Resolvin D2/GPR 18 axis ameliorates pressure overload-induced heart failure by inhibiting pro-inflammatory macrophage polarization.

Accumulating evidence has revealed that chronic unresolved inflammation can cause significant tissue damage and can be a key mediator of advanced heart failure (HF). Resolvin (Rv) D2, a member of specialized pro-resolving lipid mediators (SPMs), plays a protective role in various diseases by facilitating resolution. However, whether RvD2 participates in the pathogenesis of HF is still unclear. Our study demonstrated that RvD2 treatment mitigated cardiac remodeling and improved cardiac function in HF mice induced by pressure overload. The absence of G protein-coupled receptor 18 (GPR18), an endogenous receptor for RvD2, abolished the beneficial effects of RvD2 on HF. Additionally, RvD2 inhibited inflammatory responses and Ly6Chigh macrophage polarization during both early and late inflammatory stages involved in HF. Further investigation revealed that bone marrow transplantation from GPR18 deficient mice into WT mice blocked the protective effects of RvD2 in HF mice. Moreover, GPR18 deficiency impeded RvD2's capacity to downregulate inflammatory responses and Ly6Chigh macrophage polarization. Consistent with experiments in vivo, RvD2 treatment in bone marrow-derived macrophages (BMDMs) reduced inflammatory responses through its receptor GPR18. Mechanistically, RvD2 suppressed the phosphorylation of STAT1 and NF-κB p65, and the effects of RvD2 were reversed by the application of STAT1 or NF-κB p65 agonists in BMDMs. In conclusion, RvD2/GPR18 axis improved cardiac remodeling and function in pressure overload-induced HF mice by modulating macrophages phenotype via STAT1 and NF-κB p65 pathways. Our findings underscore the anti-inflammatory potential of RvD2/GPR18 axis, which may be a promising strategy for reducing the burden of HF.

Diagnosis of newly developed multiple myeloma without bone disease detectable on conventional computed tomography (CT) scan by using dual-energy CT.

Objective: To evaluate the diagnostic utility of fat (hydroxyapatite) density [DFat (HAP)] on dual-energy computed tomography (DECT) for identifying clinical diagnosed multiple myeloma without bone disease (MNBD) that is not visible on conventional CT scans. Material and Methods: In this age-gender-examination sites matched case control prospective study, Chest and/or abdominal images on Revolution CT of MNBDs and control subjects were consecutive enrolled in a 1:2 ratio from October 2022 to November 2023. Multiple myeloma was clinical diagnosed according to criteria of the International Myeloma Working Group. Regions of interest (ROIs) were drawn separately for all thoracolumbar vertebrae in the scanning range by two radiologists. Additionally, a radiologist specializing in musculoskeletal imaging supervised the process. DFat (HAP) was extracted from each ROI. The spine was divided into upper thoracic (UPT), middle and lower thoracic (MLT), thoracolumbar (TL), and middle and lower lumbar (MLL) vertebrae. The area under the receiver operating characteristic curve (AUC) was calculated to evaluate the diagnostic performance of DFat (HAP) in diagnosing multiple myeloma, and the sensitivity, specificity, and accuracy under the optimal cut-off were determined by Youden index (sensitivity + specificity -1). Results: A total of 32 and MNBD patients and 64 control patients were included. The total number of ROIs outlined included MNBD group (n = 493) and control group (n = 986). For all vertebrae, DFat(HAP) got average performance in the diagnosis of MNBD (AUC = 0.733, p < 0.001) with a cut-off value of 958 (mg/cm3); the sensitivity, specificity, and accuracy were 58.8 %, 77.8 %, and 71.7 %, respectively. Regarding segment analysis, the diagnostic performance was good for all (AUC, 0.803-0.837; p < 0.001) but the UPT segment (AUC = 0.692, p = 0.002). The optimal diagnostic cut-off values for the MLT, TL, and MLL vertebrae were 955 mg/cm3, 947 mg/cm3, and 947 mg/cm3, respectively; the sensitivity, specificity, and accuracy were 80.0 %-87.5 %, 71.9 %-82.6 %, and 77.1 %-81.6 %, respectively. Conclusion: DECT was effective for detecting MNBD, and better diagnostic results can be obtained by grouping different spine segments.

