An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics.

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale.

Molecular organization of the early stages of nucleosome phase separation visualized by cryo-electron tomography.

It has been proposed that the intrinsic property of nucleosome arrays to undergo liquid-liquid phase separation (LLPS) in vitro is responsible for chromatin domain organization in vivo. However, understanding nucleosomal LLPS has been hindered by the challenge to characterize the structure of the resulting heterogeneous condensates. We used cryo-electron tomography and deep-learning-based 3D reconstruction/segmentation to determine the molecular organization of condensates at various stages of LLPS. We show that nucleosomal LLPS involves a two-step process: a spinodal decomposition process yielding irregular condensates, followed by their unfavorable conversion into more compact, spherical nuclei that grow into larger spherical aggregates through accretion of spinodal materials or by fusion with other spherical condensates. Histone H1 catalyzes more than 10-fold the spinodal-to-spherical conversion. We propose that this transition involves exposure of nucleosome hydrophobic surfaces causing modified inter-nucleosome interactions. These results suggest a physical mechanism by which chromatin may transition from interphase to metaphase structures.

Open-channel metal particle superlattices.

Although tremendous advances have been made in preparing porous crystals from molecular precursors1,2, there are no general ways of designing and making topologically diversified porous colloidal crystals over the 10-1,000 nm length scale. Control over porosity in this size range would enable the tailoring of molecular absorption and storage, separation, chemical sensing, catalytic and optical properties of such materials. Here, a universal approach for synthesizing metallic open-channel superlattices with pores of 10 to 1,000 nm from DNA-modified hollow colloidal nanoparticles (NPs) is reported. By tuning hollow NP geometry and DNA design, one can adjust crystal pore geometry (pore size and shape) and channel topology (the way in which pores are interconnected). The assembly of hollow NPs is driven by edge-to-edge rather than face-to-face DNA-DNA interactions. Two new design rules describing this assembly regime emerge from these studies and are then used to synthesize 12 open-channel superlattices with control over crystal symmetry, channel geometry and topology. The open channels can be selectively occupied by guests of the appropriate size and that are modified with complementary DNA (for example, Au NPs).

The Immune Landscape of Cancer.

We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune subtypes-wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-ß dominant-characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers. Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes. Our immunogenomics pipeline to characterize these heterogeneous tumors and the resulting data are intended to serve as a resource for future targeted studies to further advance the field.

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-trans-aortic constriction C57Bl/6J lean mice, which developed pathological features of heart failure with reduced ejection fraction over time, the post-trans-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.

Kielin/chordin-like protein deficiency aggravates pressure overload-induced cardiac dysfunction and remodeling via P53/P21/CCNB1 signaling in mice.

Targeting cardiac remodeling is regarded as a key therapeutic strategy for heart failure. Kielin/chordin-like protein (KCP) is a secretory protein with 18 cysteine-rich domains and associated with kidney and liver fibrosis. However, the relationship between KCP and cardiac remodeling remains unclear. Here, we aimed to investigate the role of KCP in cardiac remodeling induced by pressure overload and explore its potential mechanisms. Left ventricular (LV) KCP expression was measured with real-time quantitative PCR, western blotting, and immunofluorescence staining in pressure overload-induced cardiac remodeling in mice. Cardiac function and remodeling were evaluated in wide-type (WT) mice and KCP knockout (KO) mice by echocardiography, which were further confirmed by histological analysis with hematoxylin and eosin and Masson staining. RNA sequence was performed with LV tissue from WT and KO mice to identify differentially expressed genes and related signaling pathways. Primary cardiac fibroblasts (CFs) were used to validate the regulatory role and potential mechanisms of KCP during fibrosis. KCP was down-regulated in the progression of cardiac remodeling induced by pressure overload, and was mainly expressed in fibroblasts. KCP deficiency significantly aggravated pressure overload-induced cardiac dysfunction and remodeling. RNA sequence revealed that the role of KCP deficiency in cardiac remodeling was associated with cell division, cell cycle, and P53 signaling pathway, while cyclin B1 (CCNB1) was the most significantly up-regulated gene. Further investigation in vivo and in vitro suggested that KCP deficiency promoted the proliferation of CFs via P53/P21/CCNB1 pathway. Taken together, these results suggested that KCP deficiency aggravates cardiac dysfunction and remodeling induced by pressure overload via P53/P21/CCNB1 signaling in mice.

