The role of parental maladaptive emotion socialization in the risk process for negative urgency and drinking behavior in adolescence.

INTRODUCTION: Negative urgency (the tendency to act rashly when experiencing negative emotions) is a robust risk factor for a number of problem behaviors, including early adolescent drinking. Little is known about the factors that precede the development of negative urgency, and hence the full etiology of this component of risk. The current study aimed to investigate the possibility that facets of childhood maladaptive emotion socialization (the tendency for children's expressions of emotions to be met with punishment, minimized, or invoke a reaction of distress from their parents/caretakers) increases risk for the development of negative urgency and drinking behavior. METHOD: Self-report measures of negative urgency, subfacets of maladaptive emotion socialization, and drinking behavior were collected during the 2021-2022 academic year from a sample of 428 high school students (mean age = 14.7, SD = 0.09, 44% female), assessed twice over the course of a semester, reflecting a 4-month longitudinal window. RESULTS: Distress emotion socialization predicted increases in negative urgency, minimizing predicted decreases in negative urgency, and punitive did not provide significant prediction. Additionally, results found that higher levels of both negative urgency and distress emotion socialization increased adolescents' likelihood of having tried alcohol. These processes were invariant across race and gender. CONCLUSIONS: The present study may inform the future creation of prevention and intervention efforts aimed at reducing maladaptive emotion socialization and increasing adaptive emotion socialization. Successful reductions in negative urgency as a consequence of increased adaptive emotion socialization may then lead to decreases in adolescent drinking and other impulsigenic behaviors.

Facile de Novo Sequencing of Tetrazine-Cyclized Peptides through UV-Induced Ring-Opening and Cleavage from the Solid Phase.

While most FDA-approved peptide drugs are cyclic, the robust cyclization chemistry of peptides and the deconvolution of cyclic peptide sequences by using tandem mass spectrometry render cyclic peptide drug discovery difficult. Here we present the successful design of cyclic peptides on solid phase that addresses both of these problems. We demonstrate that this peptide cyclization method using dichloro-s-tetrazine on solid phase allows successful cyclization of a panel of random peptide sequences with various charges and hydrophobicities. The cyclic peptides can be linearized and cleaved from the solid phase by simple UV light irradiation, and we demonstrate that accurate sequence information can be obtained for the UV-cleaved linearized peptides by using tandem mass spectrometry. The tetrazine linker used in the cyclic peptides can further be explored for inverse electron-demand Diels-Alder (IEDDA) reactions for screening or bioconjugation applications in the future.

NMP4, an Arbiter of Bone Cell Secretory Capacity and Regulator of Skeletal Response to PTH Therapy.

The skeleton is a secretory organ, and the goal of some osteoporosis therapies is to maximize bone matrix output. Nmp4 encodes a novel transcription factor that regulates bone cell secretion as part of its functional repertoire. Loss of Nmp4 enhances bone response to osteoanabolic therapy, in part, by increasing the production and delivery of bone matrix. Nmp4 shares traits with scaling factors, which are transcription factors that influence the expression of hundreds of genes to govern proteome allocation for establishing secretory cell infrastructure and capacity. Nmp4 is expressed in all tissues and while global loss of this gene leads to no overt baseline phenotype, deletion of Nmp4 has broad tissue effects in mice challenged with certain stressors. In addition to an enhanced response to osteoporosis therapies, Nmp4-deficient mice are less sensitive to high fat diet-induced weight gain and insulin resistance, exhibit a reduced disease severity in response to influenza A virus (IAV) infection, and resist the development of some forms of rheumatoid arthritis. In this review, we present the current understanding of the mechanisms underlying Nmp4 regulation of the skeletal response to osteoanabolics, and we discuss how this unique gene contributes to the diverse phenotypes among different tissues and stresses. An emerging theme is that Nmp4 is important for the infrastructure and capacity of secretory cells that are critical for health and disease.

Growth factors and their peptide mimetics for treatment of traumatic brain injury.

