FFAR4 regulates cardiac oxylipin balance to promote inflammation resolution in HFpEF secondary to metabolic syndrome.

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome, but a predominant subset of HFpEF patients has metabolic syndrome (MetS). Mechanistically, systemic, nonresolving inflammation associated with MetS might drive HFpEF remodeling. Free fatty acid receptor 4 (Ffar4) is a GPCR for long-chain fatty acids that attenuates metabolic dysfunction and resolves inflammation. Therefore, we hypothesized that Ffar4 would attenuate remodeling in HFpEF secondary to MetS (HFpEF-MetS). To test this hypothesis, mice with systemic deletion of Ffar4 (Ffar4KO) were fed a high-fat/high-sucrose diet with L-NAME in their water to induce HFpEF-MetS. In male Ffar4KO mice, this HFpEF-MetS diet induced similar metabolic deficits but worsened diastolic function and microvascular rarefaction relative to WT mice. Conversely, in female Ffar4KO mice, the diet produced greater obesity but no worsened ventricular remodeling relative to WT mice. In Ffar4KO males, MetS altered the balance of inflammatory oxylipins systemically in HDL and in the heart, decreasing the eicosapentaenoic acid-derived, proresolving oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE), while increasing the arachidonic acid-derived, proinflammatory oxylipin 12-hydroxyeicosatetraenoic acid (12-HETE). This increased 12-HETE/18-HEPE ratio reflected a more proinflammatory state both systemically and in the heart in male Ffar4KO mice and was associated with increased macrophage numbers in the heart, which in turn correlated with worsened ventricular remodeling. In summary, our data suggest that Ffar4 controls the proinflammatory/proresolving oxylipin balance systemically and in the heart to resolve inflammation and attenuate HFpEF remodeling.

Guanylyl cyclase-A phosphorylation decreases cardiac hypertrophy and improves systolic function in male, but not female, mice.

Atrial natriuretic peptide (NP) and BNP increase cGMP, which reduces blood pressure and cardiac hypertrophy by activating guanylyl cyclase (GC)-A, also known as NPR-A or Npr1. Although GC-A is highly phosphorylated, and dephosphorylation inactivates the enzyme, the significance of GC-A phosphorylation to heart structure and function remains unknown. To identify in vivo processes that are regulated by GC-A phosphorylation, we substituted glutamates for known phosphorylation sites to make GC-A8E/8E mice that express an enzyme that cannot be inactivated by dephosphorylation. GC-A activity, but not protein, was increased in heart and kidney membranes from GC-A8E/8E mice. Activities were threefold higher in female compared to male cardiac ventricles. Plasma cGMP and testosterone were elevated in male and female GC-A8E/8E mice, but aldosterone was only increased in mutant male mice. Plasma and urinary creatinine concentrations were decreased and increased, respectively, but blood pressure and heart rate were unchanged in male GC-A8E/8E mice. Heart weight to body weight ratios for GC-A8E/8E male, but not female, mice were 12% lower with a 14% reduction in cardiomyocyte cross-sectional area. Subcutaneous injection of fsANP, a long-lived ANP analog, increased plasma cGMP and decreased aldosterone in male GC-AWT/WT and GC-A8E/8E mice at 15 min, but only GC-A8E/8E mice had elevated levels of plasma cGMP and aldosterone at 60 min. fsANP reduced ventricular ERK1/2 phosphorylation to a greater extent and for a longer time in the male mutant compared to WT mice. Finally, ejection fractions were increased in male but not female hearts from GC-A8E/8E mice. We conclude that increased phosphorylation-dependent GC-A activity decreases cardiac ERK activity, which results in smaller male hearts with improved systolic function.

Guanylyl Cyclase-B Dependent Bone Formation in Mice is Associated with Youth, Increased Osteoblasts, and Decreased Osteoclasts.