Designer molecules of the synaptic organizer MDGA1 reveal 3D conformational control of biological function.

MDGAs (MAM domain-containing glycosylphosphatidylinositol anchors) are synaptic cell surface molecules that regulate the formation of trans-synaptic bridges between neurexins (NRXNs) and neuroligins (NLGNs), which promote synaptic development. Mutations in MDGAs are implicated in various neuropsychiatric diseases. MDGAs bind NLGNs in cis on the postsynaptic membrane and physically block NLGNs from binding to NRXNs. In crystal structures, the six immunoglobulin (Ig) and single fibronectin III domains of MDGA1 reveal a striking compact, triangular shape, both alone and in complex with NLGNs. Whether this unusual domain arrangement is required for biological function or other arrangements occur with different functional outcomes is unknown. Here, we show that WT MDGA1 can adopt both compact and extended 3D conformations that bind NLGN2. Designer mutants targeting strategic molecular elbows in MDGA1 alter the distribution of 3D conformations while leaving the binding affinity between soluble ectodomains of MDGA1 and NLGN2 intact. In contrast, in a cellular context, these mutants result in unique combinations of functional consequences, including altered binding to NLGN2, decreased capacity to conceal NLGN2 from NRXN1ß, and/or suppressed NLGN2-mediated inhibitory presynaptic differentiation, despite the mutations being located far from the MDGA1-NLGN2 interaction site. Thus, the 3D conformation of the entire MDGA1 ectodomain appears critical for its function, and its NLGN-binding site on Ig1-Ig2 is not independent of the rest of the molecule. As a result, global 3D conformational changes to the MDGA1 ectodomain via strategic elbows may form a molecular mechanism to regulate MDGA1 action within the synaptic cleft.

Proteogenomic characterization of difficult-to-treat breast cancer with tumor cells enriched through laser microdissection.

BACKGROUND: Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer death among women globally. Despite advances, there is considerable variation in clinical outcomes for patients with non-luminal A tumors, classified as difficult-to-treat breast cancers (DTBC). This study aims to delineate the proteogenomic landscape of DTBC tumors compared to luminal A (LumA) tumors. METHODS: We retrospectively collected a total of 117 untreated primary breast tumor specimens, focusing on DTBC subtypes. Breast tumors were processed by laser microdissection (LMD) to enrich tumor cells. DNA, RNA, and protein were simultaneously extracted from each tumor preparation, followed by whole genome sequencing, paired-end RNA sequencing, global proteomics and phosphoproteomics. Differential feature analysis, pathway analysis and survival analysis were performed to better understand DTBC and investigate biomarkers. RESULTS: We observed distinct variations in gene mutations, structural variations, and chromosomal alterations between DTBC and LumA breast tumors. DTBC tumors predominantly had more mutations in TP53, PLXNB3, Zinc finger genes, and fewer mutations in SDC2, CDH1, PIK3CA, SVIL, and PTEN. Notably, Cytoband 1q21, which contains numerous cell proliferation-related genes, was significantly amplified in the DTBC tumors. LMD successfully minimized stromal components and increased RNA-protein concordance, as evidenced by stromal score comparisons and proteomic analysis. Distinct DTBC and LumA-enriched clusters were observed by proteomic and phosphoproteomic clustering analysis, some with survival differences. Phosphoproteomics identified two distinct phosphoproteomic profiles for high relapse-risk and low relapse-risk basal-like tumors, involving several genes known to be associated with breast cancer oncogenesis and progression, including KIAA1522, DCK, FOXO3, MYO9B, ARID1A, EPRS, ZC3HAV1, and RBM14. Lastly, an integrated pathway analysis of multi-omics data highlighted a robust enrichment of proliferation pathways in DTBC tumors. CONCLUSIONS: This study provides an integrated proteogenomic characterization of DTBC vs LumA with tumor cells enriched through laser microdissection. We identified many common features of DTBC tumors and the phosphopeptides that could serve as potential biomarkers for high/low relapse-risk basal-like BC and possibly guide treatment selections.

Association of clinicopathologic and molecular factors with the occurrence of positive margins in breast cancer.