Traumatic brain injury (TBI) is a leading cause of disability in adults, caused by a physical insult damaging the brain. Growth factor-based therapies have the potential to reduce the effects of secondary injury and improve outcomes by providing neuroprotection against glutamate excitotoxicity, oxidative damage, hypoxia, and ischemia, as well as promoting neurite outgrowth and the formation of new blood vessels. Despite promising evidence in preclinical studies, few neurotrophic factors have been tested in clinical trials for TBI. Translation to the clinic is not trivial and is limited by the short in vivo half-life of the protein, the inability to cross the blood-brain barrier and human delivery systems. Synthetic peptide mimetics have the potential to be used in place of recombinant growth factors, activating the same downstream signalling pathways, with a decrease in size and more favourable pharmacokinetic properties. In this review, we will discuss growth factors with the potential to modulate damage caused by secondary injury mechanisms following a traumatic brain injury that have been trialled in other indications including spinal cord injury, stroke and neurodegenerative diseases. Peptide mimetics of nerve growth factor (NGF), hepatocyte growth factor (HGF), glial cell line-derived growth factor (GDNF), brain-derived neurotrophic factor (BDNF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) will be highlighted, most of which have not yet been tested in preclinical or clinical models of TBI.

Examining the Psychosocial Well-Being of Children and Adolescents With Coeliac Disease: A Systematic Review.

This review aimed to synthesize the available literature regarding the psychosocial well-being of children and adolescents with coeliac disease (CD). Research on psychosocial well-being outcomes in children and adolescents with CD under the age of 18 were identified through a systematic search in the PsychInfo, Medline, Embase, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases in July 2021. Outcomes, including health-related quality of life (HRQOL), psychological adjustment, mental health, and social functioning were examined. Changes in outcomes over time and the geographic representation of the included studies were also analyzed. A total of 43 studies were included. Mixed results were found in the domain of HRQOL and mental health. Both challenges with psychological adjustment and adaptive coping strategies were identified. Social functioning was found to be an area of difficulty for children and adolescents with CD. However, there was high heterogeneity in methodology and participant characteristics between studies. This review concluded there were mixed findings regarding the HRQOL and mental health of young people with CD. However, CD and the gluten-free diet initiates a need for psychological adjustment and impacts on social functioning. The review highlights the need for the integration of physical and psychosocial care, and further research to determine the most appropriate screening measures, and the most efficacious psychological interventions for this group. Future research should continue examining changes in psychosocial outcomes over time given the increase in the availability of gluten-free foods and changes in food labeling policies.

Nmp4, a Regulator of Induced Osteoanabolism, Also Influences Insulin Secretion and Sensitivity.

A bidirectional and complex relationship exists between bone and glycemia. Persons with type 2 diabetes (T2D) are at risk for bone loss and fracture, however, heightened osteoanabolism may ameliorate T2D-induced deficits in glycemia as bone-forming osteoblasts contribute to energy metabolism via increased glucose uptake and cellular glycolysis. Mice globally lacking nuclear matrix protein 4 (Nmp4), a transcription factor expressed in all tissues and conserved between humans and rodents, are healthy and exhibit enhanced bone formation in response to anabolic osteoporosis therapies. To test whether loss of Nmp4 similarly impacted bone deficits caused by diet-induced obesity, male wild-type and Nmp4-/- mice (8 weeks) were fed either low-fat diet or high-fat diet (HFD) for 12 weeks. Endpoint parameters included bone architecture, structural and estimated tissue-level mechanical properties, body weight/composition, glucose-stimulated insulin secretion, glucose tolerance, insulin tolerance, and metabolic cage analysis. HFD diminished bone architecture and ultimate force and stiffness equally in both genotypes. Unexpectedly, the Nmp4-/- mice exhibited deficits in pancreatic ß-cell function and were modestly glucose intolerant under normal diet conditions. Despite the ß-cell deficits, the Nmp4-/- mice were less sensitive to HFD-induced weight gain, increases in % fat mass, and decreases in glucose tolerance and insulin sensitivity. We conclude that Nmp4 supports pancreatic ß-cell function but suppresses peripheral glucose utilization, perhaps contributing to its suppression of induced skeletal anabolism. Selective disruption of Nmp4 in peripheral tissues may provide a strategy for improving both induced osteoanabolism and energy metabolism in comorbid patients.

