Effect of Catheter Ablation With Vein of Marshall Ethanol Infusion vs Catheter Ablation Alone on Persistent Atrial Fibrillation: The VENUS Randomized Clinical Trial.

Importance: Catheter ablation of persistent atrial fibrillation (AF) has limited success. Procedural strategies beyond pulmonary vein isolation have failed to consistently improve results. The vein of Marshall contains innervation and AF triggers that can be ablated by retrograde ethanol infusion. Objective: To determine whether vein of Marshall ethanol infusion could improve ablation results in persistent AF when added to catheter ablation. Design, Setting, and Participants: The Vein of Marshall Ethanol for Untreated Persistent AF (VENUS) trial was an investigator-initiated, National Institutes of Health-funded, randomized, single-blinded trial conducted in 12 centers in the United States. Patients (N = 350) with persistent AF referred for first ablation were enrolled from October 2013 through June 2018. Follow-up concluded in June 2019. Interventions: Patients were randomly assigned to catheter ablation alone (n = 158) or catheter ablation combined with vein of Marshall ethanol infusion (n = 185) in a 1:1.15 ratio to accommodate for 15% technical vein of Marshall ethanol infusion failures. Main Outcomes and Measures: The primary outcome was freedom from AF or atrial tachycardia for longer than 30 seconds after a single procedure, without antiarrhythmic drugs, at both 6 and 12 months. Outcome assessment was blinded to randomization treatment. There were 12 secondary outcomes, including AF burden, freedom from AF after multiple procedures, perimitral block, and others. Results: Of the 343 randomized patients (mean [SD] age, 66.5 [9.7] years; 261 men), 316 (92.1%) completed the trial. Vein of Marshall ethanol was successfully delivered in 155 of 185 patients. At 6 and 12 months, the proportion of patients with freedom from AF/atrial tachycardia after a single procedure was 49.2% (91/185) in the catheter ablation combined with vein of Marshall ethanol infusion group compared with 38% (60/158) in the catheter ablation alone group (difference, 11.2% [95% CI, 0.8%-21.7%]; P = .04). Of the 12 secondary outcomes, 9 were not significantly different, but AF burden (zero burden in 78.3% vs 67.9%; difference, 10.4% [95% CI, 2.9%-17.9%]; P = .01), freedom from AF after multiple procedures (65.2% vs 53.8%; difference, 11.4% [95% CI, 0.6%-22.2%]; P = .04), and success achieving perimitral block (80.6% vs 51.3%; difference, 29.3% [95% CI, 19.3%-39.3%]; P < .001) were significantly improved in vein of Marshall-treated patients. Adverse events were similar between groups. Conclusions and Relevance: Among patients with persistent AF, addition of vein of Marshall ethanol infusion to catheter ablation, compared with catheter ablation alone, increased the likelihood of remaining free of AF or atrial tachycardia at 6 and 12 months. Further research is needed to assess longer-term efficacy. Trial Registration: ClinicalTrials.gov Identifier: NCT01898221.

Vein of Marshall ethanol infusion for persistent atrial fibrillation: VENUS and MARS clinical trial design.

BACKGROUND: Although pulmonary vein isolation (PVI) is effective in the treatment of paroxysmal atrial fibrillation (AF), its success rates in persistent AF are suboptimal. Ablation strategies to improve outcomes including additional lesions beyond PVI have not consistently shown benefit. Recurrence as perimitral flutter (PMF) is a common form of ablation failure. The vein of Marshall (VOM) contains myocardial connections and abundant sympathetic and parasympathetic innervation implicated in the genesis and maintenance of AF, and is anatomically co-localized with the mitral isthmus, the ablation target of PMF. VOM ethanol infusion is effective in targeting these arrhythmia substrates. OBJECTIVE: To test the safety and efficacy of VOM ethanol infusion when added to PVI in patients undergoing either de novo ablation of persistent AF or after a previous ablation failure. STUDY DESIGN: VENUS-AF and MARS-AF are prospective, multicenter, randomized, controlled trials. VENUS-AF will enroll patients undergoing their first catheter ablation of persistent AF. MARS-AF will enroll patients undergoing ablation after previous ablation failure(s). Patients (n = 405) will be randomized to PVI alone or in combination with VOM ethanol infusion. The primary endpoints include procedural safety and freedom from AF or atrial tachycardia (AT) of more than 30 seconds on 30-day continuous event monitors at 6 and 12 months after randomization procedure (single-procedure success), off antiarrhythmic drugs. Key secondary endpoints include AF burden, freedom from AF/AT after repeat procedures and quality of life. CONCLUSIONS: The VENUS-AF and MARS-AF will determine the safety and potential rhythm control benefit of VOM ethanol infusion when added to PVI in patients with persistent AF undergoing de novo or repeat ablation, respectively.