PURPOSE: To explore the association of clinicopathologic and molecular factors with the occurrence of positive margins after first surgery in breast cancer. METHODS: The clinical and RNA-Seq data for 951 (75 positive and 876 negative margins) primary breast cancer patients from The Cancer Genome Atlas (TCGA) were used. The role of each clinicopathologic factor for margin prediction and also their impact on survival were evaluated using logistic regression, Fisher's exact test, and Cox proportional hazards regression models. In addition, differential expression analysis on a matched dataset (71 positive and 71 negative margins) was performed using Deseq2 and LASSO regression. RESULTS: Association studies showed that higher stage, larger tumor size (T), positive lymph nodes (N), and presence of distant metastasis (M) significantly contributed (p ≤ 0.05) to positive surgical margins. In case of surgery, lumpectomy was significantly associated with positive margin compared to mastectomy. Moreover, PAM50 Luminal A subtype had higher chance of positive margin resection compared to Basal-like subtype. Survival models demonstrated that positive margin status along with higher stage, higher TNM, and negative hormone receptor status was significant for disease progression. We also found that margin status might be a surrogate of tumor stage. In addition, 29 genes that could be potential positive margin predictors and 8 pathways were identified from molecular data analysis. CONCLUSION: The occurrence of positive margins after surgery was associated with various clinical factors, similar to the findings reported in earlier studies. In addition, we found that the PAM50 intrinsic subtype Luminal A has more chance of obtaining positive margins compared to Basal type. As the first effort to pursue molecular understanding of the margin status, a gene panel of 29 genes including 17 protein-coding genes was also identified for potential prediction of the margin status which needs to be validated using a larger sample set.

Predictors of Transition Outcomes in Cystic Fibrosis: Analysis of National Patient Registry and CF RISE (Responsibility. Independence. Self-care. Education) Data.

OBJECTIVE: To identify predictors of change in lung function and body weight during health care transition in cystic fibrosis (CF). METHODS: We conducted a retrospective cohort study using data from the CF Foundation Patient Registry and the web-based transition program CF RISE (Responsibility. Independence. Self-care. Education) for patients aged 16-25 years who transitioned to adult care from 2013 through 2019. We modeled change in forced expiratory volume in 1 second % predicted and weight using linear regression fit with generalized estimating equations. Predictors included gap in care (time between last pediatric and first adult outpatient visit), transition program engagement, and sociodemographic and medical factors. RESULTS: Among 12 420 adolescents and young adults (AYAs), 3876 transitioned to adult care with a median gap in care of 7.6 months. Patients from CF centers with greater rates of CF RISE engagement had improved lung function and weight at their first adult outpatient visit. Coverage on a parent's insurance plan and absence of CF complications predicted increased lung function. History of a nonlung transplant and sinus disease predicted increased weight. Comorbid diabetes mellitus and gaps in care >3 months predicted decreased lung function with longer gaps in care associated with greater decrease. A gap in care of 6-9 months predicted decreased weight. Control variables including baseline forced expiratory volume in 1 second and weight, and exacerbation status were also statistically significant. CONCLUSIONS: Findings suggest 2 promising targets to improve transition of AYAs with CF: increasing AYA engagement in CF RISE and reducing gaps in care during the transition period.

Nurse Practitioner Care Environments and Racial and Ethnic Disparities in Hospitalization Among Medicare Beneficiaries with Coronary Heart Disease.

BACKGROUND: Nurse practitioners care for patients with cardiovascular disease, particularly those from racial and ethnic minority groups, and can help assure equitable health outcomes. Yet, nurse practitioners practice in challenging care environments, which limits their ability to care for patients. OBJECTIVE: To determine whether primary care nurse practitioner care environments are associated with racial and ethnic disparities in hospitalizations among older adults with coronary heart disease. DESIGN: In this observational study, a cross-sectional survey was conducted among primary care nurse practitioners in 2018-2019 who completed a valid measure of care environment. The data was merged with 2018 Medicare claims data for patients with coronary heart disease. PARTICIPANTS: A total of 1244 primary care nurse practitioners and 180,216 Medicare beneficiaries 65 and older with coronary heart disease were included. MAIN MEASURES: All-cause and ambulatory care sensitive condition hospitalizations in 2018. KEY RESULTS: There were 50,233 hospitalizations, 9068 for ambulatory care sensitive conditions. About 28% of patients had at least one hospitalization. Hospitalizations varied by race, being highest among Black patients (33.5%). Care environment moderated the relationship between race (Black versus White) and hospitalization (OR 0.93; 95% CI, 0.88-0.98). The lowest care environment was associated with greater hospitalization among Black (odds ratio=1.34; 95% CI, 1.20-1.49) compared to White beneficiaries. Practices with the highest care environment had no racial differences in hospitalizations. There was no interaction effect between care environment and race for ambulatory care sensitive condition hospitalizations. Nurse practitioner care environment had a protective effect on these hospitalizations (OR, 0.96; 95% CI, 0.92-0.99) for all beneficiaries. CONCLUSIONS: Unfavorable care environments were associated with higher hospitalization rates among Black than among White beneficiaries with coronary heart disease. Racial disparities in hospitalization rates were not detected in practices with high-quality care environments, suggesting that improving nurse practitioner care environments could reduce racial disparities in hospitalizations.

