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.

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.

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.

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).

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.

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.

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.

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.

Social impairment and personality disorder features among older adults: An application of the circumplex model.

The interpersonal circumplex is a model that places interpersonal problems along two axes (communion and agency), resulting in eight theoretically derived patterns. Application of the circumplex to older adults is poorly understood. Subsequently, this study examined relationships between the interpersonal circumplex and personality disorder (PD) features among older adults, since social impairments are core components of PDs. Two models of PDs were examined: the traditional model of 10 PDs and the Alternative Model of PDs (AMPD) with its personality functioning and pathological personality trait features. Older adults (N = 202) completed the Inventory of Interpersonal Problems-Short Circumplex, Coolidge Axis II Inventory, Levels of Personality Functioning Scale-Self-Report, and Personality Inventory for DSM-5. Overlap between the interpersonal circumplex and PD features were detected, but patterns were distinct from prior studies with younger samples. Cluster B and C PD features showed meaningful relationships, whereas Cluster A did not. The circumplex was limited in its relation to the AMPD's personality functioning. The communion component of the circumplex significantly related to the AMPD's pathological trait model, whereas the agency component was limited in its association with pathological traits. Overall, the circumplex meaningfully related to PD features across two different PD models, providing some evidence of validity.

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.

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.

El Nacimiento del Pueblo Mestizo: Critical Discourse on Historical Trauma, Community Resilience and Healing.

Purpose. Historical trauma has been widely applied to American Indian/Alaska Native and other Indigenous populations and includes dimensions of language, sociocultural, and land losses and associated physical and mental disorders, as well as economic hardships. Insufficient evidence remains on the experiences of historical trauma due to waves of colonization for mixed-race Mexican people with indigenous ancestry (el pueblo mestizo). Research Question. Drawing from our critical lenses and epistemic advantages as indigenous feminist scholars, we ask, "How can historical trauma be understood through present-day discourse of two mestizo communities? What are public health practice and policy implications for healing historical trauma among mestizo populations?" Methodology and Approach. We analyzed the discourse from two community projects: focus groups and ethnographic field notes from a study in the U.S.-Mexico border region (2012-2014) and field notes and digital stories from a service-learning course in northern New Mexico (2016-2018). Findings. Our analysis describes the social and historical experiences of Mexicans, Mexican Americans, Chicanas/os, and Nuevo Mexicano peoples in the southwestern border region of the United States. We found four salient themes as manifestations of "soul-wound": (1) violence/fear, (2) discrimination/shame, (3) loss, and (4) deep sorrow. Themes mitigating the trauma were community resiliency rooted in "querencia" (deep connection to land/home/people) and "conscientizacion" (critical consciousness). Conclusion. Historical trauma experienced by mestizo Latinx communities is rooted in local cultural and intergenerational narratives that link traumatic events in the historic past to contemporary local experiences. Future public health interventions should draw on culturally centered strength-based resilience approaches for healing trauma and advancing health equity.

State health disparities research in Rural America: Gaps and future directions in an era of COVID-19.

PURPOSE: In an era of the COVID-19 pandemic, improving health outcomes for diverse rural communities requires collective and sustained actions across transdisciplinary researchers, intersectoral partners, multilevel government action, and authentic engagement with those who carry the burden-rural communities. METHODS: Drawing from an analysis of transcriptions and documents from a national workshop on the "State of Rural Health Disparities: Research Gaps and Recommendations," this brief report underscores the gaps and priorities for future strategies for tackling persistent rural health inequities. FINDINGS: Four overarching recommendations were provided by national thought leaders in rural health: (1) create mechanisms to allow the rural research community time to build sustainable community-based participatory relationships; (2) support innovative research designs and approaches relevant to rural settings; (3) sustain effective interventions relevant to unique challenges in rural areas; and (4) recognize and identify the diversity within and across rural populations and adapt culturally and language-appropriate approaches. CONCLUSION: The COVID-19 public health crisis has exacerbated disparities for rural communities and underscored the need for diverse community-centered approaches in health research and dedicated funding to rural service agencies and populations.

Alcohol and other substance use disorder recovery during pregnancy among patients with posttraumatic stress disorder symptoms: A qualitative study.

