Impact of Frailty on Outcomes after Cardiac Surgery.

OBJECTIVE(S): To evaluate whether increasing frailty, as measured by the Clinical Frailty Scale (CFS), was associated with an increased risk of hospital mortality for patients undergoing cardiac surgery. METHODS: A retrospective binational cohort study of 46,928 patients who underwent cardiac surgery in Australia and New Zealand was conducted. The primary exposure, frailty, was measured using the CFS. Associations between frailty and the primary outcome, hospital mortality, were evaluated using multivariable, mixed effects logistic regression models. Secondary outcomes including hospital and ICU length of stay, invasive ventilation hours, need for renal replacement therapy and tracheostomy, and non-home discharge were also evaluated. RESULTS: 6.7% (3122/46928) patients were classified as frail (CFS 5-8) and 93.3% (43,806/46,928) were non-frail (CFS 1-4). Raw mortality was 4.2% (132/3122) in the frail group and 1.05% (461/43,806) in the non-frail group. After multivariable adjustment for illness severity, age, elective status, type of surgery, hospital type and country, frailty was significantly associated with increased hospital mortality (OR=2.879, 95% CI 2.284-3.629, p<0.001). Increasing CFS was also significantly associated with a higher risk of secondary outcomes, including length of stay in hospital and the ICU, receipt of renal replacement therapy and tracheostomy and increased duration of mechanical ventilation. CONCLUSION: This study demonstrated that increasing Clinical Frailty Scale was strongly associated with increased hospital mortality, hospital and ICU length of stay, invasive ventilation hours, renal replacement therapy, and tracheostomy insertion, among patients undergoing cardiac surgery in Australia and New Zealand.

Association of vaccination status and severity of SARS-CoV-2 infections in hospitalized patients.

Vaccination is considered the most promising approach for addressing the COVID-19 pandemic. However, even vaccinated people remain at risk. In this study, we examined the association between levels of vaccination and clinical outcomes in hospitalized patients. We conducted a retrospective review of adults hospitalized with COVID-19 infection. Of 484 patients, fully vaccinated (OR = 0.49, p = 0.001) and updated patients (OR = 0.46, p = 0.004) had significantly lower probability of critical severity compared to unvaccinated. Vaccination status is significantly related with 30-day mortality (p = 0.005) but not significantly associated with need for respiratory support or ICU stay. Mean length of stay (LOS) of 6.6 days among boosted patients is significantly lower than patients with no vaccination status (10.7 d, p < 0.001). Our study findings provide real-world evidence of the benefit of booster vaccinations against critical infection and death as well as shortcomings in ICU stay, length of stay or need for ventilatory support.

Redox-Active Phenanthrenequinone Molecules and Nitrogen-Doped Reduced Graphene Oxide as Active Material Composites for Supercapacitor Applications.

Carbon-based supercapacitor electrodes are generally restricted in energy density, as they rely exclusively on electric double-layer capacitance (EDLC). The introduction of redox-active organic molecules to obtain pseudocapacitance is a promising route to develop electrode materials with improved energy densities. In this work, we develop a porous nitrogen-doped reduced graphene oxide and 9,10-phenanthrenequinone composite (N-HtrGO/PQ) via a facile one-step physical adsorption method. The electrochemical evaluation of N-HtrGO/PQ using cyclic voltammetry showed a high capacitance of 605 F g-1 in 1 M H2SO4 when the composite consisted of 30% 9,10-phenanthrenequinone and 70% N-HtrGO. The measured capacitance significantly exceeded pure N-HtrGO without the addition of redox-active molecules (257 F g-1). In addition to promising capacitance, the N-HtrGO/30PQ composite showed a capacitance retention of 94.9% following 20,000 charge/discharge cycles. Based on Fourier transform infrared spectroscopy, we postulate that the strong π-π interaction between PQ molecules and the N-HtrGO substrate enhances the specific capacitance of the composite by shortening pathways for electron transfer while improving structural stability.

Development and validation of a self-report measure of perceived dehumanization from officers.

