Stressors and Silver Linings during COVID-19: Implications for Supporting Families with Young Children in a Post-Pandemic World.

OBJECTIVES: To better understand impacts of the COVID-19 pandemic and resulting economic and social disruptions on families, we analyzed qualitative data capturing perspectives from parents of young children. METHODS: This study analyzes interviews of parents of children aged 1-3.5 years at enrollment, recruited from four primary care systems serving mainly lower-income Hispanic families in Los Angeles, California. Interviews were conducted over 15 months beginning September 2020. Analyses focused on the open-ended question: Please describe in your own words how the COVID-19 pandemic has affected you and your family. We used iterative, multi-step processes to identify emergent qualitative themes. RESULTS: A total of 460 parent responses were collected and coded. Key themes and subthemes were tested for interrater reliability, with Kappa ranging from 0.74 to 0.91. Thematic analysis revealed two groups of responses, one emphasizing stress and one emphasizing "silver linings." Parents cited a range of stressors, from fear of COVID-19 to social isolation. Those emphasizing "silver linings" also referenced formal or informal supports - especially government/community assistance programs and childcare access - that enabled stronger family ties and positive lifestyle modifications. CONCLUSIONS FOR PRACTICE: Experiences of families with young children during COVID-19 were not uniform. Economic stability and reliable childcare may be critical mediators of family stress. Results affirm that the pandemic's impacts were distributed through channels largely built on, and possibly exacerbating, existing disparities. For lower-income families with young children, funding for public and private programs that target economic stability and childcare assistance may merit prioritization in future socio-economic disruptions.

Arterial mechanics, extracellular matrix, and smooth muscle differentiation in carotid arteries deficient for Rac1.

Stiffening of the extracellular matrix (ECM) occurs after vascular injury and contributes to the injury-associated proliferation of vascular smooth muscle cells (SMCs). ECM stiffness also activates Rac-GTP, and SMC Rac1 deletion strongly reduces the proliferative response to injury in vivo . However, ECM stiffening and Rac can affect SMC differentiation, which, in itself, can influence ECM stiffness and proliferation. Here, we used pressure myography and immunofluorescence analysis of mouse carotid arteries to ask if the reported effect of Rac1 deletion on in vivo SMC proliferation might be secondary to a Rac effect on basal arterial stiffness or SMC differentiation. The results show that Rac1 deletion does not affect the abundance of arterial collagen-I, -III, or -V, the integrity of arterial elastin, or the arterial responses to pressure, including the axial and circumferential stretch-strain relationships that are assessments of arterial stiffness. Medial abundance of alpha-smooth muscle actin and smooth muscle-myosin heavy chain, markers of the SMC differentiated phenotype, were not statistically different in carotid arteries containing or deficient in Rac1. Nor did Rac1 deficiency have a statistically significant effect on carotid artery contraction to KCl. Overall, these data argue that the inhibitory effect of Rac1 deletion on in vivo SMC proliferation reflects a primary effect of Rac1 signaling to the cell cycle rather than a secondary effect associated with altered SMC differentiation or arterial stiffness.

Endothelial lipid droplets suppress eNOS to link high fat consumption to blood pressure elevation.

Metabolic syndrome, today affecting more than 20% of the US population, is a group of 5 conditions that often coexist and that strongly predispose to cardiovascular disease. How these conditions are linked mechanistically remains unclear, especially two of these: obesity and elevated blood pressure. Here, we show that high fat consumption in mice leads to the accumulation of lipid droplets in endothelial cells throughout the organism and that lipid droplet accumulation in endothelium suppresses endothelial nitric oxide synthase (eNOS), reduces NO production, elevates blood pressure, and accelerates atherosclerosis. Mechanistically, the accumulation of lipid droplets destabilizes eNOS mRNA and activates an endothelial inflammatory signaling cascade that suppresses eNOS and NO production. Pharmacological prevention of lipid droplet formation reverses the suppression of NO production in cell culture and in vivo and blunts blood pressure elevation in response to a high-fat diet. These results highlight lipid droplets as a critical and unappreciated component of endothelial cell biology, explain how lipids increase blood pressure acutely, and provide a mechanistic account for the epidemiological link between obesity and elevated blood pressure.

Cell contractility and focal adhesion kinase control circumferential arterial stiffness.

Arterial stiffening is a hallmark of aging and cardiovascular disease. While it is well established that vascular smooth muscle cells (SMCs) contribute to arterial stiffness by synthesizing and remodeling the arterial extracellular matrix, the direct contributions of SMC contractility and mechanosensors to arterial stiffness, and particularly the arterial response to pressure, remain less well understood despite being a long-standing question of biomedical importance. Here, we have examined this issue by combining the use of pressure myography of intact carotid arteries, pharmacologic inhibition of contractility, and genetic deletion of SMC focal adhesion kinase (FAK). Biaxial inflation-extension tests performed at physiological pressures showed that acute inhibition of cell contractility with blebbistatin or EGTA altered vessel geometry and preferentially reduced circumferential, as opposed to axial, arterial stiffness in wild-type mice. Similarly, genetic deletion of SMC FAK, which attenuated arterial contraction to KCl, reduced vessel wall thickness and circumferential arterial stiffness in response to pressure while having minimal effect on axial mechanics. Moreover, these effects of FAK deletion were lost by treating arteries with blebbistatin or by inhibiting myosin light-chain kinase. The expression of arterial fibrillar collagens, the integrity of arterial elastin, or markers of SMC differentiation were not affected by the deletion of SMC FAK. Our results connect cell contractility and SMC FAK to the regulation of arterial wall thickness and directionally specific arterial stiffening.

