Short communications: Endothelin-1 in cardiac allograft vasculopathy.

INTRODUCTION: Cardiac allograft vasculopathy (CAV) is a leading cause of death following heart transplant. Endothelin-1 (ET-1) is a highly potent vasoconstrictor peptide derived from the vascular endothelium with multiple biological actions known to be relevant for CAV. We assessed the trans-myocardial gradient (TMG: coronary sinus minus coronary artery concentration: negative = extraction, positive = secretion) of ET-1 in heart transplant patients to determine correlations with angiographic, Intravascular Ultrasound (IVUS) and Optical Coherence Tomography (OCT) features of CAV. RESULTS: Vessels with more severe CAV demonstrated significantly higher (more positive) ET-1 TMG (IVUS Stanford Grade IV: -0.05 [-0.21, 0.13] pg/ml versus Stanford Grade I-III: -0.31 [-0.64, -0.11] pg/ml, p = 0.01). ET-1 TMG was positively correlated with mean intimal thickness on both IVUS and OCT (IVUS: Kendall's tau-b = 0.254, p = 0.02 and OCT: Kendall's tau-b = 0.344, p < 0.0001). Patients who died had net ET-1 release compared with surviving patients (died: 0.21 [0.19-0.24] versus surviving: -0.28 [-0.52, -0.17], p = 0.01). CONCLUSION: In heart transplant patients, coronary arteries with more intimal thickening are associated with a higher (more positive) trans-myocardial gradient of ET-1, suggesting that up-regulated ET-1 release in the coronary circulation may be permissive for the development of CAV.

GDF15 antagonism limits severe heart failure and prevents cardiac cachexia.

AIMS: Heart failure and associated cachexia is an unresolved and important problem. This study aimed to determine the factors that contribute to cardiac cachexia in a new model of heart failure in mice that lack the integrated stress response (ISR) induced eIF2α phosphatase, PPP1R15A. METHODS AND RESULTS: Mice were irradiated and reconstituted with bone marrow cells. Mice lacking functional PPP1R15A, exhibited dilated cardiomyopathy and severe weight loss following irradiation, whilst wild-type mice were unaffected. This was associated with increased expression of Gdf15 in the heart and increased levels of GDF15 in circulation. We provide evidence that the blockade of GDF15 activity prevents cachexia and slows the progression of heart failure. We also show the relevance of GDF15 to lean mass and protein intake in patients with heart failure. CONCLUSION: Our data suggest that cardiac stress mediates a GDF15-dependent pathway that drives weight loss and worsens cardiac function. Blockade of GDF15 could constitute a novel therapeutic option to limit cardiac cachexia and improve clinical outcomes in patients with severe systolic heart failure.

Damaging mutations in liver X receptor-α are hepatotoxic and implicate cholesterol sensing in liver health.

Liver X receptor-α (LXRα) regulates cellular cholesterol abundance and potently activates hepatic lipogenesis. Here we show that at least 1 in 450 people in the UK Biobank carry functionally impaired mutations in LXRα, which is associated with biochemical evidence of hepatic dysfunction. On a western diet, male and female mice homozygous for a dominant negative mutation in LXRα have elevated liver cholesterol, diffuse cholesterol crystal accumulation and develop severe hepatitis and fibrosis, despite reduced liver triglyceride and no steatosis. This phenotype does not occur on low-cholesterol diets and can be prevented by hepatocyte-specific overexpression of LXRα. LXRα knockout mice exhibit a milder phenotype with regional variation in cholesterol crystal deposition and inflammation inversely correlating with steatosis. In summary, LXRα is necessary for the maintenance of hepatocyte health, likely due to regulation of cellular cholesterol content. The inverse association between steatosis and both inflammation and cholesterol crystallization may represent a protective action of hepatic lipogenesis in the context of excess hepatic cholesterol.

Predictive Blood Biomarkers of Targeted Intervention for Chronic Mental Health Symptoms following Traumatic Brain Injury.

