Monocyte-Mediated Thrombosis Linked to Circulating Tissue Factor and Immune Paralysis in COVID-19.

BACKGROUND: SARS-CoV-2 infections cause COVID-19 and are associated with inflammation, coagulopathy, and high incidence of thrombosis. Myeloid cells help coordinate the initial immune response in COVID-19. Although we appreciate that myeloid cells lie at the nexus of inflammation and thrombosis, the mechanisms that unite the two in COVID-19 remain largely unknown. METHODS: In this study, we used systems biology approaches including proteomics, transcriptomics, and mass cytometry to define the circulating proteome and circulating immune cell phenotypes in subjects with COVID-19. RESULTS: In a cohort of subjects with COVID-19 (n=35), circulating markers of inflammation (CCL23 [C-C motif chemokine ligand 23] and IL [interleukin]-6) and vascular dysfunction (ACE2 [angiotensin-converting enzyme 2] and TF [tissue factor]) were elevated in subjects with severe compared with mild COVID-19. Additionally, although the total white blood cell counts were similar between COVID-19 groups, CD14+ (cluster of differentiation) monocytes from subjects with severe COVID-19 expressed more TF. At baseline, transcriptomics demonstrated increased IL-6, CCL3, ACOD1 (aconitate decarboxylase 1), C5AR1 (complement component 5a receptor), C5AR2, and TF in subjects with severe COVID-19 compared with controls. Using stress transcriptomics, we found that circulating immune cells from subjects with severe COVID-19 had evidence of profound immune paralysis with greatly reduced transcriptional activation and release of inflammatory markers in response to TLR (Toll-like receptor) activation. Finally, sera from subjects with severe (but not mild) COVID-19 activated human monocytes and induced TF expression. CONCLUSIONS: Taken together, these observations further elucidate the pathological mechanisms that underlie immune dysfunction and coagulation abnormalities in COVID-19, contributing to our growing understanding of SARS-CoV-2 infections that could also be leveraged to develop novel diagnostic and therapeutic strategies.

The Social Cost of Providing Care to Older Adults With and Without Dementia.

OBJECTIVES: Social participation is known to enhance well-being. Caregiving responsibilities are more intense when caring for an older adult with than without dementia and may affect caregivers' ability for social participation. We estimate social participation restrictions among caregivers for older persons with versus without dementia, variation within racial/ethnic group, and the mediating effect of care hours. METHODS: We use the 2017 National Health and Aging Trends Study (NHATS) and National Study of Caregiving (NSOC) to study family caregivers for older adults. We estimate the prevalence of social participation (e.g., visiting family/friends, religious activities, group/club activities, going out) that were important to the caregiver but missed due to caregiving. We use logistic models to test for differences in restrictions by the older adult's dementia status overall and within race/ethnic group, adjusting for caregiver and care receiver characteristics. RESULTS: One-third of family caregivers for older adults with dementia reported restrictions due to caregiving, double the prevalence among caregivers of an older adult without dementia (33.3% vs 16.0%; p < .001). This doubling gap persisted in adjusted models (odds ratio [OR] = 2.4; p < .01) but mainly for White, non-Hispanic caregivers (OR = 3.2; p < .001). Substantially greater caregiving hours for people with versus without dementia was found (104 vs 60 hr per month), which is responsible for about 21% of the total difference in restrictions (p < .05). DISCUSSION: More time spent among caregivers of persons with versus without dementia may be an important factor undermining social participation, but hours only partially explain the gap. Future interventions should consider how to facilitate social participation among caregivers.

Glycocalyx Disruption Triggers Human Monocyte Activation in Acute Heart Failure Syndromes.

PURPOSE: Acute heart failure (AHF) syndromes manifest increased inflammation and vascular dysfunction; however, mechanisms that integrate the two in AHF remain largely unknown. The glycocalyx (GAC) is a sugar-based shell that envelops all mammalian cells. Much GAC research has focused on its role in vascular responses, with comparatively little known about how the GAC regulates immune cell function. METHODS: In this study, we sought to determine if GAC degradation products are elevated in AHF patients, how these degradation products relate to circulating inflammatory mediators, and whether the monocyte GAC (mGAC) itself modulates monocyte activation. Inflammatory markers and GAC degradation products were profiled using ELISAs. Flow cytometry was used to assess the mGAC and RNA-seq was employed to understand the role of the mGAC in regulating inflammatory activation programs. RESULTS: In a cohort of hospitalized AHF patients (n = 17), we found that (1) the GAC degradation product heparan sulfate (HS) was elevated compared with age-matched controls (4396 and 2903 ng/mL; p = 0.01) and that (2) HS and soluble CD14 (a marker of monocyte activation) levels were closely related (Pearson's r = 0.65; p = 0.002). Mechanistically, Toll-like receptor (TLR) activation of human monocytes results in GAC remodeling and a decrease in the mGAC (71% compared with no treatment; p = 0.0007). Additionally, we found that ex vivo enzymatic removal of HS and disruption of the mGAC triggers human monocyte activation and amplifies monocyte inflammatory responses. Specifically, using RNA-seq, we found that enzymatic degradation of the mGAC increases transcription of inflammatory (IL6, CCL3) and vascular (tissue factor/F3) mediators. CONCLUSION: These studies indicate that the mGAC is dynamically remodeled during monocyte activation and that mGAC remodeling itself may contribute to the heightened inflammation associated with AHF.

