Accumulation of 8,9-unsaturated sterols drives oligodendrocyte formation and remyelination.

Regeneration of myelin is mediated by oligodendrocyte progenitor cells-an abundant stem cell population in the central nervous system (CNS) and the principal source of new myelinating oligodendrocytes. Loss of myelin-producing oligodendrocytes in the CNS underlies a number of neurological diseases, including multiple sclerosis and diverse genetic diseases1-3. High-throughput chemical screening approaches have been used to identify small molecules that stimulate the formation of oligodendrocytes from oligodendrocyte progenitor cells and functionally enhance remyelination in vivo4-10. Here we show that a wide range of these pro-myelinating small molecules function not through their canonical targets but by directly inhibiting CYP51, TM7SF2, or EBP, a narrow range of enzymes within the cholesterol biosynthesis pathway. Subsequent accumulation of the 8,9-unsaturated sterol substrates of these enzymes is a key mechanistic node that promotes oligodendrocyte formation, as 8,9-unsaturated sterols are effective when supplied to oligodendrocyte progenitor cells in purified form whereas analogous sterols that lack this structural feature have no effect. Collectively, our results define a unifying sterol-based mechanism of action for most known small-molecule enhancers of oligodendrocyte formation and highlight specific targets to propel the development of optimal remyelinating therapeutics.

Sex-specific effects of calving season on joint health and biomarkers in Montana ranchers.

BACKGROUND: Agricultural workers have a higher incidence of osteoarthritis (OA), but the etiology behind this phenomenon is unclear. Calving season, which occurs in mid- to late-winter for ranchers, includes physical conditions that may elevate OA risk. Our primary aim was to determine whether OA biomarkers are elevated at the peak of calving season compared to pre-season, and to compare these data with joint health survey information from the subjects. Our secondary aim was to detect biomarker differences between male and female ranchers. METHODS: During collection periods before and during calving season, male (n = 28) and female (n = 10) ranchers completed joint health surveys and provided samples of blood, urine, and saliva for biomarker analysis. Statistical analyses examined associations between mean biomarker levels and survey predictors. Ensemble cluster analysis identified groups having unique biomarker profiles. RESULTS: The number of calvings performed by each rancher positively correlated with plasma IL-6, serum hyaluronic acid (HA) and urinary CTX-I. Thiobarbituric acid reactive substances (TBARS), a marker of oxidative stress, was significantly higher during calving season than pre-season and was also correlated with ranchers having more months per year of joint pain. We found evidence of sexual dimorphism in the biomarkers among the ranchers, with leptin being elevated and matrix metalloproteinase-3 diminished in female ranchers. The opposite was detected in males. WOMAC score was positively associated with multiple biomarkers: IL-6, IL-2, HA, leptin, C2C, asymmetric dimethylarginine, and CTX-I. These biomarkers represent enzymatic degradation, inflammation, products of joint destruction, and OA severity. CONCLUSIONS: The positive association between number of calvings performed by each rancher (workload) and both inflammatory and joint tissue catabolism biomarkers establishes that calving season is a risk factor for OA in Montana ranchers. Consistent with the literature, we found important sex differences in OA biomarkers, with female ranchers showing elevated leptin, whereas males showed elevated MMP-3.

Infective Endocarditis in Patients Addicted to Injected Opioid Drugs.

BACKGROUND: Persons who inject drugs and require surgery for infective endocarditis have 2 potentially lethal diseases. Current postoperative rehabilitation efforts seem ineffective in preventing loss to follow-up, injection drug use relapse (relapse), and death. OBJECTIVES: The purpose of this study was to characterize drug use, psychosocial issues, surgical outcome, and postoperative addiction management, as well as loss to follow-up, relapse, and mortality and their risk factors. METHODS: From January 2010 to June 2020, 227 persons who inject drugs, age 36 ± 9.9 years, underwent surgery for infective endocarditis at a quaternary hospital having special interest in developing addiction management programs. Postsurgery loss to follow-up, relapse, and death were assessed as competing risks and risk factors identified parametrically and by machine learning. CIs are 68% (±1 SE). RESULTS: Heroin was the most self-reported drug injected (n = 183 [81%]). Psychosocial issues included homelessness (n = 56 [25%]), justice system involvement (n = 150 [66%]), depression (n = 118 [52%]), anxiety (n = 104 [46%]), and post-traumatic stress disorder (n = 33 [15%]). Four (1.8%) died in-hospital. Medication for opioid use disorder prescribed at discharge increased from 0% in 2010 to 100% in 2020. At 1 and 5 years, conditional probabilities of loss to follow-up were 16% (68% CI: 13%-22%) and 59% (68% CI: 44%-65%), relapse 32% (68% CI: 28%-34%) and 79% (68% CI: 74%-83%), and mortality 21% (68% CI: 18%-23%) and 68% (68% CI: 62%-72%). Younger age, heroin use, and lower education level were predictors of relapse. CONCLUSIONS: Infective endocarditis surgery can be performed with low mortality in persons who inject drugs, but addiction is far more lethal. Risk of loss to follow-up and relapse require more effective addiction strategies without which this major loss to society will continue.