Maladaptive Emotion Socialization as a Risk Factor for the Development of Negative Urgency and Subsequent Problem Drinking.

AIMS: Negative urgency, which refers to the tendency to act rashly when experiencing intense negative emotions, consistently serves as a robust predictor of problem drinking and other maladaptive behaviors. However, very little is known about the factors that influence the development of negative urgency itself. Although urgency theory suggests that environment and temperament interact to increase risk for the development of urgency, few studies, to date, have examined environmental risk for urgency. METHOD: In a cross-sectional sample of 518 adults recruited from Amazon Mturk, the current study began the investigation of the role of childhood maladaptive emotion socialization (MES) in risk for negative urgency and the possibility that negative urgency mediates the relationship between MES and problem drinking via self-report measures completed online. Data were analyzed using structural equation modeling. RESULTS: Individual differences in childhood MES, reported retrospectively, did predict increased present-day negative urgency. In addition, results were consistent with the possibility that negative urgency mediates the relationship between MES and problem drinking when considered concurrently with trait negative affect. CONCLUSIONS: Successful identification of early environmental predictors of negative urgency may provide useful targets for intervention efforts aimed at reducing or preventing the development of negative urgency and, subsequently, problem drinking. Further longitudinal investigations are needed to better examine these processes as they develop.

Affect-Based Problem Drinking Risk: The Reciprocal Relationship between Affective Lability and Problem Drinking.

AIMS: Negative affect has been implicated in risk for the development of problematic drinking behavior. Furthermore, there is evidence for reciprocal relationships between negative affect and problem drinking, such that engagement in problem drinking also predicts increases in negative affect. However, affective models of risk often fail to consider affective lability-the experience of rapidly changing mood. Although affective lability appears to increase risk for problem drinking, it is unknown if this relationship persists above and beyond other affect-related constructs (e.g. depression, anxiety) and if it is reciprocal in nature. Accordingly, we used a longitudinal survey design to examine (a) if affective lability predicts problem drinking above and beyond depression and anxiety and (b) if affective lability and problem drinking demonstrate a reciprocal relationship. METHODS: First-year college students (n = 358) participated in a three wave longitudinal study. We constructed a structural equation model (SEM) of a random intercept cross-lagged panel model to test our hypotheses. RESULTS: Consistent with our hypotheses, affective lability predicted increases in problem drinking while anxiety and depression did not. Problem drinking and affective lability demonstrated a reciprocal relationship in which increases in one predicted increases in the other at subsequent time points. This relationship was present beyond the predictive effects of anxiety or depression. CONCLUSIONS: Affective lability appears to be an important affect-based predictor of problem drinking, and there may be a reciprocal, risk-enhancing relationship between affective lability and problem drinking.Components of negative affect, such as depression or anxiety, have been shown to predict risk for problem drinking, and vice versa. A less considered construct, affective lability, predicted problem drinking while anxiety and depression did not add any predictive power. Problem drinking and affective lability also appeared to demonstrate a reciprocal relationship.

The General Factor of Psychopathology.

An important advance in understanding and defining mental disorders has been the development of empirical approaches to mapping dimensions of dysfunction and their interrelatedness. Such empirical approaches have consistently observed intercorrelations among the many forms of psychopathology, leading to the identification of a general factor of psychopathology (the p factor). In this article, we review empirical support for p, including evidence for the stability and criterion validity of p. Further, we discuss the strong relationship between p and both the general factor of personality and the general factor of personality disorder, substantive interpretations of p, and the potential clinical utility of p. We posit that proposed substantive interpretations of p do not explain the full range of symptomatology typically included in p. The most plausible explanation is that p represents an index of impairment that has the potential to inform the duration and intensity of a client's mental health treatment.

Sex Differences in Trait Anxiety's Association with Alcohol Problems in Emerging Adults: The Influence of Symptoms of Depression and Borderline Personality.

