Impairment of an Endothelial NAD+-H2S Signaling Network Is a Reversible Cause of Vascular Aging.

A decline in capillary density and blood flow with age is a major cause of mortality and morbidity. Understanding why this occurs is key to future gains in human health. NAD precursors reverse aspects of aging, in part, by activating sirtuin deacylases (SIRT1-SIRT7) that mediate the benefits of exercise and dietary restriction (DR). We show that SIRT1 in endothelial cells is a key mediator of pro-angiogenic signals secreted from myocytes. Treatment of mice with the NAD+ booster nicotinamide mononucleotide (NMN) improves blood flow and increases endurance in elderly mice by promoting SIRT1-dependent increases in capillary density, an effect augmented by exercise or increasing the levels of hydrogen sulfide (H2S), a DR mimetic and regulator of endothelial NAD+ levels. These findings have implications for improving blood flow to organs and tissues, increasing human performance, and reestablishing a virtuous cycle of mobility in the elderly.

The health risk of social disadvantage is transplantable into a new host.

Low socioeconomic status (SES) is a risk factor for mortality and immune dysfunction across a wide range of diseases, including cancer. However, cancer is distinct in the use of allogeneic hematopoietic cell transplantation (HCT) as a treatment for hematologic malignancies to transfer healthy hematopoietic cells from one person to another. This raises the question of whether social disadvantage of an HCT cell donor, as assessed by low SES, might impact the subsequent health outcomes of the HCT recipient. To evaluate the cellular transplantability of SES-associated health risk, we analyzed the health outcomes of 2,005 HCT recipients who were transplanted for hematologic malignancy at 125 United States transplant centers and tested whether their outcomes differed as a function of their cell donor's SES (controlling for other known HCT-related risk factors). Recipients transplanted with cells from donors in the lowest quartile of SES experienced a 9.7% reduction in overall survival (P = 0.001) and 6.6% increase in treatment-related mortality within 3 y (P = 0.008) compared to those transplanted from donors in the highest SES quartile. These results are consistent with previous research linking socioeconomic disadvantage to altered immune cell function and hematopoiesis, and they reveal an unanticipated persistence of those effects after cells are transferred into a new host environment. These SES-related disparities in health outcomes underscore the need to map the biological mechanisms involved in the social determinants of health and develop interventions to block those effects and enhance the health of both HCT donors and recipients.

Race has no impact on prostate cancer-specific mortality, when comparing patients with similar risk of other-cause mortality: An analysis of a population-based cohort.

BACKGROUND: Other-cause mortality (OCM) can serve as a surrogate for access-to-care. The authors sought to compare prostate cancer-specific mortality (PCSM) in Black versus White men matched based on their calculated OCM risk. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was queried for Black and White men diagnosed with prostate cancer between 2004 to 2009, to collect long-term follow-up. A Cox regression was used to calculate the OCM risk using all available covariates. This calculated OCM risk was used to construct a 1:1 propensity score matched (PSM) cohort. Then, a competing-risks multivariable tested the impact of race on PCSM. RESULTS: A total of 94,363 patients were identified, with 19,398 Black men and 74,965 White men. The median (IQR) follow-up was 11.3 years (9.8-12.8). In the unmatched-cohort at 10-years, PCSM and OCM were 5.5% versus 3.5% and 13.8% versus 8.4% in non-Hispanic Black (NHB) versus non-Hispanic White (NHW) patients (all p < .0001). The standardized mean difference was <0.15 for all covariates, indicating a good match. In the matched cohort at 10-years, OCM was 13.6% and 10.0% in NHB versus NHW (p < .0001), whereas the PCSM was 5.3% versus 4.7% (p < .01). On competing-risks multivariable analysis on PCSM, Black men had a hazard ratio of 1.08 (95% confidence interval, 0.98-1.20) compared to White men with a p = .13. CONCLUSIONS: The results of this study showed similar PCSM in Black and White patients, when matched with their calculated OCM risk. This report is the first to indicate at a population-based level that race has no impact on PCSM. PLAIN LANGUAGE SUMMARY: Prostate cancer is a very common cancer among men and it is associated with health disparities that disproportionately impact Black men compared to White men. There is an on-going discussion of whether disparities between these two groups stem from genetic or environmental factors. This study sought to examine if matching based on overall health status, a proxy for the impact of social determinants of health, mitigated significant differences in outcomes. When matched using risk of death from any cause other than prostate cancer, Black and White men had no significant differences in prostate cancer death.