Longitudinal versus circumferential biomechanical behavior of the aneurysmal ascending aorta.

OBJECTIVES: We evaluate the independent effects of patient and aortic tissue characteristics on biaxial physiologic mechanical metrics in aneurysmal and nonaneurysmal tissues, and uniaxial failure metrics in aneurysmal tissue, comparing longitudinal and circumferential behavior. METHODS: From February 2017 to October 2022, 382 aortic specimens were collected from 134 patients; 268 specimens underwent biaxial testing, and 114 specimens underwent uniaxial testing. Biaxial testing evaluated Green-Lagrange transition strain and low and high tangent moduli. Uniaxial testing evaluated failure stretch, Cauchy stress, and low and high tangent moduli. Longitudinal gradient boosting models were implemented to estimate mechanical metrics and covariates of importance. RESULTS: On biaxial testing, nonaneurysmal tissue was less deformable and exhibited a lower transition strain than aneurysmal tissue in the longitudinal (0.18 vs 0.30, P < .001) and circumferential (0.25 vs 0.30, P = .01) directions. Older age and increasing ascending aortic length contributed most to predicting transition strain. On uniaxial testing, longitudinal specimens failed at lower stretch (1.4 vs 1.5, P = .003) and Cauchy stress (1.0 vs 1.9 kPa, P < .001) than circumferential specimens. Failure stretch and Cauchy stress were most strongly associated with tissue orientation and decreased sharply with older age. Age, ascending aortic length, and tissue thickness were the most frequent covariates predicting mechanical metrics across 10 prediction models. CONCLUSIONS: Age was the strongest predictor of mechanical behavior. After adjusting for age, nonaneurysmal tissue was less deformable than aneurysmal tissue. Differences in longitudinal and circumferential mechanics contribute to tissue dysfunction and failure in ascending aneurysms. This highlights the need to better understand the effects of age, ascending aortic length, and thickness on clinical aortic behavior.

Age is superior to aortopathy phenotype as a predictor of aortic mechanics in patients with bicuspid valve.

OBJECTIVES: Bicuspid aortic valve (BAV) aortopathy is defined by 3 phenotypes-root, ascending, and diffuse-based on region of maximal aortic dilation. We sought to determine the association between aortic mechanical behavior and aortopathy phenotype versus other clinical variables. METHODS: From August 1, 2016, to March 1, 2023, 375 aortic specimens were collected from 105 patients undergoing elective ascending aortic aneurysm repair for BAV aortopathy. Planar biaxial data (191 specimens) informed constitutive descriptors of the arterial wall that were combined with in vivo geometry and hemodynamics to predict stiffness, stress, and energy density under physiologic loads. Uniaxial testing (184 specimens) evaluated failure stretch and failure Cauchy stress. Boosting regression was implemented to model the association between clinical variables and mechanical metrics. RESULTS: There were no significant differences in mechanical metrics between the root phenotype (N = 33, 31%) and ascending/diffuse phenotypes (N = 72, 69%). Biaxial testing demonstrated older age was associated with increased circumferential stiffness, decreased stress, and decreased energy density. On uniaxial testing, longitudinally versus circumferentially oriented specimens failed at significantly lower Cauchy stress (50th [15th, 85th percentiles]: 1.0 [0.7, 1.6] MPa vs 1.9 [1.3, 3.1] MPa; P < .001). Age was associated with decreased failure stretch and stress. Elongated ascending aortas were also associated with decreased failure stress. CONCLUSIONS: Aortic mechanical function under physiologic and failure conditions in BAV aortopathy is robustly associated with age and poorly associated with aortopathy phenotype. Data suggesting that the root phenotype of BAV aortopathy portends worse outcomes are unlikely to be related to aberrant, phenotype-specific tissue mechanics.

Well-functioning bicuspid aortic valves should be preserved during aortic replacement for the ascending aortopathy phenotype.

