Youth Caregivers of Adults in the United States: Prevalence and the Association Between Caregiving and Education.

A growing proportion of individuals adopt family caregiving roles. Family caregivers are the primary providers of long-term care in the United States yet limited federal policy supports exist, despite the known negative impacts of caregiving. There is also limited information about the prevalence of youth/young adult caregivers and the impacts of caregiving at formative ages in the United States. Our objective is to estimate the prevalence of youth caregivers and examine the association of caregiving with educational investments. We use the American Time Use Survey (2013-2019) to identify and describe youth caregivers (aged 15-18) and young adult caregivers (aged 19-22) and compare them with non-caregiving peers. We estimate that there are approximately 1,623,000 youth caregivers and 1,986,000 young adult caregivers, corresponding to 9.2% and 12.7% of these age groups, respectively. However, there is a wide range in the estimated prevalence per year, from approximately 364,000 to 2.8 million youth caregivers and from 353,000 to 2.2 million young adult caregivers, depending on caregiver definition. Unlike adult caregivers, we find that young men and women were nearly equally likely to provide care. We also find that non-White individuals are disproportionately represented as youth caregivers. Compared with non-caregiving peers, both youth and young adult caregivers are less likely to be enrolled in school and, among those enrolled in school, spend significantly less time on educational activities. Considering the association of caregiving among youth/young adults and education, policies supporting youth and young adult caregivers are critical.

Temporal regulation of the Mediator complex during muscle proliferation, differentiation, regeneration, aging, and disease.

Genesis of skeletal muscle relies on the differentiation and fusion of mono-nucleated muscle progenitor cells into the multi-nucleated muscle fiber syncytium. The temporally-controlled cellular and morphogenetic changes underlying this process are initiated by a series of highly coordinated transcription programs. At the core, the myogenic differentiation cascade is driven by muscle-specific transcription factors, i.e., the Myogenic Regulatory Factors (MRFs). Despite extensive knowledge on the function of individual MRFs, very little is known about how they are coordinated. Ultimately, highly specific coordination of these transcription programs is critical for their masterfully timed transitions, which in turn facilitates the intricate generation of skeletal muscle fibers from a naïve pool of progenitor cells. The Mediator complex links basal transcriptional machinery and transcription factors to regulate transcription and could be the integral component that coordinates transcription factor function during muscle differentiation, growth, and maturation. In this study, we systematically deciphered the changes in Mediator complex subunit expression in skeletal muscle development, regeneration, aging, and disease. We incorporated our in vitro and in vivo experimental results with analysis of publicly available RNA-seq and single nuclei RNA-seq datasets and uncovered the regulation of Mediator subunits in different physiological and temporal contexts. Our experimental results revealed that Mediator subunit expression during myogenesis is highly dynamic. We also discovered unique temporal patterns of Mediator expression in muscle stem cells after injury and during the early regeneration period, suggesting that Mediator subunits may have unique contributions to directing muscle stem cell fate. Although we observed few changes in Mediator subunit expression in aging muscles compared to younger muscles, we uncovered extensive heterogeneity of Mediator subunit expression in dystrophic muscle nuclei, characteristic of chronic muscle degeneration and regeneration cycles. Taken together, our study provides a glimpse of the complex regulation of Mediator subunit expression in the skeletal muscle cell lineage and serves as a springboard for mechanistic studies into the function of individual Mediator subunits in skeletal muscle.

Integrating multisector molecular characterization into personalized peptide vaccine design for patients with newly diagnosed glioblastoma.