Differentiation of osteoblastic metastases and bone islands on dual-energy computed tomography in patients with untreated lung cancer.

OBJECTIVE: To evaluate the diagnostic efficacy of quantitative dual-energy computed tomography (CT) parameters for distinguishing osteoblastic metastases (OBMs) from bone islands (BIs) in untreated lung cancer. MATERIAL AND METHODS: Dual-energy CT images of 24 patients with OBMs and 56 patients with BIs obtained between January 2019 and December 2021 were retrospectively analyzed. The CT70keV value, calcium(water) density [Dcalcium(water)], and water(calcium) density [Dwater(calcium)] were analyzed. Diagnostic performance was assessed by measuring the area under the curve (AUC), and specificity, sensitivity, and accuracy were determined. RESULTS: A total of 70 OBMs and 67 BIs were included. The AUC values of CT70keV, Dcalcium(water), and Dwater(calcium) showed no significant differences (0.950 vs. 0.947 vs. 0.929, respectively; P > 0.05). The optimal CT70keV cutoff value was 885.1 HU, with specificity, sensitivity, and accuracy of 81.4 %, 92.5 %, and 86.9 %, respectively. When using Dcalcium(water) < 254.9 mg/cm3 and Dwater(calcium) < 1250.6 mg/cm3, respectively, 119 of 137 lesions showed consistent diagnostic results (true or false). Sub-analysis of these 119 lesions showed specificity of 92.1 %, which was higher than that of CT70keV (P = 0.021). The AUC, sensitivity, and accuracy were 0.974, 92.9 %, and 92.4 %, respectively, which were not significantly different from those of CT70keV (P = 0.230, 0.906, and 0.220, respectively). Among the 18 lesions showing inconsistent diagnoses, Dcalcium(water) diagnosed 11 lesions correctly, and Dwater(calcium) diagnosed the remaining seven lesions correctly. CONCLUSION: The combination of Dcalcium(water) and Dwater(calcium) demonstrated a promising role in the differentiation of OBMs from BIs in lung cancer patients.

The association between nurse practitioner race and ethnicity and intent to leave in primary care practices.

BACKGROUND: Retaining nurse practitioners (NPs) from diverse racial and ethnic groups is critical to achieving health equity as NPs disproportionately care for minoritized populations. Yet, little is known about intent to leave (ITL) among these NPs. PURPOSE: To examine whether NP race and ethnicity were associated with ITL and if this relationship was affected by the work environment. METHODS: Survey data from 1,232 NPs across six states were used. NPs completed measures of their ITL, work environment quality, and demographics. Regression models were used to determine if NP race and ethnicity resulted in differential reports of ITL. FINDINGS: Minoritized NPs had significantly higher cumulative odds of ITL compared with White NPs. DISCUSSION: Minoritized NPs had higher ITL, and the work environment did not demonstrate a protective effect against ITL. Future research should identify work environment features that may help retain a diverse NP workforce.

Disordered Eating in Early Adolescence: Disparities Among Minoritised Youth.

BACKGROUND: Disordered eating in early adolescence impacts development, with long-term health implications. Minoritised adolescents might be at higher risk of disordered eating due to minority stress, but most research has focused on White, heterosexual, cisgender individuals; less is known about disordered eating among minoritised adolescents. We examined sexual, gender, racial, and ethnic identities in relation to disordered eating in early adolescence. METHOD: Using 2-year follow-up data from adolescents ages 10-14 in the Adolescent Brain Cognitive Development Study (N = 9385), we examined associations between sexual, gender, racial, and ethnic identities and past-2 week disordered eating (preoccupation with weight, weight control behaviors, and binge eating). RESULTS: Compared to heterosexual peers, gay/bisexual adolescents had higher odds of all three outcomes (AOR 1.90-3.32); those "questioning" their sexual identity had higher odds of preoccupation with weight (AOR 1.82) and binge eating (AOR 2.53). Compared to cisgender adolescents, transgender adolescents had higher odds of binge eating (AOR 2.62); those "questioning" their gender identity had higher odds of preoccupation with weight (AOR 2.45). Adolescents whose racial identity was categorised as "Another" had higher odds of preoccupation with weight (AOR 1.46) and weight control behaviors (AOR 1.58) compared to White adolescents. Finally, Hispanic adolescents had higher odds of all disordered eating outcomes than non-Hispanic adolescents (AOR 1.25-1.59). DISCUSSION: This study is among the first to reveal disparities in disordered eating among minoritised early adolescents. Further examination of these disparities can inform future interventions. Healthcare providers are encouraged to screen for disordered eating, recognising that minoritised early adolescents may be at risk.