C-type natriuretic peptide (CNP) activation of guanylyl cyclase-B (GC-B) catalyzes the synthesis of cGMP in chondrocytes and osteoblasts. Elevated cGMP stimulates long bone growth, and inactivating mutations in CNP or GC-B reduce cGMP, which causes dwarfism. GC-B7E/7E mice that express a GC-B mutant that cannot be inactivated by dephosphorylation exhibit increased CNP-dependent GC-B activity, which increases bone length, as well as bone mass and strength. Importantly, how GC-B increases bone mass is not known. Here, we injected 12-week-old, wild type mice once daily for 28 days with or without BMN-111 (Vosoritide), a proteolytically resistant CNP analog. We found that BMN-111 treated mice had elevated levels of osteocalcin and collagen 1 C-terminal telopeptide (CTX) as well as increased osteoblasts and osteoclasts. In BMN-111 injected mice, tibial mRNAs for Rank ligand and osteoprotegrin were increased and decreased, respectively, whereas sclerostin mRNA was elevated 400-fold, consistent with increased osteoclast activity and decreased osteoblast activity. Mineral apposition rates and trabecular bone mass were not elevated in response to BMN-111. Because 9-week-old male GC-B7E/7E mice have increased bone mass but do not exhibit increased mineral apposition rates, we examined 4-week-old male GC-B7E/7E mice and found that these animals had increased serum osteocalcin, but not CTX. Importantly, tibias from these mice had 37% more osteoblasts, 26% fewer osteoclasts as well as 36% and 40% higher mineral apposition and bone formation rates, respectively. We conclude that GC-B-dependent bone formation is coupled to an early juvenile process that requires both increased osteoblasts and decreased osteoclasts.

Acute care utilization and housing hardships in American children.

Millions of families in the United States are economically vulnerable: one shock can lead to hardship. We use data from the Fragile Families and Child Wellbeing Study to examine the association between acute healthcare utilization - emergency room visits or hospitalizations - and subsequent housing hardships, such as being evicted for financial reasons. Further, we explore whether this association differs by who in the family utilized the care and whether perceived social support protects against hardship when these experiences occur. Using lagged dependent variable regression models, we find that families that visited the emergency room or were hospitalized, regardless if it was a child or parent with this experience, were five percentage points more likely to experience any housing hardship than families that did not use acute care. Among families in which a child utilized acute care, perceived social support buffered the impact of using acute care. That perceived social support is associated with a lower likelihood of housing hardship among families that experienced acute care utilization for a child, but not parent, suggests that social support may be able to offset the challenges arising from children's, but not adults', use of acute care. In the face of economic precarity, informal safety nets may be insufficient to reduce the impact of acute care utilization on housing hardships.

Geography of intergenerational mobility and child development.

Recent research by Chetty and colleagues finds that children's chances of upward mobility are affected by the communities in which they grow up [Chetty R, Hendren N (2016) Working paper 23002]. However, the developmental pathways through which communities of origin translate into future economic gain are not well understood. In this paper we examine the association between Chetty and Hendren's county-level measure of intergenerational mobility and children's cognitive and behavioral development. Focusing on children from low-income families, we find that growing up in a county with high upward mobility is associated with fewer externalizing behavioral problems by age 3 years and with substantial gains in cognitive test scores between ages 3 and 9 years. Growing up in a county with 1 SD better intergenerational mobility accounts for ∼20% of the gap in developmental outcomes between children from low- and high-income families. Collectively, our findings suggest that the developmental processes through which residential contexts promote upward mobility begin early in childhood and involve the enrichment of both cognitive and social-emotional development.

"My BMI is too high for Plan B." A changing population of women seeking ulipristal acetate emergency contraception online.

Emergency contraceptive (EC) pills may be less effective for women with higher body mass index (BMI), but little is known about public response to the fact that EC may lose efficacy as weight increases. In November 2013, European authorities changed the label for a levonorgestrel EC product to warn of a reduction in effectiveness for women with higher BMI, garnering significant media coverage in the United States. Ulipristal acetate (UPA) EC may be more effective than levonorgestrel for women with BMI levels designated as obese. Among 8,019 women who received UPA from the online pharmacy KwikMed from 2011 to 2015 and self-reported their height, weight and reasons for seeking UPA online, we analyzed changes in the proportion of women in different BMI categories before and after the label change. For the 25 month-period after the label change, the proportion of women in the obese category rose by 26.7 percentage points relative to the 35 months before (B = 0.2665, p < .01). Mean BMI (25.5 versus 29.4, p < .001) and average weight (148.6 pounds versus 175.5 pounds, p < .001) of users were higher after the label change. Some women appear to have acted on the information that EC efficacy may be associated with body weight.

Sleep Duration and Telomere Length in Children.

