PRDM9 losses in vertebrates are coupled to those of paralogs ZCWPW1 and ZCWPW2.

In most mammals and likely throughout vertebrates, the gene PRDM9 specifies the locations of meiotic double strand breaks; in mice and humans at least, it also aids in their repair. For both roles, many of the molecular partners remain unknown. Here, we take a phylogenetic approach to identify genes that may be interacting with PRDM9 by leveraging the fact that PRDM9 arose before the origin of vertebrates but was lost many times, either partially or entirely-and with it, its role in recombination. As a first step, we characterize PRDM9 domain composition across 446 vertebrate species, inferring at least 13 independent losses. We then use the interdigitation of PRDM9 orthologs across vertebrates to test whether it coevolved with any of 241 candidate genes coexpressed with PRDM9 in mice or associated with recombination phenotypes in mammals. Accounting for the phylogenetic relationship among a subsample of 189 species, we find two genes whose presence and absence is unexpectedly coincident with that of PRDM9: ZCWPW1, which was recently shown to facilitate double strand break repair, and its paralog ZCWPW2, as well as, more tentatively, TEX15 and FBXO47ZCWPW2 is expected to be recruited to sites of PRDM9 binding; its tight coevolution with PRDM9 across vertebrates suggests that it is a key interactor within mammals and beyond, with a role either in recruiting the recombination machinery or in double strand break repair.

Exploring the conformational landscapes of protein kinases: perspectives from FRET and DEER.

Conformational changes of catalytically-important structural elements are a key feature of the regulation mechanisms of protein kinases and are important for dictating inhibitor binding modes and affinities. The lack of widely applicable methods for tracking kinase conformational changes in solution has hindered our understanding of kinase regulation and our ability to design conformationally selective inhibitors. Here we provide an overview of two recently developed methods that detect conformational changes of the regulatory activation loop and αC-helix of kinases and that yield complementary information about allosteric mechanisms. An intramolecular Förster resonance energy transfer-based approach provides a scalable platform for detecting and classifying structural changes in high-throughput, as well as quantifying ligand binding cooperativity, shedding light on the energetics governing allostery. The pulsed electron paramagnetic resonance technique double electron-electron resonance provides lower throughput but higher resolution information on structural changes that allows for unambiguous assignment of conformational states and quantification of population shifts. Together, these methods are shedding new light on kinase regulation and drug interactions and providing new routes for the identification of novel kinase inhibitors and allosteric modulators.

Machine learning uncovers the most robust self-report predictors of relationship quality across 43 longitudinal couples studies.

Given the powerful implications of relationship quality for health and well-being, a central mission of relationship science is explaining why some romantic relationships thrive more than others. This large-scale project used machine learning (i.e., Random Forests) to 1) quantify the extent to which relationship quality is predictable and 2) identify which constructs reliably predict relationship quality. Across 43 dyadic longitudinal datasets from 29 laboratories, the top relationship-specific predictors of relationship quality were perceived-partner commitment, appreciation, sexual satisfaction, perceived-partner satisfaction, and conflict. The top individual-difference predictors were life satisfaction, negative affect, depression, attachment avoidance, and attachment anxiety. Overall, relationship-specific variables predicted up to 45% of variance at baseline, and up to 18% of variance at the end of each study. Individual differences also performed well (21% and 12%, respectively). Actor-reported variables (i.e., own relationship-specific and individual-difference variables) predicted two to four times more variance than partner-reported variables (i.e., the partner's ratings on those variables). Importantly, individual differences and partner reports had no predictive effects beyond actor-reported relationship-specific variables alone. These findings imply that the sum of all individual differences and partner experiences exert their influence on relationship quality via a person's own relationship-specific experiences, and effects due to moderation by individual differences and moderation by partner-reports may be quite small. Finally, relationship-quality change (i.e., increases or decreases in relationship quality over the course of a study) was largely unpredictable from any combination of self-report variables. This collective effort should guide future models of relationships.

Connecting Dementia Caregivers to Recommended Services: Care to Plan.

The current mixed methods, embedded study evaluated the use of an online tool (Care to Plan [CtP]) that generates tailored service and support recommendations for dementia caregivers as well as information that can connect dementia caregiver users to recommended resources. Forty-three dementia caregivers identified in a health care system were randomly assigned to receive either CtP or usual care. The embedded, mixed methods design resulted in no quantitative, direct evidence for CtP's efficacy. Qualitative data revealed important insights into facilitators of and barriers to CtP use. Qualitative data also demonstrated that CtP helped caregivers obtain a better awareness of their needs and experiences. Clinicians may find CtP useful as an initial tool to spur memory care/case management and facilitate conversations about caregivers' needs and resources to meet individualized challenges. [Journal of Gerontological Nursing, 49(10), 5-11.].