PURPOSE: Emerging evidence indicates that incarcerated populations' perceptions of dehumanization by officers are prevalent, yet measures of it are few, and to our knowledge, no self-report measure of dehumanization from officers exists. To fill this gap, we have developed the Perceived Dehumanization from Officers Scale (PDOS), which is designed as a brief measure to assess perception of officer treatment as dehumanizing. METHODS: In this article, we provide preliminary evidence from two studies examining the reliability and validity of the PDOS. In study 1, a jail sample (n = 411), we analyzed the exploratory factor structure, internal consistency, and discriminant validity (in relation to procedural justice [PJ]) of the PDOS. Additionally, using a cross-sectional ordinary least squares (OLS) regression analysis, we related independent variables with the PDOS, the dependent variable. In Study 2, a prison sample (n = 2993), we confirmed the findings from study 1. RESULTS: The PDOS appears to be a psychometrically sound measure of perceived dehumanization from officers with strong association between perceptions of PJ and perceived dehumanization from officers. CONCLUSIONS: The PDOS provides opportunity for future research, intervention through rehumanization efforts, and signals the important officer treatment. Importantly We close by discussing implications of these studies, limitations, and future research directions to further develop and test the PDOS.

The Current Status and Use of Microphysiological Systems by the Pharmaceutical Industry: The International Consortium for Innovation and Quality Microphysiological Systems Affiliate Survey and Commentary.

Microphysiological systems (MPS) are comprised of one or multiple cell types of human or animal origins that mimic the biochemical/electrical/mechanical responses and blood-tissue barrier properties of the cells observed within a complex organ. The goal of incorporating these in vitro systems is to expedite and advance the drug discovery and development paradigm with improved predictive and translational capabilities. Considering the industry need for improved efficiency and the broad challenges of model qualification and acceptance, the International Consortium for Innovation and Quality (IQ) founded an IQ MPS working group in 2014 and Affiliate in 2018. This group connects thought leaders and end users, provides a forum for crosspharma collaboration, and engages with regulators to qualify translationally relevant MPS models. To understand how pharmaceutical companies are using MPS, the IQ MPS Affiliate conducted two surveys in 2019, survey 1, and 2021, survey 2, which differed slightly in the scope of definition of the complex in vitro models under question. The surveys captured demographics, resourcing, rank order for organs of interest, compound modalities tested, and MPS organ-specific questions, including nonclinical species needs and cell types. The major focus of this manuscript is on results from survey 2, where we specifically highlight the context of use for MPS within safety, pharmacology, or absorption, disposition, metabolism, and excretion and discuss considerations for including MPS data in regulatory submissions. In summary, these data provide valuable insights for developers, regulators, and pharma, offering a view into current industry practices and future considerations while highlighting key challenges impacting MPS adoption. SIGNIFICANCE STATEMENT: The application of microphysiological systems (MPS) represents a growing area of interest in the drug discovery and development framework. This study surveyed 20+ pharma companies to understand resourcing, current areas of application, and the key challenges and barriers to internal MPS adoption. These results will provide regulators, tech providers, and pharma industry leaders a starting point to assess the current state of MPS applications along with key learnings to effectively realize the potential of MPS as an emerging technology.

Preclinical Investigation of a Lipoglycopeptide Dry Powder Inhalation Therapy for the Treatment of Pulmonary MRSA Infection.

The increased prevalence of pulmonary methicillin-resistant Staphylococcus aureus (MRSA) infection in patients living with cystic fibrosis (CF) is concerning due to a correlation with reduced life expectancy and lack of available treatment options. RV94 is a next generation lipoglycopeptide designed for pulmonary delivery that preclinically demonstrated high potency against MRSA in planktonic and protected colonies and improved pulmonary clearance relative to same class molecules. Here, RV94 was formulated into a dry powder for inhalation (DPI) to investigate the localized treatment of pulmonary MRSA presented in a potentially more convenient dosage form. RV94 DPI was generated using a spray-drying process with 12.5 wt% trileucine and demonstrated aerosol characteristics (2.0 µm MMAD and 73% FPF) predictive of efficient pulmonary deposition. In vivo PK from a single dose of RV94 DPI delivered by inhalation to rats yielded lung levels (127 µg/g) much greater than the MRSA minimum inhibitory concentration (0.063 µg/mL), low systemic levels (0.1 µg/mL), and a lung t1/2 equal to 3.5 days. In a rat acute pulmonary MRSA model, a single dose of RV94 DPI delivered by inhalation either up to seven days prior to or 24 h after infection resulted in a statistically significant reduction in lung MRSA titer.

Effect of Inhalation Profile on Delivery of Treprostinil Palmitil Inhalation Powder.