OBJECTIVES: Consensus has not been reached on whether or not to replace or preserve a well-functioning bicuspid aortic valve (BAV) in patients undergoing aortic replacement for the ascending phenotype of BAV aortopathy. We characterize morphology, evaluate progression of aortic regurgitation or aortic stenosis, and investigate the need for aortic valve replacement in patients whose well-functioning BAV was preserved during ascending aortic replacement ≥10 years prior. METHODS: From January 1991 to August 2011, 191 patients with a well-functioning BAV underwent supracoronary aortic replacement (113 valves were minimally repaired). Aortic morphology was evaluated, aortic regurgitation grade and transvalvular aortic gradient modeled parametrically, and survival assessed by the Kaplan-Meier method. Median follow-up was 10 years. RESULTS: Mean aortic diameter was 2.9 ± 0.53 cm at the annulus and 4.2 ± 0.55 cm at the sinuses. Mean maximum ascending diameter was 5.1 ± 0.49 cm. All patients exhibited a cusp-fusion BAV phenotype. Fifteen-year progression to severe aortic regurgitation was 3.2%. Mean aortic valve gradient began to rise 5 years postoperatively to 27 mm Hg by 14 years. Freedom from aortic valve replacement at 1, 5, 10, and 15 years was 100%, 95%, 83%, and 63%, respectively. Minimal valve repair was not associated with late aortic valve replacement. Fifteen-year survival was 74%. CONCLUSIONS: Preserving a well-functioning BAV should be considered in carefully selected patients undergoing aortic replacement for the ascending phenotype of BAV aortopathy. The valves remain durable in the long term, with slow progression of regurgitation or stenosis, and low probability of aortic valve replacement through 10 years.

Ultra-Hybrid Repair: Open Thoracoabdominal Completion After Descending Stent Grafting.

To characterize patient risk profiles and outcomes associated with staged ultra-hybrid repair of extensive aortic disease, in which open thoracoabdominal completion was performed after thoracic stent grafting. From 1/2006 to 1/2021, 92 patients underwent open thoracoabdominal repair of chronic dissection (n=58, 63%), degenerative aneurysm (n=28, 30%), endoleak (n=4, 4.3%), or symptomatic acute type B dissection (n=2, 2.2%) after descending thoracic stent grafting (69, 75%), frozen elephant trunk (5, 5%), or both (18, 20%). The surgical graft was sewn to the distal endovascular device in situ, reducing the extent of the open procedure and eliminating the need for hypothermic circulatory arrest. Mean age was 58±13 years, 89 (97%) were hypertensive, 38 (43%) had chronic obstructive pulmonary disease, 63 (72%) were smokers, 20 (24%) had a prior stroke, and 33 (36%) had a suspected or confirmed heritable aortic condition. Hospital mortality was 7.6% (n=7). Complications included dialysis (16, 20%), tracheostomy (8, 8.7%), stroke (5, 5.7%), and permanent paralysis (6, 6.9%). Survival at 1, 3, and 5 years was 80%, 71%, and 66%, respectively. Mortality was associated with higher blood urea nitrogen and longer distance between the distal endograft edge and proximal patent visceral vessel (P=0.004 and .01, respectively). Patients with extensive aortic disease undergoing open aortic repair after thoracic stent grafting are often young with chronic dissection, multiple comorbidities, or a heritable aortic condition. Success of staged ultra-hybrid operations demonstrates open and endovascular repair strategies are complementary, even when performed in a high-risk patient population.

Solvent-mediated charge redistribution in photodissociation of IBr(-) and IBr(-)(CO2).

A combined experimental and theoretical investigation of photodissociation dynamics of IBr(-) and IBr(-)(CO(2)) on the B ((2)Σ(1/2)(+)) excited electronic state is presented. Time-resolved photoelectron spectroscopy reveals that in bare IBr(-) prompt dissociation forms exclusively I∗ + Br(-). Compared to earlier dissociation studies of IBr(-) excited to the A' ((2)Π(1∕2)) state, the signal rise is delayed by 200 ± 20 fs. In the case of IBr(-)(CO(2)), the product distribution shows the existence of a second major (∼40%) dissociation pathway, Br∗ + I(-). In contrast to the primary product channel, the signal rise associated with this pathway shows only a 50 ± 20 fs delay. The altered product branching ratio indicates that the presence of one solvent-like CO(2) molecule dramatically affects the electronic structure of the dissociating IBr(-). We explore the origins of this phenomenon with classical trajectories, quantum wave packet studies, and MR-SO-CISD calculations of the six lowest-energy electronic states of IBr(-) and 36 lowest-energy states of IBr. We find that the CO(2) molecule provides sufficient solvation energy to bring the initially excited state close in energy to a lower-lying state. The splitting between these states and the time at which the crossing takes place depend on the location of the solvating CO(2) molecule.

