysplasia, characterized by formation of folds and (pseudo-)rosettes in the outer retina, is associated with loss of functional nuclear receptor subfamily 2 group E member 3 (NR2E3) and neural retina leucine-zipper (NRL) in both humans and mice. A sensitized chemical mutagenesis study to identify genetic modifiers that suppress photoreceptor dysplasia in Nr2e3rd7mutant mice identified line Tvrm222, which exhibits a normal fundus appearance in the presence of the rd7 mutation. The Tvrm222 modifier of Nr2e3rd7/rd7 was localized to Chromosome 6 and identified as a missense mutation in the FERM domain containing 4B (Frmd4b) gene. The variant is predicted to cause the substitution of a serine residue 938 with proline (S938P). The Frmd4bTvrm222 allele was also found to suppress outer nuclear layer (ONL) rosettes in Nrl-/- mice. Fragmentation of the external limiting membrane (ELM), normally observed in rd7 and Nrl-/-mouse retinas, was absent in the presence of the Frmd4bTvrm222 allele. FRMD4B, a binding partner of cytohesin 3, is proposed to participate in cell junction remodeling. Its biological function in photoreceptor dysplasia has not been previously examined. In vitro experiments showed that the FRMD4B938P variant fails to be efficiently recruited to the cell surface upon insulin stimulation. In addition, we found a reduction in protein kinase B phosphorylation and increased levels of cell junction proteins, Catenin beta 1 and tight junction protein 1, associated with the cell membrane in Tvrm222 retinas. Taken together, this study reveals a critical role of FRMD4B in maintaining ELM integrity and in rescuing morphological abnormalities of the ONL in photoreceptor dysplasia.

Disruption of murine Adamtsl4 results in zonular fiber detachment from the lens and in retinal pigment epithelium dedifferentiation.

Human gene mutations have revealed that a significant number of ADAMTS (a disintegrin-like and metalloproteinase (reprolysin type) with thrombospondin type 1 motifs) proteins are necessary for normal ocular development and eye function. Mutations in human ADAMTSL4, encoding an ADAMTS-like protein which has been implicated in fibrillin microfibril biogenesis, cause ectopia lentis (EL) and EL et pupillae. Here, we report the first ADAMTSL4 mouse model, tvrm267, bearing a nonsense mutation in Adamtsl4. Homozygous Adamtsl4(tvrm267) mice recapitulate the EL phenotype observed in humans, and our analysis strongly suggests that ADAMTSL4 is required for stable anchorage of zonule fibers to the lens capsule. Unexpectedly, homozygous Adamtsl4(tvrm267) mice exhibit focal retinal pigment epithelium (RPE) defects primarily in the inferior eye. RPE dedifferentiation was indicated by reduced pigmentation, altered cellular morphology and a reduction in RPE-specific transcripts. Finally, as with a subset of patients with ADAMTSL4 mutations, increased axial length, relative to age-matched controls, was observed and was associated with the severity of the RPE phenotype. In summary, the Adamtsl4(tvrm267) model provides a valuable tool to further elucidate the molecular basis of zonule formation, the pathophysiology of EL and ADAMTSL4 function in the maintenance of the RPE.

Mouse Models of NMNAT1-Leber Congenital Amaurosis (LCA9) Recapitulate Key Features of the Human Disease.

The nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) enzyme is essential for regenerating the nuclear pool of NAD(+) in all nucleated cells in the body, and mounting evidence also suggests that it has a separate role in neuroprotection. Recently, mutations in the NMNAT1 gene were associated with Leber congenital amaurosis, a severe retinal degenerative disease that causes blindness during infancy. Availability of a reliable mammalian model of NMNAT1-Leber congenital amaurosis would assist in determining the mechanisms through which disruptions in NMNAT1 lead to retinal cell degeneration and would provide a resource for testing treatment options. To this end, we identified two separate N-ethyl-N-nitrosourea-generated mouse lines that harbor either a p.V9M or a p.D243G mutation. Both mouse models recapitulate key aspects of the human disease and confirm the pathogenicity of mutant NMNAT1. Homozygous Nmnat1 mutant mice develop a rapidly progressing chorioretinal disease that begins with photoreceptor degeneration and includes attenuation of the retinal vasculature, optic atrophy, and retinal pigment epithelium loss. Retinal function deteriorates in both mouse lines, and, in the more rapidly progressing homozygous Nmnat1(V9M) mutant mice, the electroretinogram becomes undetectable and the pupillary light response weakens. These mouse models offer an opportunity for investigating the cellular mechanisms underlying disease pathogenesis, evaluating potential therapies for NMNAT1-Leber congenital amaurosis, and conducting in situ studies on NMNAT1 function and NAD(+) metabolism.

A Chemical Mutagenesis Screen Identifies Mouse Models with ERG Defects.

Mouse models provide important resources for many areas of vision research, pertaining to retinal development, retinal function and retinal disease. The Translational Vision Research Models (TVRM) program uses chemical mutagenesis to generate new mouse models for vision research. In this chapter, we report the identification of mouse models for Grm1, Grk1 and Lrit3. Each of these is characterized by a primary defect in the electroretinogram. All are available without restriction to the research community.

The promise of community-based participatory research for health equity: a conceptual model for bridging evidence with policy.