Shear-wave elastography of the ulnar collateral ligament of the elbow in healthy volunteers: a pilot study.

OBJECTIVE: To estimate the intra-observer repeatability of shear wave elastography in the UCL of the elbow, and to compare shear wave velocities between dominant and non-dominant arms. MATERIALS AND METHODS: Twenty elbows in ten healthy volunteers were evaluated [five males, five females; mean age, 31.8 ± 10.3 years]. Shear wave velocity was measured on three separate days during the span of 1 week utilizing a linear 18-MHz transducer. Elastograms were obtained until ten ROIs were drawn, not drawing more than two ROIs on any elastogram. Elastograms were considered diagnostic if any portion of the UCL was colored in and free of boundary artifacts. Median velocity and interquartile range were recorded. A result was considered reliable if the IQR/median ratio of the ten measurements was < 0.3. RESULTS: IQR/median was < 0.3 in 88% of sessions, although in 28% of sessions fewer than 60% of elastograms were diagnostic. The ICC was 0.05 (95% CI; - 0.18-0.36; poor). Repeatability coefficient (95% limits of agreement) was 1.95 m/s (95% CI; 1.61-2.37 m/s). Mean velocity in dominant arms was 5.14 ± 0.53 m/s and 5.24 ± 0.39 m/s in non-dominant (p = 0.558). CONCLUSIONS: Mean shear wave velocity was similar between dominant and non-dominant arms. Although repeatability was poor as assessed by ICC, the repeatability coefficient may be a more useful indicator of clinical utility once shear wave velocities in diseased ligaments are explored. Future studies should therefore evaluate velocities in diseased ligaments and develop techniques to improve elastogram quality.

Small Molecule Docking of DNA Repair Proteins Associated with Cancer Survival Following PCNA Metagene Adjustment: A Potential Novel Class of Repair Inhibitors.

Natural and synthetic small molecules from the NCI Developmental Therapeutics Program (DTP) were employed in molecular dynamics-based docking with DNA repair proteins whose RNA-Seq based expression was associated with overall cancer survival (OS) after adjustment for the PCNA metagene. The compounds employed were required to elicit a sensitive response (vs. resistance) in more than half of the cell lines tested for each cancer. Methodological approaches included peptide sequence alignments and homology modeling for 3D protein structure determination, ligand preparation, docking, toxicity and ADME prediction. Docking was performed for unique lists of DNA repair proteins which predict OS for AML, cancers of the breast, lung, colon, and ovaries, GBM, melanoma, and renal papillary cancer. Results indicate hundreds of drug-like and lead-like ligands with best-pose binding energies less than -6 kcal/mol. Ligand solubility for the top 20 drug-like hits approached lower bounds, while lipophilicity was acceptable. Most ligands were also blood-brain barrier permeable with high intestinal absorption rates. While the majority of ligands lacked positive prediction for HERG channel blockage and Ames carcinogenicity, there was a considerable variation for predicted fathead minnow, honey bee, and Tetrahymena pyriformis toxicity. The computational results suggest the potential for new targets and mechanisms of repair inhibition and can be directly employed for in vitro and in vivo confirmatory laboratory experiments to identify new targets of therapy for cancer survival.

Cross-linking of porcine acellular dermal matrices negatively affects induced neovessel formation using platelet-rich plasma in a rat model of hernia repair.

