Association of COVID-19 Visitor Limitations and Goals of Care Discussions in the Intensive Care Unit.

INTRODUCTION: The COVID-19 pandemic led to visitor restrictions in many hospitals. Since care in the surgical intensive care unit (SICU) often engages visitors as surrogate decision-makers, we investigated whether there was an association between COVID-19-related visitor restrictions, goals of care discussions (GOCD), and patient outcomes in SICU patients. METHODS: We conducted a retrospective review of trauma and emergency general surgery (EGS) patients admitted to a rural tertiary SICU between July 2019 and April 2021, dividing patients into those admitted during COVID-19 visitor restrictions and those admitted at other times. Using univariate and multivariate logistic regression analyses, we compared the primary outcome, incidence of GOCD, and incidence of prolonged hospital (> 14 d) and intensive care unit length of stay (LOS, > 7 d) between the two groups. RESULTS: One hundred seventy nine of 368 study patients (48.6%) presented during restricted visitation. The proportion of GOCD was 38.0% and 36.5% in the restricted and nonrestricted visitation cohorts, respectively (P = 0.769). GOCD timing and outcomes were similar in both groups. The use of telecommunication increased during restricted visitation, as did the proportion of trauma patients admitted to the SICU. On multivariable logistic regression, age and patient category were independent predictors of GOCD. On outcomes analysis, visitor restriction was associated with prolonged hospital LOS for EGS patients (odds ratio 2.44, 95% confidence interval 1.01-5.91, P value 0.048). CONCLUSIONS: Restricted visitation was not associated with changes in frequency or outcome of GOCD, but was associated with prolonged hospital LOS among EGS patients who had SICU admissions. Further investigation of patient/surrogate satisfaction with virtual GOCD in the SICU setting is needed.

Cannabinoid Receptor-2 Regulates Embryonic Hematopoietic Stem Cell Development via Prostaglandin E2 and P-Selectin Activity.

Cannabinoids (CB) modulate adult hematopoietic stem and progenitor cell (HSPCs) function, however, impact on the production, expansion, or migration of embryonic HSCs is currently uncharacterized. Here, using chemical and genetic approaches targeting CB-signaling in zebrafish, we show that CB receptor (CNR) 2, but not CNR1, regulates embryonic HSC development. During HSC specification in the aorta-gonad-mesonephros (AGM) region, CNR2 stimulation by AM1241 increased runx1;cmyb(+) HSPCs, through heightened proliferation, whereas CNR2 antagonism decreased HSPC number; FACS analysis and absolute HSC counts confirmed and quantified these effects. Epistatic investigations showed AM1241 significantly upregulated PGE2 synthesis in a Ptgs2-dependent manner to increase AGM HSCs. During the phases of HSC production and colonization of secondary niches, AM1241 accelerated migration to the caudal hematopoietic tissue (CHT), the site of embryonic HSC expansion, and the thymus; however these effects occurred independently of PGE2. Using a candidate approach for HSC migration and retention factors, P-selectin was identified as the functional target of CNR2 regulation. Epistatic analyses confirmed migration of HSCs into the CHT and thymus was dependent on CNR2-regulated P-selectin activity. Together, these data suggest CNR2-signaling optimizes the production, expansion, and migration of embryonic HSCs by modulating multiple downstream signaling pathways.

Changes in self-esteem and chronic disease across adulthood: A 16-year longitudinal analysis.