Insufficient attention has been paid to how research can be leveraged to promote health policy or how locality-based research strategies, in particular community-based participatory research (CBPR), influences health policy to eliminate racial and ethnic health inequities. To address this gap, we highlighted the efforts of 2 CBPR partnerships in California to explore how these initiatives made substantial contributions to policymaking for health equity. We presented a new conceptual model and 2 case studies to illustrate the connections among CBPR contexts and processes, policymaking processes and strategies, and outcomes. We extended the critical role of civic engagement by those communities that were most burdened by health inequities by focusing on their political participation as research brokers in bridging evidence and policymaking.

Process evaluation of a promotora de salud intervention for improving hypertension outcomes for Latinos living in a rural U.S.-Mexico border region.

Hypertension is a growing public health problem for U.S.-Mexico border Latinos, who commonly experience low levels of awareness, treatment, and control. We report on a process evaluation that assessed the delivery of Corazón por la Vida, a 9-week promotora de salud-led curriculum to help Latinos manage and reduce hypertension risks in two rural/frontier counties in the New Mexico border region. Ninety-six adults participated in the program, delivered in three waves and in three communities. We assessed program delivery and quality, adherence, exposure, and participant responsiveness. Participant outcome measures included self-reported eating and physical activities and assessment of community resources. Findings suggest that the program was fully delivered (99%) and that most participants (81.7%) were very satisfied with the educational sessions. The average participant attendance for educational sessions was 77.47%. We found significant differences in self-reported behavioral changes depending on the number of sessions completed: The higher the dose of sessions, the better the self-reported outcomes. These findings suggest that a promotora-led curriculum may be useful for promoting self-management of chronic disease in rural/frontier border Latino populations. Future evaluation should focus on training and implementation adaptations within evidence-based chronic disease programs for diverse Latino communities.

Contact hours, skills fairs, and competency assessment.

Various regulatory agencies have indicated the need to measure initial and ongoing competency among health care workers. Yet, what is competency and how can it be measured? In reality, competency assessment is about outcomes. Maintaining and advancing our knowledge, skills, and analytical abilities is important for achieving optimal patient outcomes. Competency assessment should go beyond the act of attending lectures and skills fairs. Competency assessment should be a time when nurses can demonstrate and document their problem-solving and decision-making skills, inclusion of best practices, and evidence of how those skills make a difference for the patients they care for.

Associations between physical health and the alternative model of personality disorders: A cross-sectional age study.

The Alternative Model of Personality Disorders (AMPD) is a relatively new dimensional model of personality disorders (PDs) that assesses two diagnostic constructs: personality functioning and pathological personality traits. Thus far, research on the AMPD among older adults has been limited, but the research that does exist suggests limited generalizability to the unique biopsychosocial context of later life. To further examine the applicability of the AMPD to older adults, the purpose of this study was to examine relationships between the AMPD's two constructs with perceived physical health status among younger and older adult samples. Older adults (n = 222) and younger adults (n = 215) completed the Short Form-36 (SF-36), Levels of Personality Functioning Scale-Self-Report (LPFS-SR), and Personality Inventory for DSM-5-Brief Form (PID-5-BF). Correlations and Fisher's z-tests revealed significantly stronger relationships between the SF-36 with the LPFS-SR and PID-5-BF domains for older adults than younger adults. Additionally, age group significantly moderated the relationships between personality functioning and pathological personality traits and health. The stronger relationships between health and the AMPD's constructs for older adults suggest meaningful overlap between negative health outcomes and PD pathology. Future research should further investigate specific mechanisms in which personality pathology negatively impacts health in older adults.

The CTSA Diversity, Equity, Inclusion, and Accessibility (DEIA) Task Force's recommendations for the CTSA program consortium.

The Clinical and Translational Science Award (CTSA) Program recognizes that advancing diversity, equity, inclusion, and accessibility (DEIA) requires moving beyond statements of commitment to transformative actions. In 2021, the CTSA Program created a Task Force (TF) to initiate work in support of structural and transformational initiatives that advance DEIA for the consortium and its individual hubs. We describe the process of forming the expertise-driven (DEIA) TF and our activities to date. We 1) developed and adopted the DEIA Learning Systems Framework to guide our approach; 2) defined a set of recommendations across four focus areas (Institutional; Programmatic; Community-Centered; and Social, Cultural, Environmental); and 3) designed and disseminated a survey to capture the CTSA Program's baseline demographic, community, infrastructural, and leadership diversity. The CTSA Consortium also elevated the TF to a standing Committee to extend our understanding, development, and implementation of DEIA approaches to translational and clinical science. These initial steps provide a foundation for collectively fostering environment that support DEIA across the research continuum.

The Social Determinants of Perinatal Maternal Distress.

This pilot study examined associations between prenatal individual and socioenvironmental determinants of health and symptoms of perinatal maternal distress (PMD) in women enrolled in midwifery practice and living in a rural state. Pearson's correlations between prenatal predictors and PMD scores were calculated. Having experienced emotional abuse in one's lifetime, total number of past year stressors, and everyday discrimination score were all statistically significant predictors of PMD at study enrollment and follow-up. Result suggest shifting to a multi-symptom, life course assessment and intervention paradigm, tailored to the context of specific populations, may improve perinatal care and reduce disparities.