Depressive Symptoms in Older African Immigrants with Mobility Limitations: A Descriptive Study.

OBJECTIVES: Before, during, and after their immigration to the United States, immigrants face stressful life circumstances that may render them at risk for depressive symptoms. However, there is a dearth of research on the mental health of African immigrants. We performed secondary data analyses of two studies in the Baltimore-Washington area to describe and identify correlates of depressive symptoms in older African immigrants. METHODS: Chi square tests, one-way ANOVAs, and linear regressions were used to describe and examine associations between depressive symptoms and immigrant-related risk factors. RESULTS: This sample included 148 participants who had a mean age of 62 (SD ± 8.2). Clinical depressive symptoms were present in 8.1% of participants, and trouble falling asleep for more than half of the days was the most prevalent symptom (20%). Levels of education, income, and migration reasons differed significantly from clinical depressive symptoms, but these were not significantly associated with more depressive symptoms after controlling for covariates. CONCLUSIONS: Longitudinal designs may further elucidate incidence, correlates, and long-term effects of depressive symptoms within this population. CLINICAL IMPLICATIONS: Knowledge of depressive symptom burden and risk factors can inform timely assessment, referral, and treatment of depressive symptoms and other mental health outcomes in older African immigrants.

Age Differences in Determinants of Self-Rated Health among Recipients of Publicly Funded Home-and-Community-Based Services.

This research examined determinants of self-rated health (SRH) of publicly funded home-and-community-based services (HCBS) recipients and tested if the effects of determinants differ between older recipients and younger recipients with disabilities. Using Minnesota's data of 2015-2016 National Core Indicators - Aging and Disabilities survey (n = 3,426), this study revealed that functional status and community inclusion had both direct and indirect effects on SRH, with negative mood as a mediator. Community inclusion had a more pronounced effect on SRH in younger recipients than in older recipients. HCBS should address psychosocial needs and be tailored for recipients of different age groups.

"I Have Accepted My Father's Death; I was not Sad but Relieved." Adaptive Grief Responses for Bereaved Dementia Family Caregivers: A Scoping Review.

This scoping review explores findings from the psychological and medical literature on the adaptive grieving experiences of bereaved dementia family caregivers and integrates what healthcare professionals can do to support bereaved dementia family caregivers transition into a post-death role. Bereaved dementia family caregivers are particularly susceptible to prolonged grief disorder post-death due to the protracted caregiving demands and progressive course of the illness. The mention of caregiver grief while the person with dementia is living is quite common in the literature; however, limited research focuses on the bereaved dementia family caregiver and the methods they use to grieve adaptively. Three overarching adaptive grieving themes emerged from the review: 1) social health, 2) emotional and spiritual fitness, and 3) reclaiming activities. Given the growing prevalence of bereaved family dementia caregivers, understanding how they might most adaptively grieve and experience the greatest possible well-being should be a top focus for research.

Association Between Fear of Pain and Sports-Related Concussion Recovery in a Pediatric Population.

OBJECTIVE: To determine whether an association exists between fear of pain and recovery time from sports-related concussion in a pediatric population. DESIGN: Prospective observational study. SETTING: Primary outpatient sports medicine clinic of a large pediatric hospital. PATIENTS: One hundred twenty-eight pediatric patients aged 8 to 18 years who presented to clinic with a primary diagnosis of concussion from September 2018 to March 2020. Inclusion criteria included presentation within 2 weeks of injury and symptomatic on initial visit. Patients who sustained a concussion because of motor vehicle collisions or assault were excluded. INDEPENDENT VARIABLES: There was no intervention. Study participants who met inclusion criteria were administered the Fear of Pain Questionnaire (FOPQ) at their initial visit. MAIN OUTCOME MEASURES: Time to clinical recovery was the main outcome measure and was determined by the fellowship-trained sports medicine physician based on resolution of concussion symptoms, resumption of normal physical and cognitive daily activities, no use of accommodations or medications, and normalization of physical exam. RESULTS: There was a significant difference in FOPQ scores for those with prolonged recovery (M = 33.12, SD = 18.36) compared with those recovering in fewer than 28 days (M = 26.16, SD = 18.44; t [126] = -2.18, P = 0.036). CONCLUSIONS: Consistent with the adult literature, we found that pediatric patients are more likely to have a prolonged recovery from concussion when they have higher fear of pain.

