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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

Impact of Cardiovascular Risk on the Relative Benefit and Harm of Intensive Treatment of Hypertension.

BACKGROUND: The lower rate of primary outcome events in the intensive treatment group in SPRINT (Systolic Pressure Intervention Trial) was associated with increased clinically significant serious adverse events (SAEs). In 2017, the American College of Cardiology/American Heart Association issued risk-based blood pressure treatment guidelines. The authors hypothesized that stratification of the SPRINT population by degree of future cardiovascular disease (CVD) risk might identify a group which could benefit the most from intensive treatment. OBJECTIVES: This study investigated the effect of baseline 10-year CVD risk on primary outcome events and all-cause SAEs in SPRINT. METHODS: Stratifying by quartiles of baseline 10-year CVD risk, Cox proportional hazards models were used to examine the associations of treatment group with the primary outcome events and SAEs. Using multiplicative Poisson regression, a predictive model was developed to determine the benefit-to-harm ratio as a function of CVD risk. RESULTS: Within each quartile, there was a lower rate of primary outcome events in the intensive treatment group, with no differences in all-cause SAEs. From the first to fourth quartiles, the number needed to treat to prevent primary outcomes decreased from 91 to 38. The number needed to harm for all-cause SAEs increased from 62 to 250. The predictive model demonstrated significantly increasing benefit-to-harm ratios (± SE) of 0.50 ± 0.15, 0.78 ± 0.26, 2.13 ± 0.73, and 4.80 ± 1.86, for the first, second, third, and fourth quartile, respectively (p for trend <0.001). All possible pairwise comparisons of between-quartile mean values of benefit-to-harm ratios were significantly different (p < 0.001). CONCLUSIONS: In SPRINT, those with lower baseline CVD risk had more harm than benefit from intensive treatment, whereas those with higher risk had more benefit. With the 2017 American College of Cardiology/American Heart Association blood pressure treatment guidelines, this analysis may help providers and patients make decisions regarding the intensity of blood pressure treatment.

The Measurement of Orthopaedic Surgeon Quality and Quantity of Sleep Using a Validated Wearable Device.

INTRODUCTION: Recurrent episodes of partial sleep deprivation resulting from shift work or call schedules are commonly seen in physicians. This study measures the quantity and quality of sleep in orthopaedic surgeons and determines the factors that are correlated with decreased quantity and quality of sleep. METHODS: Orthopaedic surgery residents and attending surgeons at a single institution were prospectively enrolled and provided with a validated wearable device to objectively determine sleep quantity (total hours of sleep) and quality (sleep disturbances; sleep latency; sleep efficiency; and amount of rapid eye movement [REM] sleep, deep sleep, and light sleep). Sleep deprivation was defined as getting less than 7 hours of sleep per day. Bivariate correlations were determined using Spearman rank correlation. Multiple linear regression models were constructed to determine the effect of independent variables (age, attending physician, resident, postgraduate year [PGY] level, sex, number of calls, and total hours worked) and sleep quantity and quality. All P values were reported, and a significance level of α = 0.05 was used (ie, P < 0.05). RESULTS: Of 26 enrolled subjects, 21 (80.8%; 12 residents and 9 attending surgeons, where 15 were men and 6 women, with mean age of 37.2 ± 10.9 years) completed the 4-week duration of the study. Orthopaedic surgeons obtained 6.5 ± 0.8 hours of sleep per night (17.7% REM, 19.4% deep sleep, and 62.6% light sleep; 4.5 ± 1.1 minutes of sleep latency; 4.9 ± 1.7 sleep disturbances; and 89.9% sleep efficiency). Fourteen orthopaedic surgeons (66.7%) of the 21 slept less than the recommended 7 hours of sleep per night. The total hours worked had a moderate negative correlation (r = -0.550; P = 0.010) with total sleep. PGY level had a moderate positive correlation with sleep latency (r = 0.546; P = 0.010). DISCUSSION: Diminished sleep quantity is considered sleeping less than 7 hours per night, whereas decreased sleep quality is associated with decreased REM sleep, decreased deep sleep, increased light sleep, decreased sleep latency, decreased sleep efficiency, and increased sleep disturbances. Sleep deprivation in orthopaedic surgeons poses notable health and safety risks for both surgeons and patients. CONCLUSION: Orthopaedic surgeons demonstrate poor sleep quantity and quality which is markedly worse than the general population, with increased work hours markedly correlated with decreased hours of sleep.