The degree of cross-linking within acellular dermal matrices (ADM) seems to correlate to neovascularization when used in ventral hernia repair (VHR). Platelet-rich plasma (PRP) enhances wound healing through several mechanisms including neovascularization, but research regarding its effect on soft tissue healing in VHR is lacking. We sought to study the effect of cross-linking on PRP-induced neovascularization in a rodent model of bridging VHR. We hypothesized that ADM cross-linking would negatively affect PRP-induced neovessel formation. PRP was extracted and characterized from pooled whole blood. Porcine cross-linked (cADM) and non-cross-linked ADMs (ncADM) were implanted in a rat model of chronic VHR after treatment with saline (control) or PRP. Neovascularization of samples at 2, 4, and 6 weeks was assessed by hematoxylin and eosin and immunohistochemical staining of CD 31. Adhesion severity at necropsy was compared using a previously validated scale. Addition of PRP increased neovascularization in both cADM and ncADM at 2- and 4-week time points but appeared to do so in a dependent fashion, with significantly greater neovascularization in the PRP-treated ncADMs compared to cADMs. Omental adhesions were increased in all PRP-treated groups. Results indicate that, for 2-week measurements when compared with the cADM group without PRP therapy, the mean change in neovascularization due to ncADM was 3.27 (Z = 2.75, p = 0.006), PRP was 17.56 (Z = 14.77, p < 0.001), and the combined effect of ncADM and PRP was 9.41 (Z = 5.6, p < 0.001). The 4-week data indicate that the average neovascularization change due to ncADM was 0.676 (Z = 0.7, p = 0.484), PRP was 7.69 (Z = 7.95, p < 0.001), and combined effect of ncADM and PRP was 5.28 (Z = 3.86, p < 0.001). These findings validate PRP as a clinical adjunct to enhance the native tissue response to implantable biomaterials and suggest that ncADM is more amenable than cADM to induced neovascularization. PRP use could be advantageous in patients undergoing VHR where poor incorporation is anticipated and early-enhanced neovascularization is desired.

Postoperative antimicrobials after lung transplantation and the development of multidrug-resistant bacterial and Clostridium difficile infections: an analysis of 500 non-cystic fibrosis lung transplant patients.

BACKGROUND: Broad-spectrum antimicrobials are given prophylactically post-transplant, although these agents are a risk factor for multidrug-resistant (MDR) infections and Clostridium difficile infection (CDI). This study aimed to determine whether an association exists between the duration of antimicrobials given early post-transplant and the development of MDR infections or CDI. METHODS: A single-center retrospective analysis was performed on lung transplants from September 2009 to August 2014. Patients were excluded for cystic fibrosis (CF) or postoperative survival less than 30 d. Qualifying infections were defined as any new positive MDR bacterial culture or C. difficile assay from postoperative day 7-90 d after a broad-spectrum antimicrobial. RESULTS: A total of 500 patients, 61% male, were identified, median age of 62 yr. MDR infections occurred in 169 (34%) and CDI in 31 (6%). Non-ICU days were associated with a decreased risk of MDR/CDI (OR 0.891, p = 0.0002), and duration of Gram-positive antimicrobials (OR 1.073, p = 0.0219) was associated with an increased risk. CONCLUSIONS: One-third (34%) of non-CF lung transplants develop MDR infections and 6% develop CDI within 90 d of postoperative antimicrobials. The duration of Gram-positive antimicrobials may increase the risk of MDR/CDI, while early transfer from the ICU may have a protective effect.

Low-dose radiation affects cardiac physiology: gene networks and molecular signaling in cardiomyocytes.

There are 160,000 cancer patients worldwide treated with particle radiotherapy (RT). With the advent of proton, and high (H) charge (Z) and energy (E) HZE ionizing particle RT, the cardiovascular diseases risk estimates are uncertain. In addition, future deep space exploratory-type missions will expose humans to unknown but low doses of particle irradiation (IR). We examined molecular responses using transcriptome profiling in left ventricular murine cardiomyocytes isolated from mice that were exposed to 90 cGy, 1 GeV proton ((1)H) and 15 cGy, 1 GeV/nucleon iron ((56)Fe) over 28 days after exposure. Unsupervised clustering analysis of gene expression segregated samples according to the IR response and time after exposure, with (56)Fe-IR showing the greatest level of gene modulation. (1)H-IR showed little differential transcript modulation. Network analysis categorized the major differentially expressed genes into cell cycle, oxidative responses, and transcriptional regulation functional groups. Transcriptional networks identified key nodes regulating expression. Validation of the signal transduction network by protein analysis and gel shift assay showed that particle IR clearly regulates a long-lived signaling mechanism for ERK1/2, p38 MAPK signaling and identified NFATc4, GATA4, STAT3, and NF-κB as regulators of the response at specific time points. These data suggest that the molecular responses and gene expression to (56)Fe-IR in cardiomyocytes are unique and long-lasting. Our study may have significant implications for the efforts of National Aeronautics and Space Administration to develop heart disease risk estimates for astronauts and for patients receiving conventional and particle RT via identification of specific HZE-IR molecular markers.