Non-averaged single-molecule tertiary structures reveal RNA self-folding through individual-particle cryo-electron tomography.

Large-scale and continuous conformational changes in the RNA self-folding process present significant challenges for structural studies, often requiring trade-offs between resolution and observational scope. Here, we utilize individual-particle cryo-electron tomography (IPET) to examine the post-transcriptional self-folding process of designed RNA origami 6-helix bundle with a clasp helix (6HBC). By avoiding selection, classification, averaging, or chemical fixation and optimizing cryo-ET data acquisition parameters, we reconstruct 120 three-dimensional (3D) density maps from 120 individual particles at an electron dose of no more than 168 e-Å-2, achieving averaged resolutions ranging from 23 to 35 Å, as estimated by Fourier shell correlation (FSC) at 0.5. Each map allows us to identify distinct RNA helices and determine a unique tertiary structure. Statistical analysis of these 120 structures confirms two reported conformations and reveals a range of kinetically trapped, intermediate, and highly compacted states, demonstrating a maturation folding landscape likely driven by helix-helix compaction interactions.

LGR6 protects against myocardial ischemia-reperfusion injury via suppressing necroptosis.

Regulated necrosis (necroptosis) and apoptosis are important biological features of ischemia-reperfusion (I/R) injury. However, the molecular mechanisms underlying myocardial necroptosis remain elusive. Leucine rich repeat containing G protein-coupled receptor 6 (LGR6) has been reported to play important roles in various cardiovascular disease. In this study, we aimed to determine whether LGR6 suppresses I/R-induced myocardial necroptosis and the underlying molecular mechanisms. We generated LGR6 knockout mice and used ligation of left anterior descending coronary artery to produce an in vivo I/R model. The effects of LGR6 and its downstream molecules were subsequently identified using RNA sequencing and CHIP assays. We observed significantly downregulated LGR6 expression in hearts post myocardial I/R and cardiomyocytes post hypoxia and reoxygenation (HR). LGR6 deficiency promoted and LGR6 overexpression inhibited necroptosis and acute myocardial injury after I/R. Mechanistically, in vivo and in vitro experiments suggest that LGR6 regulates the expression of STAT2 and ZBP1 by activating the Wnt signaling pathway, thereby inhibiting cardiomyocyte necroptosis after HR. Inhibiting STAT2 and ZBP1 effectively alleviated the aggravating effect of LGR6 deficiency on myocardial necroptosis after I/R. Furthermore, activating LGR6 with RSPO3 also effectively protected mice from acute myocardial I/R injury. Our findings reveal that RSPO3-LGR6 axis downregulates the expression of STAT2 and ZBP1 through the Wnt signaling pathway, thereby inhibiting I/R-induced myocardial injury and necroptosis. Targeting the RSPO3-LGR6 axis may be a potential therapeutic strategy to treat myocardial I/R injury.

Interleukin-12p40 deficiency attenuates myocardial ferroptosis in doxorubicin-induced chronic cardiomyopathy by inhibiting Th17 differentiation and interleukin-17A production.