Macrophage neogenin deficiency exacerbates myocardial remodeling and inflammation after acute myocardial infarction through JAK1-STAT1 signaling.

Immune response plays a crucial role in post-myocardial infarction (MI) myocardial remodeling. Neogenin (Neo1), a multifunctional transmembrane receptor, plays a critical role in the immune response; however, whether Neo1 participates in pathological myocardial remodeling after MI is unclear. Our study found that Neo1 expression changed significantly after MI in vivo and after LPS + IFN-γ stimulation in bone marrow-derived macrophages (BMDMs) in vitro. Neo1 functional deficiency (using a neutralizing antibody) and macrophage-specific Neo1 deficiency (induced by Neo1flox/flox;Cx3cr1cre mice) increased infarction size, enhanced cardiac fibrosis and cardiomyocyte apoptosis, and exacerbated left ventricular dysfunction post-MI in mice. Mechanistically, Neo1 deficiency promoted macrophage infiltration into the ischemic myocardium and transformation to a proinflammatory phenotype, subsequently exacerbating the inflammatory response and impairing inflammation resolution post-MI. Neo1 deficiency regulated macrophage phenotype and function, possibly through the JAK1-STAT1 pathway, as confirmed in BMDMs in vitro. Blocking the JAK1-STAT1 pathway with fludarabine phosphate abolished the impact of Neo1 on macrophage phenotype and function, inflammatory response, inflammation resolution, cardiomyocyte apoptosis, cardiac fibrosis, infarction size and cardiac function. In conclusion, Neo1 deficiency aggravates inflammation and left ventricular remodeling post-MI by modulating macrophage phenotypes and functions via the JAK1-STAT1 signaling pathway. These findings highlight the anti-inflammatory potential of Neo1, offering new perspectives for therapeutic targets in MI treatment. Neo1 deficiency aggravated inflammation and left ventricular remodeling after MI by modulating macrophage phenotypes and functions via the JAK1-STAT1 signaling pathway.

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 due to 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 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.

Assessing Associations Between Health Information Technology Maturity and Nursing Home Survey Deficiencies.

One in three nursing home (NH) residents experience adverse events. One strategy for safer NH care is health information technology (HIT). Two national NH surveys measuring HIT maturity were administered in 2020 (N = 719) and 2021 (N = 312). Quarterly NH survey deficiencies from the same years were linked to HIT maturity surveys. Descriptive statistics and logistic regression were used in analysis. NHs were of similar size and location, with more for-profit facilities. Most (67.5% and 61.9%, respectively) NH administrators reported having capabilities to share data internally within their facility, and not externally. Mean HIT maturity scores increased from Year 1 to Year 2. Over 2 years, 5,406 deficiencies were reported, mostly (31.3%) for nutrition and dietary deficiencies. There were negative associations between HIT maturity and deficiency scope. With a 1-unit increase in HIT maturity, relative risk of widespread scope decreased by 14%. Among covariates, bed size, staffing, and year were significant factors associated with deficiency scope. [Journal of Gerontological Nursing, 50(1), 8-14.].

Facet Engineering and Pore Design Boost Dynamic Fe Exchange in Oxygen Evolution Catalysis to Break the Activity-Stability Trade-Off.