Regadenoson provides perfusion results comparable to adenosine in heterogeneous patient populations: a quantitative analysis from the ADVANCE MPI trials.

BACKGROUND: Total and reversible left ventricular (LV) perfusion defect size (PDS) predict patient outcome. Limited data exist as to whether regadenoson induces similar perfusion abnormalities as observed with adenosine. We sought to determine whether regadenoson induces a similar LV PDS as seen with adenosine across varying patient populations. METHODS AND RESULTS: ADVANCE MPI were prospective, double-blind randomized trials comparing regadenoson to standard adenosine myocardial perfusion tomography (SPECT). Following an initial adenosine SPECT, patients were randomized to either regadenoson (N = 1284) or a second adenosine study (N = 660). SPECT quantification was performed blinded to randomization and image sequence. Propensity analysis was used to define comparability of regadenoson and adenosine perfusion results. Baseline clinical and SPECT results were similar in the two randomized groups. There was a close correlation between adenosine and regadenoson-induced total (r (2) = 0.98, P < .001) and reversible (r (2) = 0.92, P < .001) PDS. Serial differences in total (0.00 ± 3.51 vs -0.11 ± 3.46, P = .51) and reversible (0.15 ± 3.79 vs 0.07 ± 3.33, P = .65) PDS were also comparable in patients randomized to regadenoson vs adenosine, respectively, and irrespective of age, gender, diabetic status, body mass index, or prior cardiovascular history. By propensity analysis, regadenoson-induced total PDS was significantly larger than observed with adenosine. CONCLUSION: This is the first study to show that regadenoson induces similar, if not larger, perfusion defects than those observed with adenosine across different patient populations and demonstrates the value of quantitative analysis for defining serial changes in SPECT perfusion results. Regadenoson should provide comparable diagnostic and prognostic SPECT information to that obtained with adenosine.

Inducible FGFR-1 activation leads to irreversible prostate adenocarcinoma and an epithelial-to-mesenchymal transition.

Fibroblast Growth Factor Receptor-1 (FGFR1) is commonly overexpressed in advanced prostate cancer (PCa). To investigate causality, we utilized an inducible FGFR1 (iFGFR1) prostate mouse model. Activation of iFGFR1 with chemical inducers of dimerization (CID) led to highly synchronous, step-wise progression to adenocarcinoma that is linked to an epithelial-to-mesenchymal transition (EMT). iFGFR1 inactivation by CID withdrawal led to full reversion of prostatic intraepithelial neoplasia, whereas PCa lesions became iFGFR1-independent. Gene expression profiling at distinct stages of tumor progression revealed an increase in EMT-associated Sox9 and changes in the Wnt signaling pathway, including Fzd4, which was validated in human PCa. The iFGFR1 model clearly implicates FGFR1 in PCa progression and demonstrates how CID-inducible models can help evaluate candidate molecules in tumor progression and maintenance.

HLA-restricted NY-ESO-1 peptide immunotherapy for metastatic castration resistant prostate cancer.

BACKGROUND: Given the immunogenicity of NY-ESO-1 peptides in prostate cancer, a phase I clinical trial was designed to evaluate HLA class-I and class-II restricted NY-ESO-1 peptides in metastatic castration-resistant prostate cancer (mCRPC). METHODS: Patients with progressive mCRPC, Zubrod Performance Status ≤2, PSA ≥10 ng/ml who had appropriate HLA class I (A2) and class II haplotypes (DR4, DP4) were eligible. Three groups with 3 patients each received the vaccine subcutaneously every 2 weeks for 6 doses. Group 1 received a peptide presented by an HLA class I haplotype (HLA-A2), Group 2 with a peptide presented by HLA class II haplotype (DR4, DP4), and Group 3 with peptides presented by both Class I and II haplotypes. Androgen-deprivation was continued. Owing to a myocardial infarction, the protocol was amended to omit the use of GM-CSF. RESULTS: Fourteen patients were evaluable for toxicities and 9 received all 6 doses and were evaluable for efficacy. One death from myocardial infarction following GM-CSF occurred in a patient with generalized myalgias. After omitting GM-CSF, no grade >2 toxicities were observed. Among 9 patients evaluable for efficacy, the median PSA doubling time pre-therapy and during therapy were 3.1 and 4.92 months, respectively. NY-ESO-1 specific T-cell response observed by ELISPOT appeared more frequent in docetaxel-naïve patients (4 of 4) than docetaxel-pretreated patients (2 of 5). CONCLUSION: In men with mCRPC, individualized HLA class-I and/or class-II restricted NY-ESO-1 peptides were tolerable, appeared to slow PSA doubling time and yielded antigen-specific T-cell responses more often in chemonaïve patients.