AIMS: Interleukin (IL)-12p40 is a common subunit of the bioactive cytokines IL-12 and IL-23, and it also has its own intrinsic functional activity. However, its role in doxorubicin-induced chronic cardiomyopathy (DICCM) as well as the underlying mechanisms are still unknown. METHODS AND RESULTS: In this study, we used IL-12p40-knockout mice, IL-23p19-knockout mice, Rag1-knockout mice, a ferroptosis inhibitor, recombinant IL-12 (rIL-12), rIL-23, rIL-12p40, rIL-12p80, and anti-IL17A to investigate the effects of IL-12p40 on DICCM and elucidate the underlying mechanisms. We found that myocardial ferroptosis were increased in DICCM and that the inhibition of ferroptosis protected against DICCM. The expression of IL-12p40 was upregulated, and IL-12p40 was predominantly expressed by CD4+ T cells in the hearts of mice with DICCM. IL-12p40 knockout attenuated cardiac dysfunction, fibrosis and ferroptosis in DICCM, and similar results were observed in the context of CD4+ T cell IL-12p40 deficiency in Rag1-/- mice. Treatment with rIL-23, but not rIL-12, rIL-12p40 monomer or rIL-12p80, abolished the protective effects of IL-12p40 knockout. Moreover, rIL-23 treatment and IL-23p19 knockout exacerbated and ameliorated DICCM, respectively. IL-12p40 knockout might protect against DICCM by inhibiting Th17 differentiation and IL-17A production but not Th1, Th2 and Treg differentiation. Neutralizing IL-17A with an antibody also attenuated cardiac dysfunction, fibrosis and ferroptosis. The IL-12p40/Th17/IL-17A axis might promote cardiomyocyte ferroptosis by activating TNF receptor-associated factor 6 (TRAF6)/mitogen-activated protein kinase (MAPK)/P53 signaling in DICCM. CONCLUSIONS: Interleukin-12p40 deficiency protects against DICCM by inhibiting Th17 differentiation and the production of IL-17A, which plays critical roles in cardiomyocyte ferroptosis in DICCM via activating TRAF6/MAPK/P53 signaling. Our study may provide novel insights for the identification of therapeutic targets for treating DICCM in the clinic.

Racial and Ethnic Disparities in Emergency Department Use Among Older Adults With Asthma and Primary Care Nurse Practitioner Work Environments.

BACKGROUND: Older adults from specific racial and ethnic minoritized groups experience disproportionately higher asthma prevalence, morbidity, and mortality. They also often use emergency departments (EDs) to manage their asthma. High-quality primary care can improve asthma control and prevent ED use. Nurse practitioners (NPs) provide an increasing proportion of primary care to minoritized patients, yet often, they work in poor work environments that strain NP care. OBJECTIVES: We examined whether racial and ethnic health disparities in ED visits among older adults with asthma are moderated by the NP work environment in primary care practices. METHODS: In 2018-2019, we used a cross-sectional design to collect survey data on NP work environments from 1,244 NPs in six geographically diverse states (i.e., Arizona, California, New Jersey, Pennsylvania, Texas, and Washington). We merged the survey data with 2018 Medicare claims data from 46,658 patients with asthma to assess the associations of all-cause and ambulatory care-sensitive conditions, ED visits with NPs' work environment, and race and ethnicity using logistic regression. RESULTS: More than one third of patients with asthma visited the ED in 1 year, and a quarter of them had an ambulatory care sensitive condition ED visit. Black and Hispanic patients were more likely than White patients to have all-cause and ambulatory care sensitive condition ED visits. NP work environment moderated the association of race with all-cause and ambulatory care sensitive condition ED visits among patients with asthma. Greater standardized NP work environment scores were associated with lower odds of all-cause and ambulatory care sensitive condition ED visits between Black and White patients. DISCUSSION: Disparities in ED visits between Black and White patients with asthma decrease when these patients receive care in care clinics with more favorable NP work environments. Preventing unnecessary ED visits among older adults with asthma is a likely benefit of favorable NP work environments. As the NP workforce grows, creating favorable work environments for NPs in primary care is vital for narrowing the health disparity gap.

Topological Synthesis of 2D High-Entropy Multimetallic (Oxy)hydroxide for Enhanced Lattice Oxygen Oxidation Mechanism.