Identifying drivers of cost in pediatric liver transplantation.

Understanding the economics of pediatric liver transplantation (LT) is central to high-value care initiatives. We examined cost and resource utilization in pediatric LT nationally to identify drivers of cost and hospital factors associated with greater total cost of care. We reviewed 3295 children (<21 y) receiving an LT from 2010 to 2020 in the Pediatric Health Information System to study cost, both per LT and service line, and associated mortality, complications, and resource utilization. To facilitate comparisons, patients were stratified into high-cost, intermediate-cost, or low-cost tertiles based on LT cost. The median cost per LT was $150,836 [IQR $104,481-$250,129], with marked variance in cost within and between hospital tertiles. High-cost hospitals (HCHs) cared for more patients with the highest severity of illness and mortality risk levels (67% and 29%, respectively), compared to intermediate-cost (60%, 21%; p <0.001) and low-cost (51%, 16%; p <0.001) hospitals. Patients at HCHs experienced a higher prevalence of mechanical ventilation, total parental nutrition use, renal comorbidities, and surgical complications than other tertiles. Clinical (27.5%), laboratory (15.1%), and pharmacy (11.9%) service lines contributed most to the total cost. Renal comorbidities ($69,563) and total parental nutrition use ($33,192) were large, independent contributors to total cost, irrespective of the cost tertile ( p <0.001). There exists a significant variation in pediatric LT cost, with HCHs caring for more patients with higher illness acuity and resource needs. Studies are needed to examine drivers of cost and associated outcomes more granularly, with the goal of defining value and standardizing care. Such efforts may uniquely benefit the sicker patients requiring the strategic resources located within HCHs to achieve the best outcomes.

Unimer suppression enables supersaturated homopolymer swollen micelles with long-term stability after glassy entrapment.

Micelle sizes are critical for a range of applications where the simple ability to adjust and lock in specific stable sizes has remained largely elusive. While micelle swelling agents are well-known, their dynamic re-equilibration in solution implies limited stability. Here, a non-equilibrium processing sequence is studied where supersaturated homopolymer swelling is combined with glassy-core ("persistent") micelles. This path-dependent process was found to sensitively depend on unimer concentration as revealed by DLS, SAXS, and TEM analysis. Here, lower-selectivity solvent combinations led to the formation of unimer-homopolymer aggregates and eventual precipitation, reminiscent of anomalous micellization. In contrast, higher-selectivity solvents enabled supersaturated homopolymer loadings favored by rapid homopolymer insertion. The demonstrated ∼40-130 nm core-size tuning exceeded prior equilibrium demonstrations and subsequent core-vitrification enabled size persistence beyond 6 months. Lastly, the linear change in micelle diameter with homopolymer addition was found to correlate with a plateau in the interfacial area per copolymer chain.

Association of Radial Artery Access with Reduced Incidence of Acute Kidney Injury.

Objectives: To determine if radial artery (RA) access compared with femoral artery (FA) access for percutaneous coronary intervention (PCI) is associated with a lower incidence of acute kidney injury (AKI). Background: AKI results in substantial morbidity and cost following PCI. Prior studies comparing the occurrence of AKI associated with radial artery (RA) versus femoral artery (FA) access have mixed results. Methods: Using a large state-wide database, 14,077 patients (8,539 with RA and 5,538 patents with FA access) were retrospectively compared to assess the occurrence of AKI following PCI. To reduce selection bias and balance clinical data across the two groups, a novel machine learning method called a Generalized Boosted Model was conducted on the arterial access site generating a weighted propensity score for each variable. A logistic regression analysis was then performed on the occurrence of AKI following PCI using the weighted propensity scores from the Generalized Boosted Model. Results: As shown in other studies, multiple variables were associated with an increase in AKI after PCI. Only RA access (OR 0.82; 95% CI 0.74-0.91) and male gender (OR 0.80; 95% CI 0.72-0.89) were associated with a lower occurrence of AKI. Based on the calculated Mehran scores, patients were stratified into groups with an increasing risk of AKI. RA access was consistently found to have a lower risk of AKI compared with FA access across these groups of increasing risk. Conclusions: Compared with FA access, RA access is associated with an 18% lower rate of AKI following PCI. This effect was observed among different levels of risk for developing AKI. Although developed from a retrospective analysis, this study supports the use of RA access when technically possible in a diverse group of patients.

