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The release of paused RNA polymerase II (RNAPII) from promoter-proximal regions is tightly controlled to ensure proper regulation of gene expression. The elongation factor PTEF-b is known to release paused RNAPII via phosphorylation of the RNAPII C-terminal domain by its cyclin-dependent kinase component, CDK9. However, the signal and stress-specific roles of the various RNAPII-associated macromolecular complexes containing PTEF-b/CDK9 are not yet clear. Here, we identify and characterize the CDK9 complex required for transcriptional response to hypoxia. Contrary to previous reports, our data indicate that a CDK9 complex containing BRD4 but not AFF1/4 is essential for this hypoxic stress response. We demonstrate that BRD4 bromodomains (BET) are dispensable for the release of paused RNAPII at hypoxia-activated genes and that BET inhibition by JQ1 is insufficient to impair hypoxic gene response. Mechanistically, we demonstrate that the C-terminal region of BRD4 is required for Polymerase-Associated Factor-1 Complex (PAF1C) recruitment to establish an elongation-competent RNAPII complex at hypoxia-responsive genes. PAF1C disruption using a small-molecule inhibitor (iPAF1C) impairs hypoxia-induced, BRD4-mediated RNAPII release. Together, our results provide insight into potentially targetable mechanisms that control the hypoxia-responsive transcriptional elongation. [ABSTRACT FROM AUTHOR]

Patients are faced with many questions surrounding the after effects of the various surgical procedures and their ability to return to preoperative activities. While patients often question whether surgery would provide alleviation of pain, weakness, and instability, they often have additional questions about sexual activity during their convalescence that are not always addressed. Although the literature shows postsurgical improvement in sexual activity in association with improved low back pain, reports vaguely address the variability in sexual activity recommendations based on anatomic location and type of spinal surgery. We conducted a PubMed search of the English language from 1990 to 2018 with the following keywords: sexual activity, postoperative, spinal fusion, spinal decompression, functional outcomes, laminectomy, rehabilitation, biomechanics, lumbar disc surgery, metabolic energy expenditure, coital position, and Oswestry Disability Index. Additional studies are needed that survey both patients and spine surgeons to examine current recommendations and to help formulate future guidelines.

This literature review examines the relative placement of the interbody cage with respect to the unilateral screw construct to address the need for bilateral screw placement versus unilateral screw placement. Transforaminal lumbar interbody fusion (TLIF) has become a widely used technique for correcting lumbar intervertebral pathologies. This review addresses the necessity for further study on the effects of the relative position of intervertebral cage placement on the outcome of lumbar spine surgery after TLIF with unilateral pedicle screw fixation. Previous studies have addressed various factors, including posterior screw fixation, cage size, cage shape, and number of levels fused, that impact the biomechanics of the lumbar spine following TLIF. A simple survey of the literature was conducted. A search of the English literature was conducted using the keywords ‘TLIF,’ ‘transforaminal lumbar interbody fusion,’ ‘graft placement,’ ‘graft position,’ ‘cage position,’ ‘cage placement,’ ‘unilateral pedicle screw,’ ‘unilateral TLIF cage placement,’ ‘lumbar biomechanics,’ ‘lumbar stability,’ ‘lumbar fusion,’ and ‘lumbar intervertebral cage’ with various combinations of the operators ‘AND’ and ‘OR’ and no date restrictions. Seventeen articles in the English literature that were most relevant to this research question were identified. To the best of our knowledge, there are no published data addressing the effects of cage placement relative to the unilateral screw on lumbar stability in TLIF with unilateral pedicle screw fixation. Investigation of the effects of cage placement is, thus, warranted to achieve optimal clinical outcomes in patients undergoing TLIF with unilateral pedicle screw fixation.

Objective: To assess the quality of reporting in diagnostic accuracy studies (DAS) referenced by the Quality Improvement Guidelines for Diagnostic Arteriography and their adherence to the Standards for Reporting of Diagnostic Accuracy (STARD) statement. Materials and Methods: Citations specific to the Society of Interventional Radiology's Quality Improvement Guidelines for Diagnostic Arteriography were collected. Using the 34-item STARD checklist, two authors in a duplicate and blinded fashion documented the number of items reported per diagnostic accuracy study. Authors met, and any discrepancies were resolved in a resolution meeting. Results: Of the 26 diagnostic accuracy studies included, the mean number of STARD items reported was 17.8 (SD ± 3.1). The median adherence was 18 (IQR, 17-19) items. Ten articles were published prior to 2003, the original date of STARD publication, and 16 articles were published after 2003. The mean number of reported items for the articles published prior to STARD 2003, and after STARD 2003 was 17.4 (SD ± 2.4) and 18.1 (SD ± 3.5), respectively. There were 14 STARD items that demonstrated an adherence of < 25%, and 13 an adherence > 75%. Conclusion: The dichotomous distribution of adherence to the STARD statement by DAS investigated demonstrates that areas of deficient reporting may be present and require attention to ensure complete and transparent reporting in the future. [ABSTRACT FROM AUTHOR]

