Clinical biomarker innovation: when is it worthwhile?

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Traumatic Meniscal Tears Are Associated With Meniscal Degeneration

Background: Meniscal tears are traditionally classified into traumatic versus degenerative tears. Although this classification plays a major role in clinical decision making, no consensus exists on the exact definition of a traumatic or degenerative tear, and the histopathological basis for thi

Effects of new anti-adhesion polyvinyl alcohol gel on healing of colon anastomoses in rats

Background: Adhesions follow abdominal surgery with an incidence as high as 95%, resulting in invalidating complications such as bowel obstruction, female infertility, and chronic pain. Searches have been performed for a safe and effective adhesion barrier; however, such barriers have impaired anastomotic site healing. The primary aim of this study was to investigate the effect of a new adhesion barrier, polyvinyl alcohol gel, on healing of colonic anastomoses using a rat model. Methods: Thirty-two Wistar rats were divided in two groups. In all animals, an anastomosis was constructed in the ascending colon. The first group received no adhesion barrier, whereas in the second group, 2mL of polyvinyl alcohol gel (A-Part Gel®; Aesculap AG, Tuttlingen, Germany) was applied circularly around the anastomosis. All animals were sacrificed on the seventh post-operative day, and the abdomen was inspected for signs of anastomotic leakage. The anastomotic bursting pressure, the adhesions around the anastomosis, and the collagen content of the excised anastomosis were measured. Results: No significant differences were observed between the two groups in the incidence of anastomotic leakage, the anastomotic bursting pressure (p=0.08), or the collagen concentration (p=0.91). No significant reduction in amount of adhesions was observed in the rats receiving polyvinyl alcohol gel. Conclusions: This experimental study showed no significant differences in anastomotic leakage, anastomotic bursting pressure, or collagen content of the anastomosis when using the adhesion barrier polyvinyl alcohol around colonic anastomoses. The barrier did not prevent adhesion formation

Hyperbaric oxygen therapy improves colorectal anastomotic healing

Purpose: Hyperbaric oxygen treatment (HBOT) has been found to improve the healing of poorly oxygenated tissues. This study aimed to investigate the influence of HBOT on the healing in ischemic colorectal anastomosis. Methods: Forty Wistar rats were randomly divided into a treatment group that received HBOT for 10 consecutive days (7 days before and 3 days after surgery), or in a control group, which did not receive the therapy. Colectomy with an ischemic anastomosis was performed in all rats. In each group, the rats were followed for 3 or 7 days after surgery to determine the influence of HBOT on anastomotic healing. Results: Five rats from each group died during follow-up. No anastomotic dehiscence was seen in the HBOT group, compared to 37.5 % and 28.6 % dehiscence in the control group on postoperative day (POD) 3 and 7, respectively. The HBOT group had a significantly higher bursting pressure (130.9 ± 17.0 mmHg) than the control group (88.4 ± 46.7 mmHg; p = 0.03) on POD 3. On POD 3 and POD 7, the adhesion severity was significantly higher in the control groups than in the HBOT groups (p < 0.005). Kidney function (creatinine level) of the HBOT group was significantly better than of the control group on POD 7 (p = 0.001). Interestingly, a significantly higher number of CD206+ cells (marker for type 2 macrophages) was observed in the HBOT group at the anastomotic area on POD 3. Conclusion: Hyperbaric oxygen enhanced the healing of ischemic anastomoses in rats and improved the postoperative kidney function

Are Insider Sales Always Bad News? Evidence On Large Sales By Key Insiders

Investors often scrutinize stock trades by corporate insiders, hoping to infer the nature of any privileged information which may have motivated the trades. Conventional wisdom suggests that sales of stock by insiders reveal negative information; this interpretation is supported by empirical work such as the series of papers by Seyhun. However, this common interpretation fails to distinguish between sales by atomistic insiders and sales by controlling blockholders.&nbsp; In this paper, I present evidence which suggests that sales by controlling insiders should not be considered bad news. Using both a series of logit regressions and traditional event-study tests, I examine the relationship between a firm's performance and the willingness of its controlling shareholder to sell a significant proportion of his shares. I find that firm value is just as likely to rise on the news of large insider sales as it is to fall, so that large sales need not imply negative private information.&nbsp; One possible explanation for a positive response to a controlling blockholder's large sale is that such a sale makes the insider vulnerable to meaningful oversight by outside shareholders. Thus, a large sale may be a signal of the insider's willingness to expose himself to shareholder monitoring and discipline. However, regardless of the interpretation, the empirical evidence presented in the paper forces the conclusion that it is inappropriate to interpret all insider sales as bad news: insider sales occur in a variety of contexts, and creating buy/sell rules which ignore those contexts is simplistic and erroneous

Characterization of anticoagulant heparinoids by immunoprofiling

Heparinoids are used in the clinic as anticoagulants. A specific pentasaccharide in heparinoids activates antithrombin III, resulting in inactivation of factor Xa and–when additional saccharides are present–inactivation of factor IIa. Structural and functional analysis of the heterogeneous heparinoids generally requires advanced equipment, is time consuming, and needs (extensive) sample preparation. In this study, a novel and fast method for the characterization of heparinoids is introduced based on reactivity with nine unique anti-heparin antibodies. Eight heparinoids were biochemically analyzed by electrophoresis and their reactivity with domain-specific anti-heparin antibodies was established by ELISA. Each heparinoid displayed a distinct immunoprofile matching its structural characteristics. The immunoprofile could also be linked to biological characteristics, such as the anti-Xa/anti-IIa ratio, which was reflected by reactivity of the heparinoids with antibodies HS4C3 (indicative for 3-O-sulfates) and HS4E4 (indicative for domains allowing anti-factor IIa activity). In addition, the immunoprofile could be indicative for heparinoid-induced side-effects, such as heparin-induced thrombocytopenia, as illustrated by reactivity with antibody NS4F5, which defines a very high sulfated domain. In conclusion, immunoprofiling provides a novel, fast, and simple methodology for the characterization of heparinoids, and allows high-throughput screening of (new) heparinoids for defined structural and biological characteristics