Extra-cardiac BCAA catabolism lowers blood pressure and protects from heart failure.

Pharmacologic activation of branched-chain amino acid (BCAA) catabolism is protective in models of heart failure (HF). How protection occurs remains unclear, although a causative block in cardiac BCAA oxidation is widely assumed. Here, we use in vivo isotope infusions to show that cardiac BCAA oxidation in fact increases, rather than decreases, in HF. Moreover, cardiac-specific activation of BCAA oxidation does not protect from HF even though systemic activation does. Lowering plasma and cardiac BCAAs also fails to confer significant protection, suggesting alternative mechanisms of protection. Surprisingly, activation of BCAA catabolism lowers blood pressure (BP), a known cardioprotective mechanism. BP lowering occurred independently of nitric oxide and reflected vascular resistance to adrenergic constriction. Mendelian randomization studies revealed that elevated plasma BCAAs portend higher BP in humans. Together, these data indicate that BCAA oxidation lowers vascular resistance, perhaps in part explaining cardioprotection in HF that is not mediated directly in cardiomyocytes.

Beyond the mother-child dyad: Is co-residence with a grandmother associated with adolescent girls' family planning knowledge?

BACKGROUND: In South Asian countries, adolescent girls are generally embedded in multigenerational households. Nevertheless, public health research continues to focus on the nuclear family and overlook the role of grandmothers in adolescent socialization and the transfer of health information. This study compares family planning knowledge of adolescent girls in households with and without a resident grandmother. Two main types of family planning knowledge were assessed: (1) modern contraceptive knowledge and (2) healthy timing and spacing of pregnancy knowledge. METHODS: This study is a secondary data analysis of the 2017 Suaahara II cross-sectional survey in 16 of Nepal's 77 districts. Family planning knowledge among 769 adolescent girls was assessed and compared between those living with a grandmother (n = 330) and those not living with a grandmother (n = 439). An analysis of the relationship between co-residence and family planning knowledge was carried out using multivariate logistic regression, adjusting for potential confounders and clustering. Additionally, we used the same method to analyze the association between grandmothers' family planning knowledge and that of co-resident adolescents. RESULTS: The odds of correct adolescent modern family planning knowledge were 1.81 (95% CI = 1.27,2.58) times higher in households with a grandmother. The study also identified higher odds of adolescent knowledge of modern contraceptives in households where grandmothers also had correct knowledge (OR 2.00, 95%, CI = 0.97,4.11), although this association was not statistically significant at the 0.05 alpha level. There was insufficient evidence to support the association between grandmother's co-residency and correct adolescent knowledge of the healthy timing and spacing of pregnancy. CONCLUSION: This study provides support for expanding adolescent reproductive health to include the role of senior women in promoting and transmitting health care knowledge to younger women in the household.

Decreased vascular smooth muscle contractility in Hutchinson-Gilford Progeria Syndrome linked to defective smooth muscle myosin heavy chain expression.

Children with Hutchinson-Gilford Progeria Syndrome (HGPS) suffer from multiple cardiovascular pathologies due to the expression of progerin, a mutant form of the nuclear envelope protein Lamin A. Progerin expression has a dramatic effect on arterial smooth muscle cells (SMCs) and results in decreased viability and increased arterial stiffness. However, very little is known about how progerin affects SMC contractility. Here, we studied the LaminAG609G/G609G mouse model of HGPS and found reduced arterial contractility at an early age that correlates with a decrease in smooth muscle myosin heavy chain (SM-MHC) mRNA and protein expression. Traction force microscopy on isolated SMCs from these mice revealed reduced force generation compared to wild-type controls; this effect was phenocopied by depletion of SM-MHC in WT SMCs and overcome by ectopic expression of SM-MHC in HGPS SMCs. Arterial SM-MHC levels are also reduced with age in wild-type mice and humans, suggesting a common defect in arterial contractility in HGPS and normal aging.

Arterial stiffness and cardiac dysfunction in Hutchinson-Gilford Progeria Syndrome corrected by inhibition of lysyl oxidase.

Arterial stiffening and cardiac dysfunction are hallmarks of premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS), but the molecular regulators remain unknown. Here, we show that the LaminAG609G mouse model of HGPS recapitulates the premature arterial stiffening and early diastolic dysfunction seen in human HGPS. Lysyl oxidase (LOX) is up-regulated in the arteries of these mice, and treatment with the LOX inhibitor, ß-aminopropionitrile, improves arterial mechanics and cardiac function. Genome-wide and mechanistic analysis revealed reduced expression of the LOX-regulator, miR-145, in HGPS arteries, and forced expression of miR-145 restores normal LOX gene expression in HGPS smooth muscle cells. LOX abundance is also increased in the carotid arteries of aged wild-type mice, but its spatial expression differs from HGPS and its up-regulation is independent of changes in miR-145 abundance. Our results show that miR-145 is selectively misregulated in HGPS and that the consequent up-regulation of LOX is causal for premature arterial stiffening and cardiac dysfunction.