Owing to sluggish reaction kinetics and high potential, oxygen evolution reaction (OER) electrocatalysts face a trade-off between activity and stability. Herein, an innovative topological strategy is presented for preparing 2D multimetallic (oxy)hydroxide, including ternary CoFeZn, quaternary CoFeMnZn, and high-entropy CoFeMnCuZn. The key to the synthesis lies in using Ca-rich brownmillerite oxide as a precursor, which possesses inherent structural flexibility enabling tailored elemental adjustments and topologically transforms from a point-shared structure of metal-oxygen octahedrons into an edge-shared structure under alkaline conditions. The presence of Zn in the catalysts causes a shift in the center of the O2p band toward the Fermi level, resulting in more Co4+ species, which drive holes into oxygen ligands to promote intramolecular oxygen coupling. The triggered lattice oxidation mechanism is identified by detecting peroxo-like (O2 2-) negative species using tetramethylammonium chemical probe, along with 18O isotope labeling experiments. As a result, the catalyst demonstrates an overpotential of 267 mV at 10 mA cm-2, ranking it among the top-performing non-Ni-based catalysts. Importantly, the catalysts also show high Fe-leaching resistance during OER compared to conventional NiFe and CoFe hydroxides/(oxy)hydroxides. The assembled zinc-air battery enables stable operation for over 225 h at a low charging voltage of 1.93 V.

Foam fractionation studies of recombinant human apolipoprotein A-I.

Apolipoprotein A-I (apoA-I), the primary protein component of plasma high-density lipoproteins (HDL), is comprised of two structural regions, an N-terminal amphipathic α-helix bundle domain (residues 1-184) and a hydrophobic C-terminal domain (residues 185-243). When a recombinant fusion protein construct [bacterial pelB leader sequence - human apoA-I (1-243)] was expressed in Escherichia coli shaker flask cultures, apoA-I was recovered in the cell lysate. By contrast, when the C-terminal domain was deleted from the construct, large amounts of the truncated protein, apoA-I (1-184), were recovered in the culture medium. Consequently, following pelB leader sequence cleavage in the E. coli periplasmic space, apoA-I (1-184) was secreted from the bacteria. When the pelB-apoA-I (1-184) fusion construct was expressed in a 5 L bioreactor, substantial foam production (~30 L) occurred. Upon foam collection and collapse into a liquid foamate, SDS-PAGE revealed that apoA-I (1-184) was the sole major protein present. Incubation of apoA-I (1-184) with phospholipid vesicles yielded reconstituted HDL (rHDL) particles that were similar in size and cholesterol efflux capacity to those generated with full-length apoA-I. Mass spectrometry analysis confirmed that pelB leader sequence cleavage occurred and that foam fractionation did not result in unwanted protein modifications. The facile nature and scalability of bioreactor-based apolipoprotein foam fractionation provide a novel means to generate a versatile rHDL scaffold protein.

Differences in Self-Reported Stress Versus Hair and Nail Cortisol Among Adolescent and Young Adult Males.

BACKGROUND: Chronic stress causes harmful physiological responses that yield increased inflammation and subsequent health conditions. Stress is an important measure among minoritized populations who face social situations that predispose risk to developing mental health problems. Hair and fingernail cortisol have been studied as retrospective measures of chronic stress and to demonstrate biological response to social situations. OBJECTIVES: The objective of this study was to compare the Perceived Stress Scale (PSS) with hair and nail cortisol concentrations and assess the risk factors associated with stress levels among heterosexual and sexual and gender-minoritized adolescent males. METHODS: We recruited a cohort of adolescents who were assigned male sex at birth. Approximately half of our cohort consisted of sexual and gender-minoritized people, and half consisted of heterosexual cisgender males. Participants provided hair and nail samples and completed a survey that included demographic and hair hygiene questions and the PSS. Hair and nail samples were processed in a laboratory, and survey results were analyzed descriptively. RESULTS: Several samples were not provided or received, and some survey data were missing. Hair and nail cortisol values were significantly associated. There was no significant relationship between the PSS and hair and nail cortisol values. No significant differences were found between the heterosexual and sexual minoritized groups. Black participants reported lower perceived stress scores compared to White participants. Participants whose gender was nonbinary or genderqueer had higher hair cortisol values compared to those who identified as male. Older participants had higher hair cortisol values compared to younger participants. DISCUSSION: Previous researchers have similarly found no correlation between self-report stress scales and cortisol values, increased stress experience among nonbinary or genderqueer individuals compared to cisgender individuals, and a positive correlation between aging and stress. Yet, our finding that Black participants reported lower stress levels than White participants is unexpected. Our study demonstrates a high correlation between hair and nail cortisol values, suggesting the potential to substitute these markers as needed.