RATIONALE: Self-esteem is an adaptive personality factor that has been associated with good physical health. While research has observed that self-esteem and physical health typically decline in older adulthood, there is a paucity of research investigating the associations between changes in self-esteem and physical health across the adult lifespan. OBJECTIVE: The present study examined whether changes in selfesteem and chronic disease exert reciprocal effects on subsequent changes in self-esteem and disease. In addition, it investigated whether individuals' age would moderate these associations. METHODS: The study analyzed data from 14,117 adult (18+) Canadians who completed surveys over 16 years, from cycles 1 to 9 of the National Population Health Survey (NPHS). Self-esteem, chronic diseases, and demographic information were collected. RESULTS: Cross-lagged panel analyses indicated reciprocal age-related associations between changes in self-esteem and chronic disease. Initial decline in self-esteem predicted subsequent increases in chronic disease, and initial increases in chronic disease predicted subsequent declines in self-esteem, only among young adults, and not middle-aged or older adults. CONCLUSION: These results suggest that age may qualify the associations between declines in self-esteem and physical health and that adverse changes in both factors may be particularly problematic for young adults' prospective personality functioning and physical health.

HIF1α-induced PDGFRß signaling promotes developmental HSC production via IL-6 activation.

Hematopoietic stem cells (HSCs) have the ability to both self-renew and differentiate each of the mature blood cell lineages and thereby reconstitute the entire blood system. Therefore, HSCs are therapeutically valuable for treatment of hematological malignances and bone marrow failure. We showed recently that transient glucose elevation elicited dose-dependent effects on HSCs through elevated metabolic activity and subsequent reactive oxygen species-mediated induction of Hypoxia-Inducible Factor 1α (Hif1α). Platelet-Derived Growth Factor B (pdgfb), a Hif1α-target, and its receptor, pdgfrb, were significantly upregulated in response to metabolic stimulation. Although the function of PDGF signaling is well established in vascular development, its role in hematopoiesis is less understood. Exposure to either a pan-PDGF inhibitor or a PDGFRß-selective antagonist in the context of Hif1α stimulation blocked elevations in hematopoietic stem and progenitor cell (HSPC) formation as determined by runx1;cmyb whole-mount in situ hybridization (WISH) and HSPC-reporter flow cytometry analysis. Similar results were observed for morpholino (MO) knockdown of pdgfrb or dominant-negative pdgfrb expression, indicating that PDGFRß signaling is a key downstream mediator of Hif1α-mediated induction of HSPCs. Notably, overexpression of Pdgfb ligand enhanced HSPC numbers in the aorta-gonado-mesonephros (AGM) at 36 hours postfertilization (hpf) and in the caudal hematopoietic tissue at 48 hpf. A survey of known PDGF-B/PDGFRß regulatory targets by expression analysis revealed a significant increase in inflammatory intermediates, including Interleukin 6 (IL-6) and its receptor (IL-6R). MO-mediated knockdown of il6 or chemical inhibition of IL-6R antagonized the effect of Pdgfb overexpression. Furthermore, epistatic analysis of IL-6/IL-6R function confirmed activity downstream of Hif1α. Together, these findings define a Hif1α-regulated signaling axis mediated through PBFGB/PDGFRß and IL-6/IL-6R that acts to control embryonic HSPC production.

Distinct Roles for Matrix Metalloproteinases 2 and 9 in Embryonic Hematopoietic Stem Cell Emergence, Migration, and Niche Colonization.

Hematopoietic stem/progenitor cells (HSPCs) are formed during ontogeny from hemogenic endothelium in the ventral wall of the dorsal aorta (VDA). Critically, the cellular mechanism(s) allowing HSPC egress and migration to secondary niches are incompletely understood. Matrix metalloproteinases (MMPs) are inflammation-responsive proteins that regulate extracellular matrix (ECM) remodeling, cellular interactions, and signaling. Here, inhibition of vascular-associated Mmp2 function caused accumulation of fibronectin-rich ECM, retention of runx1/cmyb+ HSPCs in the VDA, and delayed caudal hematopoietic tissue (CHT) colonization; these defects were absent in fibronectin mutants, indicating that Mmp2 facilitates endothelial-to-hematopoietic transition via ECM remodeling. In contrast, Mmp9 was dispensable for HSPC budding, being instead required for proper colonization of secondary niches. Significantly, these migration defects were mimicked by overexpression and blocked by knockdown of C-X-C motif chemokine-12 (cxcl12), suggesting that Mmp9 controls CHT homeostasis through chemokine regulation. Our findings indicate Mmp2 and Mmp9 play distinct but complementary roles in developmental HSPC production and migration.