Treprostinil palmitil (TP), a prodrug of treprostinil, is being developed as an inhalation powder (TPIP) for the treatment of patients with pulmonary arterial hypertension (PAH) and pulmonary hypertension due to interstitial lung disease (PH-ILD). In ongoing human clinical trials, TPIP is administered via a commercially available high resistance (HR) RS01 capsule-based dry powder inhaler (DPI) device manufactured by Berry Global (formerly Plastiape), which utilizes the patient's inspiratory flow to provide the required energy to deagglomerate and disperse the powder for delivery to their lungs. In this study, we characterized the aerosol performance of TPIP in response to changes in inhalation profiles to model more realistic use scenarios, i.e., for reduced inspiratory volumes and with inhalation acceleration rates that differ from those described in the compendia. The emitted dose of TP for all combinations of inhalation profiles and volumes ranged narrowly between 79 and 89% for the 16 and 32 mg TPIP capsules at the 60 LPM inspiratory flow rate but was reduced to 72-76% for the 16 mg TPIP capsule under the scenarios at the 30 LPM peak inspiratory flow rate. There were no meaningful differences in the fine particle dose (FPD) at all conditions at 60 LPM with the 4 L inhalation volume. The FPD values for the 16 mg TPIP capsule ranged narrowly between 60 and 65% of the loaded dose for all inhalation ramp rates with a 4 L volume and at both extremes of ramp rates for inhalation volumes down to 1 L, while the FPD values for the 32 mg TPIP capsule ranged between 53 and 65% of the loaded dose for all inhalation ramp rates with a 4 L volume and at both extremes of ramp rates for inhalation volumes down to 1 L for the 60 LPM flow rate. At the 30 LPM peak flow rate, the FPD values for the 16 mg TPIP capsule ranged narrowly between 54 and 58% of the loaded dose at both extremes of the ramp rates for inhalation volumes down to 1 L. Based on these in vitro findings, the TPIP delivery system appears not to be affected by the changes in inspiratory flow profiles or inspiratory volumes that might be expected to occur in patients with PAH or PH associated with underlying lung conditions such as ILD.

A Phase 2b, Randomised, Double-blind, Placebo-controlled, Parallel-arm, Multicenter Study Evaluating the Safety and Efficacy of Tesnatilimab in Patients with Moderately to Severely Active Crohn's Disease.

BACKGROUND AND AIMS: Tesnatilimab, a monoclonal antibody targeting NKG2D, was evaluated in Crohn's disease [CD] patients who had failed or were intolerant to biologic or conventional therapy. METHODS: TRIDENT was a phase 2b, two-part, randomised, double-blind, placebo-controlled, parallel-arm, multicenter study. In Part 1 [proof of concept], 145 patients who were biologic intolerant or refractory [Bio-IR] or had not failed biologic therapy [Bio-NF] were randomised in a 1:1 ratio to placebo subcutaneously [SC] or tesnatilimab 400 mg SC. In Part 2 [dose ranging], 243 Bio-IR and Bio-NF patients were randomised in a 1:1:1:1:1 ratio to placebo, tesnatilimab [50 mg, 150 mg, 400 mg], or intravenous infusion of ustekinumab ~6 mg/kg at Week 0 and 90 mg SC at Weeks 8 and 16. The primary endpoint was mean change from baseline in Crohn's Disease Activity Index [CDAI] at Week 8 [Part 1] and Week 12 [Part 2]. Clinical and endoscopic remission/response were evaluated. Efficacy analyses were also assessed by NKG2D and MICB single nucleotide polymorphism [SNP] status [SNP-positive means positive in at least one of two SNPs]. Safety events were summarised. RESULTS: In Part 1, mean change from baseline in CDAI score was significantly greater with tesnatilimab vs placebo at Week 8 [-103.6 vs -60.0; p < 0.01]. In Part 2, no dose-response signal was detected. Mean changes from baseline in CDAI at Week 12 were -93.2, -72.2, and -84.3 for low, middle, and high doses of tesnatilimab, respectively, vs -59.2 for placebo and -148.8 for ustekinumab. Similar reductions from baseline in CDAI score were observed in patients receiving tesnatilimab, regardless of SNP status. Clinical remission rates were greater with tesnatilimab than placebo in Parts 1 and 2, whereas endoscopic response rates were greater with tesnatilimab only in Part 1. No unexpected safety events occurred. CONCLUSIONS: Tesnatilimab was well tolerated. The efficacy of tesnatilimab in patients with CD was significant for the primary endpoint in Part 1; however, no dose-response signal was detected for the primary endpoint in Part 2. Based on these inconsistent findings, tesnatilimab was not considered an effective treatment for patients with CD and no further development is planned. CLINICALTRIALS.GOV IDENTIFIER: NCT02877134.