Repurposing low-dose naltrexone for the prevention and treatment of immunothrombosis in COVID-19.

Coronavirus disease 2019 (COVID-19) is characterized by striking dysregulation of the immune system, with evidence of hyperinflammation, an impaired induction of interferons, and delayed adaptive immune responses. In addition to dysfunctional immune responses, thrombosis is a hallmark of severe COVID-19. Because traditional anticoagulation strategies are associated with increased bleeding, novel strategies that address both the immune and thrombotic dysfunction associated with COVID-19 would be of tremendous benefit. In this commentary, we discuss the unique properties of low dose naltrexone (LDN) which could be leveraged to reduce the immune-mediated thrombotic complications in COVID-19. Mechanistically, LDN can blunt innate immune responses and Toll-like receptor (TLR) signaling, reducing interleukin1 (IL-1), tumor necrosis factor-alpha (TNF-α), and interferon (IFN) levels. Because of the immune-mediated thrombotic mechanisms that underlie COVID-19, we hypothesize that the immune-modulating and known pharmacologic properties of LDN could be leveraged as a novel therapeutic strategy in COVID-19.

Short- and Long-term Effects of Support Visibility on Support Providers' Negative Affect.

OBJECTIVES: Seminal research with spouses of chronic pain patients indicates that providing patients with instrumental support can be either costly or beneficial for spouses' well-being. Drawing from the invisible support literature, this study evaluated the extent to which patients' recognition of spouses' support moderated daily and long-term associations between spouses' support provision and negative affect. METHOD: Data came from a sample of spouses (N = 145) of knee osteoarthritis (OA) patients, and the patients themselves. Participants completed a baseline interview, 22 days of daily diaries, and two follow-up interviews 6 and 18 months after baseline. Multilevel models were estimated to test study hypotheses. RESULTS: As expected, support visibility moderated daily and long-term associations between spouses' instrumental support provision and negative affect. Spouses reported elevated levels of negative affect in response to providing patients with extra care and attention, but only when their support was not recognized (i.e., reported) by patients. DISCUSSION: Findings from the current study pinpoint support visibility as a protective factor that may mitigate negative short- and long-term effects of spousal instrumental support provision on spouses' negative affect. Promoting patients' awareness of their spouses' support may offset negative emotional consequences of caregiving in the context of chronic health stressors.

Different Types of Childhood Experience with Mothers and Caregiving Outcomes in Adulthood.

OBJECTIVE AND BACKGROUND: The current study examines the types of childhood experiences with mothers (i.e., maternal abuse, affection, discipline) among caregivers of aging mothers, and investigates whether membership in specific latent classes, particularly maternal maltreatment, is associated with psychological functioning among caregivers. METHOD: Using data from the Midlife in the United States (MIDUS), we used the Bolck, Croon, and Hagenaars (BCH) approach of latent class analysis (LCA) to predict distal outcomes. RESULTS: We identified four latent classes (prevalence rate noted): "Affectionate and authoritative" (65%), "affectionate and permissive" (11%), "emotionally abusive and neglectful" (8%), and "emotionally/physically abusive and authoritative" (16%). Caregivers in the "emotionally/physically abusive and authoritative" class endorsed high probabilities of both maternal affection and abuse and were most negatively affected across the three psychological functioning outcomes (i.e., self-rated mental health, psychological distress, and psychological well-being). CONCLUSION AND IMPLICATIONS: In support of the life course perspective, our findings emphasized the importance of examining adult children caregivers' early life experiences with aging mothers and how those experiences can impact the psychological effects of caregiving. This study suggests specific practice implications; for example, assessment tools for evaluating caregiver burden should consider life course factors such as caregivers' childhood experiences with aging parents.

Spousal understanding and marital satisfaction in pain patients and their spouses.

The current study tested the hypotheses that knee osteoarthritis (OA) patients and spouses who report more spousal understanding of patient's pain would report greater marital satisfaction. A total of 124 couples completed interviews at three time points across 18 months. Results from dyadic analyses showed that patients who felt more understood by their spouse report, and have spouses who report, higher marital satisfaction concurrently. In addition, patients who felt more understood by their spouse reported higher marital satisfaction over time. Spouses' reports of understanding also had a significant influence on the patients' and their own marital satisfaction concurrently. Results highlight the importance of spouses understanding knee OA patients' pain for both dyad members' marital satisfaction.