Background: About 5% of women are pregnant at substance use disorder (SUD) treatment entry, and pregnant women with SUD often belong to marginalized groups experiencing social, economic, and health care barriers associated with stigma from prenatal substance use. Pregnant women in SUD treatment have high rates of trauma and posttraumatic stress disorder (PTSD). This study sought to (1) examine the lived experiences of pregnant individuals with PTSD symptoms in SUD treatment and (2) understand the roles of systematic or contextual barriers to the pursuit of prenatal abstinence. Methods: We draw upon in-depth semi-structured interviews to examine relationships between SUD, psychological trauma/PTSD experience, social resources, and lived experiences among patients in prenatal SUD treatment with PTSD symptoms. Our sample was pregnant patients (N = 13) with prior DSM-5 Criterion A trauma and current PTSD symptoms enrolled in a comprehensive program integrating prenatal care, substance use counseling, medication for opioid use disorder and case management at three sites affiliated with an urban academic medical center in New Mexico. Results: Using thematic analysis, four main themes identified structural forces influencing alcohol and drug use: (a) lack of access or ability to obtain resources, (b) substance use to cope with negative affect, (c) social stigma, and (d) interpersonal relationships. Conclusions: Despite receiving high-quality integrated prenatal and SUD care, these pregnant patients with PTSD symptoms in SUD treatment still experienced substantial social and structural hurdles to achieving abstinence during pregnancy.

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.

Psychometric evaluation of the Levels of Personality Functioning Scale-Brief Form 2.0 among older adults.

The Levels of Personality Functioning Scale-Brief Form 2.0 (LPFS-BF 2.0) is a new measure of personality functioning according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition's, alternative model of personality disorders, containing a total personality functioning score and two subscales (Self and Interpersonal). The LPFS-BF 2.0 has limited evidence of validity among older adults. Subsequently, this study examined relationships between the LPFS-BF 2.0 and anxiety, interpersonal functioning, and normative personality traits to establish convergent validity. In all, 130 community-dwelling older adults (Mage = 64.61) completed the LPFS-BF 2.0, Geriatric Anxiety Scale, Circumplex Scales of Interpersonal Problems (CSIP), and Big Five Inventory-2 (BFI-2). Internal consistency (Cronbach's α) was acceptable to good for each of the LPFS-BF 2.0 scale scores (Self, α = .74; Interpersonal, α = .85; Total Personality Functioning, α = .79). Correlations were computed between the LPFS-BF 2.0 scales and the Geriatric Anxiety Scale, CSIP, and BFI-2. Overall, significant correlations were detected in expected directions. Additionally, to further establish convergent validity, regression analyses were conducted with the CSIP and BFI-2 scales predicting each of the LPFS-BF 2.0 scales. The models accounted for significant variance, and significant predictors were found in anticipated and theoretically consistent directions. Results provide strong but initial psychometric support for the use of the LPFS-BF 2.0 as an assessment tool for measuring personality functioning among older adults. An implication is that this measure may be used to identify important personality features that are part of a full assessment of personality pathology. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

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.

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss.

Inherited retinal degeneration (RD) leads to the impairment or loss of vision in millions of individuals worldwide, most frequently due to the loss of photoreceptor (PR) cells. Animal models, particularly the laboratory mouse, have been used to understand the pathogenic mechanisms that underlie PR cell loss and to explore therapies that may prevent, delay, or reverse RD. Here, we reviewed entries in the Mouse Genome Informatics and PubMed databases to compile a comprehensive list of monogenic mouse models in which PR cell loss is demonstrated. The progression of PR cell loss with postnatal age was documented in mutant alleles of genes grouped by biological function. As anticipated, a wide range in the onset and rate of cell loss was observed among the reported models. The analysis underscored relationships between RD genes and ciliary function, transcription-coupled DNA damage repair, and cellular chloride homeostasis. Comparing the mouse gene list to human RD genes identified in the RetNet database revealed that mouse models are available for 40% of the known human diseases, suggesting opportunities for future research. This work may provide insight into the molecular players and pathways through which PR degenerative disease occurs and may be useful for planning translational studies.

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.