OBJECTIVE: The co-occurrence of alcohol use disorder (AUD) and internalizing psychopathology, such as anxiety and depression, has been well documented. However, most studies of the association between alcohol problems and anxiety, and do not simultaneously consider depression or borderline personality, which covary strongly with both anxiety symptoms and AUDs. The current study examined sex differences in the association between alcohol problems and anxiety, while accounting for depressive and borderline personality (BPD) symptoms. METHOD: A sample 810 (364 females) young adults aged 18-30 recruited from the community, who varied widely in lifetime alcohol problems, were administered diagnostic interviews and measures of a trait anxiety, depression, and BPD symptoms. RESULTS: Analyses revealed that trait anxiety, depression, and borderline symptoms were all significantly associated with higher lifetime alcohol problems in both males and females. However, the association between trait anxiety and alcohol problems was significantly stronger for males compared with females, even when controlling for depression and BPD symptoms. There were no significant sex differences in the association between alcohol problems and symptoms of either depression or BPD symptoms. CONCLUSION: This suggests specific sex differences in the mechanisms by which trait anxiety is associated with alcohol problems.

Growth and nutrition in children with trichothiodystrophy.

OBJECTIVES: Trichothiodystrophy (TTD) is a rare autosomal recessive disorder of DNA repair and transcription. Patients have multisystem abnormalities, including alterations in growth and development. This report characterizes the growth and nutritional status of a cohort of children with TTD. METHODS: Twenty-five patients with TTD were evaluated through a natural history study of patients with DNA repair diseases at the National Institutes of Health. Mean length of follow-up was 2.7 years. Retrospective and prospective data on nutritional status and height/weight were collected. RESULTS: In general, patients with TTD had considerable abnormalities in growth, with a mean height-for-age z score of -2.75 and a mean weight-for-age z score of -2.60 at baseline clinical evaluation. The median weight-for-length at baseline was, however, 50th percentile and indicators of adequate nutrition such as serum albumin, hemoglobin, and vitamins D and B12 were largely within normal limits. Changes in growth parameters as children aged were characterized by further separation from standard growth curves (change height-for-age z score/year [-0.18 ± 0.42] and weight-for-age z score/year [-0.36 ± 0.51]). Patients who died during follow-up (n = 5) had significantly lower standardized height (P = 0.03) and weight (P = 0.006), weight-for-length (<0.0001), and higher heart rates (P = 0.02) compared with the remainder of the cohort. CONCLUSIONS: Children with TTD have markedly diminished weight-for-age and height-for-age relative to reference populations. The cause for this stunted growth remains unclear but does not appear to be related to poor nutrient absorption or malnutrition.

Global Approaches to Primary, Secondary, and Tertiary Elder Abuse Prevention: A Scoping Review.

Public health professionals use a three-pronged approach to address broad-reaching issues of societal concern: primary prevention, secondary prevention, and tertiary prevention. Applying this framework to the study of elder abuse, the purpose of this review is to describe the status of elder abuse prevention research on a global scale. Elder abuse prevention articles published between 2015 and 2021 were identified through electronic bibliographic searches (PubMed, Medline, CINAHL, APA PsycINFO, and AgeLine). After removing articles based on inclusion and exclusion criteria, articles were sorted into the three main prevention types and further divided into subcategories for a more in-depth review. Most of the studies identified were conducted in North America (n = 42). Of the 72 articles identified, 13 articles focused on primary prevention (agism, education, and intervention), 35 articles focused on secondary prevention (developing and evaluating screening tools, identifying and reporting abuse, and barriers to detecting and reporting abuse), and 21 focused on tertiary prevention (professional response to cases of abuse, intervention methods, and impact of policy). Collectively, findings bring greater understanding of elder abuse as a public health problem and identify ways of addressing the complexities of elder abuse. Several gaps were identified in the elder abuse prevention literature including the need for global research that includes older adults as stakeholders, evidence-based education and intervention programs, and cultural sensitive and valid tools to identify elder abuse.

Addressing the SUD training gap: Two pilot feasibility studies in the Department of Veteran's Affairs Health Care System.