Fast Progression in Amyotrophic Lateral Sclerosis Is Associated With Greater TDP-43 Burden in Spinal Cord.

Upper and lower motor neuron pathologies are critical to the autopsy diagnosis of amyotrophic lateral sclerosis (ALS). Further investigation is needed to determine how the relative burden of these pathologies affects the disease course. We performed a blinded, retrospective study of 38 ALS patients, examining the association between pathologic measures in motor cortex, hypoglossal nucleus, and lumbar cord with clinical data, including progression rate and disease duration, site of symptom onset, and upper and lower motor neuron signs. The most critical finding in our study was that TAR DNA-binding protein 43 kDa (TDP-43) pathologic burden in lumbar cord and hypoglossal nucleus was significantly associated with a faster progression rate with reduced survival (p < 0.02). There was no correlation between TDP-43 burden and the severity of cell loss, and no significant clinical associations were identified for motor cortex TDP-43 burden or severity of cell loss in motor cortex. C9orf72 expansion was associated with shorter disease duration (p < 0.001) but was not significantly associated with pathologic measures in these regions. The association between lower motor neuron TDP-43 burden and fast progression with reduced survival in ALS provides further support for the study of TDP-43 as a disease biomarker.

Hippocampal Transcriptome Changes After Subarachnoid Hemorrhage in Mice.

After subarachnoid hemorrhage (SAH), up to 95% of surviving patients suffer from post-SAH syndrome, which includes cognitive deficits with impaired memory, executive functions, and emotional disturbances. Although these long-term cognitive deficits are thought to result from damage to temporomesial-hippocampal areas, the underlying mechanisms remain unknown. To fill this gap in knowledge, we performed a systematic RNA sequencing screen of the hippocampus in a mouse model of SAH. SAH was induced by perforation of the circle of Willis in mice. Four days later, hippocampal RNA was obtained from SAH and control (sham perforation) mice. Next-generation RNA sequencing was used to determine differentially expressed genes in the whole bilateral hippocampi remote from the SAH bleeding site. Functional analyses and clustering tools were used to define molecular pathways. Differential gene expression analysis detected 642 upregulated and 398 downregulated genes (false discovery rate <0.10) in SAH compared to Control group. Functional analyses using IPA suite, Gene Ontology terms, REACTOME pathways, and MsigDB Hallmark gene set collections revealed suppression of oligodendrocytes/myelin related genes, and overexpression of genes related to complement system along with genes associated with innate and adaptive immunity, and extracellular matrix reorganization. Interferon regulatory factors, TGF-ß1, and BMP were identified as major orchestrating elements in the hippocampal tissue response. The MEME-Suite identified binding motifs of Krüppel-like factors, zinc finger transcription factors, and interferon regulatory factors as overrepresented DNA promoter motifs. This study provides the first systematic gene and pathway database of the hippocampal response after SAH. Our findings suggest that damage of the entorhinal cortex by subarachnoid blood may remotely trigger specific hippocampal responses, which include suppression of oligodendrocyte function. Identification of these novel pathways may allow for development of new therapeutic approaches for post-SAH cognitive deficits.

Determinants of outcome impact of vein of Marshall ethanol infusion when added to catheter ablation of persistent atrial fibrillation: A secondary analysis of the VENUS randomized clinical trial.