Cytokine levels in breast cancer are highly dependent on cytomegalovirus (CMV) status.

PURPOSE: Breast cancer accounts for 30% of all female cancers in the US. Cytomegalovirus (CMV), a herpesvirus that establishes lifelong infection, may play a role in breast cancer. CMV is not oncogenic, yet viral DNA and proteins have been detected in breast tumors, indicating possible contribution to tumor development. CMV encodes cmvIL-10, a homolog of human cellular IL-10 (cIL-10) with potent immunosuppressive activities. We investigated the relationship between CMV infection, cytokines, and breast cancer. METHODS: We evaluated CMV serostatus and cytokine levels in plasma of women with benign breast disease (n = 38), in situ carcinoma (n = 41), invasive carcinoma, no lymph node involvement (Inv/LN-; n = 41), and invasive with lymph node involvement (Inv/LN+; n = 37). RESULTS: Fifty percent of the patient samples (n = 79) were CMV seropositive. There was no correlation between CMV status and diagnosis (p = 0.75). For CMV+ patients, there was a trend toward higher CMV IgG levels in invasive disease (p = 0.172). CmvIL-10 levels were higher in CMV+ in situ patients compared to the Inv/LN- and Inv/LN+ groups (p = 0.020). Similarly, cIL-10 levels were higher in CMV+ in situ patients compared to the Inv/LN- and Inv/LN+ groups (p = 0.043). The results were quite different in CMV- patients where cIL-10 levels were highest in Inv/LN- compared to benign, in situ, or Inv/LN+ (p = 0.019). African American patients were significantly associated with CMV+ status (p = 0.001) and had lower cmvIL-10 levels than Caucasian patients (p = 0.046). CONCLUSION: No association was observed between CMV IgG and diagnosis, but CMV infection influences cytokine production and contributes to altered cytokine profiles in breast cancer.

Nurse Practitioner Work Environment and Rural Primary Care for Substance Use.

We examined the relationship between the nurse practitioner (NP) work environment and realized access (i.e., utilization) to primary care among rural older adults with substance use disorders (SUD). We analyzed cross-sectional NP survey data merged with Medicare claims and utilized fractional logistic regression. With one unit improvement in NP work environment, the odds of having older adults with SUDs in the practice increased by 20% (adjusted odds ratio=1.20, 95% confidence interval=1.01-1.44, p=0.04). Favorable work environments for NPs, including organizational support, collegiality, and role visibility, are associated with increased realized access to primary care among rural older adults with SUDs.

Molecular mechanism of contactin 2 homophilic interaction.

Contactin 2 (CNTN2) is a cell adhesion molecule involved in axon guidance, neuronal migration, and fasciculation. The ectodomains of CNTN1-CNTN6 are composed of six Ig domains (Ig1-Ig6) and four FN domains. Here, we show that CNTN2 forms transient homophilic interactions (KD ∼200 nM). Cryo-EM structures of full-length CNTN2 and CNTN2_Ig1-Ig6 reveal a T-shaped homodimer formed by intertwined, parallel monomers. Unexpectedly, the horseshoe-shaped Ig1-Ig4 headpieces extend their Ig2-Ig3 tips outwards on either side of the homodimer, while Ig4, Ig5, Ig6, and the FN domains form a central stalk. Cross-linking mass spectrometry and cell-based binding assays confirm the 3D assembly of the CNTN2 homodimer. The interface mediating homodimer formation differs between CNTNs, as do the homophilic versus heterophilic interaction mechanisms. The CNTN family thus encodes a versatile molecular platform that supports a very diverse portfolio of protein interactions and that can be leveraged to strategically guide neural circuit development.

Acute Care Use Among Patients With Multiple Chronic Conditions Receiving Care From Nurse Practitioner Practices in Health Professional Shortage Areas.