INTRODUCTION: Substance use disorders (SUDs) are an ongoing public health crisis in the United States. A large body of research indicates an urgent need for increased training in SUD research and treatment for trainees in mental health service disciplines. The VA Health Care System is well positioned, as the largest trainer and employer of health service psychologists and other mental health professionals, to address the SUD training gap and serve as a leader in training the upcoming health care workforce. METHOD: To this end, we conducted two pilot studies to (1) examine the feasibility of implementing supplemental SUD training for VA health service trainees, among current VA mental health service providers in psychology, social work, and medical care (N = 37) and (2) the efficacy of a single 2-hour interdisciplinary SUD training seminar for VA health service trainees in mental health (N = 13). The training seminar consisted of several components including lecture, facilitated discussion, and role play, aimed at increasing trainee self-efficacy in assessing and diagnosing SUDs. RESULTS: Findings suggest that current providers are supportive of supplemental SUD training for VA trainees and believe that such training is beneficial for those wishing to pursue a career within the VA Health Care System. Additionally, results suggest that a single session didactic seminar improved trainees' self-reported efficacy in the assessment and referral of veterans diagnosed with SUDs. CONCLUSIONS: Overall, the above studies support additional feasibility investigations that would pave the way for successful implementation of widespread SUD training programs across the VA Health Care System and beyond. Successful implementation would then serve to reduce the increasingly critical SUD provider shortage, thus leading to significant public health gains.

Retrospective study of laboratory-based surveillance of rabies in wild and domestic animals in the southern United States, 2010-2021.

We performed a retrospective study of all case submissions for the rabies virus (RABV) direct fluorescent antibody test (DFAT) requested of the Tifton Veterinary Diagnostic and Investigational Laboratory (Tifton, GA, USA) between July 2010 and June 2021. Submitted were 792 samples from 23 animal species from 89 counties in Georgia, and 4 neighboring counties in Florida, 1 in South Carolina, and 1 in Alabama. In 13 (1.6%) cases, the DFAT result was inconclusive; 779 (98.4%) cases had a conclusive (positive or negative) test result. Of these 779 cases, 79 (10.1%) tested positive across 10 species. The remaining 700 (89.9%) cases were negative. The main reason for submission for RABV testing was human exposure to a potentially rabid animal in 414 (52.3%) cases. Among the 79 positive cases, 74 (93.7%) involved wildlife; raccoons (51 cases; 68.9%) were the primary host confirmed with RABV infection, followed by skunk and fox (8 cases each; 10.8%), bobcat (5 cases; 6.8%), and bats (2 cases; 2.7%). Only 5 domestic animals (6.3% of the positive cases) tested positive during our study period; one from each of the bovine, canine, caprine, equine, and feline species. Hence, the sylvatic cycle plays the predominant role in circulating RABV infection in our study area.

Vigilance, risk, and service use among caregivers of people living with dementia.

OBJECTIVE: The purpose of this investigation was to understand the dynamics among dementia caregiving, vigilance, and home and community-based service use. METHODS: This paper is derived from a larger, mixed-methods study on caregiving. We used a descriptive qualitative approach to analyze interview data of 30 family caregivers of relatives with dementia. RESULTS: We found five domains of vigilance in which caregivers felt "on duty": ensuring attentiveness, ensuring safety, ensuring resources, ensuring healthcare, and ensuring closeness. Formal service use did not necessarily give caregivers relief from vigilance, with the language of risk often employed by caregivers. CONCLUSION: Because service use could contribute to feelings of vigilance, rather than give caregivers a break from a sense of watchfulness, these findings support calls for dementia-specific training for service providers. In future caregiving research, the relationship between vigilance, caregiver distress, and role captivity should be explored.

What do we learn when we adapt to reading regional constructions?