BACKGROUND: The Vein of Marshall Ethanol for Untreated Persistent AF (VENUS) trial demonstrated that adding vein of Marshall (VOM) ethanol infusion to catheter ablation (CA) improves ablation outcomes in persistent atrial fibrillation (AF). There was significant heterogeneity in the impact of VOM ethanol infusion on rhythm control. OBJECTIVE: The purpose of this study was to assess the association between outcomes and (1) achievement of bidirectional perimitral conduction block and (2) procedural volume. METHODS: The VENUS trial randomized patients with persistent AF (N = 343) to CA combined with VOM ethanol or CA alone. The primary outcome (freedom from AF or atrial tachycardia [AT] lasting longer than 30 seconds after a single procedure) was analyzed by 2 categories: (1) successful vs no perimitral block and (2) high- (>20 patients enrolled) vs low-volume centers. RESULTS: In patients with perimitral block, the primary outcome was reached 54.3% after VOM-CA and 37% after CA alone (P = .01). Among patients without perimitral block, freedom from AF/AT was 34.0% after VOM-CA and 37.0% after CA (P = .583). In high-volume centers, the primary outcome was reached in 56.4% after VOM-CA and 40.2% after CA (P = .01). In low-volume centers, freedom from AF/AT was 30.77% after VOM-CA and 32.61% after CA (P = .84). In patients with successful perimitral block from high-volume centers, the primary outcome was reached in 59% after VOM-CA and 39.1% after CA (P = .01). Tests for interaction were significant (P = .002 for perimitral block and P = .04 for center volume). CONCLUSION: Adding VOM ethanol infusion to CA has a greater impact on outcomes when associated with perimitral block and performed in high-volume centers. Perimitral block should be part of the VOM procedure.

Coronary artery calcium scoring in the emergency department: identifying which patients with chest pain can be safely discharged home.

STUDY OBJECTIVE: Coronary artery calcium scoring (CACS) is a simple and readily available test for identifying coronary artery disease. Our objective is to evaluate whether a CACS of zero will identify chest pain patients who can be safely discharged home, without need for further cardiac testing. METHODS: This was a prospective observational cohort study conducted at an urban tertiary care hospital of stable patients presenting to the emergency department (ED) with chest pain of uncertain cardiac cause. Patients with a normal initial troponin level, nonischemic ECG, and no history of coronary artery disease had stress myocardial perfusion imaging (SPECT) and CACS within 24 hours of ED admission. Cardiac events were defined as an acute coronary syndrome during the index hospitalization or in follow-up. CACS results were assessed in relation to SPECT findings and cardiac events. RESULTS: The 1,031 patients enrolled (mean [SD] age 54 [13] years) had a median CACS of 0 (61% with CACS of 0). The frequency of an abnormal SPECT ranged from 0.8% (CACS of 0) to17% (CACS>400). Cardiac events occurred in 32 patients (3.1%) during the index hospitalization (N=28) or after hospital discharge (N=4) (mean 7.4 [3.3] months). Only 2 events occurred in 625 patients with a CACS of 0 (0.3%; 95% confidence interval 0.04% to 1.1%). Thus, 2 of 32 patients with a cardiac event had a CACS of 0 (6%; 95% confidence interval 0.8% to 21%). Both of these patients developed increased troponin levels during their index visit but had normal serial ECG and SPECT study results and no cardiac events at 6-month follow-up. CONCLUSION: A majority of patients (61% in our sample) evaluated for chest pain of uncertain cardiac cause have a CACS of 0, which predicts both a normal SPECT result and an excellent short-term outcome. Our results suggest that patients with a CACS of 0 can be discharged home, without further cardiac testing.

Is there a relationship between femoral neck-shaft angle and ischiofemoral impingement in patients with hip pain?

Ischiofemoral impingement (IFI) is a cause of deep gluteal space syndrome. The prevalence of radiographic findings in patients with hip pain is unknown. To assess if there is a correlation between femoral neck-shaft angle (NSA) and the distance of the ischiofemoral space (IFS) and quadratus femoris space (QFS) and to determine the prevalence of quadratus femoris (QF) edema in patients with hip pain. A retrospective case series was conducted involving 100 consecutive hip or pelvis magnetic resonance imaging scans on patients presenting with hip pain. NSA, IFS and QFS distances were measured and presence of QF edema was noted. Analysis of the groups (QF edema vs no edema) was performed using two-tailed t-test and Pearson correlation. There were 18 hips in the edema group (mean age 51.11 years ± 10.5) and 82 hips in the non-edema group (mean age 40.79 years ± 15.9). Within the edema group, there was a moderate positive correlation between NSA and QFS (r = 0.498, P = 0.036) and a weak positive correlation between NSA and IFI (0.312, P = 0.208). The prevalence of QF edema in this study was 18% with only 28% of those subjects having clinical symptoms of IFI. Patients with QF edema had significantly narrower QFS and IFS distances (P < 0.001). The prevalence of QF edema is 18% in a consecutive sample of adults with hip pain. In patients with QF edema, only 28% have symptoms of IFI. In patients with QF edema, there was a moderate positive correlation between NSA and QFS.

High Prevalence of Connective Tissue Gene Variants in Professional Ballet.