PURPOSE: Glioblastoma (GBM) patient outcomes remain poor despite multimodality treatment with surgery, radiation, and chemotherapy. There are few immunotherapy options due to the lack of tumor immunogenicity. Several clinical trials have reported promising results with cancer vaccines. To date, studies have used data from a single tumor site to identify targetable antigens, but this approach limits the antigen pool and is antithetical to the heterogeneity of GBM. We have implemented multisector sequencing to increase the pool of neoantigens across the GBM genomic landscape that can be incorporated into personalized peptide vaccines called NeoVax. PATIENTS AND METHODS: Here, we report the findings of four subjects enrolled onto the NeoVax clinical trial (NCT0342209). RESULTS: Immune reactivity to NeoVax neoantigens was assessed in peripheral blood mononuclear cells (PBMCs) pre- and post-NeoVax for subjects 1-3 using IFNg-ELISPOT assay. A statistically significant increase in IFNg producing T cells at the post-NeoVax time point for several neoantigens was observed. Furthermore, a post-NeoVax tumor biopsy was obtained from subject 3 and, upon evaluation, revealed evidence of infiltrating, clonally expanded T cells. CONCLUSIONS: Collectively, our findings suggest NeoVax did stimulate expansion of neoantigen-specific effector T cells and provide encouraging results to aid in the development of future neoantigen vaccine-based clinical trials in patients with GBM. Herein, we demonstrate the feasibility of incorporating multisector sampling in cancer vaccine design and provide information on the clinical applicability of clonality, distribution, and immunogenicity of the neoantigen landscape in GBM patients.

Full-length isoform concatenation sequencing to resolve cancer transcriptome complexity.

BACKGROUND: Cancers exhibit complex transcriptomes with aberrant splicing that induces isoform-level differential expression compared to non-diseased tissues. Transcriptomic profiling using short-read sequencing has utility in providing a cost-effective approach for evaluating isoform expression, although short-read assembly displays limitations in the accurate inference of full-length transcripts. Long-read RNA sequencing (Iso-Seq), using the Pacific Biosciences (PacBio) platform, can overcome such limitations by providing full-length isoform sequence resolution which requires no read assembly and represents native expressed transcripts. A constraint of the Iso-Seq protocol is due to fewer reads output per instrument run, which, as an example, can consequently affect the detection of lowly expressed transcripts. To address these deficiencies, we developed a concatenation workflow, PacBio Full-Length Isoform Concatemer Sequencing (PB_FLIC-Seq), designed to increase the number of unique, sequenced PacBio long-reads thereby improving overall detection of unique isoforms. In addition, we anticipate that the increase in read depth will help improve the detection of moderate to low-level expressed isoforms. RESULTS: In sequencing a commercial reference (Spike-In RNA Variants; SIRV) with known isoform complexity we demonstrated a 3.4-fold increase in read output per run and improved SIRV recall when using the PB_FLIC-Seq method compared to the same samples processed with the Iso-Seq protocol. We applied this protocol to a translational cancer case, also demonstrating the utility of the PB_FLIC-Seq method for identifying differential full-length isoform expression in a pediatric diffuse midline glioma compared to its adjacent non-malignant tissue. Our data analysis revealed increased expression of extracellular matrix (ECM) genes within the tumor sample, including an isoform of the Secreted Protein Acidic and Cysteine Rich (SPARC) gene that was expressed 11,676-fold higher than in the adjacent non-malignant tissue. Finally, by using the PB_FLIC-Seq method, we detected several cancer-specific novel isoforms. CONCLUSION: This work describes a concatenation-based methodology for increasing the number of sequenced full-length isoform reads on the PacBio platform, yielding improved discovery of expressed isoforms. We applied this workflow to profile the transcriptome of a pediatric diffuse midline glioma and adjacent non-malignant tissue. Our findings of cancer-specific novel isoform expression further highlight the importance of long-read sequencing for characterization of complex tumor transcriptomes.

Comprehensive Caregiver Supports and Ascertainment and Treatment of Veteran Pain.

Disabled Veterans commonly experience pain. The Program of Comprehensive Assistance for Family Caregivers (PCAFC) provides training, a stipend, and services to family caregivers of eligible Veterans to support their caregiving role. We compared ascertainment of veteran pain and pain treatment through health care encounters and medications (pain indicators) of participants (treated group) and non-participants (comparison group) using inverse probability treatment weights. Modeled results show that the proportion of Veterans with a pain indicator in the first year post-application was higher than that pre-application for both groups. However, the proportion of Veterans with a pain indicator was substantially higher in the treatment group: 76.1% versus 63.9% in the comparison group (p < .001). Over time, the proportion of Veterans with any pain indicator fell and group differences lessened. However, differences persisted through 8 years post-application (p < .001). PCAFC caregivers appear to help Veterans engage in pain treatment at higher rates than caregivers not in PCAFC.