OBJECTIVE: To test the association between sleep duration and telomere length in a pediatric population. STUDY DESIGN: We analyzed cross-sectional data for 1567 children from the age 9 study wave of the Fragile Families and Child Wellbeing Study, a population-based birth cohort of children born between 1998 and 2000 in large American cities (population >200 000). We measured telomere length using quantitative polymerase chain reaction, and children's typical nightly sleep duration was reported by their primary caregivers. Using linear regression, we estimated the association between sleep duration and telomere length both in unadjusted models and adjusting for a number of covariates. RESULTS: We found that children with shorter sleep durations have shorter telomeres than children with longer sleep durations. Each hour less of nightly sleep duration is associated with having telomeres that are 0.015 log-kilobases per chromosome shorter (P < .05). We found no difference in this association by race, sex, or socioeconomic status. CONCLUSIONS: We provide preliminary evidence that children with shorter sleep durations have shorter telomeres. This finding is consistent with a broader literature indicating that suboptimal sleep duration is a risk for increased physiological stress and impaired health. Future research should address the limitations of our study design by using longitudinal study designs and telomere measurements, measuring sleep duration via polysomnography or actigraphy, and assessing the intermediate biological mechanisms of the link between sleep and telomere dynamics.

Genital Self-Image and Considerations of Elective Genital Surgery.

The present study explores how genital self-image may be related to considerations of surgically altering one's genitals and documents the wanted genital changes among young adults. Evidence of a nontrivial proportion of respondents (98 of 1,110) had seriously considered elective genital surgery. Regression models indicate that, for both men and women, identifying as heterosexual and reporting lower composite genital self-image scores results in higher odds of considering genital surgery. Additionally for men, feeling unsatisfied with penis size increased the odds. Clinical and educational efforts to normalize and celebrate genital variation may influence considerations for genital modification in young adults.

Increases in retail sales of over-the-counter levonorgestrel emergency contraception in the United States, 2016-2022.

OBJECTIVES: To understand patterns in demand for emergency contraception (EC), we characterize the sales of over-the-counter (OTC) levonorgestrel (LNG) EC in the United States from traditional retail outlets. STUDY DESIGN: We describe sales of OTC LNG EC using retail sales data aggregated from traditional retail channels, including grocery stores, drug stores, mass merchandisers, club stores, dollar stores, and military outlets. RESULTS: Sales of OTC LNG EC doubled between 2016 and 2022 (approximately 7.2-14.8 million). CONCLUSIONS: Increasing sales of EC are consistent with increased use and use frequency of EC by those at risk of pregnancy in the United States. IMPLICATIONS: OTC LNG EC sales since 2016 exceed what national survey usage estimates would suggest, indicating that national surveys underreport EC use, those using EC purchase it somewhat frequently, and/or individuals stockpile EC for later use. The role of EC in individual contraceptive strategies, particularly as access to reproductive healthcare is restricted, warrants further study.

"A Lot of My Friends Don't Know How It Works": Student Activists Describe Gaps in College Students' Emergency Contraception Knowledge.

INTRODUCTION: Despite the high potential need for emergency contraception (EC) among college students, lack of accurate knowledge may decrease the likelihood of its use in this population. We examined knowledge about EC methods, potential outcomes of use, and access among college students in the United States. METHODS: We recruited college students from a listserv devoted to EC campus activism for an online survey about EC knowledge (N = 150) and conducted 24 follow-up in-depth interviews. We describe the share of respondents that correctly answered each question and provide additional context and insight from interview respondents. RESULTS: Gaps in EC knowledge were noted in our sample of college student EC activists. Awareness of different methods of EC was not universal; 38% of the sample was unaware of ulipristal acetate (ella®) and 61% was unaware of the intrauterine device inserted after intercourse as EC. Many respondents also incorrectly perceived additional barriers to acquiring EC such as minimum age or an ID requirement to purchase EC (64% and 49%, respectively). Interview respondents describe how medical providers, such as student health services and pharmacists, can pose barriers to EC access through either their actions or how college students expect they will act. CONCLUSIONS: We document several gaps in knowledge surrounding EC in college students, even in an activist sample. Additional efforts to inform students about the variety of available EC methods and address mistaken perceptions about barriers to access may allow college students to better meet their needs for EC.

Role of Surface Tension on Heat Feedback and Power from Energetic Composites.