The Central Nervous System Regulates Embryonic HSPC Production via Stress-Responsive Glucocorticoid Receptor Signaling.

Hematopoietic stem and progenitor cell (HSPC) specification is regulated by numerous defined factors acting locally within the hemogenic niche; however, it is unclear whether production can adapt to fluctuating systemic needs. Here we show that the CNS controls embryonic HSPC numbers via the hypothalamic-pituitary-adrenal/interrenal (HPA/I) stress response axis. Exposure to serotonin or the reuptake inhibitor fluoxetine increased runx1 expression and Flk1(+)/cMyb(+) HSPCs independent of peripheral innervation. Inhibition of neuronal, but not peripheral, tryptophan hydroxlyase (Tph) persistently reduced HSPC number. Consistent with central HPA/I axis induction and glucocorticoid receptor (GR) activation, GR agonists enhanced, whereas GR loss diminished, HSPC formation. Significantly, developmental hypoxia, as indicated by Hif1α function, induced the HPA/I axis and cortisol production. Furthermore, Hif1α-stimulated HSPC enhancement was attenuated by neuronal tph or GR loss. Our data establish that embryonic HSC production responds to physiologic stress via CNS-derived serotonin synthesis and central feedback regulation to control HSC numbers.

Developmental Vitamin D Availability Impacts Hematopoietic Stem Cell Production.

Vitamin D insufficiency is a worldwide epidemic affecting billions of individuals, including pregnant women and children. Despite its high incidence, the impact of active vitamin D3 (1,25(OH)D3) on embryonic development beyond osteo-regulation remains largely undefined. Here, we demonstrate that 1,25(OH)D3 availability modulates zebrafish hematopoietic stem and progenitor cell (HSPC) production. Loss of Cyp27b1-mediated biosynthesis or vitamin D receptor (VDR) function by gene knockdown resulted in significantly reduced runx1 expression and Flk1+cMyb+ HSPC numbers. Selective modulation in vivo and in vitro in zebrafish indicated that vitamin D3 acts directly on HSPCs, independent of calcium regulation, to increase proliferation. Notably, ex vivo treatment of human HSPCs with 1,25(OH)D3 also enhanced hematopoietic colony numbers, illustrating conservation across species. Finally, gene expression and epistasis analysis indicated that CXCL8(IL-8) was a functional target of vitamin D3-mediated HSPC regulation. Together, these findings highlight the relevance of developmental 1,25(OH)D3 availability for definitive hematopoiesis and suggest potential therapeutic utility in HSPC expansion.

Chronic illness and loneliness in older adulthood: The role of self-protective control strategies.

OBJECTIVES: This study examined whether levels of chronic illness predict enhanced feelings of loneliness in older adulthood. In addition, it investigated whether engagement in health-related self-protection (e.g., positive reappraisals), but not in health engagement control strategies (e.g., investment of time and effort), would buffer the adverse effect of chronic illness on older adults' feelings of loneliness. METHOD: Loneliness was examined repeatedly in 2-year intervals over 8 years in a longitudinal study of 121 community-dwelling older adults (Time 1 age = 64 to 83 years). In addition, levels of chronic illness, health-related control strategies, and sociodemographic variables were assessed at baseline. RESULTS: Growth-curve models showed that loneliness linearly increased over time and that this effect was observed only among participants who reported high, but not low, baseline levels of chronic illness. In addition, health-related self-protection, but not health engagement control strategies, buffered the adverse effect of chronic illness on increases in loneliness. CONCLUSIONS: Loneliness increases in older adulthood as a function of chronic illness. Older adults who engage in self-protective strategies to cope with their health threats might be protected from experiencing this adverse effect.