BACKGROUND: There is a high prevalence of hypermobility spectrum disorder (HSD) in dancers. While there is no known genetic variant for HSD, hypermobile Ehlers-Danlos syndrome is a genetic disorder that exists within HSD. There are many connective tissue disorders (CTDs) with known (and unknown) genes associated with hypermobility. Hypermobility has distinct advantages for participation in flexibility sports, including ballet. PURPOSE: To determine the prevalence of gene variants associated with hypermobility in a large professional ballet company. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: In this cross-sectional investigation, 51 professional male and female dancers from a large metropolitan ballet company were eligible and offered participation after an oral and written informed consent process. Whole blood was obtained from peripheral venipuncture, and DNA was isolated. Isolated DNA was subsequently enriched for the coding exons of 60 genes associated with CTD that included hypermobility as a phenotype, including Ehlers-Danlos syndromes, osteogenesis imperfecta, Marfan syndrome, and others. Genes were targeted with hybrid capture technology. Prepared DNA libraries were then sequenced with next-generation sequencing technology. Genetic database search tools (Human Gene Mutation Database and e!Ensembl, http://useast.ensembl.org/ ) were used to query specific variants. Descriptive statistics were calculated. RESULTS: Of 51 dancers, 32 (63%) agreed to participate in DNA analysis (mean ± SD age, 24.3 ± 4.4 years; 18 men, 14 women). Twenty-eight dancers had at least 1 variant in the 60 genes tested, for an 88% prevalence. A total of 80 variants were found. A variant in 26 of the 60 genes was found in at least 1 dancer. Among the 28 dancers with variants, 16 were found in the TTN gene; 10 in ZNF469; 5 in RYR1; 4 in COL12A1; 3 in ABCC6 and COL6A2; 2 in ADAMTS2, CBS, COL1A2, COL6A3, SLC2A10, TNC, and TNXB; and 1 in ATP6V0A2, B4GALT7, BMP1, COL11A1, COL5A2, COL6A1, DSE, FBN1, FBN2, NOTCH1, PRDM5, SMAD3, and TGFBR1. Nine variants found in this population have never been reported. No identified variant was identical to any other variant. No identified variant was known to be disease causing. In the general population, the prevalence of each variant ranges from never reported to 0.33%. In the study population, the prevalence of each variant was 3.13%. There was no association between hypermobility scores and genetic variants. CONCLUSION: Genetic variants in CTD-associated genes are highly prevalent (88%) in professional ballet dancers. This may significantly account for the high degree of motion in this population.

An Injury Prevention Program for Professional Ballet: A Randomized Controlled Investigation.

BACKGROUND: Few investigations have examined dance-specific injury prevention programs (IPPs), and no published randomized controlled trials are available that evaluate IPPs for dance. HYPOTHESIS: The implementation of an IPP will significantly reduce the risk of injury in professional ballet dancers. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: A randomized controlled trial was designed that entailed a superiority model for the intervention group. All professional dancers from a single ballet company were eligible to participate. Randomization and allocation were performed before the start of the season. The control group practiced and performed without change to preexisting standard operating practice. The IPP group was instructed to perform a 30-minute exercise program 3 times per week over the 52-week study period. Injuries were recorded. Standard continuous and categorical data comparisons and correlations were used. Cox proportional hazards regression models for recurrent failures were used wherein the hazard ratio indicates the relative likelihood of injury in the control versus intervention groups. RESULTS: Of the 52 eligible dancers, 75% (n = 39) participated. Of these 39 dancers, 19 (9 males, 10 females; mean age, 26.6 ± 4.0 years) were randomized to the control group and 20 (11 males, 9 females; mean age, 25.1 ± 5.1 years) to the IPP group. No significant (P > .05) difference was found in baseline demographics between groups. A total of 116 injuries were recorded for the entire study population (49 IPP; 67 control). Traumatic and chronic injuries accounted for 54% and 46% of injuries, respectively. The injury rate was 82% less (IPP hazard ratio, 0.18; z = -2.29; P = .022) in the IPP group after adjustment for confounding variables, and time between injuries was 45% longer (IPP hazard ratio, 0.55; z = -2.20; P = .028) than for controls. CONCLUSION: The present study is the first prospective randomized controlled investigation of an IPP for professional ballet. The results showed an 82% decrease in injury rate for the intervention group and an extended period from previous injury to subsequent injury. REGISTRATION: NCT04110002 (ClinicalTrials.gov identifier).