Discovery of a brain-sparing GIRK1/4 inhibitor for pharmacological cardioversion of atrial fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and a significant risk factor for ischemic stroke and heart failure. Marketed anti-arrhythmic drugs can restore sinus rhythm, but with limited efficacy and significant toxicities, including potential to induce ventricular arrhythmia. Atrial-selective ion channel drugs are expected to restore and maintain sinus rhythm without risk of ventricular arrhythmia. One such atrial-selective channel target is GIRK1/4 (G-protein regulated inwardly rectifying potassium channel 1/4). Here we describe 14b, a potent GIRK1/4 inhibitor developed to cardiovert AF to sinus rhythm while minimizing central nervous system exposure - an issue with preceding GIRK1/4 clinical candidates.

INTRAOPERATIVE BLEB BEHAVIOR IN SUBRETINAL GENE AUGMENTATION THERAPY FOR INHERITED RETINAL DISEASES.

PURPOSE: In subretinal gene therapy for inherited retinal diseases (IRDs), blebs may not propagate predictably in the direction of the injection cannula. We evaluated factors that influenced bleb propagation among various IRDs. METHODS: Retrospective review of all subretinal gene therapy procedures performed by a single surgeon between September 2018 and March 2020 for various IRDs. Main outcome measures were directional bias of bleb propagation and intraoperative foveal detachment. RESULTS: Desired injection volumes and/or foveal treatment were successfully achieved in all 70 eyes of 46 patients with IRD regardless of IRD indication. Bullous foveal detachment was associated with retinotomy closer to the fovea, posterior bleb bias, and greater bleb volumes ( P < 0.01). Blebs biased anteriorly or posteriorly based on disease indication ( P = 0.04) and age ( P < 0.001). Retinotomy location ≤ 3.7 mm (approximately two disk diameters) from the fovea favored foveal detachment ( P < 0.001). Multiple retinotomies and blebs allowed greater surface area coverage in some eyes, but intersecting blebs did not propagate further. CONCLUSION: Bleb formation and propagation are predictable based on patient age, retinotomy location, disease indication, and how tangentially fluid is directed into the subretinal space.

An isolated mid-anterolateral wall true ventricular aneurysm due to coronary artery disease.

Aneurysms following a myocardial infarction usually involve the apical wall segments. We present a case of a rare isolated mid-anterolateral wall aneurysm due to occlusion of a diagonal branch. We review the echocardiographic criteria for diagnosing a left ventricular (LV) aneurysm and discuss how to differentiate one from a more critical pseudoaneurysm. We demonstrate the utility of using ultrasound enhancing contrast and review imaging protocols for ruling out associated LV thrombus.

Ultrasound as a Useful Tool for a Peripheral Nerve Surgeon: Examples in Clinical Practice.

BACKGROUND: Peripheral nerve surgeons often require additional imaging for examination, diagnostic testing, and preoperative planning. Point-of-care ultrasound (US) is a cost-effective, accessible, and well-established technique that can assist the surgeon in diagnosing and treating select peripheral nerve pathologies. With this knowledge, the properly trained surgeon may perform US-guided nerve blocks to help accurately diagnose and treat causes of neuropathic pain. We offer this paper, not as an exhaustive review, but as a selection of various peripheral nerve pathologies, which the senior author treats, and their associated US examination findings. Our goal is to encourage other peripheral nerve surgeons to incorporate US into their practices. METHODS: We provide various cases from our outpatient peripheral nerve clinic demonstrating relevant US anatomy. We also review techniques for US guided nerve blocks with relevant anatomic landmarks. RESULTS: US imaging successfully assisted in identification and injection techniques for various peripheral nerve pathologies in a surgeon's practice. Examples were presented from the neck, trunk, upper extremity, and lower extremity. CONCLUSION: Our review highlights the use of US by a peripheral nerve surgeon in an outpatient private practice clinic to diagnose and treat select peripheral nerve pathologies. We encourage reconstructive surgeons to add US to their arsenal of diagnostic tools.

CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing's sarcoma.