BACKGROUND: Patients with multiple chronic conditions often have many care plans, polypharmacy, and unrelieved symptoms that contribute to high emergency department and hospital use. High-quality primary care delivered in practices that employ nurse practitioners can help prevent the need for such acute care services. However, such practices located in primary care health professional shortage areas face challenges caring for these patients because of higher workloads and fewer resources. OBJECTIVE: We examined differences in hospitalization and emergency department use among patients with multiple chronic conditions who receive care from practices that employ nurse practitioners in health professional shortage areas compared to practices that employ nurse practitioners in non-health professional shortage areas. METHODS: We performed an analysis of Medicare claims, merged with Health Resources and Services Administration data on health professional shortage area status in five states. Our sample included 394,424 community-dwelling Medicare beneficiaries aged ≥65 years, with at least two of 15 common chronic conditions who received care in 779 practices that employ nurse practitioners. We used logistic regression to assess the relationship between health professional shortage area status and emergency department visits or hospitalizations. RESULTS: We found a higher likelihood of emergency department visits among patients in health professional shortage areas compared to those in non-health professional shortage areas and no difference in the likelihood of hospitalization. DISCUSSION: Emergency department use differences exist among older adults with multiple chronic conditions receiving care in practices that employ nurse practitioners in health professional shortage areas, compared to those in non-health professional shortage areas. To address this disparity, the health professional shortage area program should invest in recruiting and retaining nurse practitioners to health professional shortage areas to ease workforce shortages.

Cardiomyocyte LGR6 alleviates ferroptosis in diabetic cardiomyopathy via regulating mitochondrial biogenesis.

AIMS: The majority of people with diabetes are susceptible to cardiac dysfunction and heart failure, and conventional drug therapy cannot correct the progression of diabetic cardiomyopathy. We assessed the potential role and therapeutic value of LGR6 (G protein-coupled receptor containing leucine-rich repeats 6) in diabetic cardiomyopathy. METHODS AND RESULTS: Type 2 diabetes models were established using high-fat diet/streptozotocin-induced diabetes in mice. LGR6 knockout mice were generated. Recombinant adeno-associated virus serotype 9 carrying LGR6 under the cardiac troponin T promoter was injected into diabetic mice. Cardiomyocytes incubated with high glucose (HG) were used to imitate diabetic cardiomyopathy in vitro. The molecular mechanism was explored through RNA sequencing and a chromatin immunoprecipitation assay. We found that LGR6 expression was upregulated in diabetic hearts and HL1 cardiomyocytes treated with HG. The LGR6 knockout aggravated, but cardiomyocyte-specific LGR6 overexpression ameliorated, cardiac dysfunction and remodeling in diabetic mice. Mechanistically, in vivo and in vitro experiments revealed that LGR6 deletion aggravated, whereas LGR6 overexpression alleviated, ferroptosis and disrupted mitochondrial biogenesis by regulating STAT3/Pgc1a signaling. STAT3 inhibition and Pgc1a activation abrogated LGR6 knockout-induced mitochondrial dysfunction and ferroptosis in diabetic mice. In addition, LGR6 activation by recombinant RSPO3 treatment ameliorated cardiac dysfunction, ferroptosis and mitochondrial dysfunction in diabetic mice. CONCLUSIONS: We identified a previously undescribed signaling pathway of the LGR6-STAT3-Pgc1a axis that plays a critical role in ferroptosis and mitochondrial disorders during diabetic cardiomyopathy and provides an option for treatment of diabetic hearts.

Hair and nail cortisol levels are associated and affected by glucocorticoid use.

Hair and nail cortisol is increasingly studied as a physiologic proxy for chronic stress response. Glucocorticoid use is an expected confounder for cortisol measurement, yet there remains little evidence of whether external cortisol use should be subject to exclusion in study subjects. In a group of 209 youth (15-22 year-olds), we analyzed hair and fingernail cortisol concentrations. We assessed topical, nasal, oral, and injectable glucocorticoid use via a questionnaire. Extensively validated methods were used for hair and nail cortisol extraction and measurements. The median value of hair cortisol was 10.2 pg/mg (n=200), and the median value of nail cortisol was 7.06 pg/mg (n=203). Topical glucocorticoid use significantly increased hair and nail cortisol concentrations (p<0.005). Hair and nail cortisol concentrations were positively associated (p<0.0001, n=194). Spearman correlation coefficients demonstrated that the positive correlation between hair and nail cortisol values was higher in participants who used external glucocorticoids. Topical glucocorticoids moderated the association between hair and nail cortisol values (p=0.006). Based on these findings, we recommend that the assessment of topical glucocorticoid use must be performed when collecting hair/nail samples and that subjects reporting glucocorticoid use should be excluded from all future hair and nail cortisol studies; also, all outliers must be excluded to account for glucocorticoid medication underreporting and yet-unknown confounders.