The oxygen evolution reaction (OER) plays a vital role in renewable energy technologies, including in fuel cells, metal-air batteries, and water splitting; however, the currently available catalysts still suffer from unsatisfactory performance due to the sluggish OER kinetics. Herein, we developed a new catalyst with high efficiency in which the dynamic exchange mechanism of active Fe sites in the OER was regulated by crystal plane engineering and pore structure design. High-density nanoholes were created on cobalt hydroxide as the catalyst host, and then Fe species were filled inside the nanoholes. During the OER, the dynamic Fe was selectively and strongly adsorbed by the (101̅0) sites on the nanohole walls rather than the (0001) basal plane, and at the same time the space-confining effect of the nanohole slowed down the Fe diffusion from catalyst to electrolyte. As a result, a local high-flux Fe dynamic equilibrium inside the nanoholes for OER was achieved, as demonstrated by the Fe57 isotope labeled mass spectrometry, thereby delivering a high OER activity. The catalyst showed a remarkably low overpotential of 228 mV at a current density of 10 mA cm-2, which is among the best cobalt-based catalysts reported so far. This special protection strategy for Fe also greatly improved the catalytic stability, reducing the Fe leaching amount by 2 orders of magnitude compared with the pure Fe hydroxide catalyst and thus delivering a long-term stability of 130 h. An assembled Zn-air battery was stably cycled for 170 h with a low discharge/charge voltage difference of 0.72 V.

Rapid Bacteriophage Quantification by Digital Biosensing on a SlipChip Microfluidic Device.

The rise of antimicrobial resistance (AMR) is a major global public health concern, and it is urgent to develop new antimicrobial drugs and alternative therapies. There has been growing interest in the use of phage therapy as an alternative to treat AMR, and it has shown promising results in early studies and clinical trials. Phage quantification is a crucial step in the development and application of phage therapy. The traditional double-layer plaque assay requires cumbersome manual operations and typically takes up to 18 h to yield a rough phage estimation. Spectrophotometry, flow cytometry, and PCR-based methods cannot distinguish between infectious and noninfectious phages. Here, we developed a digital biosensing method for rapid bacteriophage quantification on a digital phage SlipChip (dp-SlipChip) microfluidic device containing 2304 microdroplets in 3 nL. By compartmentalizing the phages and bacteria in nanoliter droplets and analyzing the growth profile of bacteria at 3 h, the number of infectious phages can be precisely quantified. The results from the dp-SlipChip were consistent with the traditional double-layer plaque assay method and exhibited higher consistency and repeatability. The dp-SlipChip does not require a complex fluidic handling instrument to generate and manipulate droplets. This SlipChip-based digital biosensing method not only provides a promising tool for rapid phage quantification, which is important for the use of phages in clinical practice to treat antimicrobial-resistant bacteria, but can also be used as an ultrasensitive, high-specificity method to detect bacteria. Furthermore, this approach can be applied to other digital biology studies that require analysis at the single-object level.

The Impact of Primary Care Practice Structural Capabilities on Nurse Practitioner Burnout, Job Satisfaction, and Intent to Leave.

BACKGROUND: Lack of structure for care delivery (ie, structural capabilities) has been linked to lower quality of care and negative patient outcomes. However, little research examines the relationship between practice structural capabilities and nurse practitioner (NP) job outcomes. OBJECTIVES: We investigated the association between structural capabilities and primary care NP job outcomes (ie, burnout, job dissatisfaction, and intent to leave). RESEARCH DESIGN: Secondary analysis of 2018-2019 cross-sectional data. SUBJECTS: A total of 1110 NPs across 1002 primary care practices in 6 states. MEASURES: We estimated linear probability models to assess the association between structural capabilities and NP job outcomes, controlling for NP work environment, demographics, and practice features. RESULTS: The average structural capabilities score (measured on a scale of 0-1) across practices was 0.6 (higher score indicates more structural capabilities). After controlling for potential confounders, we found that a 10-percentage point increase in the structural capabilities score was associated with a 3-percentage point decrease in burnout ( P <0.001), a 2-percentage point decrease in job dissatisfaction ( P <0.001), and a 3-percentage point decrease in intent to leave ( P <0.001). CONCLUSIONS: Primary care NPs report lower burnout, job dissatisfaction, and intent to leave when working in practices with greater structural capabilities for care delivery. These findings suggest that efforts to improve structural capabilities not only facilitate effective care delivery and benefit patients but they also support NPs and strengthen their workforce participation. Practice leaders should further invest in structural capabilities to improve primary care provider job outcomes.