The post-genomic era has seen many advances in our understanding of cancer pathways, yet resistance and tumor heterogeneity necessitate multiple approaches to target even monogenic tumors. Here, we combine phenotypic screening with chemical genetics to identify pre-messenger RNA endonuclease cleavage and polyadenylation specificity factor 3 (CPSF3) as the target of JTE-607, a small molecule with previously unknown target. We show that CPSF3 represents a synthetic lethal node in a subset of acute myeloid leukemia (AML) and Ewing's sarcoma cancer cell lines. Inhibition of CPSF3 by JTE-607 alters expression of known downstream effectors in AML and Ewing's sarcoma lines, upregulates apoptosis and causes tumor-selective stasis in mouse xenografts. Mechanistically, it prevents the release of newly synthesized pre-mRNAs, resulting in read-through transcription and the formation of DNA-RNA hybrid R-loop structures. This study implicates pre-mRNA processing, and specifically CPSF3, as a druggable target providing an avenue to therapeutic intervention in cancer.

Author Correction: CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing's sarcoma.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

COVID-19 Testing in African American Churches Using a Faith-Health- Academic Partnership.

Increasing access to COVID-19 testing in influential, accessible community settings is needed to address COVID-19 disparities among African Americans. We describe COVID-19 testing intervention approaches conducted in Kansas City, Missouri, African American churches via a faith-health-academic partnership. Trained faith leaders promoted COVID-19 testing with church and community members by implementing multilevel interventions using a tailored toolkit and standard education information. The local health department conducted more than 300 COVID-19 tests during or after Sunday church services and outreach ministry activities. (Am J Public Health. 2022;112(S9):S887-S891. https://doi.org/10.2105/AJPH.2022.306981).

High-χ, low-N micelles from partially perfluorinated block polymers.

Kinetically trapped ("persistent") micelles enable emerging applications requiring a constant core diameter. Preserving a χN barrier to chain exchange with low-N requires a commensurately higher χcore-solvent for micelle persistence. Low-N, high-χ micelles containing fluorophobic interactions were studied using poly(ethylene oxide-b-perfluorooctyl acrylate)s (O45FX, x = 8, 11) in methanolic solutions. DLS analysis of micelles revealed chain exchange only for O45F8 while SAXS analysis suggested elongated core block conformations commensurate with the contour lengths. Micelle chain exchange from solution perturbations were examined by characterizing their behavior as templates for inorganic materials via SAXS and SEM. In contrast to the F8 analog, the larger χN barrier for the O45F11 enabled persistent micelle behavior in both thin films and bulk samples despite the low Tg micelle core. Careful measures of micelle core diameters and pore sizes revealed that the nanoparticle distribution extended through the corona and 0.52 ± 0.15 nm into the core-corona interface, highlighting thermodynamics favoring both locations simultaneously.

How Well Do Emission Factors Approximate Emission Changes from Electricity System Models?

Multiple forms of marginal and average emission factors have been developed to estimate the carbon emissions of adding technologies, such as electric vehicles or solar panels, to the electricity grid. Different methods can produce very different results and conclusions, indicating that choosing between methods is not trivial. Researchers would therefore like to know how well these emission factors can approximate emission changes in the actual power grid. This question remains unanswered because of the difficulty in characterizing the accuracy of these methods. Ideally, estimates would be compared to measured emission changes, but it is implausible to measure these changes on an actual grid. Instead, we propose testing these emission factor methods in a controlled environment, using an electricity system dispatch model as a reference for comparison. We find that average emission factors have lower accuracy when estimating emissions from demand shifts and observe the same for demand-based marginal emission factors at an hourly resolution. In contrast, incremental and thermal marginal emission factors can reproduce the emission changes of a power grid model under many testing conditions and scenarios. We also find that easier-to-use annual time averages offer similar results to finer time resolutions for marginal and average factors, except demand-based.

Complex regional pain syndrome patient treated with a below knee amputation, implanting nerves directly into muscle: A case report.

Persistent, disabling lower extremity pain, outside the distribution of a single nerve, is termed chronic regional pain syndrome (CRPS), but, in reality, this chronic pain is often due to multiple peripheral nerve injuries. It is the purpose of this report to describe the first application of the "traditional," nerve implantation into muscle, usually used in the treatment of a painful neuroma, as a pre-emptive surgical technique in doing a below knee amputation (BKA). In 2011, a 51-year-old woman developed severe, disabling CRPS, after a series of operations to treat an enchondroma of the left fifth metatarsal. When appropriate peripheral nerve surgeries failed to relieve distal pain, a BKA was elected. The approach to the BKA included implantation of each transected peripheral nerve directly into an adjacent muscle. At 5.0 years after the patient's BKA, the woman reported full use of this extremity, using the prosthesis, and was free of phantom limb and residual limb pain. This anecdotal experience gives insight that long-term relief of lower extremity CRPS can be achieved by a traditional BKA utilizing the approach of implanting each transected nerve into an adjacent muscle.