The importance of REM sleep fragmentation in the effects of stress on sleep: Perspectives from preclinical studies.

Psychological stress poses a risk for sleep disturbances. Importantly, trauma-exposed individuals who develop posttraumatic stress disorder (PTSD) frequently report insomnia and recurrent nightmares. Clinical studies have provided insight into the mechanisms of these sleep disturbances. We review polysomnographic findings in PTSD and identify analogous measures that have been made in animal models of PTSD. There is a rich empirical and theoretical literature on rapid eye movement sleep (REMS) substrates of insomnia and nightmares, with an emphasis on REMS fragmentation. For future investigations of stress-induced sleep changes, we recommend a focus on tonic, phasic and other microarchitectural REMS measures. Power spectral density analysis of the sleep EEG should also be utilized. Animal models with high construct validity can provide insight into gender and time following stressor exposure as moderating variables. Ultimately, preclinical studies with translational potential will lead to improved treatment for stress-related sleep disturbances.

Identifying predictors of the amount of veteran participation in cognitive behavioral therapy for insomnia in the Veterans Affairs health care system.

Insomnia is a prevalent and negatively impactful disorder among veterans. The Department of Veterans Affairs (VA) has committed significant resources to the development and dissemination of training related to cognitive behavioral therapy for insomnia (CBT-I), the recommended first-line intervention for chronic insomnia disorder. It has been established that VA clinicians can be effectively trained to deliver high fidelity CBT-I and that treatment results in significant improvements in insomnia. However, there is a paucity of research examining rates and predictors of veterans' participation in CBT-I in routine VA clinical care. In this study, we conducted a secondary analysis of data from VA electronic health records (EHR) to determine individual predisposing, enabling, and need factors associated with CBT-I participation. The sample included veterans who had at least one CBT-I templated note from the VA mid-Atlantic region of the United States (VISN4) between 2015 and 2019 in their chart (N = 2,801). CBT-I participation was defined by number of CBT-I templated notes occurring within a 6-month period from the initial note. Findings indicated that veterans most often completed only one session of CBT-I and, on average, completed approximately three sessions. Results from multinomial logistic regression identified significant associations of race, the presence of comorbid mental health disorders, rurality, presence of insomnia diagnosis, and insomnia medication with CBT-I participation; associations varied depending on how CBT-I participation was defined. More work is needed to better understand factors contributing to participation and reasons for completion and noncompletion of CBT-I. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Post-zygotic rescue of meiotic errors causes brain mosaicism and focal epilepsy.

Somatic mosaicism is a known cause of neurological disorders, including developmental brain malformations and epilepsy. Brain mosaicism is traditionally attributed to post-zygotic genetic alterations arising in fetal development. Here we describe post-zygotic rescue of meiotic errors as an alternate origin of brain mosaicism in patients with focal epilepsy who have mosaic chromosome 1q copy number gains. Genomic analysis showed evidence of an extra parentally derived chromosome 1q allele in the resected brain tissue from five of six patients. This copy number gain is observed only in patient brain tissue, but not in blood or buccal cells, and is strongly enriched in astrocytes. Astrocytes carrying chromosome 1q gains exhibit distinct gene expression signatures and hyaline inclusions, supporting a novel genetic association for astrocytic inclusions in epilepsy. Further, these data demonstrate an alternate mechanism of brain chromosomal mosaicism, with parentally derived copy number gain isolated to brain, reflecting rescue in other tissues during development.

Economic costs of family caregiving for persons with advanced stage cancer: a longitudinal cohort study.