Sexual and Gender Minority Sleep Health Disparities and Minority Stress in Early Adolescence.

PURPOSE: Sleep is essential to adolescent development. Sexual and gender minority (SGM; e.g., lesbian, gay, bisexual, transgender) adults are at high risk for poor sleep, partially due to minority stress (e.g., discrimination). However, sleep has rarely been studied among SGM adolescents. In a national sample of early adolescents, we analyzed sexual minority (SM) and gender minority (GM) identity, gender incongruence, and gender nonconformity in association with sleep and tested minority and general stressors as mediators. METHODS: We cross-sectionally analyzed data from 10,070 adolescents aged 10-14 in the Adolescent Brain Cognitive Development℠ Study. Using logistic regression models, we analyzed associations between identity (SM and GM), sexual identity discrimination, minority and general stressors (sexual identity discrimination, teasing, and conflict with parents) and sleep health (duration, latency, and disturbance). We used Baron and Kenny's method to test for mediation. RESULTS: Participants reported sexual identity (4% SM, 4% questioning) and gender identity (0.4% GM, 0.6% questioning); 65% were White, 20% were Hispanic, and 52% were assigned male at birth. Compared to heterosexual, SM participants had higher odds of short sleep duration, long sleep latency, and sleep disturbance. GM participants and those reporting gender incongruence and nonconformity had higher odds of long sleep latency and sleep disturbance. Sexual identity discrimination and general social stressors partially mediated some associations. DISCUSSION: SGM participants reported poorer sleep. Minority and general social stressors partially accounted for some disparities. Policies need to address SGM identity-based discrimination and challenge social norms that produce minority stress for SGM early adolescents.

Glucagon Receptor Antagonist for Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is an emerging major unmet need and one of the most significant clinic challenges in cardiology. The pathogenesis of HFpEF is associated with multiple risk factors. Hypertension and metabolic disorders associated with obesity are the 2 most prominent comorbidities observed in patients with HFpEF. Although hypertension-induced mechanical overload has long been recognized as a potent contributor to heart failure with reduced ejection fraction, the synergistic interaction between mechanical overload and metabolic disorders in the pathogenesis of HFpEF remains poorly characterized. METHOD: We investigated the functional outcome and the underlying mechanisms from concurrent mechanic and metabolic stresses in the heart by applying transverse aortic constriction in lean C57Bl/6J or obese/diabetic B6.Cg-Lepob/J (ob/ob) mice, followed by single-nuclei RNA-seq and targeted manipulation of a top-ranked signaling pathway differentially affected in the 2 experimental cohorts. RESULTS: In contrast to the post-transverse aortic constriction C57Bl/6J lean mice, which developed pathological features of heart failure with reduced ejection fraction over time, the post-transverse aortic constriction ob/ob mice showed no significant changes in ejection fraction but developed characteristic pathological features of HFpEF, including diastolic dysfunction, worsened cardiac hypertrophy, and pathological remodeling, along with further deterioration of exercise intolerance. Single-nuclei RNA-seq analysis revealed significant transcriptome reprogramming in the cardiomyocytes stressed by both pressure overload and obesity/diabetes, markedly distinct from the cardiomyocytes singularly stressed by pressure overload or obesity/diabetes. Furthermore, glucagon signaling was identified as the top-ranked signaling pathway affected in the cardiomyocytes associated with HFpEF. Treatment with a glucagon receptor antagonist significantly ameliorated the progression of HFpEF-related pathological features in 2 independent preclinical models. Importantly, cardiomyocyte-specific genetic deletion of the glucagon receptor also significantly improved cardiac function in response to pressure overload and metabolic stress. CONCLUSIONS: These findings identify glucagon receptor signaling in cardiomyocytes as a critical determinant of HFpEF progression and provide proof-of-concept support for glucagon receptor antagonism as a potential therapy for the disease.