Progression inference for somatic mutations in cancer.

Computational methods were employed to determine progression inference of genomic alterations in commonly occurring cancers. Using cross-sectional TCGA data, we computed evolutionary trajectories involving selectivity relationships among pairs of gene-specific genomic alterations such as somatic mutations, deletions, amplifications, downregulation, and upregulation among the top 20 driver genes associated with each cancer. Results indicate that the majority of hierarchies involved TP53, PIK3CA, ERBB2, APC, KRAS, EGFR, IDH1, VHL, etc. Research into the order and accumulation of genomic alterations among cancer driver genes will ever-increase as the costs of nextgen sequencing subside, and personalized/precision medicine incorporates whole-genome scans into the diagnosis and treatment of cancer.

Clinical Significance of TDP-43 Neuropathology in Amyotrophic Lateral Sclerosis.

To determine the significance of TAR DNA binding protein 43 kDa (TDP-43) pathology in amyotrophic lateral sclerosis (ALS), we examined the whole brains and spinal cords of 57 patients (35 men; 22 women; mean age 63.3 years; 15 patients with c9orf72-associated ALS [c9ALS]). TDP-43 pathologic burden was determined relative to symptom onset site, disease duration, progression rate, cognitive status, and c9ALS status. There was a trend for greater TDP-43 pathologic burden in cognitively impaired patients (p = 0.07), though no association with disease duration or progression rate was seen. Shorter disease duration (p = 0.0016), more severe striatal pathology (p = 0.0029), and a trend toward greater whole brain TDP-43 pathology (p = 0.059) were found in c9ALS. Cluster analysis identified "TDP43-limited," "TDP43-moderate," and "TDP43-severe" subgroups. The TDP43-limited group contained more cognitively intact (p = 0.005) and lower extremity onset site (p = 0.019) patients, while other subgroups contained more cognitively impaired patients. We conclude that TDP-43 pathologic burden in ALS is associated with cognitive impairment and c9ALS, but not duration of disease or rate of progression. Further, we demonstrate a subgroup of patients with low TDP-43 burden, lower extremity onset, and intact cognition, which requires further investigation.

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.

Transcript Analysis for Internal Biodosimetry Using Peripheral Blood from Neuroblastoma Patients Treated with (131)I-mIBG, a Targeted Radionuclide.

Calculating internal dose from therapeutic radionuclides currently relies on estimates made from multiple radiation exposure measurements, converted to absorbed dose in specific organs using the Medical Internal Radiation Dose (MIRD) schema. As an alternative biodosimetric approach, we utilized gene expression analysis of whole blood from patients receiving targeted radiotherapy. Collected blood from patients with relapsed or refractory neuroblastoma who received (131)I-labeled metaiodobenzylguanidine ((131)I-mIBG) at the University of California San Francisco (UCSF) was used to compare calculated internal dose with the modulation of chosen gene expression. A total of 40 patients, median age 9 years, had blood drawn at baseline, 72 and 96 h after (131)I-mIBG infusion. Whole-body absorbed dose was calculated for each patient based on the cumulated activity determined from injected mIBG activity and patient-specific time-activity curves combined with (131)I whole-body S factors. We then assessed transcripts that were the most significant for describing the mixed therapeutic treatments over time using real-time polymerase chain reaction (RT-PCR). Modulation was evaluated statistically using multiple regression analysis for data at 0, 72 and 96 h. A total of 10 genes were analyzed across 40 patients: CDKN1A; FDXR; GADD45A; BCLXL; STAT5B; BAX; BCL2; DDB2; XPC; and MDM2. Six genes were significantly modulated upon exposure to (131)I-mIBG at 72 h, as well as at 96 h. Four genes varied significantly with absorbed dose when controlling for time. A gene expression biodosimetry model was developed to predict absorbed dose based on modulation of gene transcripts within whole blood. Three transcripts explained over 98% of the variance in the modulation of gene expression over the 96 h (CDKN1A, BAX and DDB2). To our knowledge, this is a novel study, which uses whole blood collected from patients treated with a radiopharmaceutical, to characterize biomarkers that may be useful for biodosimetry. Our data indicate that transcripts, which have been previously identified as biomarkers of external exposures in ex vivo whole blood and in vivo radiotherapy patients, are also good early indicators of internal exposure. However, for internal sources of radiation, the biokinetics and physical decay of the radionuclide strongly influence the gene expression.