PURPOSE: To form a multifaceted picture of family caregiver economic costs in advanced cancer. METHODS: A multi-site cohort study collected prospective longitudinal data from caregivers of patients with advanced solid tumor cancers. Caregiver survey and out-of-pocket (OOP) receipt data were collected biweekly in-person for up to 24 weeks. Economic cost measures attributed to caregiving were as follows: amount of OOP costs, debt accrual, perceived economic situation, and working for pay. Descriptive analysis illustrates economic outcomes over time. Generalized linear mixed effects models asses the association of objective burden and economic outcomes, controlling for subjective burden and other factors. Objective burden is number of activities and instrumental activities of daily living (ADL/IADL) tasks, all caregiving tasks, and amount of time spent caregiving over 24 h. RESULTS: One hundred ninety-eight caregivers, 41% identifying as Black, were followed for a mean period of 16 weeks. Median 2-week out-of-pocket costs were $111. One-third of caregivers incurred debt to care for the patient and 24% reported being in an adverse economic situation. Whereas 49.5% reported working at study visit 1, 28.6% of caregivers at the last study visit reported working. In adjusted analysis, a higher number of caregiving tasks overall and ADL/IADL tasks specifically were associated with lower out-of-pocket expenses, a lower likelihood of working, and a higher likelihood of incurring debt and reporting an adverse economic situation. CONCLUSIONS: Most caregivers of cancer patients with advanced stage disease experienced direct and indirect economic costs. IMPLICATIONS FOR CANCER SURVIVORS: Results support the need to find solutions to lessen economic costs for caregivers of persons with advanced cancer.

Oncolytic virus-driven immune remodeling revealed in mouse medulloblastomas at single cell resolution.

Oncolytic viruses, modified for tumor-restricted infection, are a promising cancer immunotherapeutic, yet much remains to be understood about factors driving their activity and outcome in the tumor microenvironment. Here, we report that oncolytic herpes simplex virus C134, previously found to exert T cell-dependent efficacy in mouse models of glioblastoma, exerts T cell-independent efficacy in mouse models of medulloblastoma, indicating this oncolytic virus uses different mechanisms in different tumors. We investigated C134's behavior in mouse medulloblastomas, using single cell RNA sequencing to map C134-induced gene expression changes across cell types, timepoints, and medulloblastoma subgroup models at whole-transcriptome resolution. Our work details substantial oncolytic virus-induced transcriptional remodeling of medulloblastoma-infiltrating immune cells, 10 subpopulations of monocytes and macrophages collectively demonstrating M1-like responses to C134, and suggests C134 be investigated as a potential new therapy for medulloblastoma.

Neighborhood disadvantage is associated with sleep disturbance in a sample of trauma-exposed Veterans.

OBJECTIVES: This study examined associations among neighborhood disadvantage, all-night respiratory sinus arrhythmia, fear of sleep, nightmare frequency, and sleep duration in a sample of trauma-exposed Veterans. METHODS: Participants completed baseline assessments and slept on a mattress actigraphy system for seven nights. Neighborhood disadvantage was assessed with the Area Deprivation Index, a census-based socioeconomic index. Differences between the least and most disadvantaged groups on the sleep variables were analyzed. RESULTS: Data were available from 37 Veterans. Residing in neighborhoods with greater disadvantage was associated with elevated fear of sleep and reduced sleep-period respiratory sinus arrhythmia. No significant differences were observed for nightmare frequency or sleep duration. A regression confirmed that neighborhood context had a significant effect on respiratory sinus arrhythmia, after controlling for other baseline sleep variables. CONCLUSIONS: In this sample of Veterans, sleep context may increase hypervigilance in turn serving as a mechanism by which trauma-induced sleep disruptions are maintained.

Use of high cost care among Veterans with comorbid mental illness and Alzheimer's Disease and related dementias.