Patients are faced with many questions surrounding the after effects of the various surgical procedures and their ability to return to preoperative activities. While patients often question whether surgery would provide alleviation of pain, weakness, and instability, they often have additional questions about sexual activity during their convalescence that are not always addressed. Although the literature shows postsurgical improvement in sexual activity in association with improved low back pain, reports vaguely address the variability in sexual activity recommendations based on anatomic location and type of spinal surgery. We conducted a PubMed search of the English language from 1990 to 2018 with the following keywords: sexual activity, postoperative, spinal fusion, spinal decompression, functional outcomes, laminectomy, rehabilitation, biomechanics, lumbar disc surgery, metabolic energy expenditure, coital position, and Oswestry Disability Index. Additional studies are needed that survey both patients and spine surgeons to examine current recommendations and to help formulate future guidelines. [ABSTRACT FROM AUTHOR]

This literature review examines the relative placement of the interbody cage with respect to the unilateral screw construct to address the need for bilateral screw placement versus unilateral screw placement. Transforaminal lumbar interbody fusion (TLIF) has become a widely used technique for correcting lumbar intervertebral pathologies. This review addresses the necessity for further study on the effects of the relative position of intervertebral cage placement on the outcome of lumbar spine surgery after TLIF with unilateral pedicle screw fixation. Previous studies have addressed various factors, including posterior screw fixation, cage size, cage shape, and number of levels fused, that impact the biomechanics of the lumbar spine following TLIF. A simple survey of the literature was conducted. A search of the English literature was conducted using the keywords ‘TLIF,’ ‘transforaminal lumbar interbody fusion,’ ‘graft placement,’ ‘graft position,’ ‘cage position,’ ‘cage placement,’ ‘unilateral pedicle screw,’ ‘unilateral TLIF cage placement,’ ‘lumbar biomechanics,’ ‘lumbar stability,’ ‘lumbar fusion,’ and ‘lumbar intervertebral cage’ with various combinations of the operators ‘AND’ and ‘OR’ and no date restrictions. Seventeen articles in the English literature that were most relevant to this research question were identified. To the best of our knowledge, there are no published data addressing the effects of cage placement relative to the unilateral screw on lumbar stability in TLIF with unilateral pedicle screw fixation. Investigation of the effects of cage placement is, thus, warranted to achieve optimal clinical outcomes in patients undergoing TLIF with unilateral pedicle screw fixation. [ABSTRACT FROM AUTHOR]

Introduction: Recent evidence suggests a lack of standardization of shoulder arthroplasty outcomes. This issue is a limiting factor in systematic reviews. Core outcome set (COS) methodology could address this problem by delineating a minimum set of outcomes for measurement in all shoulder arthroplasty trials. Methods: A ClinicalTrials.gov search yielded 114 results. Eligible trials were coded on the following characteristics: study status, study type, arthroplasty type, sample size, measured outcomes, outcome measurement device, specific metric of measurement, method of aggregation, outcome classification, and adverse events. Results: Sixty-six trials underwent data abstraction and data synthesis. Following abstraction, 383 shoulder arthroplasty outcomes were organized into 11 outcome domains. The most commonly reported outcomes were shoulder outcome score (n = 58), pain (n = 33), and quality of life (n = 15). The most common measurement devices were the Constant-Murley Shoulder Outcome Score (n = 38) and American Shoulder and Elbow Surgeons Shoulder Score (n = 33). Temporal patterns of outcome use was also found. Conclusion: Our study suggests the need for greater standardization of outcomes and instruments. The lack of consistency across trials indicates that developing a core outcome set for shoulder arthroplasty trials would be worthwhile. Such standardization would allow for more effective comparison across studies in systematic reviews, while at the same time consider important outcomes that may be underrepresented otherwise. This review of outcomes provides an evidence-based foundation for the development of a COS for shoulder arthroplasty. [ABSTRACT FROM AUTHOR]