Building eConsult (Electronic Consults) Capability at an Academic Medical Center to Improve Efficiencies in Delivering Specialty Care.

As the COVID-19 health crisis continues to reshape healthcare, systems across the country face increasing pressure to adapt their models of care to expand access to care, while also improving efficiency and quality in the face of limited resources. Consequently, many have shown a growing interest and receptivity to the expansion of telehealth models to help meet these demands. Electronic consultations (eConsults) are a telehealth modality that allow for a non-face-to-face asynchronous consultation between a primary care provider (PCP) and a specialist aimed at facilitating specialist input without the need for a patient visit. The aim of this case study is to describe eConsults, how they differ from traditional in person models of care and other models of telemedicine and to review the evidence related to the effectiveness of eConsults by PCPs and clinicians from multiple specialties at the University of Colorado School of Medicine. We have worked to develop an infrastructure, delivery system integration, and care model adaptations that aim to improve delivery system performance by ensuring proper care in appropriate settings and lowering costs through reduced utilization. Lastly, we have increased care coordination, improved collaboration and better care transitions through strengthening of relationships between community-based PCPs and academic medical center-based specialists. This work has resulted in cost savings to patients and positive provider satisfaction.

The TAT Protein Transduction Domain as an Intra-Articular Drug Delivery Technology.

OBJECTIVE: Intra-articular drug delivery holds great promise for the treatment of joint diseases such as osteoarthritis. The objective of this study was to evaluate the TAT peptide transduction domain (TAT-PTD) as a potential intra-articular drug delivery technology for synovial joints. DESIGN: Experiments examined the ability of TAT conjugates to associate with primary chondrocytes and alter cellular function both in vitro and in vivo. Further experiments examined the ability of the TAT-PTD to bind to human osteoarthritic cartilage. RESULTS: The results show that the TAT-PTD associates with chondrocytes, is capable of delivering siRNA for chondrocyte gene knockdown, and that the recombinant enzyme TAT-Cre is capable of inducing in vivo genetic recombination within the knee joint in a reporter mouse model. Last, binding studies show that osteoarthritic cartilage preferentially uptakes the TAT-PTD from solution. CONCLUSIONS: The results suggest that the TAT-PTD is a promising delivery strategy for intra-articular therapeutics.

A combined experimental/theoretical investigation of the near-infrared photodissociation of IBr- (CO2)n.

We report the collaborative experimental and theoretical study of the time-resolved recombination dynamics of photodissociated IBr(-)(CO(2))(n) clusters. Excitation of the bare anionic chromophore to the dissociative A(') (2)Pi(1/2) state yields only I(-) and Br products. Interestingly, however, the addition of a few solvent molecules promotes recombination of the dissociating chromophore on the X (2)Sigma(1/2)(+) ground state, which correlates asymptotically with Br(-) and I products. This process is studied experimentally using time-resolved, pump-probe techniques and theoretically via nonadiabatic molecular dynamics simulations. In sharp contrast to previous I(2)(-) studies where more kinetic energy was released to the photofragments, the observed recombination times increase from picoseconds to nanoseconds with increasing cluster size up to n=10. The recombination times then drop dramatically back to picoseconds for cluster sizes n=11-14. This trend, seen both in experiment and theory, is explained by the presence of a solvent-induced well on the A(') state, the depth of which directly corresponds to the asymmetry of the solvation about the chromophore. The results seen for both the branching ratios and recombination times from experiment and theory show good qualitative agreement.

Assessing the Grell-Freitas Convection Parameterization in the NASA GEOS Modeling System.

We implemented and began to evaluate an alternative convection parameterization for the NASA Goddard Earth Observing System (GEOS) general circulation model (GCM). The proposed parameterization follows the mass flux approach with several closures, for equilibrium and nonequilibrium convection, and includes scale and aerosol aware functionalities. Recently, we extended the scheme to a trimodal spectral size distribution of allowed convective plumes to simulate the transition among shallow, congestus, and deep convection regimes. In addition, the inclusion of a new closure for nonequilibrium convection resulted in a substantial gain of realism in the model representation of the diurnal cycle of convection over the land. We demonstrated the scale-dependence functionality with a cascade of global-scale simulations from a nominal horizontal resolution of 50 km down to 6 km. The ability to realistically simulate the diurnal cycle of precipitation over various regions of the earth was verified against several remote sensing-derived intradiurnal precipitation estimates. We extended the model performance evaluation for weather-scale applications by bringing together some available operational short-range weather forecast models and global atmospheric reanalyses. Our results demonstrate that the GEOS GCM with the alternative convective parameterization has good properties and competitive skill in comparison with state-of-the-art observations and numerical simulations.