INTRODUCTION/OBJECTIVE: Alzheimer's Disease and Other Related Dementias (AD/ADRD) leads to frequent emergency department (ED) and inpatient use. Mental health symptoms among persons with AD/ADRD increases cognitive and functional disabilities and could contribute to these high rates of intensive health care use. The objective of this paper is to assess the relationship of mental illness on 12-month patterns in hospitalization and ED use among Veterans aged 65 and over with a new AD/ADRD diagnosis. METHODS: We used an existing dataset of administrative electronic health record data of Veterans with AD/ADRD from the US Veterans Health Administration linked with Medicare claims data from 2011-2015. We use multivariable logistic regression to examine the association between no pre-existing mental illness, pre-existing mental illness (e.g., major depressive disorder, generalized anxiety disorder, or post-traumatic stress disorder), and pre-existing severe mental illness-or SMI-(e.g., bipolar disorder, major depressive disorder with psychosis, or schizophrenia) and 12- month ED and hospitalization use and readmissions among Veterans who had an initial hospitalization visit. We estimated predicted probabilities, differential effect, and associated 95% confidence intervals. RESULTS: In our sample, 1.4% had SMI and 11% had non-SMI mental illness. The unadjusted percentage with inpatient and ED use was higher among Veterans with SMI (34% and 26%, respectively) and Veterans with non-SMI mental illness (20%, 16%) compared with Veterans without pre-existing mental illness (12%, 9%). Compared to individuals with no pre-existing mental illness, having a pre-existing mental illness (1.27 percentage points, 95% CI: 0.76, 1.78) and a pre-existing SMI (7.17 percentage points, 95% CI: 5.66, 8.69) were both associated with an increased likelihood of ED use. The same pattern was observed for any inpatient use (mental illness 2.18, 95% CI: 1.59, 2.77; SMI 9.91, 95% CI: 8.21, 11.61). Only pre-existing SMI was associated higher hospitalization readmission. DISCUSSION: Pre-existing mental illness increases use of high cost, intensive health care and this association is higher of more severe mental health conditions. We also show that pre-existing mental illness exerts a unique influence, above and beyond other comorbidities, such as diabetes, on ED and inpatient visits. More needs to be done to increase recognition of the unique risks of this combination of health conditions and encourage strategies to address them. Developing, testing, and implementing comprehensive strategies that address the intersection of ADRD and mental illness is promising approach that requires more focused attention.

Rural disparities in use of family and formal caregiving for older adults with disabilities.

BACKGROUND: As federal and state policies rebalance long-term care from institutional settings to home- and community-based settings, reliance on formal (paid) and family (unpaid) caregivers for support at home nationally has increased in recent years. Yet, it is unknown if use of formal and family care varies by rurality. METHODS: Using the Health and Retirement Study, we describe patterns in receipt of combinations of formal and family home care and self-reported expectation of nursing home use by rurality among community-dwelling adults aged 65+ with functional limitations from 2004 to 2016. RESULTS: Older adults residing in rural areas are more likely to receive any family care than those in urban areas. From 2004 to 2016, a higher proportion of older adults in rural areas receive care from family caregivers exclusively while a lower proportion receive care from formal caregivers exclusively. When examining older adults in urban areas, we find the opposite - a higher proportion of urban adults rely exclusively on formal care and a lower proportion rely exclusively on family care in 2016 compared to 2004. CONCLUSION: We find that national estimates of sources of caregiving and their changes over time mask significant heterogeneity in uptake by rurality. Understanding how older adults in rural areas are, or are not, receiving home-based care compared to their urban peers and how these patterns are changing over time is the first step to informing supports for family and formal caregivers.

Longitudinal profiles of sleep during residential PTSD treatment.

We investigated longitudinal profiles of objectively measured sleep periods (SP) over the course of residential treatment for posttraumatic stress disorder (PTSD) in a cohort of U.S. male veterans. Participants (N = 190) slept on mattress-actigraphy systems in a Veterans Affairs (VA) residential PTSD program. The final sample included 4078 sleep periods. Latent class mixed model analyses were used to identify between-subject profiles in sleep period durations, controlling for daily medication intake, over the first fifty days of residency. Logistic regression was used to determine the association of pre-treatment characteristics with identified profiles. Three longitudinal profiles of sleep period characterized most of the sample: 'stable' (56%), 'decreasing' (35%), and 'increasing' (8%). Less severe pre-treatment PTSD avoidance symptoms predicted membership in the 'decreasing' class and increased depression symptoms were predictive of membership in the 'increasing' class. Nearly half of the sample reported a summary change of 1 h or more over the course of the initial 50-nights in the program. Future work is needed to identify how these profiles might drive inpatient treatment decisions regarding the provision of adjunctive sleep-focused treatment such as cognitive-behavioral treatment for insomnia or hypnotic medications.

A novel transcriptional signature identifies T-cell infiltration in high-risk paediatric cancer.