Heat feedback to the unburned reaction interface is an important controlling factor of the velocity of the reaction front and power delivery. In this paper, we investigate the effect of agglomerate surface tension and its relationship to surface residence time and heat feedback on the combustion characteristics by Si addition to an Al/KClO4 composite. Macroscopic imaging demonstrates a significant increase in burn rate with the addition of Si despite the fact that Si/KClO4 has a slightly lower energy density than Al/KClO4. Microscopic imaging coupled with three-color pyrometry reveals that molten liquid forms and evolves into spherical droplets on the burning surface, which are subsequently ejected from the surface. We find that the addition of Si results in a small increase in droplet size and a negligible impact on droplet temperature. However, the droplet formation rate on the surface is slower, leading to a significantly longer surface residence time. This leads to enhanced conductive heat feedback to the unburnt materials, thereby increasing the burn rate and energy release rate. We attribute the decreased droplet growth rate to the lowered surface tension of the liquid mixture with Si addition. This study highlights the crucial role of agglomerate physical property (e.g., surface tension) in influencing the combustion behavior of energetic composites.

Gene-environment correlation: difficulties and a natural experiment-based strategy.

OBJECTIVES: We explored how gene-environment correlations can result in endogenous models, how natural experiments can protect against this threat, and if unbiased estimates from natural experiments are generalizable to other contexts. METHODS: We compared a natural experiment, the College Roommate Study, which measured genes and behaviors of college students and their randomly assigned roommates in a southern public university, with observational data from the National Longitudinal Study of Adolescent Health in 2008. We predicted exposure to exercising peers using genetic markers and estimated environmental effects on alcohol consumption. A mixed-linear model estimated an alcohol consumption variance that was attributable to genetic markers and across peer environments. RESULTS: Peer exercise environment was associated with respondent genotype in observational data, but not in the natural experiment. The effects of peer drinking and presence of a general gene-environment interaction were similar between data sets. CONCLUSIONS: Natural experiments, like random roommate assignment, could protect against potential bias introduced by gene-environment correlations. When combined with representative observational data, unbiased and generalizable causal effects could be estimated.

Retail demand for emergency contraception in United States following New Year holiday: time series study.

OBJECTIVE: To estimate the increase in sales of emergency contraception following the New Year's Eve/New Year's Day holiday. DESIGN: Time series analysis using autoregressive integrated moving average (ARIMA) model. SETTING: Traditional (that is, "bricks and mortar") retail outlets-grocery stores, drug stores, mass merchandisers, club stores, dollar stores, and military outlets-in the United States from 2016 to 2022. DATA SOURCE: Marketing data on weekly aggregated sales of items classified as emergency contraception gathered between 2016 and 2022 (n=362). On the basis of dates, weeks were classified as following the New Year holiday (n=6) or not (n=356). MAIN OUTCOME MEASURE: Weekly sales of levonorgestrel emergency contraception per 1000 women of reproductive age in the US population. RESULTS: Sales of levonorgestrel emergency contraception significantly increased after the New Year holiday (0.63 (95% confidence interval 0.58 to 0.69) unit increase per 1000 women aged 15-44). Holidays that share some aspects of the elevated risks of unprotected sexual intercourse with the New Year holiday (Valentine's Day, St Patrick's Day, US Independence Day) were associated with increased sales, albeit to a lesser degree, with respective sales increases per 1000 women aged 15-44 of 0.31 (0.25 to 0.38), 0.14 (0.06 to 0.23), and 0.20 (0.11 to 0.29). Holidays without these expectations (Easter, Mother's Day, Father's Day) were not significantly associated with sales of levonorgestrel emergency contraception. CONCLUSIONS: Increased sales of emergency contraception following the New Year's holiday suggest that this period is associated with increased risks of unprotected vaginal intercourse compared with other holidays. Targeting behavioral risks, prevention strategies to mitigate sexual violence, and improving access to contraception around holidays may limit the risks associated with unprotected vaginal intercourse.

Enhancing the Combustion of Magnesium Nanoparticles via Low-Temperature Plasma-Induced Hydrogenation.

The hydrogenation of metal nanoparticles provides a pathway toward tuning their combustion characteristics. Metal hydrides have been employed as solid-fuel additives for rocket propellants, pyrotechnics, and explosives. Gas generation during combustion is beneficial to prevent aggregation and sintering of particles, enabling a more complete fuel utilization. Here, we discuss a novel approach for the synthesis of magnesium hydride nanoparticles based on a two-step aerosol process. Mg particles are first nucleated and grown via thermal evaporation, followed immediately by in-flight exposure to a hydrogen-rich low-temperature plasma. During the second step, atomic hydrogen generated by the plasma rapidly diffuses into the Mg lattice, forming particles with a significant fraction of MgH2. We find that hydrogenated Mg nanoparticles have an ignition temperature that is reduced by ∼200 °C when combusted with potassium perchlorate as an oxidizer, compared to the non-hydrogenated Mg material. This is due to the release of hydrogen from the fuel, jumpstarting its combustion. In addition, characterization of the plasma processes suggests that a careful balance between the dissociation of molecular hydrogen and heating of the nanoparticles must be achieved to avoid hydrogen desorption during production and achieve a significant degree of hydrogenation.