Automated entire thrombus density measurements for robust and comprehensive thrombus characterization in patients with acute ischemic stroke

Background and Purpose: In acute ischemic stroke (AIS) management, CT-based thrombus density has been associated with treatment success. However, currently used thrombus measurements are prone to inter-observer variability and oversimplify the heterogeneous thrombus composition. Our aim was first to introduce an automated method to assess the entire thrombus density and then to compare the measured entire thrombus density with respect to current standard manual measurements. Materials and Method: In 135 AIS patients, the density distribution of the entire thrombus was determined. Density distributions were described usingmedians, interquartile ranges (IQR), kurtosis, and skewedness. Differences between themedian of entire thrombusmeasurements and commonly applied manualmeasurements using 3 regions of interest were determined using linear regression. Results: Density distributions varied considerably with medians ranging from 20.0 to 62.8 HU and IQRs ranging from 9.3 to 55.8 HU. The average median of the thrombus density distributions (43.5 ± 10.2 HU) was lower than the manual assessment (49.6 ± 8.0 HU) (p<0.05). The difference between manual measurements and median density of entire thrombus decreased with increasing density (r = 0.64; p<0.05), revealing relatively higher manual measurements for low density thrombi such that manual density measurement tend overestimates the real thrombus density. Conclusions: Automatic measurements of the full thrombus expose a wide variety of thrombi density distribution, which is not grasped with currently used manual measurement. Furthermore, d

Exploring the Bimodal Solar System via Sample Return from the Main Asteroid Belt: The Case for Revisiting Ceres

Abstract: Sample return from a main-belt asteroid has not yet been attempted, but appears technologically feasible. While the cost implications are significant, the scientific case for such a mission appears overwhelming. As suggested by the “Grand Tack” model, the structure of the main belt was likely forged during the earliest stages of Solar System evolution in response to migration of the giant planets. Returning samples from the main belt has the potential to test such planet migration models and the related geochemical and isotopic concept of a bimodal Solar System. Isotopic studies demonstrate distinct compositional differences between samples believed to be derived from the outer Solar System (CC or carbonaceous chondrite group) and those that are thought to be derived from the inner Solar System (NC or non-carbonaceous group). These two groups are separated on relevant isotopic variation diagrams by a clear compositional gap. The interface between these two regions appears to be broadly coincident with the present location of the asteroid belt, which contains material derived from both groups. The Hayabusa mission to near-Earth asteroid (NEA) (25143) Itokawa has shown what can be learned from a sample-return mission to an asteroid, even with a very small amount of sample. One scenario for main-belt sample return involves a spacecraft launching a projectile that strikes an object and flying through the debris cloud, which would potentially allow multiple bodies to be sampled if a number of projectiles are used on different asteroids. Another scenario is the more traditional method of landing on an asteroid to obtain the sample. A significant range of main-belt asteroids are available as targets for a sample-return mission and such a mission would represent a first step in mineralogically and isotopically mapping the asteroid belt. We argue that a sample-return mission to the asteroid belt does not necessarily have to return material from both the NC and CC groups to viably test the bimodal Solar System paradigm, as material from the NC group is already abundantly available for study. Instead, there is overwhelming evidence that we have a very incomplete suite of CC-related samples. Based on our analysis, we advocate a dedicated sample-return mission to the dwarf planet (1) Ceres as the best means of further exploring inherent Solar System variation. Ceres is an ice-rich world that may be a displaced trans-Neptunian object. We almost certainly do not have any meteorites that closely resemble material that would be brought back from Ceres. The rich heritage of data acquired by the Dawn mission makes a sample-return mission from Ceres logistically feasible at a realistic cost. No other potential main-belt target is capable of providing as much insight into the early Solar System as Ceres. Such a mission should be given the highest priority by the international scientific community

Colorectal liver metastases: Surgery versus thermal ablation (COLLISION) - a phase III single-blind prospective randomized controlled trial

Background: Radiofrequency ablation (RFA) and microwave ablation (MWA) are widely accepted techniques to eliminate small unresectable colorectal liver metastases (CRLM). Although previous studies labelled thermal ablation inferior to surgical resection, the apparent selection bias when comparing patients with unresectable disease to surgical candidates, the superior safety profile, and the competitive overall survival results for the more recent reports mandate the setup of a randomized controlled trial. The objective of the COLLISION trial is to prove non-inferiority of thermal ablation compared to hepatic resection in patients with at least one resectable and ablatable CRLM and no extrahepatic disease. Methods: In this two-arm, single-blind multi-center phase-III clinical trial, six hundred and eighteen patients with at least one CRLM (≤3cm) will be included to undergo either surgical resection or thermal ablation of appointed target lesion(s) (≤3cm). Primary endpoint is OS (overall survival, intention-to-treat analysis). Main secondary endpoints are overall disease-free survival (DFS), time to progression (TTP), time to local progression (TTLP), primary and assisted technique efficacy (PTE, ATE), procedural morbidity and mortality, length of hospital stay, assessment of pain and quality of life (QoL), cost-effectiveness ratio (ICER) and quality-adjusted life years (QALY). Discussion: If thermal ablation proves to be non-inferior in treating lesions ≤3cm, a switch in treatment-method may lead to a reduction of the post-procedural morbidity and mortality, length of hospital stay and incremental costs without compromising oncological outcome for patients with CRLM. Trial registration:NCT03088150 , January 11th 2017