Longitudinal Care Network Changes and Associated Healthcare Utilization Among Care Recipients.

This study examines caregiver networks, including size, composition, and stability, and their associations with the likelihood of hospitalization and skilled-nursing facility (SNF) admissions. Data from the National Health and Aging Trends Study linked to Center for Medicare and Medicaid Services data were analyzed for 3855 older adults across five survey waves. Generalized estimating equation models assessed the associations. The findings indicate each additional paid caregiver was associated with higher adjusted risk ratios (aRR) for hospitalization (aRR = 1.24, 95% CI 1.10-1.41) and SNF admission (aRR = 1.28, 95% CI 1.06-1.54) among care recipients, a pattern that is also observed with the addition of unpaid caregivers (hospitalization: aRR = 1.13, 95% CI 1.06-1.20; SNF: aRR = 1.12, 95% CI 1.02-1.23). These results suggest that policies and approaches to enhance the quality and coordination of caregivers may be warranted to support improved outcomes for care recipients.

Early cellular and molecular signatures correlate with severity of West Nile virus infection.

Infection with West Nile virus (WNV) drives a wide range of responses, from asymptomatic to flu-like symptoms/fever or severe cases of encephalitis and death. To identify cellular and molecular signatures distinguishing WNV severity, we employed systems profiling of peripheral blood from asymptomatic and severely ill individuals infected with WNV. We interrogated immune responses longitudinally from acute infection through convalescence employing single-cell protein and transcriptional profiling complemented with matched serum proteomics and metabolomics as well as multi-omics analysis. At the acute time point, we detected both elevation of pro-inflammatory markers in innate immune cell types and reduction of regulatory T cell activity in participants with severe infection, whereas asymptomatic donors had higher expression of genes associated with anti-inflammatory CD16+ monocytes. Therefore, we demonstrated the potential of systems immunology using multiple cell-type and cell-state-specific analyses to identify correlates of infection severity and host cellular activity contributing to an effective anti-viral response.

Dectin-1 stimulation promotes a distinct inflammatory signature in the setting of HIV-infection and aging.

Dectin-1 is an innate immune receptor that recognizes and binds ß-1, 3/1, 6 glucans on fungi. We evaluated Dectin-1 function in myeloid cells in a cohort of HIV-positive and HIV-negative young and older adults. Stimulation of monocytes with ß-D-glucans induced a pro-inflammatory phenotype in monocytes of HIV-infected individuals that was characterized by increased levels of IL-12, TNF-α, and IL-6, with some age-associated cytokine increases also noted. Dendritic cells showed a striking HIV-associated increase in IFN-α production. These increases in cytokine production paralleled increases in Dectin-1 surface expression in both monocytes and dendritic cells that were noted with both HIV and aging. Differential gene expression analysis showed that HIV-positive older adults had a distinct gene signature compared to other cohorts characterized by a robust TNF-α and coagulation response (increased at baseline), a persistent IFN-α and IFN-γ response, and an activated dendritic cell signature/M1 macrophage signature upon Dectin-1 stimulation. Dectin-1 stimulation induced a strong upregulation of MTORC1 signaling in all cohorts, although increased in the HIV-Older cohort (stimulation and baseline). Overall, our study demonstrates that the HIV Aging population has a distinct immune signature in response to Dectin-1 stimulation. This signature may contribute to the pro-inflammatory environment that is associated with HIV and aging.

Modeling pandemic to endemic patterns of SARS-CoV-2 transmission using parameters estimated from animal model data.

The contours of endemic coronaviral disease in humans and other animals are shaped by the tendency of coronaviruses to generate new variants superimposed upon nonsterilizing immunity. Consequently, patterns of coronaviral reinfection in animals can inform the emerging endemic state of the SARS-CoV-2 pandemic. We generated controlled reinfection data after high and low risk natural exposure or heterologous vaccination to sialodacryoadenitis virus (SDAV) in rats. Using deterministic compartmental models, we utilized in vivo estimates from these experiments to model the combined effects of variable transmission rates, variable duration of immunity, successive waves of variants, and vaccination on patterns of viral transmission. Using rat experiment-derived estimates, an endemic state achieved by natural infection alone occurred after a median of 724 days with approximately 41.3% of the population susceptible to reinfection. After accounting for translationally altered parameters between rat-derived data and human SARS-CoV-2 transmission, and after introducing vaccination, we arrived at a median time to endemic stability of 1437 (IQR = 749.25) days with a median 15.4% of the population remaining susceptible. We extended the models to introduce successive variants with increasing transmissibility and included the effect of varying duration of immunity. As seen with endemic coronaviral infections in other animals, transmission states are altered by introduction of new variants, even with vaccination. However, vaccination combined with natural immunity maintains a lower prevalence of infection than natural infection alone and provides greater resilience against the effects of transmissible variants.

Design and implementation of a prospective cohort study of persons living with and without HIV infection who are initiating medication treatment for opioid use disorder.

BACKGROUND: Opioid use disorder (OUD) negatively impacts the HIV continuum of care for persons living with HIV. Medication treatment for OUD (MOUD) may have differential biological effects in individuals with HIV and OUD. To address the question of modulation of immune responses by MOUDs, we describe state of the art systems biology approaches to carry out the first prospective, longitudinal study of persons with and without HIV infection with OUD initiating MOUD. METHODS: A prospective cohort study of persons with DSM-5 diagnosed OUD who are living with and without HIV infection and initiating treatment with methadone or buprenorphine is underway to assess biological effects of these medications on immunobiological outcomes. RESULTS: We describe the recruitment, laboratory, and statistical methods of this study as well as the protocol details. Of those screened for enrollment into the study, 468 (36%) were eligible and 135 were enrolled thus far. Retention through month 6 has been high at 80%. CONCLUSIONS: This study will use state of the art systems biology approaches to carry out the first prospective, longitudinal studies of persons living with and without HIV with DSM-5 OUD initiating treatment with MOUD.