No Ordinary Coronary: A Case Series of Two Large Coronary Artery Aneuryms Found on Chest X-Ray.

BACKGROUND: Post-procedural coronary aneurysms can have high morbidity and mortality. Although found more commonly on ultrasound or computed tomography imaging, if large enough, they may appear on chest x-ray studies. CASE REPORTS: We present two cases of coronary artery aneurysm visible on chest x-ray study-one originating from a saphenous vein graft and the other a left anterior descending artery pseudoaneurysm 1 week post heart catheterization. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: It is important for emergency physicians to recognize abnormal chest x-ray studies and to look for post-procedural complications, such as coronary artery aneurysm. Coronary artery aneurysm can be a potentially life-threatening condition requiring prompt recognition and surgical consultation.

The Reemergence of Measles.

OBJECTIVES: Present-day pathologists may be unfamiliar with the histopathologic features of measles, which is a reemerging disease. Awareness of these features may enable early diagnosis of measles in unsuspected cases, including those with an atypical presentation. Using archived tissue samples from historic patients, a unique source of histopathologic information about measles and other reemerging infectious diseases, we performed a comprehensive analysis of the histopathologic features of measles seen in commonly infected tissues during prodrome, active, and late phases of the disease. METHODS: Subspecialty pathologists analyzed H&E-stained slides of specimens from 89 patients accessioned from 1919 to 1998 and correlated the histopathologic findings with clinical data. RESULTS: Measles caused acute and chronic histopathologic changes, especially in the respiratory, lymphoid (including appendix and tonsils), and central nervous systems. Bacterial infections in lung and other organs contributed significantly to adverse outcomes, especially in immunocompromised patients. CONCLUSIONS: Certain histopathologic features, especially Warthin-Finkeldey cells and multinucleated giant cells without inclusions, allow pathologists to diagnose or suggest the diagnosis of measles in unsuspected cases.

Do Sheriff-Coroners Underreport Officer-Involved Homicides?

Introduction: In the United States, each state sets its own standards for its death investigation system. These may require independent medical examiners and coroners or allow for the sheriff to assume the role of coroner. Motivated by the well-established fact that counts of officer-involved homicides in official data sets grossly undercount the number of these incidents, we examine the possibility that different death investigation systems may lead to different death classification outcomes. Methods: To examine the potential differences in officer-involved homicide underreporting by presence of sheriff-coroner and violent death type (gunshot, intentional use of force, pursuit, or other vehicle accident), we compare ratios of incidents from both the Federal Bureau of Investigation's Supplementary Homicide Reports and the restricted Multiple-Cause of Death files from the National Vital Statistics System to the Fatal Encounters data across coroner contexts in California between 2000 and 2018; we quantify differences descriptively and examine bivariate tests of means. Results: We find significantly greater underreporting of officer-involved deaths in sheriff-coroner counties in both official data sets for all incidents compared with non-sheriff-coroner counties, independently of the period considered. These underreporting differences in the National Vital Statistics System are robust to restricting to gunshot and intentional use of force deaths, the type of incident expected to be less prone to misclassification in that data set. Conclusions: Officer-involved death underreporting in sheriff-coroner counties necessitates further scrutiny. Disparities in officer-involved death reporting suggest political pressure may play a role in classifying deaths.

Novel Smooth Muscle Ca2+-Signaling Nanodomains in Blood Pressure Regulation.

BACKGROUND: Ca2+ signals in smooth muscle cells (SMCs) contribute to vascular resistance and control blood pressure. Increased vascular resistance in hypertension has been attributed to impaired SMC Ca2+ signaling mechanisms. In this regard, transient receptor potential vanilloid 4 (TRPV4SMC) ion channels are a crucial Ca2+ entry pathway in SMCs. However, their role in blood pressure regulation has not been identified. METHODS: We used SMC-specific TRPV4-/- (TRPV4SMC-/-) mice to assess the role of TRPV4SMC channels in blood pressure regulation. We determined the contribution of TRPV4SMC channels to the constrictor effect of α1 adrenergic receptor (α1AR) stimulation and elevated intraluminal pressure: 2 main physiologic stimuli that constrict resistance-sized arteries. The contribution of spatially separated TRPV4SMC channel subpopulations to elevated blood pressure in hypertension was evaluated in angiotensin II-infused mice and patients with hypertension. RESULTS: We provide first evidence that TRPV4SMC channel activity elevates resting blood pressure in normal mice. α1AR stimulation activated TRPV4SMC channels through PKCα (protein kinase Cα) signaling, which contributed significantly to vasoconstriction and blood pressure elevation. Intraluminal pressure-induced TRPV4SMC channel activity opposed vasoconstriction through activation of Ca2+-sensitive K+ (BK) channels, indicating functionally opposite pools of TRPV4SMC channels. Superresolution imaging of SMCs revealed spatially separated α1AR:TRPV4 and TRPV4:BK nanodomains in SMCs. These data suggest that spatially separated α1AR-TRPV4SMC and intraluminal pressure-TRPV4SMC-BK channel signaling have opposite effects on blood pressure, with α1AR-TRPV4SMC signaling dominating under resting conditions. Furthermore, in patients with hypertension and a mouse model of hypertension, constrictor α1AR-PKCα-TRPV4 signaling was upregulated, whereas dilator pressure-TRPV4-BK channel signaling was disrupted, thereby increasing vasoconstriction and elevating blood pressure. CONCLUSIONS: Our data identify novel smooth muscle Ca2+-signaling nanodomains that regulate blood pressure and demonstrate their impairment in hypertension.