Guanfacine toxic ingestion with subsequent cardiogenic pulmonary edema.

Guanfacine is a central alpha-2 agonist often prescribed for Attention-deficit hyperactive disorder as well as tic disorder, with a usual dose of 1-4 mg per day. Due to its sympatholytic mechanism of action, Guanfacine can cause autonomic instability and hypotension. It can additionally cause cardiac dysfunction to include symptomatic bradycardias and contractility suppression. The authors present a case of a 17 year-old male with an ingestion of 80 mg of extended release Guanfacine with delayed onset cardiogenic pulmonary edema requiring mechanical ventilation. Previous pediatric ingestions have generated bradycardia, hypotension, and decreased level of consciousness, responsive to intravenous fluids, vasopressors, and occasionally naloxone. However, cardiogenic pulmonary edema from reduced cardiac contractility is a novel consequence of extended release Guanfacine ingestion. With Guanfacine's extended half-life, this unique case underscores the importance of emergency providers' familiarity with this toxidrome as well the necessity for prolonged, close observation following Guanfacine ingestion.

Remote activity monitoring for family caregivers of persons living with dementia: a mixed methods, randomized controlled evaluation.

BACKGROUND: The goal of the present study was to determine whether a remote activity monitoring (RAM) system benefited caregivers who aided relatives with Alzheimer's disease or related dementias (ADRD) living at home. We hypothesized that over 18 months, families randomly assigned to receive RAM technology in the home of the person with ADRD would experience statistically significant (p < .05): 1) improvements in caregiver self-efficacy and sense of competence when managing their relative's dementia; and 2) reductions in caregiver distress (e.g., burden, role captivity, and depression). METHODS: An embedded mixed methods design was utilized, where 179 dementia caregivers were randomly assigned to receive RAM or not. Caregivers were surveyed bi-annually over an 18-month period to collect quantitative and qualitative data on RAM's effects. Semi-structured interviews with 30 caregivers were completed following the 18-month data collection period to explore more in-depth how and why RAM was perceived as helpful or not. RESULTS: Growth curve models showed no direct or moderation effect of RAM on dementia caregiver outcomes. The qualitative data revealed a complex utilization process of RAM influenced by the care environment/context as well as the temporal progression of ADRD and the caregiving trajectory. CONCLUSIONS: The findings suggest the need for developing more effective mechanisms to match appropriate technologies with the heterogeneous needs and care contexts of people living with ADRD and their caregivers. A triadic approach that incorporates professional care management alongside passive monitoring systems such as RAM may also enhance potential benefits. TRIAL REGISTRATION: ClinicalTrials.gov NCT03665909 , retrospectively registered on 11 Sept 2018.

Correction: The population genetics of human disease: The case of recessive, lethal mutations.

[This corrects the article DOI: 10.1371/journal.pgen.1006915.].

The association between BOLD-based cerebrovascular reactivity (CVR) and end-tidal CO2 in healthy subjects.

Cerebrovascular reactivity (CVR) mapping using CO2-inhalation can provide important insight into vascular health. At present, blood-oxygenation-level-dependent (BOLD) MRI acquisition is the most commonly used CVR method due to its high sensitivity, high spatial resolution, and relatively straightforward processing. However, large variations in CVR across subjects and across different sessions of the same subject are often observed, which can cloud the ability of this promising measure in detecting diseases or monitoring treatment responses. The present work aims to identify the physiological components underlying the observed variability in CVR data. When studying the association between CVR value and the subject's CO2 levels in a total of N = 253 healthy participants, we found that CVR was lower in individuals with a higher basal end-tidal CO2, EtCO2 (slope = -0.0036 ±â€¯0.0008%/mmHg2, p < 0.001), or with a greater EtCO2 change (ΔEtCO2) with hypercapnic condition (slope = -0.0072 ±â€¯0.0018%/mmHg2, p < 0.001). In a within-subject setting, when studying the CVR difference between two repeated scans (with repositioning) in relation to the corresponding differences in basal EtCO2 and ΔEtCO2 (n = 11), it was found that CVR values were lower if the basal EtCO2 or ΔEtCO2 during that particular scan session was greater. The present work suggests that basal physiological state and the level of hypercapnic stimulus intensity should be considered in application studies of CVR in order to reduce inter-subject and intra-subject variations in the data. Potential approaches to use these findings to reduce noise and augment sensitivity are proposed.

The population genetics of human disease: The case of recessive, lethal mutations.