Reducing burnout and enhancing work engagement among clinicians: The Minnesota experience.

BACKGROUND: The Minnesota Hospital Association (MHA) recognized the impact that burnout and disengagement had on the clinician population. A clinician task force developed a conceptual framework, followed by annual surveys and a series of interventions. Features of the job demands-resources model were used as the conceptual underpinning to this analysis. PURPOSE: The aim of this study was to assess the applicability of a clinician-driven conceptual model in understanding burnout and work engagement in the state of Minnesota. METHODOLOGY: Four thousand nine hundred ninety clinicians from 94 MHA member hospitals/systems responded to a 2018 survey using a brief instrument adapted, in part, from previously validated measures. RESULTS: As hypothesized, job demands were strongly related to burnout, whereas resources were most related to work engagement. Variables from the MHA model explained 40% of variability in burnout and 24% of variability in work engagement. Variables related to burnout with the highest beta weights included having sufficient time for work (-0.266), values alignment with leaders (-0.176), and teamwork efficiency (-0.123), all ps < .001. Variables most associated with engagement included values alignment (0.196), feeling appreciated (0.163), and autonomy (0.093), ps < .001. CONCLUSION: Findings support the basic premises of the proposed conceptual model. Remediable work-life conditions, such as having sufficient time to do the job, values alignment with leadership, teamwork efficiency, feeling appreciated, and clinician autonomy, manifested the strongest associations with burnout and work engagement. PRACTICE IMPLICATIONS: Interventions reducing job demands and strengthening resources such as values alignment, teamwork efficiency, and clinician autonomy are seen as having the greatest potential efficacy.

Factors associated with patient trust in their clinicians: Results from the Healthy Work Place Study.

BACKGROUND: Patient trust in their clinicians is an important aspect of health care quality, but little evidence exists on what contributes to patient trust. PURPOSE: The aim of this study was to determine workplace, clinician, and patient correlates of patient trust in their clinician. METHODOLOGY/APPROACH: The sample used baseline data from the Healthy Work Place trial, a randomized trial of 34 Midwest and East Coast primary care practices to explore factors associated with patient trust in their clinicians. A multivariate "best subset" regression modeling approach was used, starting with an item pool of 45 potential variables. Over 7 million models were tested, with a best subset of correlates determined using standard methods for scale optimization. Skewed variables were transformed to the fifth power using a Box-Cox algorithm. RESULTS: The final model of nine variables explained 38% of variance in patient trust at the patient level and 49% at the clinician level. Trust was related mainly to several aspects of care variables (including satisfaction with explanations, overall satisfaction with provider, and learning about their medical conditions and their clinician's personal manner), with lesser association with patient characteristics and clinician work conditions. CONCLUSION: Trust appears to be primarily related to what happens between clinicians and patients in the examination room. PRACTICE IMPLICATIONS: System changes such as patient-centered medical homes may have difficulty succeeding if the primacy of physician-patient interactions in inspiring patient trust and satisfaction is not recognized.

Mesoporous TiO2 Microparticles with Tailored Surfaces, Pores, Walls, and Particle Dimensions Using Persistent Micelle Templates.

Mesoporous microparticles are an attractive platform to deploy high-surface-area nanomaterials in a convenient particulate form that is broadly compatible with diverse device manufacturing methods. The applications for mesoporous microparticles are numerous, spanning the gamut from drug delivery to catalysis and energy storage. For most applications, the performance of the resulting materials depends upon the architectural dimensions including the mesopore size, wall thickness, and microparticle size, yet a synthetic method to control all these parameters has remained elusive. Furthermore, some mesoporous microparticle reports noted a surface skin layer which has not been tuned before despite the important effect of such a skin layer upon transport/encapsulation. In the present study, material precursors and block polymer micelles are combined to yield mesoporous materials in a microparticle format due to phase separation from a homopolymer matrix. The skin layer thickness was kinetically controlled where a layer integration via diffusion (LID) model explains its production and dissipation. Furthermore, the independent tuning of pore size and wall thickness for mesoporous microparticles is shown for the first time using persistent micelle templates (PMT). Last, the kinetic effects of numerous processing parameters upon the microparticle size are shown.