Solvent-mediated electron hopping: long-range charge transfer in IBr-(CO2) photodissociation.

Chemical bond breaking involves coupled electronic and nuclear dynamics that can take place on multiple electronic surfaces. Here we report a time-resolved experimental and theoretical investigation of nonadiabatic dynamics during photodissociation of a complex of iodine monobromide anion with carbon dioxide [IBr-(CO2)] on the second excited (A') electronic state. Previous experimental work showed that the dissociation of bare IBr- yields only I- + Br products. However, in IBr-(CO2), time-resolved photoelectron spectroscopy reveals that a subset of the dissociating molecules undergoes an electron transfer from iodine to bromine 350 femtoseconds after the initial excitation. Ab initio calculations and molecular dynamics simulations elucidate the mechanism for this charge hop and highlight the crucial role of the carbon dioxide molecule. The charge transfer between two recoiling atoms, assisted by a single solvent-like molecule, provides a notable limiting case of solvent-driven electron transfer over a distance of 7 angstroms.

Time-resolved study of solvent-induced recombination in photodissociated IBr-(CO2)n clusters.

We report the time-resolved recombination of photodissociated IBr-(CO2)n (n = 5-10) clusters following excitation to the dissociative IBr-A' 2Pi12 state of the chromophore via a 180 fs, 795 nm laser pulse. Dissociation from the A' state of the bare anion results in I- and Br products. Upon solvation with CO2, the IBr- chromophore regains near-IR absorption only after recombination and vibrational relaxation on the ground electronic state. The recombination time was determined by using a delayed femtosecond probe laser, at the same wavelength as the pump, and detecting ionic photoproducts of the recombined IBr- cluster ions. In sharp contrast to previous studies involving solvated I2-, the observed recombination times for IBr-(CO2)n increase dramatically with increasing cluster size, from 12 ps for n = 5 to 900 ps for n = 8,10. The nanosecond recombination times are especially surprising in that the overall recombination probability for these cluster ions is unity. Over the range of 5-10 solvent molecules, calculations show that the solvent is very asymmetrically distributed, localized around the Br end of the IBr- chromophore. It is proposed that this asymmetric solvation delays the recombination of the dissociating IBr-, in part through a solvent-induced well in the A' state that (for n = 8,10) traps the evolving complex. Extensive electronic structure calculations and nonadiabatic molecular dynamics simulations provide a framework to understand this unexpected behavior.

Photodissociation dynamics of IBr(-)(CO(2))(n), n<15.

We report the ionic photoproducts produced following photoexcitation of mass selected IBr(-)(CO(2))(n), n=0-14, cluster ions at 790 and 355 nm. These wavelengths provide single state excitation to two dissociative states, corresponding to the A(') (2)Pi(1/2) and B 2 (2)Sigma(1/2) (+) states of the IBr(-) chromophore. Excitation of these states in IBr(-) leads to production of I(-)+Br and Br(-)+I( *), respectively. Potential energy curves for the six lowest electronic states of IBr(-) are calculated, together with structures for IBr(-)(CO(2))(n), n=1-14. Translational energy release measurements on photodissociated IBr(-) determine the I-Br(-) bond strength to be 1.10+/-0.04 eV; related measurements characterize the A(') (2)Pi(1/2)<--X (2)Sigma(1/2) (+) absorption band. Photodissociation product distributions are measured as a function of cluster size following excitation to the A(') (2)Pi(1/2) and B 2 (2)Sigma(1/2) (+) states. The solvent is shown to drive processes such as spin-orbit relaxation, charge transfer, recombination, and vibrational relaxation on the ground electronic state. Following excitation to the A(') (2)Pi(1/2) electronic state, IBr(-)(CO(2))(n) exhibits size-dependent cage fractions remarkably similar to those observed for I(2) (-)(CO(2))(n). In contrast, excitation to the B 2 (2)Sigma(1/2) (+) state shows extensive trapping in excited states that dominates the recombination behavior for all cluster sizes we investigated. Finally, a pump-probe experiment on IBr(-)(CO(2))(8) determines the time required for recombination on the ground state following excitation to the A(') state. While the photofragmentation experiments establish 100% recombination in the ground electronic state for this and larger IBr(-) cluster ions, the time required for recombination is found to be approximately 5 ns, some three orders of magnitude longer than observed for the analogous I(2) (-) cluster ion. Comparisons are made with similar experiments carried out on I(2) (-)(CO(2))(n) and ICl(-)(CO(2))(n) cluster ions.