High-Throughput Dispensing of Viscous Solutions for Biomedical Applications.

Cells cultured in three-dimensional scaffolds express a phenotype closer to in vivo cells than cells cultured in two-dimensional containers. Natural polymers are suitable materials to make three-dimensional scaffolds to develop disease models for high-throughput drug screening owing to their excellent biocompatibility. However, natural polymer solutions have a range of viscosities, and none of the currently available liquid dispensers are capable of dispensing highly viscous polymer solutions. Here, we report the development of an automated scaffold dispensing system for rapid, reliable, and homogeneous creation of scaffolds in well-plate formats. We employ computer-controlled solenoid valves to regulate air pressure impinging upon a syringe barrel filled with scaffold solution to be dispensed. Automated dispensing of scaffold solution is achieved via a programmable software interface that coordinates solution extrusion and the movement of a dispensing head. We show that our pneumatically actuated dispensing system can evenly distribute high-viscosity, chitosan-based polymer solutions into 96- and 384-well plates to yield highly uniform three-dimensional scaffolds after lyophilization. We provide a proof-of-concept demonstration of high-throughput drug screening by culturing glioblastoma cells in scaffolds and exposing them to temozolomide. This work introduces a device that can hasten the creation of three-dimensional cell scaffolds and their application to high-throughput testing.

Epitope-tagged and phosphomimetic mouse models for investigating natriuretic peptide-stimulated receptor guanylyl cyclases.

The natriuretic peptide receptors NPR1 and NPR2, also known as guanylyl cyclase A and guanylyl cyclase B, have critical functions in many signaling pathways, but much remains unknown about their localization and function in vivo. To facilitate studies of these proteins, we developed genetically modified mouse lines in which endogenous NPR1 and NPR2 were tagged with the HA epitope. To investigate the role of phosphorylation in regulating NPR1 and NPR2 guanylyl cyclase activity, we developed mouse lines in which regulatory serines and threonines were substituted with glutamates, to mimic the negative charge of the phosphorylated forms (NPR1-8E and NPR2-7E). Here we describe the generation and applications of these mice. We show that the HA-NPR1 and HA-NPR2 mice can be used to characterize the relative expression levels of these proteins in different tissues. We describe studies using the NPR2-7E mice that indicate that dephosphorylation of NPR2 transduces signaling pathways in ovary and bone, and studies using the NPR1-8E mice that indicate that the phosphorylation state of NPR1 is a regulator of heart, testis, and adrenal function.

Free fatty acid receptor 4 responds to endogenous fatty acids to protect the heart from pressure overload.

AIMS: Free fatty acid receptor 4 (Ffar4) is a G-protein-coupled receptor for endogenous medium-/long-chain fatty acids that attenuates metabolic disease and inflammation. However, the function of Ffar4 in the heart is unclear. Given its putative beneficial role, we hypothesized that Ffar4 would protect the heart from pathologic stress. METHODS AND RESULTS: In mice lacking Ffar4 (Ffar4KO), we found that Ffar4 is required for an adaptive response to pressure overload induced by transverse aortic constriction (TAC), identifying a novel cardioprotective function for Ffar4. Following TAC, remodelling was worsened in Ffar4KO hearts, with greater hypertrophy and contractile dysfunction. Transcriptome analysis 3-day post-TAC identified transcriptional deficits in genes associated with cytoplasmic phospholipase A2α signalling and oxylipin synthesis and the reduction of oxidative stress in Ffar4KO myocytes. In cultured adult cardiac myocytes, Ffar4 induced the production of the eicosapentaenoic acid (EPA)-derived, pro-resolving oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE). Furthermore, the activation of Ffar4 attenuated cardiac myocyte death from oxidative stress, while 18-HEPE rescued Ffar4KO myocytes. Systemically, Ffar4 maintained pro-resolving oxylipins and attenuated autoxidation basally, and increased pro-inflammatory and pro-resolving oxylipins, including 18-HEPE, in high-density lipoproteins post-TAC. In humans, Ffar4 expression decreased in heart failure, while the signalling-deficient Ffar4 R270H polymorphism correlated with eccentric remodelling in a large clinical cohort paralleling changes observed in Ffar4KO mice post-TAC. CONCLUSION: Our data indicate that Ffar4 in cardiac myocytes responds to endogenous fatty acids, reducing oxidative injury, and protecting the heart from pathologic stress, with significant translational implications for targeting Ffar4 in cardiovascular disease.