The purpose of this study was to assess the performance of predictive blood biomarkers in predicting responsiveness to targeted treatments for chronic psychological issues years after traumatic brain injury (TBI). Targeted Evaluation Action and Monitoring of TBI (TEAM-TBI) was a prospective six-month interventional trial of participants with chronic TBI sequelae (n=95). Plasma biomarkers were analyzed pre-intervention: glial fibrillary acidic protein (GFAP), tau, hyperphosphorylated tau Thr231 (p-Tau), von Willebrand factor (vWF), brain lipid binding protein (BLBP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), vascular endothelial growth factor-a (VEGFa) and claudin-5 (CLDN5). Clinical outcomes included the PTSD Checklist for DSM-5 (PCL-5) and Brief Symptom Inventory-18 (BSI-18). Regression models were built for change in PCL5/BSI-18. Biomarkers and covariates were included. Two models were built to identify responders (improved beyond the minimum clinically important difference). The model to predict change in PCL5 (R2=0.64; p<0.001) included vWF ( p=0.032), BLBP (p=0.001), tau (p=0.002), VEGFa (p=0.015), female sex (p=0.06) and military status (p=0.014).The model to predict change in BSI-18 (R2=0.42; p=0.003) included vWF (p=0.042), VEGFa (p=0.09), BLBP (p=0.01), CLDN5 (p<0.001), female sex (p=0.012), and military status (p=0.004) as predictors. The model to differentiate participants who improved for PCL5 (R2=0.68; p<0.001; AUC=0.93) included vWF (p=0.02), VEGFa (p=0.008), and BLBP (p=0.006). The model to differentiate participants who improved for BSI-18 (R2=0.25; p=0.04; AUC=0.75) included UCH-L1 (p=0.03), GFAP (p=0.06), and vWF (p=0.03). Combinations of pre-intervention blood biomarkers were able to differentiate responders from non-responders in both post-traumatic stress and overall psychological health domains.

Dynamics of amylopectin granule accumulation during the course of the chronic Toxoplasma infection is linked to intra-cyst bradyzoite replication.

The contribution of amylopectin granules (AG), comprised of a branched chain storage homopolymer of glucose, to the maintenance and progression of the chronic Toxoplasma gondii infection has remained undefined. Here we describe the role of AG in the physiology of encysted bradyzoites by using a custom developed imaging-based application AmyloQuant that permitted quantification of relative levels of AG within in vivo derived tissue cysts during the initiation and maturation of the chronic infection. Our findings establish that AG are dynamic entities, exhibiting considerable heterogeneity among tissue cysts at all post infection time points examined. Quantification of relative AG levels within tissue cysts exposes a previously unrecognized temporal cycle defined by distinct phases of AG accumulation and utilization over the first 6 weeks of the chronic phase. This AG cycle is temporally coordinated with overall bradyzoite mitochondrial activity implicating amylopectin in the maintenance and progression of the chronic infection. In addition, the staging of AG accumulation and it rapid utilization within encysted bradyzoites was associated with a burst of coordinated replication. As such our findings suggest that AG levels within individual bradyzoites, and across bradyzoites within tissue cysts may represent a key component in the licensing of bradyzoite replication, intimately linking stored metabolic potential to the course of the chronic infection. This extends the impact of AG beyond the previously assigned role that focused exclusively on parasite transmission. These findings force a fundamental reassessment of the chronic Toxoplasma infection, highlighting the critical need to address the temporal evolution of this crucial stage in the parasite life cycle.

Peptide nucleic acids can form hairpins and bind RNA-binding proteins.

RNA-binding proteins (RBPs) are a major class of proteins that interact with RNAs to change their fate or function. RBPs and the ribonucleoprotein complexes they constitute are involved in many essential cellular processes. In many cases, the molecular details of RBP:RNA interactions differ between viruses, prokaryotes and eukaryotes, making prokaryotic and viral RBPs good potential drug targets. However, targeting RBPs with small molecules has so far been met with limited success as RNA-binding sites tend to be extended, shallow and dynamic with a mixture of charged, polar and hydrophobic interactions. Here, we show that peptide nucleic acids (PNAs) with nucleic acid-like binding properties and a highly stable peptide-like backbone can be used to target some RBPs. We have designed PNAs to mimic the short RNA stem-loop sequence required for the initiation of prokaryotic signal recognition particle (SRP) assembly, a target for antibiotics development. Using a range of biophysical and biochemical assays, the designed PNAs were demonstrated to fold into a hairpin structure, bind the targeted protein and compete with the native RNA hairpin to inhibit SRP formation. To show the applicability of PNAs against other RBPs, a PNA was also shown to bind Nsp9 from SARS-CoV-2, a protein that exhibits non-sequence-specific RNA binding but preferentially binds hairpin structures. Taken together, our results support that PNAs can be a promising class of compounds for targeting RNA-binding activities in RBPs.