Background: Selective outcome reporting is a significant methodological concern. Comparisons between the outcomes reported in clinical trial registrations and those later published allow investigators to understand the extent of selection bias among trialists. We examined the possibility of selective outcome reporting in randomized controlled trials (RCTs) published in neurology journals. Methods: We searched PubMed for randomized controlled trials from Jan 1, 2010 –Dec 31, 2015 published in the top 3 impact factor neurology journals. These articles were screened according to specific inclusion criteria. Each author individually extracted data from trials following a standardized protocol. A second author verified each extracted element and discrepancies were resolved. Consistency between registered and published outcomes was evaluated and correlations between discrepancies and funding, journal, and temporal trends were examined. Results: 180 trials were included for analysis. 10 (6%) primary outcomes were demoted, 38 (21%) primary outcomes were omitted from the publication, and 61 (34%) unregistered primary outcomes were added to the published report. There were 18 (10%) cases of secondary outcomes being upgraded to primary outcomes in the publication, and there were 53 (29%) changes in timing of assessment. Of 82 (46%) major discrepancies with reported p-values, 54 (66.0%) favored publication of statistically significant results. Conclusion: Across trials, we found 180 major discrepancies. 66% of major discrepancies with a reported p-value (n = 82) favored statistically significant results. These results suggest a need within neurology to provide more consistent and timely registration of outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Acute traumatic coagulopathy has been associated with shock and tissue injury, and may be mediated via activation of the protein C pathway. Patients with acute traumatic coagulopathy have prolonged PT and PTT, and decreased activity of factors V and VIII; they are also hypocoagulable by thromboelastometry (ROTEM) and other viscoelastic assays. To test the etiology of this phenomenon, we hypothesized that such coagulopathy could be induced in vitro in healthy human blood with the addition of activated protein C (aPC). Methods: Whole blood was collected from 20 healthy human subjects, and was “spiked” with increasing concentrations of purified human aPC (control, 75, 300, 2000 ng/mL). PT/PTT, factor activity assays, and ROTEM were performed on each sample. Mixed effect regression modeling was performed to assess the association of aPC concentration with PT/PTT, factor activity, and ROTEM parameters. Results: In all subjects, increasing concentrations of aPC produced ROTEM tracings consistent with traumatic coagulopathy. ROTEM EXTEM parameters differed significantly by aPC concentration, with stepwise prolongation of clotting time (CT) and clot formation time (CFT), decreased alpha angle (α), impaired early clot formation (a10 and a20), and reduced maximum clot firmness (MCF). PT and PTT were significantly prolonged at higher aPC concentrations, with corresponding significant decreases in factor V and VIII activity. Conclusion: A phenotype of acute traumatic coagulopathy can be induced in healthy blood by the in vitro addition of aPC alone, as evidenced by viscoelastic measures and confirmed by conventional coagulation assays and factor activity. This may lend further mechanistic insight to the etiology of coagulation abnormalities in trauma, supporting the central role of the protein C pathway. Our findings also represent a model for future investigations in the diagnosis and treatment of acute traumatic coagulopathy. [ABSTRACT FROM AUTHOR]

Abstract: Building on ideas of Vatsal [Uniform distribution of Heegner points, Invent. Math. 148(1) (2002) 1–46], Cornut [Mazur''s conjecture on higher Heegner points, Invent. Math. 148(3) (2002) 495–523] proved a conjecture of Mazur asserting the generic nonvanishing of Heegner points on an elliptic curve as one ascends the anticyclotomic -extension of a quadratic imaginary extension . In the present article, Cornut''s result is extended by replacing the elliptic curve E with the Galois cohomology of Deligne''s two-dimensional -adic representation attached to a modular form of weight , and replacing the family of Heegner points with an analogous family of special cohomology classes. [Copyright &y& Elsevier]

The biological role of the repetitive DNA sequences in the human genome remains an outstanding question. Recent long-read human genome assemblies have allowed us to identify a function for one of these repetitive regions. We have uncovered a tandem array of conserved primate-specific retrogenes encoding the protein Elongin A3 (ELOA3), a homolog of the RNA polymerase II (RNAPII) elongation factor Elongin A (ELOA). Our genomic analysis shows that the ELOA3 gene cluster is conserved among primates and the number of ELOA3 gene repeats is variable in the human population and across primate species. Moreover, the gene cluster has undergone concerted evolution and homogenization within primates. Our biochemical studies show that ELOA3 functions as a promoter-associated RNAPII pause-release elongation factor with distinct biochemical and functional features from its ancestral homolog, ELOA. We propose that the ELOA3 gene cluster has evolved to fulfil a transcriptional regulatory function unique to the primate lineage that can be targeted to regulate cellular hyperproliferation. [ABSTRACT FROM AUTHOR]