Primary Care Practice Structural Capabilities and Emergency Department Utilization Among High-Need High-Cost Patients.

BACKGROUND: US primary care practices are actively identifying strategies to improve outcomes and reduce costs among high-need high-cost (HNHC) patients. HNHC patients are adults with high health care utilization who suffer from multiple chronic medical and behavioral health conditions such as depression or substance abuse. HNHC patients with behavioral health conditions face heightened challenges accessing timely primary care and managing their conditions, which is reflected by their high rates of emergency department (ED) utilization and preventable spending. Structural capabilities (i.e., care coordination, chronic disease registries, shared communication systems, and after-hours care) are key attributes of primary care practices which can enhance access and quality of chronic care delivery. OBJECTIVE: The purpose of this study was to analyze the association between structural capabilities and ED utilization among HNHC patients with behavioral health conditions. DESIGN AND MEASURES: We merged cross-sectional survey data on structural capabilities from 240 primary care practices in Arizona and Washington linked with Medicare claims data on 70,182 HNHC patients from 2019. KEY RESULTS: Using multivariable Poisson models, we found shared communication systems were associated with lower rates of all-cause and preventable ED utilization among HNHC patients with alcohol use (all-cause: aRR 0.72, 95% CI: 0.62, 0.84; preventable: aRR 0.5, 95% CI: 0.40, 0.64) and HNHC patients with substance use disorders (all-cause: aRR 0.76, 95% CI: 0.68, 0.85; preventable: aRR 0.61, 95% CI: 0.52, 0.71). Care coordination was also associated with decreased rates of ED utilization among the overall HNHC population and those with alcohol use, but not among HNHC patients with depression or substance use disorders. CONCLUSION: Shared communication systems and care coordination have the potential to increase the effectiveness of primary care delivery for specific HNHC patients.

Structure-based mechanism and inhibition of cholesteryl ester transfer protein.

PURPOSE OF REVIEW: Cholesteryl ester transfer proteins (CETP) regulate plasma cholesterol levels by transferring cholesteryl esters (CEs) among lipoproteins. Lipoprotein cholesterol levels correlate with the risk factors for atherosclerotic cardiovascular disease (ASCVD). This article reviews recent research on CETP structure, lipid transfer mechanism, and its inhibition. RECENT FINDINGS: Genetic deficiency in CETP is associated with a low plasma level of low-density lipoprotein cholesterol (LDL-C) and a profoundly elevated plasma level of high-density lipoprotein cholesterol (HDL-C), which correlates with a lower risk of atherosclerotic cardiovascular disease (ASCVD). However, a very high concentration of HDL-C also correlates with increased ASCVD mortality. Considering that the elevated CETP activity is a major determinant of the atherogenic dyslipidemia, i.e., pro-atherogenic reductions in HDL and LDL particle size, inhibition of CETP emerged as a promising pharmacological target during the past two decades. CETP inhibitors, including torcetrapib, dalcetrapib, evacetrapib, anacetrapib and obicetrapib, were designed and evaluated in phase III clinical trials for the treatment of ASCVD or dyslipidemia. Although these inhibitors increase in plasma HDL-C levels and/or reduce LDL-C levels, the poor efficacy against ASCVD ended interest in CETP as an anti-ASCVD target. Nevertheless, interest in CETP and the molecular mechanism by which it inhibits CE transfer among lipoproteins persisted. Insights into the structural-based CETP-lipoprotein interactions can unravel CETP inhibition machinery, which can hopefully guide the design of more effective CETP inhibitors that combat ASCVD. Individual-molecule 3D structures of CETP bound to lipoproteins provide a model for understanding the mechanism by which CETP mediates lipid transfer and which in turn, guide the rational design of new anti-ASCVD therapeutics.

The role of semaphorins in cardiovascular diseases: Potential therapeutic targets and novel biomarkers.

Semaphorins (Semas), which belongs to the axonal guidance molecules, include 8 classes and could affect axon growth in the nervous system. Recently, semaphorins were found to regulate other pathophysiological processes, such as immune response, oncogenesis, tumor angiogenesis, and bone homeostasis, through binding with their plexin and neuropilin receptors. In this review, we summarized the detailed role of semaphorins and their receptors in the pathological progression of various cardiovascular diseases (CVDs), highlighting that semaphorins may be potential therapeutic targets and novel biomarkers for CVDs.