We present four experiments investigating adaptation to a regional grammatical structure through reading exposure, using both the needs + past participle construction (e.g., The car needs washed) and the double modal construction (e.g. You might could go there). In each experiment, participants read two stories containing informal dialogue. Half of the participants were exposed to one of the regional constructions and half were not. Those readers exposed to the regional constructions adapted, gradually reading the novel constructions faster over 9 to 15 exemplars. The degree to which the exposed group learned the construction was tested in two ways. In the first two experiments, learning was measured by comparing reading times to acceptable and unacceptable variants of the novel constructions. Readers did not learn either the verb tense rule for the needs construction (Experiment 1) or a simple ordering rule for double modal constructions (Experiment 2). Similarly, in Experiments 3 and 4, metalinguistic judgments used to test learning revealed that participants had failed to acquire the regional grammar of either novel construction. These experiments suggest that the adaptation effects reflect learning some general properties of the experimental stimuli, not learning the syntactic constructions themselves.

Financial Fraud of Older Adults During the Early Months of the COVID-19 Pandemic.

BACKGROUND AND OBJECTIVES: Coronavirus disease 2019 (COVID-19) created a "perfect storm" for financial fraud targeting older adults. Guided by the Contextual Theory of Elder Abuse, we focused on individual and systemic contexts to examine how older adults became prey to financial fraud. RESEARCH DESIGN AND METHODS: In July 2020, 998 adults who were 60-98 years of age (93% White; 64% female) completed an online survey about experiences with financial fraud. Participants were recruited from gerontology research registries at Florida State University, University of Pittsburg, Virginia Tech, and Wayne State University. RESULTS: Over half (65.9%) of the respondents experienced a COVID-19-related scam attempt, with charity contributions (49%) and COVID-19 treatments (42%) being the most common. Perpetrators commonly contacted older adults electronically (47%) two or more times (64%). Although most respondents ignored the request (i.e., hung up the phone and deleted text/e-mail), 11.3% sent a requested payment, and 5.3% provided personal information. Predictors of vulnerability included contentment with financial situation, concern about finances in the aftermath of the pandemic, and wishing to talk to someone about financial decisions. Respondents targeted for a non-COVID-19 scam attempt were less likely to be targets of a COVID-19-related scam. DISCUSSION AND IMPLICATIONS: Older adults who were financially secure, worried about their financial situation, or wished they could speak with someone about their financial decisions appeared susceptible to falling victim to a fraud attempt. The high number of attempts indicates a need for a measurable and concerted effort to prevent the financial fraud of older adults.

Loss of Nmp4 enhances bone gain from sclerostin antibody administration.

Severe osteoporosis is often treated with one of three Food and Drug Administration (FDA)-approved osteoanabolics. These drugs act by (1) parathyroid hormone (PTH) receptor stimulation using analogues to PTH (teriparatide) or PTH-related peptide (abaloparatide) or by (2) monoclonal antibody neutralization of sclerostin, an innate Wnt inhibitor (Scl-mAb, romosozumab-aqqg). The efficacies of both strategies wane over time. The transcription factor Nmp4 (Nuclear Matrix Protein 4) is expressed in all tissues yet mice lacking this gene are healthy and exhibit enhanced PTH-induced bone formation. Conditional deletion of Nmp4 in mesenchymal stem progenitor cells (MSPCs) phenocopies the elevated response to PTH in global Nmp4-/- mice. However, targeted deletion in later osteoblast stages does not replicate this response. In this study we queried whether loss of Nmp4 improves Scl-mAb potency. Experimental cohorts included global Nmp4-/- and Nmp4+/+ littermates and three conditional knockout models. Nmp4-floxed (Nmp4fl/fl) mice were crossed with mice harboring one of three Cre-drivers (i) Prx1Cre+ targeting MSPCs, (ii) BglapCre+ (mature osteocalcin-expressing osteoblasts), and (iii) Dmp1Cre+ (osteocytes). Female mice were treated with Scl-mAb or 0.9 % saline vehicle for 4 or 7 weeks from 10 weeks of age. Skeletal response was assessed using micro-computed tomography, dual-energy X-ray absorptiometry, bone histomorphometry, and serum analysis. Global Nmp4-/- mice exhibited enhanced Scl-mAb-induced increases in trabecular bone in the femur and spine and a heightened increase in whole body areal bone mineral density compared to global Nmp4+/+ controls. This improved Scl-mAb potency was primarily driven by enhanced increases in bone formation. Nmp4fl/fl;PrxCre+ mice showed an exaggerated Scl-mAb-induced increase in femoral bone but not in the spine since Prrx1 is not expressed in vertebra. The Nmp4fl/fl;BglapCre+ and Nmp4fl/fl;Dmp1Cre+ mice did not exhibit an improved Scl-mAb response. We conclude that Nmp4 expression in MSPCs interferes with the bone anabolic response to anti-sclerostin therapy.