Blood-based DNA methylation and exposure risk scores predict PTSD with high accuracy in military and civilian cohorts.

BACKGROUND: Incorporating genomic data into risk prediction has become an increasingly popular approach for rapid identification of individuals most at risk for complex disorders such as PTSD. Our goal was to develop and validate Methylation Risk Scores (MRS) using machine learning to distinguish individuals who have PTSD from those who do not. METHODS: Elastic Net was used to develop three risk score models using a discovery dataset (n = 1226; 314 cases, 912 controls) comprised of 5 diverse cohorts with available blood-derived DNA methylation (DNAm) measured on the Illumina Epic BeadChip. The first risk score, exposure and methylation risk score (eMRS) used cumulative and childhood trauma exposure and DNAm variables; the second, methylation-only risk score (MoRS) was based solely on DNAm data; the third, methylation-only risk scores with adjusted exposure variables (MoRSAE) utilized DNAm data adjusted for the two exposure variables. The potential of these risk scores to predict future PTSD based on pre-deployment data was also assessed. External validation of risk scores was conducted in four independent cohorts. RESULTS: The eMRS model showed the highest accuracy (92%), precision (91%), recall (87%), and f1-score (89%) in classifying PTSD using 3730 features. While still highly accurate, the MoRS (accuracy = 89%) using 3728 features and MoRSAE (accuracy = 84%) using 4150 features showed a decline in classification power. eMRS significantly predicted PTSD in one of the four independent cohorts, the BEAR cohort (beta = 0.6839, p=0.006), but not in the remaining three cohorts. Pre-deployment risk scores from all models (eMRS, beta = 1.92; MoRS, beta = 1.99 and MoRSAE, beta = 1.77) displayed a significant (p < 0.001) predictive power for post-deployment PTSD. CONCLUSION: The inclusion of exposure variables adds to the predictive power of MRS. Classification-based MRS may be useful in predicting risk of future PTSD in populations with anticipated trauma exposure. As more data become available, including additional molecular, environmental, and psychosocial factors in these scores may enhance their accuracy in predicting PTSD and, relatedly, improve their performance in independent cohorts.

Film swelling and contaminant adsorption at polymer coated surfaces: Insights from density functional theory.

Designing coatings and films that can protect surfaces is important in a wide variety of applications from corrosion prevention to anti-fouling. These systems are challenging from a modeling perspective because they are invariably multicomponent, which quickly leads to an expansive design space. At a minimum, the system has a substrate, a film (often composed of a polymeric material), a ubiquitous carrier solvent, which may be either a vapor or liquid phase, and one or more contaminants. Each component has an impact on the effectiveness of coating. This paper focuses on films that are used as a barrier to surface contamination, but the results also extend to surface coatings that are designed to extract a low density species from the fluid phase as in liquid chromatography. A coarse-grained model is developed using Yukawa potentials that encompasses both repulsive and attractive interactions among the species. Classical density functional theory calculations are presented to show how contaminant adsorption is controlled by the molecular forces in the system. Two specific vectors through the parameter space are considered to address likely experimental manipulations that change either the solvent or the polymer in a system. We find that all the adsorption results can be unified by considering an appropriate combination of molecular parameters. As a result, these calculations provide a link between molecular interactions and film performance and may serve to guide the rational design of films.

Outcomes for Mechanically Ventilated Patients With Acute Myocardial Infarction Admitted to Medical vs Cardiac Intensive Care Units.

Background: Acute myocardial infarction (AMI) remains a common reason for admission to the intensive care unit (ICU). However, there is limited data comparing outcomes for patients with AMI admitted to specific ICUs. Objectives: The purpose of this study was to assess clinical outcomes between patients with AMI requiring invasive mechanical ventilation admitted to the medical ICU (MICU) compared to cardiac (CICU). Methods: We utilized the Vizient Clinical Data Base to identify patients with a primary diagnosis of AMI between October 2015 and December 2019 and requiring invasive mechanical ventilation. Using multivariable logistic regression, we compared clinical outcomes for patients admitted to the MICU vs CICU. Results: We identified 12,639 patients, 25.2% (n = 3,185) of which were admitted to a MICU and 74.8% (n = 9,454) to a CICU. Patients admitted to a CICU were more likely to present with STEMI (57.0% vs 42.8%), cardiogenic shock (46.0% vs 37.4%), and require mechanical circulatory support and vasoactive medications (all, P < 0.001). Median ventilator days were 4 days in both ICUs and not statistically different after multivariable adjustment (P = 0.81). In-hospital mortality was 42.7% compared to 41.3% for MICU vs CICU admissions, respectively (P = 0.15). After multivariable adjustment, CICU admission was associated with lower in-hospital mortality (OR: 0.85, 95% CI: 0.78-0.93, P = 0.001), which persisted when stratified by cardiogenic shock, cardiac arrest, STEMI, largest hospital size (>750 beds), and teaching hospitals (all, P < 0.05). Conclusions: Admission to the CICU, as compared to MICU, was associated with lower in-hospital mortality for patients with AMI. These findings may support optimal triage of critically ill patients with AMI.