National Profiles of Coronavirus Disease 2019 Mortality Risks by Age Structure and Preexisting Health Conditions.

BACKGROUND AND OBJECTIVES: Although individual age and preexisting health conditions are well-documented risk factors for coronavirus disease 2019 (COVID-19) mortality, it is unclear whether these 2 factors capture unique dimensions of risk for epidemic severity at the national level. In addition, no studies have examined whether national distributions of these factors are associated with epidemic experiences to date. RESEARCH DESIGN AND METHODS: Drawing on surveys of older adults from 42 countries and estimated case fatality ratios by age and preexisting health conditions, we document and compare national profiles of COVID-19 mortality risks among older adults. We develop 2 measures of national risk profiles: one based on age structures and another based on distributions of preexisting health conditions. Our analysis compares these constructs and documents their associations with national COVID-19 mortality rates. RESULTS: National profiles of COVID-19 mortality risk based on age structure and preexisting health conditions are moderately uncorrelated, capturing different aspects of risk. Both types of national risk profiles correlate meaningfully with countries' COVID-19 mortality experiences to date. DISCUSSION AND IMPLICATIONS: Measures of population age structure are readily available for every country in the world, while cross-national measures of older adult population health are more limited. In the COVID-19 crisis, these factors give different pictures of the countries with high and low risks of COVID-19 mortality. Moreover, our results suggest that both types of national risk profiles based on population health reflect current COVID-19 mortality severity in several countries, highlighting the need for more cross-national comparative data on older adult population health.

Prevention of guanylyl cyclase-B dephosphorylation rescues achondroplastic dwarfism.

Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) or inactivating mutations in guanylyl cyclase-B (GC-B), also known as NPR-B or Npr2, cause short-limbed dwarfism. FGFR3 activation causes dephosphorylation and inactivation of GC-B, but the contribution of GC-B dephosphorylation to achondroplasia (ACH) is unknown. GC-B7E/7E mice that express a glutamate-substituted version of GC-B that cannot be inactivated by dephosphorylation were bred with mice expressing FGFR3-G380R, the most common human ACH mutation, to determine if GC-B dephosphorylation is required for ACH. Crossing GC-B7E/7E mice with FGFR3G380R/G380R mice increased naso-anal and long (tibia and femur), but not cranial, bone length twice as much as crossing GC-B7E/7E mice with FGFR3WT/WT mice from 4 to 16 weeks of age. Consistent with increased GC-B activity rescuing ACH, long bones from the GC-B7E/7E/FGFR3G380R/G380R mice were not shorter than those from GC-BWT/WT/FGFR3WT/WT mice. At 2 weeks of age, male but not female FGFR3G380R/G380R mice had shorter long bones and smaller growth plate hypertrophic zones, whereas female but not male GC-B7E/7E mice had longer bones and larger hypertrophic zones. In 2-week-old males, crossing FGFR3G380R/G380R mice with GC-B7E/7E mice increased long bone length and hypertrophic zone area to levels observed in mice expressing WT versions of both receptors. We conclude that preventing GC-B dephosphorylation rescues reduced axial and appendicular skeleton growth in a mouse model of achondroplasia.

Decline in Marriage Associated with the COVID-19 Pandemic in the United States.

In the social upheaval arising from the coronavirus disease 2019 (COVID-19) pandemic, we do not yet know how union formation, particularly marriage, has been affected. Using administration records-marriage certificates and applications-gathered from settings representing a variety of COVID-19 experiences in the United States, the authors compare counts of recorded marriages in 2020 against those from the same period in 2019. There is a dramatic decrease in year-to-date cumulative marriages in 2020 compared with 2019 in each case. Similar patterns are observed for the Seattle metropolitan area when analyzing the cumulative number of marriage applications, a leading indicator of marriages in the near future. Year-to-date declines in marriage are unlikely to be due solely to closure of government agencies that administer marriage certification or reporting delays. Together, these findings suggest that marriage has declined during the COVID-19 outbreak and may continue to do so, at least in the short term.