Accumulation of the Vitamin D Precursor Cholecalciferol Antagonizes Hedgehog Signaling to Impair Hemogenic Endothelium Formation.

Hematopoietic stem and progenitor cells (HSPCs) are born from hemogenic endothelium in the dorsal aorta. Specification of this hematopoietic niche is regulated by a signaling axis using Hedgehog (Hh) and Notch, which culminates in expression of Runx1 in the ventral wall of the artery. Here, we demonstrate that the vitamin D precursor cholecalciferol (D3) modulates HSPC production by impairing hemogenic vascular niche formation. Accumulation of D3 through exogenous treatment or inhibition of Cyp2r1, the enzyme required for D3 25-hydroxylation, results in Hh pathway antagonism marked by loss of Gli-reporter activation, defects in vascular niche identity, and reduced HSPCs. Mechanistic studies indicated the effect was specific to D3, and not active 1,25-dihydroxy vitamin D3, acting on the extracellular sterol-binding domain of Smoothened. These findings highlight a direct impact of inefficient vitamin D synthesis on cell fate commitment and maturation in Hh-regulated tissues, which may have implications beyond hemogenic endothelium specification.

Self-esteem change and diurnal cortisol secretion in older adulthood.

OBJECTIVE: Research suggests that self-esteem can decline in older adulthood. This process could remove a buffer that normally protects individuals against distress-related changes in cortisol secretion. We examined this possibility by testing whether change in self-esteem would predict alterations in cortisol secretion, particularly among older adults who reported high levels of depressive symptoms or perceived stress. METHODS: 147 older adults (aged 60+) completed three days of diurnal cortisol measurements at three different time points, namely every two years over a total period of four years. Measures of self-esteem, depressive symptoms, and perceived stress were assessed at T1 and T2. Potential demographic and health-related confounds were measured at baseline (partnership status, SES, mortality risk index, and medication). RESULTS: Linear regression models indicated that a decline in self-esteem from T1 to T2 predicted elevated cortisol output (AUCG) from T2 to T3, F (1, 137)=8.09, ß=-.25, R(2)=.05, p=.005. Interaction analyses revealed that this association was particularly strong among participants who experienced higher T1 or T2 levels of depressive symptoms or perceived stress, +1SD: ßs=-.34 to -.51, ps<.001, but not significant among their counterparts who reported relatively lower levels of depressive symptoms or perceived stress, -1SD: ßs=.03 to 11, ps>.43. CONCLUSIONS: Declines in self-esteem represent a mechanism that contributes to higher levels of diurnal cortisol secretion if older adults experience psychological distress. Increases in self-esteem, by contrast, can ameliorate older adults' cortisol regulation in stressful circumstances.

Estrogen defines the dorsal-ventral limit of VEGF regulation to specify the location of the hemogenic endothelial niche.

Genetic control of hematopoietic stem and progenitor cell (HSPC) function is increasingly understood; however, less is known about the interactions specifying the embryonic hematopoietic niche. Here, we report that 17ß-estradiol (E2) influences production of runx1+ HSPCs in the AGM region by antagonizing VEGF signaling and subsequent assignment of hemogenic endothelial (HE) identity. Exposure to exogenous E2 during vascular niche development significantly disrupted flk1+ vessel maturation, ephrinB2+ arterial identity, and specification of scl+ HE by decreasing expression of VEGFAa and downstream arterial Notch-pathway components; heat shock induction of VEGFAa/Notch rescued E2-mediated hematovascular defects. Conversely, repression of endogenous E2 activity increased somitic VEGF expression and vascular target regulation, shifting assignment of arterial/venous fate and HE localization; blocking E2 signaling allowed venous production of scl+/runx1+ cells, independent of arterial identity acquisition. Together, these data suggest that yolk-derived E2 sets the ventral boundary of hemogenic vascular niche specification by antagonizing the dorsal-ventral regulatory limits of VEGF.