Airway obstruction secondary to vocal cord polyp.

ABSTRACT: Patients with vocal cord polyps commonly present with symptoms of hoarseness. Although rare, large polyps can cause shortness of breath and stridor and should be included in the differential for patients with airway obstruction. Dysphonia or hoarseness can be a symptom of underlying disease, such as head and neck cancer. This case illustrates the importance of prompt and accurate diagnosis in a patient with persistent symptoms and a history of smoking. Obtaining a laryngoscopy is crucial to appropriately evaluate the larynx. Proper visualization of the laryngeal structures will help direct patient care toward further diagnostic imaging and medical or surgical intervention if indicated.

A qPCR assay for specific detection of Pseudomonas cannabina pv. alisalensis.

Pseudomonas cannabina pv. alisalensis is a gram-negative bacterium that causes bacterial leaf blight in Brassica crops, an important disease that could bring severe damage to the host plants. The aim of this study was to develop a tool that can reliably and accurately quantify P. cannabina pv. alisalensis and distinguish it from other closely related bacterial pathogens. Two species and six pathovars of Pseudomonas were tested: three pathovars, P. syringae pv. coriandricola, P. syringae pv. philadelphi, and P. syringae strains from Vicia faba were found or confirmed to be members of P. cannabina based on the multi-locus sequence analysis and rep-PCR results. The qPCR assay was evaluated for specificity and examined for detection limit in pure bacterial cells and bacteria-spiked plant samples. The assay was applied in monitoring the quantities of the P. cannabina pv. alisalensis DNA over time in inoculated turnip green leaves. As results, the newly developed qPCR assay detected the target DNA in P. cannabina pv. alisalensis suspension as low as 100 CFU/ml and did not detect any of the nontarget bacteria. The qPCR assay detected P. cannabina pv. alisalensis in all the inoculated samples at least 5 days before the symptoms became visible; bacterial quantity increased significantly in the first three days after inoculation but slowed down afterwards. The new qPCR assay for P. cannabina pv. alisalensis detection will facilitate early detection and disease diagnosis, assist research to provide epidemiological insights for the pathogen, and guide implementation of strategies to manage disease and prevent its spread.

Management of Shoulder Instability in the Overhead Athletes.

Overhead athletes with anterior, posterior, and multidirectional shoulder instability present with a wide range of symptoms, especially considering the injury mechanism and affected supportive structures. As such, the management of shoulder instability is widely variable and relies on rehabilitation, operative management, and sport-specific considerations, such as positional and seasonal demands on the athlete. Biomechanical analysis may further aid in the recovery process or serve as a predictive tool to identify an increased risk for injury.

Progression of Gummy Stem Blight Epidemics on Watermelon with and without Fungicide Inputs.

Gummy stem blight (GSB), caused primarily by the fungus Stagonosporopsis citrulli in the southeastern United States, affects cucurbits and is particularly destructive on watermelon. Previous epidemiological models of GSB constructed for greenhouse cucumber showed leaf wetness and temperature were the primary and secondary environmental factors, respectively, that explained epidemic progress. The objective of this study was to construct a model that predicted GSB severity on field-grown watermelon based on environmental factors. Disease and weather data from six fungicide experiments in Charleston, South Carolina, in spring and fall 1997 and fall 2017, 2018, 2019, and 2022 were used as inputs. Fungicide treatments were grouped into nonsprayed, protectant (chlorothalonil and mancozeb) and GSB-specific (cyprodinil, difenoconazole and fludioxonil) applications. Cumulative hours of leaf wetness was the primary explanatory variable that modeled the increase in proportion GSB severity ≥2% across all epidemics. Incorporation of temperature or other environmental variables did not improve the model. Fit of the overall model was evaluated with k-fold cross validation, where individual experiments were each excluded from the model fitting process. Slopes of predicted disease progress curves were lowered significantly compared to the nonsprayed treatments by applications of protectant fungicides. Applying GSB-specific fungicides alternated with chlorothalonil further reduced slope values. The model successfully predicted progress of GSB epidemics under different weather patterns and fungicide applications.