Sociodemographic Factors and Characteristics of Caregivers as Determinants of Skilled Nursing Facility Admissions When Modeled Jointly With Functional Limitations.

OBJECTIVES: We examined whether previously identified relationships between sociodemographic factors and caregivers for skilled nursing facility (SNF) admissions are replicated when jointly accounting for longitudinal change in functional limitations. We further explored the impact of caregivers by investigating the relationship between caregiver's characteristics and SNF admissions. DESIGN: Longitudinal follow-up study. SETTING: The United States of America. PARTICIPANTS: In total, 3875 older Americans from the 2011-2015 rounds of the National Health and Aging Trends Study linked with Centers for Medicare and Medicaid Services. MEASURES: Sociodemographic factors and caregiver's characteristics were used to predict change in functional limitations from baseline and time to first SNF admission using a joint modeling approach. RESULTS: In total, 11.3% of the study population had a SNF admission during follow-up. For sociodemographic factors, non-Hispanic white, <9th grade education, and having at least 1 caregiver were associated with higher hazards of SNF admission than other race/ethnicity, college or higher education, and no caregiver, respectively. In contrast, living with a partner or living with others was associated with lower hazard of SNF admissions. For characteristics of caregivers, medical-supportive caregiver was associated with increased hazard of SNF admissions, whereas partner caregiver was protective of SNF admissions. Jointly modeling SNF admissions and change in functional limitations resulted in greater precision of effect estimates than modeling these outcomes separately. CONCLUSIONS AND IMPLICATIONS: The study provides insight that can help identify high-risk populations for future interventions to prevent or delay SNF admissions. The relation between caregivers and SNF admissions depended on caregiver's characteristics. Future work should focus on providing help to those without a partner caregiver or needing help managing their health to ensure independent living and improve the well-being of older adults. Precision increased when jointly modeling the SNF admission with change in functional limitations.

Normalization of brain morphology after surgery in sagittal craniosynostosis.

OBJECT Nonsyndromic craniosynostosis (NSC) is associated with significant learning disability later in life. Surgical reconstruction is typically performed before 1 year of age to correct the cranial vault morphology and to allow for normalized brain growth with the goal of improving cognitive function. Yet, no studies have assessed to what extent normalized brain growth is actually achieved. Recent advances in MRI have allowed for automated methods of objectively assessing subtle and pronounced brain morphological differences. The authors used one such technique, deformation-based morphometry (DBM) Jacobian mapping, to determine how previously treated adolescents with sagittal NSC (sNSC) significantly differ in brain anatomy compared with healthy matched controls up to 11.5 years after surgery. METHODS Eight adolescent patients with sNSC, previously treated via whole-vault cranioplasty at a mean age of 7 months, and 8 age- and IQ-matched control subjects without craniosynostosis (mean age for both groups = 12.3 years), underwent functional 3-T MRI. Statistically significant group tissue-volume differences were assessed using DBM, a whole-brain technique that estimates morphological differences between 2 groups at each voxel (p < 0.01). Group-wise Jacobian volume maps were generated using a spacing of 1.5 mm and a resolution of 1.05 × 1.05 × 1.05 mm(3). RESULTS There were no significant areas of volume reduction or expansion in any brain areas in adolescents with sNSC compared with controls at a significance level of p < 0.01. At the more liberal threshold of p < 0.05, two areas of brain expansion extending anteroposteriorly in the right temporooccipital and left frontoparietal regions appeared in patients with sNSC compared with controls. CONCLUSIONS Compared with previous reports on untreated infants with sNSC, adolescents with sNSC in this cohort had few areas of brain dysmorphology many years after surgery. This result suggests that comprehensive cranioplasty performed at an early age offers substantial brain normalization by adolescence, but also that some effects of vault constriction may still persist after treatment. Specifically, few areas of expansion in frontoparietal and temporooccipital regions may persist. Overall, data from this small cohort support the primary goal of surgery in allowing for more normalized brain growth. Larger samples, and correlating degree of normalization with cognitive performance in NSC, are warranted.

Brain mechanisms for prepulse inhibition in adults with Tourette syndrome: initial findings.

Prepulse inhibition (PPI) of the startle reflex is disrupted in a number of developmental neuropsychiatric disorders, including Tourette syndrome (TS). This disruption is hypothesized to reflect abnormalities in sensorimotor gating. We applied whole-brain functional magnetic resonance imaging (fMRI) to elucidate the neural correlates of PPI in adult TS subjects using airpuff stimuli to the throat to elicit a tactile startle response. We used a cross-sectional, case-control study design and a blocked-design fMRI paradigm. There were 33 participants: 17 with TS and 16 healthy individuals. As a measure of PPI-related brain activity, we looked for differential cerebral activation to prepulse-plus-pulse stimuli versus activation to pulse-alone stimuli. In healthy subjects, PPI was associated with increased activity in multiple brain regions, of which activation in the left middle frontal gyrus in the healthy controls showed a significant linear correlation with the degree of PPI measured outside of the magnet. Group comparisons identified nine regions where brain activity during PPI differed significantly between TS and healthy subjects. Among the TS subjects, activation in the left caudate was significantly correlated with current tic severity as measured by the total score on the Yale Global Tic Severity Scale. Differential activation of the caudate nucleus associated with current tic severity is consistent with neuropathological data and suggests that portions of cortical-striatal circuits may modulate the severity of tic symptoms in adulthood.