Do the frequencies of disease mutations in human populations reflect a simple balance between mutation and purifying selection? What other factors shape the prevalence of disease mutations? To begin to answer these questions, we focused on one of the simplest cases: recessive mutations that alone cause lethal diseases or complete sterility. To this end, we generated a hand-curated set of 417 Mendelian mutations in 32 genes reported to cause a recessive, lethal Mendelian disease. We then considered analytic models of mutation-selection balance in infinite and finite populations of constant sizes and simulations of purifying selection in a more realistic demographic setting, and tested how well these models fit allele frequencies estimated from 33,370 individuals of European ancestry. In doing so, we distinguished between CpG transitions, which occur at a substantially elevated rate, and three other mutation types. Intriguingly, the observed frequency for CpG transitions is slightly higher than expectation but close, whereas the frequencies observed for the three other mutation types are an order of magnitude higher than expected, with a bigger deviation from expectation seen for less mutable types. This discrepancy is even larger when subtle fitness effects in heterozygotes or lethal compound heterozygotes are taken into account. In principle, higher than expected frequencies of disease mutations could be due to widespread errors in reporting causal variants, compensation by other mutations, or balancing selection. It is unclear why these factors would have a greater impact on disease mutations that occur at lower rates, however. We argue instead that the unexpectedly high frequency of disease mutations and the relationship to the mutation rate likely reflect an ascertainment bias: of all the mutations that cause recessive lethal diseases, those that by chance have reached higher frequencies are more likely to have been identified and thus to have been included in this study. Beyond the specific application, this study highlights the parameters likely to be important in shaping the frequencies of Mendelian disease alleles.

Let it go: Relationship autonomy predicts pro-relationship responses to partner transgressions.

OBJECTIVE: The purpose of the present research is to better understand how relationship autonomy-having more self-determined reasons for being committed to a relationship-contributes to pro-relationship responses to transgressions in romantic relationships (e.g., forgiveness and accommodation). METHOD: Study 1 employed a cross-sectional design (N = 350) and Study 2 used a weekly diary (N = 121) to test associations between relationship autonomy and pro-relationship responses to transgressions. Studies 3 and 4 utilized dyadic designs (Study 3: N = 200 couples, 400 individuals; Study 4: N = 275 couples, 550 individuals) to determine how both partners' relationship autonomy is associated with pro-relationship responses. RESULTS: Results revealed that relationship autonomy is robustly associated with pro-relationship responses to transgressions, both as general tendencies and as responses to idiosyncratic transgressions. Results of actor-partner interdependence model (APIM) analyses in Studies 3 and 4 provide evidence that one's partner's relationship autonomy is important for promoting pro-relationship responses as well. Study 4 also found that people perceive that partners respond better to transgressions if their partner is high in relationship autonomy. CONCLUSIONS: This research provides consistent and compelling evidence that the degree of self-determination underlying commitment is important for understanding how people respond to transgressions in their relationships, beyond their current levels of commitment.

Racial Differences in Nursing Home Quality of Life Among Residents Living With Alzheimer's Disease and Related Dementias.

ObjectivesAmong nursing home (NH) residents with Alzheimer's disease (AD) and AD-related dementias (AD/ADRD), racial/ethnic disparities in quality of care exist. However, little is known about quality of life (QoL). This study examines racial/ethnic differences in self-reported QoL among NH residents with AD/ADRD. Methods: Validated, in-person QoL surveys from 12,562 long-stay NH residents with AD/ADRD in Minnesota (2012-2015) were linked to Minimum Data Set assessments and facility characteristics. Hierarchical linear models assessed disparities in resident-reported mean QoL score (range, 0-100 points), adjusting for case-mix and facility factors. Results: Compared to White residents, racially/ethnically minoritized residents reported significantly lower total mean QoL scores (75.53 points vs. 80.34 points, p < .001). After adjustment for resident- and facility-level characteristics, significant racial/ethnic differences remained, with large disparities in food enjoyment, attention from staff, and engagement domains. Discussion: Policy changes and practice guidelines are needed to address racial/ethnic disparities in QoL of NH residents with AD/ADRD.

Advancing Gerontology through Exceptional Scholarship (AGES): a Mentorship Initiative for Early Career Faculty.