Does the Primary Tumor Site Drive Biology for Patients With Synovial Sarcoma?

OBJECTIVE: We evaluated survival outcomes by primary tumor site in synovial sarcoma (SS) patients with localized and metastatic disease at diagnosis. METHODS: We conducted a retrospective review of 504 SS patients diagnosed from 1974 to 2020. Kaplan-Meier method, log-rank test, and Cox-proportional hazards regression were used. RESULTS: Among 504 patients, 401 (79.6%) presented with localized disease, and 103 (20.4%) with metastases. For patients with localized disease, (1) 5-year OS by tumor site was as follows: 80% (95% CI, 67%-89%) for head/neck, 30% (95% CI, 18%-42%) for intrathoracic, 51% (95% CI, 35%-65%) for abdomen/pelvis, 71% (95% CI, 62%-79%) for proximal-extremity, and 83% (71%, 91%) for distal-extremity. (2) On multivariable analysis, tumor site (compared with proximal-extremity: intrathoracic tumors [HR: 1.95; 95% CI, 1.22-3.16]; hand/foot [HR: 0.52; 95% CI, 0.28-0.97]), tumor size (compared with <5 cm, 5-10 cm [HR: 1.80; 95% CI, 1.14-2.85]; ≥10 cm [HR: 4.37; 95% CI, 2.69-7.11]), and use of neo/adjuvant radiation (HR: 0.54; 95% CI, 0.37-0.79) remained significantly associated with OS. For patients with metastatic disease, (1) 5-year OS was 12% (95% CI, 6%-21%) and (2) the only factor that remained significantly associated with OS on multivariable analysis was surgical resection for the primary tumor (HR: 0.14; 95% CI, 0.08-0.26). CONCLUSIONS: The primary tumor location plays a significant role in predicting outcomes for patients with localized SS. Even though patients present with metastatic disease, surgical resection of the primary tumor improves their survival. These findings are critical for patient counseling and designing a personalized treatment plan that reflects the corresponding outcomes.

Slipped capital femoral epiphysis: emphasis on early recognition and potential pitfalls.

Slipped capital femoral epiphysis is a shearing injury through the growth plate of the proximal femur and is the most common hip disorder in adolescence. Delays in diagnosis persist across practice settings despite ongoing innovations in imaging. Recent insights into pathomechanics highlight the importance of femoral head surface morphology and rotational microinstability centered at the epiphyseal tubercle in causing early physeal changes, which can be detected on imaging prior to frank slip. Scrutiny of physeal morphology and comparison to the contralateral hip is critical at all stages of disease progression, and improper technique may result in undue diagnostic delay. Selective use of cross-sectional imaging can be helpful for troubleshooting equivocal early slips and can inform operative technique and adjuvant therapy candidacy in more severe cases. This review provides a comprehensive approach to imaging suspected slipped capital femoral epiphysis, with an emphasis on early detection and potential pitfalls.

Zoom Boom or Bust? Understanding Post-Pandemic Interest in Facial Plastic Surgery via Google Trends.

OBJECTIVE: To understand post-pandemic interest in plastic surgery procedures via Joinpoint analysis of Google Trends search data. METHODS: Google Trends was used to quantify search volumes from January 2019-December 2022 for select cosmetic face and body procedures in the United States. A keyword analytic tool (Keywords Everywhere) extracted absolute search volumes (average monthly searches). Joinpoint analysis assessed search trends over time reported as monthly percentage change (MPC). RESULTS: All procedures queried, including a non-cosmetic control (cataract surgery), demonstrated expected declines at the start of the COVID-19 pandemic. Blepharoplasty, face lift, neck lift, and Botox demonstrated statistically significant increase in search volumes that remained elevated relative to pre-pandemic levels. Rhinoplasty, fillers, and abdominoplasty interest increased initially followed by return to pre-pandemic levels by the end of 2022. The remainder of search terms did not show a clear temporal associated with COVID-19 lockdowns. CONCLUSION: The "Zoom Boom" appears to be a real phenomenon reflected by sustained increase in public interest in relation to facial plastic procedures. LEVEL OF EVIDENCE: NA Laryngoscope, 2024.