Conditional Loss of Nmp4 in Mesenchymal Stem Progenitor Cells Enhances PTH-Induced Bone Formation.

Activation of bone anabolic pathways is a fruitful approach for treating severe osteoporosis, yet FDA-approved osteoanabolics, eg, parathyroid hormone (PTH), have limited efficacy. Improving their potency is a promising strategy for maximizing bone anabolic output. Nmp4 (Nuclear Matrix Protein 4) global knockout mice exhibit enhanced PTH-induced increases in trabecular bone but display no overt baseline skeletal phenotype. Nmp4 is expressed in all tissues; therefore, to determine which cell type is responsible for driving the beneficial effects of Nmp4 inhibition, we conditionally removed this gene from cells at distinct stages of osteogenic differentiation. Nmp4-floxed (Nmp4fl/fl ) mice were crossed with mice bearing one of three Cre drivers including (i) Prx1Cre+  to remove Nmp4 from mesenchymal stem/progenitor cells (MSPCs) in long bones; (ii) BglapCre+  targeting mature osteoblasts, and (iii) Dmp1Cre+  to disable Nmp4 in osteocytes. Virgin female Cre+  and Cre- mice (10 weeks of age) were sorted into cohorts by weight and genotype. Mice were administered daily injections of either human PTH 1-34 at 30 µg/kg or vehicle for 4 weeks or 7 weeks. Skeletal response was assessed using dual-energy X-ray absorptiometry, micro-computed tomography, bone histomorphometry, and serum analysis for remodeling markers. Nmp4fl/fl ;Prx1Cre+  mice virtually phenocopied the global Nmp4-/- skeleton in the femur, ie, a mild baseline phenotype but significantly enhanced PTH-induced increase in femur trabecular bone volume/total volume (BV/TV) compared with their Nmp4fl/fl ;Prx1Cre- controls. This was not observed in the spine, where Prrx1 is not expressed. Heightened response to PTH was coincident with enhanced bone formation. Conditional loss of Nmp4 from the mature osteoblasts (Nmp4fl/fl ;BglapCre+ ) failed to increase BV/TV or enhance PTH response. However, conditional disabling of Nmp4 in osteocytes (Nmp4fl/fl ;Dmp1Cre+ ) increased BV/TV without boosting response to hormone under our experimental regimen. We conclude that Nmp4-/- Prx1-expressing MSPCs drive the improved response to PTH therapy and that this gene has stage-specific effects on osteoanabolism. © 2022 American Society for Bone and Mineral Research (ASBMR).

Dual Caregivers of Persons living with Dementia: The Added Stress of COVID-19 Pandemic.

Serving in dual caregiving roles presents challenges and has consequences for caregivers' physical and mental health. Forty-six dual caregivers in rural southwest Virginia participated in one semi-structured telephone interview pre-pandemic. Of these caregivers, nine dual caregivers of multiple older adults (MOA) and six caregivers of multiple generations (MG) participated in two telephone interviews during the COVID-19 pandemic. Pre-pandemic health, stress, and support data were used to compare dual caregivers of MOA and MG; differences were minimal. Responses to interviews conducted during the pandemic highlighted the effects of social restrictions on MOA and MG caregivers, revealing five themes (1) Increased isolation, (2) Increased need for vigilance, (3) Negative impact on mental health, (4) Tendency to "do it all," and (5) Increased informal help. MOA and MG caregivers differed on managing care responsibilities and ensuring the health of care recipients. In general, dual caregivers experienced decreased mental health, increased social isolation, and increased caregiving responsibilities. Antecedents of the pandemic experiences differentiated MOA and MG caregiver. Findings suggest that programs and services should target dual caregivers' unique needs.