NASA study of cataract in astronauts (NASCA). Report 1: Cross-sectional study of the relationship of exposure to space radiation and risk of lens opacity.

The NASA Study of Cataract in Astronauts (NASCA) is a 5-year longitudinal study of the effect of space radiation exposure on the severity/progression of nuclear, cortical and posterior subcapsular (PSC) lens opacities. Here we report on baseline data that will be used over the course of the longitudinal study. Participants include 171 consenting astronauts who flew at least one mission in space and a comparison group made up of three components: (a) 53 astronauts who had not flown in space, (b) 95 military aircrew personnel, and (c) 99 non-aircrew ground-based comparison subjects. Continuous measures of nuclear, cortical and PSC lens opacities were derived from Nidek EAS 1000 digitized images. Age, demographics, general health, nutritional intake and solar ocular exposure were measured at baseline. Astronauts who flew at least one mission were matched to comparison subjects using propensity scores based on demographic characteristics and medical history stratified by gender and smoking (ever/never). The cross-sectional data for matched subjects were analyzed by fitting customized non-normal regression models to examine the effect of space radiation on each measure of opacity. The variability and median of cortical cataracts were significantly higher for exposed astronauts than for nonexposed astronauts and comparison subjects with similar ages (P=0.015). Galactic cosmic space radiation (GCR) may be linked to increased PSC area (P=0.056) and the number of PSC centers (P=0.095). Within the astronaut group, PSC size was greater in subjects with higher space radiation doses (P=0.016). No association was found between space radiation and nuclear cataracts. Cross-sectional data analysis revealed a small deleterious effect of space radiation for cortical cataracts and possibly for PSC cataracts. These results suggest increased cataract risks at smaller radiation doses than have been reported previously.

DNA Repair Gene Expression Adjusted by the PCNA Metagene Predicts Survival in Multiple Cancers.

Removal of the proliferation component of gene expression by proliferating cell nuclearantigen (PCNA) adjustment via statistical methods has been addressed in numerous survivalprediction studies for breast cancer and all cancers in the Cancer Genome Atlas (TCGA). Thesestudies indicate that the removal of proliferation in gene expression by PCNA adjustment removesthe statistical significance for predicting overall survival (OS) when gene selection is performed ona genome-wide basis. Since cancers become addicted to DNA repair as a result of forced cellularreplication, increased oxidation, and repair deficiencies from oncogenic loss or geneticpolymorphisms, we hypothesized that PCNA adjustment of DNA repair gene expression does notremove statistical significance for OS prediction. The rationale and importance of this translationalhypothesis is that new lists of repair genes which are predictive of OS can be identified to establishnew targets for inhibition therapy. A candidate gene approach was employed using TCGARNA-Seq data for 121 DNA repair genes in 8 molecular pathways to predict OS for 18 cancers.Statistical randomization test results indicate that after PCNA adjustment, OS could be predictedsignificantly by sets of DNA repair genes for 61% (11/18) of the cancers. These findings suggest thatremoval of the proliferation signal in expression by PCNA adjustment does not remove statisticalsignificance for predicting OS. In conclusion, it is likely that previous studies on PCNA adjustmentand survival were biased because genes identified through a genome-wide approach are stronglyco-regulated by proliferation.

Inositol polyphosphate 4-phosphatase type II regulation of androgen receptor activity.

Activation and transcriptional reprogramming of AR in advanced prostate cancer frequently coincides with the loss of two tumor suppressors, INPP4B and PTEN, which are highly expressed in human and mouse prostate epithelium. While regulation of AR signaling by PTEN has been described by multiple groups, it is not known whether the loss of INPP4B affects AR activity. Using prostate cancer cell lines, we showed that INPP4B regulates AR transcriptional activity and the oncogenic signaling pathways Akt and PKC. Analysis of gene expression in prostate cancer patient cohorts showed a positive correlation between INPP4B expression and both AR mRNA levels and AR transcriptional output. Using an Inpp4b-/- mouse model, we demonstrated that INPP4B suppresses Akt and PKC signaling pathways and modulates AR transcriptional activity in normal mouse prostate. Remarkably, PTEN protein levels and phosphorylation of S380 were the same in Inpp4b-/- and WT males, suggesting that the observed changes were due exclusively to the loss of INPP4B. Our data show that INPP4B modulates AR activity in normal prostate and its loss contributes to the AR-dependent transcriptional profile in prostate cancer.