Mentorship is critical to supporting professional development and growth of new and emerging faculty members. Working with the Gerontological Society of America (GSA), we created the Advancing Gerontology through Exceptional Scholarship (AGES) Initiative as a mentorship model to promote productivity and peer support for new and early career faculty members. In this commentary, we highlight the AGES Program as a prototype to facilitate peer support, collective learning, and co-authorship opportunities to advance new and early career faculty members, especially in the field of aging. Moreover, we identify four crucial strategies that cultivated and refined our AGES Program including: i) ensuring flexibility to address mentee needs; ii) establishing check-ins and accountability to enhance productivity; iii) fostering peer support and collective learning; and iv) delivering motivational and educational activities. Drawing on our experience with the AGES Program, this commentary provides recommendations to support other groups looking to develop high-quality mentorship programs to support new and early career faculty members in academia.

Evidence Map of Non-Pharmacological Dementia Care Partner Interventions Implemented in the US: Gaps and Impact Opportunities.

There are 200+ tested interventions for care partners (family, friends, and fictive kin) of people living with dementia (PLWD). But these interventions do not systematically cover relevant settings. Nor do these interventions affect all relevant outcomes that matter to people and healthcare systems. We present an evidence map of settings and outcomes from translated interventions to identify gaps. Of 190 studies identified, 31 unique interventions were retained in the evidence map. Identified setting gaps included studies set solely in hospitals/medical centers or set in multiple settings. Identified outcome gaps included interventions that improved care partner beliefs about providing care, care partner negative coping strategies, PLWD resources (e.g., social support), and PLWD coping strategies. Armed with an understanding of present gaps, we call on researchers to fill the identified gaps to ensure systematic coverage of settings and evaluation of outcomes that matter to people and healthcare systems.

Efficacy of the residential care transition module: A telehealth intervention for dementia family caregivers of relatives living in residential long-term care settings.

The purpose of this study was to evaluate the efficacy of the Residential Care Transition Module, a six-session, psychosocial, and psychoeducational telehealth intervention for family caregivers of cognitively impaired relatives living in a residential long-term care setting. Eligible participants (including care recipients, regardless of time since admission) were randomized to treatment or usual care control conditions. Survey data were collected at baseline, 4 months, 8 months, and 12 months (N = 240). Primary analytic outcomes included caregiver subjective stress (a stress process mechanism) and depressive symptoms (a measure of global well-being). Secondary analytic outcomes included secondary role strains, residential care stress, caregiver sense of competence, and self-efficacy (additional mechanisms of action). General linear models tested for the main effects of the intervention at 4 months, and longitudinal mixed models examined the 12-month effects of the intervention. Post hoc analyses also examined the influence of moderators. No significant differences between the treatment and control groups for any primary analytic outcome were apparent. Caregivers in the treatment group whose relatives were admitted to residential long-term care in the prior 3 months were more likely to indicate reductions in depressive symptoms over the first 4 months of participation. Over the 12-month study period, caregivers in the treatment group who were employed reported increased self-efficacy over time. The heterogeneity of dementia care requires a broader consideration of key contextual factors that may influence the efficacy of nonpharmacological interventions. Aligning measures with the preferences, goals, and values of dementia caregivers may further demonstrate the direct benefits of interventions such as the Residential Care Transition Module. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Using Hybrid Effectiveness Studies to Facilitate Implementation in Community-Based Settings: Three Case Studies in Dementia Care Research.

The pipeline from discovery to testing and then implementing evidence-based innovations in real-world contexts may take 2 decades or more to achieve. Implementation science innovations, such as hybrid studies that combine effectiveness and implementation research questions, may help to bridge the chasm between intervention testing and implementation in dementia care. This paper describes hybrid effectiveness studies and presents 3 examples of dementia care interventions conducted in various community-based settings. Studies that focus on outcomes and implementation processes simultaneously may result in a truncated and more efficient implementation pipeline, thereby providing older persons, their families, health care providers, and communities with the best evidence to improve quality of life and care more rapidly. We offer post-acute and long-term care researchers considerations related to study design, sampling, data collection, and analysis that they can apply to their own dementia and other chronic disease care investigations.

Patterns of recombination in snakes reveal a tug-of-war between PRDM9 and promoter-like features.

In some mammals, notably humans, recombination occurs almost exclusively where the protein PRDM9 binds, whereas in vertebrates lacking an intact PRDM9, such as birds and canids, recombination rates are elevated near promoter-like features. To determine whether PRDM9 directs recombination in nonmammalian vertebrates, we focused on an exemplar species with a single, intact PRDM9 ortholog, the corn snake (Pantherophis guttatus). Analyzing historical recombination rates along the genome and crossovers in pedigrees, we found evidence that PRDM9 specifies the location of recombination events, but we also detected a separable effect of promoter-like features. These findings reveal that the uses of PRDM9 and promoter-like features need not be mutually exclusive and instead reflect a tug-of-war that is more even in some species than others.