Surface Properties and Architectures of Male Moth Trichoid Sensilla Investigated Using Atomic Force Microscopy.

The surfaces of trichoid sensilla on male moth antennae have been sculpted over evolutionary time to capture pheromone odorant molecules emitted by the females of their species and transport the molecules in milliseconds into the binding protein milieu of the sensillum lumen. The capture of pheromone molecules likely has been optimized by the topographies and spacings of the numerous ridges and pores on these sensilla. A monolayer of free lipids in the outer epicuticle covers the sensillar surfaces and must also be involved in optimal pheromone odorant capture and transport. Using electro-conductive atomic force microscopy probes, we found that electrical surface potentials of the pores, ridges and flat planar areas between ridges varied in consistent ways, suggesting that there is a heterogeneity in the distribution of surface lipid mixtures amongst these structures that could help facilitate the capture and transport of pheromone molecules down through the pores. We also performed experiments using peak force atomic force microscopy in which we heated the sensilla to determine whether there is a temperature-related change of state of some of the surface lipid exudates such as the prominent domes covering many of the pores. We found that these exudates were unaffected by heating and did not melt or change shape significantly under high heat. Additionally, we measured and compared the topographies of the trichoid sensilla of five species of moths, including the distributions, spacings, heights and diameters of ridges, pores and pore exudates.

Futurelessness and Commitment to Institutional Rules Among People in Jail.

The current study builds on prior work examining the association between futurelessness and commitment institutional rules among correctional populations. Using cross-sectional data from a sample of 413 people incarcerated in United States jails from 2018 to 2019, this study employs Ordinary Least Squares regression to examine the association between futurelessness and commitment to institutional rules controlling for various importation and deprivation factors previously linked with institutional misconduct. Results provide support for the importance of futurelessness for commitment to institutional rules, suggesting that this finding is consistent across correctional environments. In addition, findings suggest that an index measure of futurelessness is a stronger construct for testing futurelessness than single-item measures used in prior studies. Consistent with prior literature on futurelessness, our findings suggest that among people incarcerated in jail futurelessness is linked to a weaker commitment to institutional rules.

Prison Visitation and Concerns about Reentry: Variations in Frequency and Quality of Visits are Associated with Reentry Concerns among People Incarcerated in Prison.

Prior studies suggest that visitation may have an impact on successful reentry. At the same time, the impact of visitation on incarcerated people's concerns about reentry has received little empirical attention. Understanding how factors such as visitation affect concerns about reentry can provide correctional officials with policy directions on how to reduce strains and enhance successful reintegration. Further, while some studies have evaluated frequency of visitation far fewer have examined the impact of quality of visitation. Using a sample of males and females incarcerated in five correctional facilities (n = 3,084), this study examines how frequency and quality of visitation impact incarcerated people's concerns about employment, housing, debt, and recidivism upon reentry. Findings suggest that more visits reduce concerns, while negative visits increase concerns about reentry.

Healthcare Use After Buprenorphine Prescription in a Community Emergency Department: A Cohort Study.