BACKGROUND: Molecular profiling of the tumour immune microenvironment (TIME) has enabled the rational choice of immunotherapies in some adult cancers. In contrast, the TIME of paediatric cancers is relatively unexplored. We speculated that a more refined appreciation of the TIME in childhood cancers, rather than a reliance on commonly used biomarkers such as tumour mutation burden (TMB), neoantigen load and PD-L1 expression, is an essential prerequisite for improved immunotherapies in childhood solid cancers. METHODS: We combined immunohistochemistry (IHC) with RNA sequencing and whole-genome sequencing across a diverse spectrum of high-risk paediatric cancers to develop an alternative, expression-based signature associated with CD8+ T-cell infiltration of the TIME. Furthermore, we explored transcriptional features of immune archetypes and T-cell receptor sequencing diversity, assessed the relationship between CD8+ and CD4+ abundance by IHC and deconvolution predictions and assessed the common adult biomarkers such as neoantigen load and TMB. RESULTS: A novel 15-gene immune signature, Immune Paediatric Signature Score (IPASS), was identified. Using this signature, we estimate up to 31% of high-risk cancers harbour infiltrating T-cells. In addition, we showed that PD-L1 protein expression is poorly correlated with PD-L1 RNA expression and TMB and neoantigen load are not predictive of T-cell infiltration in paediatrics. Furthermore, deconvolution algorithms are only weakly correlated with IHC measurements of T-cells. CONCLUSIONS: Our data provides new insights into the variable immune-suppressive mechanisms dampening responses in paediatric solid cancers. Effective immune-based interventions in high-risk paediatric cancer will require individualised analysis of the TIME.

Trends in Supply of Nursing Home Beds, 2011-2019.

Importance: Nursing homes play a vital role in providing postacute and long-term care for individuals whose needs cannot be met in the home or community. Whether the supply of nursing home beds and, specifically, the supply of high-quality beds has kept pace with the growth of the older adult population is unknown. Objective: To describe changes in the supply of population-adjusted nursing home beds from 2011 to 2019. Design, Setting, and Participants: This cross-sectional study examines changes in the population-adjusted supply of nursing home beds across all US counties from 2011 to 2019 and describes county and nursing home characteristics where the supply of nursing home beds has increased vs decreased. Main Outcomes and Measures: Number of nursing home beds adjusted per 10 000 adults aged 65 years and older. Results: The population-adjusted supply of nursing home beds declined from 2011 to 2019 for 86.4% of US counties, by a mean (SD) of 129.9 (123.8) beds per 10 000 adults aged 65 years or older per county from a baseline mean (SD) of 552.5 (274.4) beds per 10 000 adults aged 65 years or older per county in 2011. The share of beds that were high quality (4- or 5-star ratings) also declined, which was driven by a small number of counties where nursing home bed supply increased due to a proliferation of lower-quality beds. Simultaneously, metropolitan counties with declining numbers of nursing home beds also experienced declining number of senior housing residential beds (-11.3 [54.6] beds per 10 000 adults aged 65 years or older per county from a baseline mean [SD] of 354.8 [222.3]). Conclusions and Relevance: The findings of this cross-sectional study suggest that the supply of nursing home beds, specifically high-quality nursing home beds, and senior residential housing beds have not kept pace with the demographics of an aging population. Understanding the supply of high-quality nursing home beds and associated geographic variation can inform targeted policies to best support older adults requiring nursing home care.

Single-cell RNA sequencing reveals immunosuppressive myeloid cell diversity during malignant progression in a murine model of glioma.

Recent studies have shown the importance of the dynamic tumor microenvironment (TME) in high-grade gliomas (HGGs). In particular, myeloid cells are known to mediate immunosuppression in glioma; however, it is still unclear if myeloid cells play a role in low-grade glioma (LGG) malignant progression. Here, we investigate the cellular heterogeneity of the TME using single-cell RNA sequencing in a murine glioma model that recapitulates the malignant progression of LGG to HGG. LGGs show increased infiltrating CD4+ and CD8+ T cells and natural killer (NK) cells in the TME, whereas HGGs abrogate this infiltration. Our study identifies distinct macrophage clusters in the TME that show an immune-activated phenotype in LGG but then evolve to an immunosuppressive state in HGG. We identify CD74 and macrophage migration inhibition factor (MIF) as potential targets for these distinct macrophage populations. Targeting these intra-tumoral macrophages in the LGG stage may attenuate their immunosuppressive properties and impair malignant progression.