INTRODUCTION: Recent studies from urban academic centers have shown the promise of emergency physician-initiated buprenorphine for improving outcomes in opioid use disorder (OUD) patients. We investigated whether emergency physician-initiated buprenorphine in a rural, community setting decreases subsequent healthcare utilization for OUD patients. METHODS: We performed a retrospective chart review of patients presenting to a community hospital emergency department (ED) who received a prescription for buprenorphine from June 15, 2018-June 15, 2019. Demographic and opioid-related International Classification of Diseases, 10th Revision, (ICD-10) codes were documented and used to create a case-matched control cohort of demographically matched patients who presented in a similar time frame with similar ICD-10 codes but did not receive buprenorphine. We recorded 12-month rates of ED visits, all-cause hospitalizations, and opioid overdoses. Differences in event occurrences between groups were assessed with Poisson regression. RESULTS: Overall 117 patients were included in the study: 59 who received buprenorphine vs 58 controls. The groups were well matched, both roughly 90% White and 60% male, with an average age of 33.4 years for both groups. Controls had a median two ED visits (range 0-33), median 0.5 hospitalizations (range 0-8), and 0 overdoses (range 0-3), vs median one ED visit (range 0-8), median 0 hospitalizations (range 0-4), and median 0 overdoses (range 0-3) in the treatment group. The incidence rate ratio (IRR) for counts of ED visits was 0.61, 95% confidence interval (CI), 0.49, 0.75, favoring medication-assisted treatment (MAT). For hospitalizations, IRR was 0.34, 95% CI, 0.22, 0.52 favoring MAT, and for overdoses was 1.04, 95% CI, 0.53, 2.07. CONCLUSION: Initiation of buprenorphine by ED providers was associated with lower 12-month ED visit and all-cause hospitalization rates with comparable overdose rates compared to controls. These findings show the ED's potential as an initiation point for medication-assisted treatment in OUD patients.

Solvent-free production of thermoplastic lignocellulose from wood pulp by reactive extrusion.

A novel acylation approach suited to rapid bulk thermoplasticization of lignocellulose without solvents was previously demonstrated by the authors in benchtop batch studies. The method relies upon a benzethonium chloride/sulfuric acid functionalizing agent at low concentrations to act as a wetting agent for the wood pulp, similar to an ionic liquid, yet binds to the lignocellulose ester as a flow aid in the final thermoplastic. The present investigation evaluates the approach in a residence time-limited (45-90 s) continuous twin-screw reactor, where intensive mixing and heat were found to yield high acylation. The modified lignocellulose exhibited desired thermoplasticity by being melt moldable without the need for plasticizers and maintained much of the excellent stiffness of cellulose, demonstrating a maximum flexural modulus of 5.4 GPa and tensile modulus of 1.8 GPa. The influence of extrusion conditions on thermoplasticity was examined by a Design of Experiments (DOE) analysis.

Discovery and Early Clinical Development of LY3202626, a Low-Dose, CNS-Penetrant BACE Inhibitor.

The beta-site APP cleaving enzyme 1, known as BACE1, has been a widely pursued Alzheimer's disease drug target owing to its critical role in the production of amyloid-beta. We have previously reported the clinical development of LY2811376 and LY2886721. LY2811376 advanced to Phase I before development was terminated due to nonclinical retinal toxicity. LY2886721 advanced to Phase II, but development was halted due to abnormally elevated liver enzymes. Herein, we report the discovery and clinical development of LY3202626, a highly potent, CNS-penetrant, and low-dose BACE inhibitor, which successfully addressed these key development challenges.

Caveolar peroxynitrite formation impairs endothelial TRPV4 channels and elevates pulmonary arterial pressure in pulmonary hypertension.

Recent studies have focused on the contribution of capillary endothelial TRPV4 channels to pulmonary pathologies, including lung edema and lung injury. However, in pulmonary hypertension (PH), small pulmonary arteries are the focus of the pathology, and endothelial TRPV4 channels in this crucial anatomy remain unexplored in PH. Here, we provide evidence that TRPV4 channels in endothelial cell caveolae maintain a low pulmonary arterial pressure under normal conditions. Moreover, the activity of caveolar TRPV4 channels is impaired in pulmonary arteries from mouse models of PH and PH patients. In PH, up-regulation of iNOS and NOX1 enzymes at endothelial cell caveolae results in the formation of the oxidant molecule peroxynitrite. Peroxynitrite, in turn, targets the structural protein caveolin-1 to reduce the activity of TRPV4 channels. These results suggest that endothelial caveolin-1-TRPV4 channel signaling lowers pulmonary arterial pressure, and impairment of endothelial caveolin-1-TRPV4 channel signaling contributes to elevated pulmonary arterial pressure in PH. Thus, inhibiting NOX1 or iNOS activity, or lowering endothelial peroxynitrite levels, may represent strategies for restoring vasodilation and pulmonary arterial pressure in PH.