Technical report: surgical preparation of human brain tissue for clinical and basic research.

BACKGROUND: The study of the distinct structure and function of the human central nervous system, both in healthy and diseased states, is becoming increasingly significant in the field of neuroscience. Typically, cortical and subcortical tissue is discarded during surgeries for tumors and epilepsy. Yet, there is a strong encouragement to utilize this tissue for clinical and basic research in humans. Here, we describe the technical aspects of the microdissection and immediate handling of viable human cortical access tissue for basic and clinical research, highlighting the measures needed to be taken in the operating room to ensure standardized procedures and optimal experimental results. METHODS: In multiple rounds of experiments (n = 36), we developed and refined surgical principles for the removal of cortical access tissue. The specimens were immediately immersed in cold carbogenated N-methyl-D-glucamine-based artificial cerebrospinal fluid for electrophysiology and electron microscopy experiments or specialized hibernation medium for organotypic slice cultures. RESULTS: The surgical principles of brain tissue microdissection were (1) rapid preparation (<1 min), (2) maintenance of the cortical axis, (3) minimization of mechanical trauma to sample, (4) use of pointed scalpel blade, (5) avoidance of cauterization and blunt preparation, (6) constant irrigation, and (7) retrieval of the sample without the use of forceps or suction. After a single round of introduction to these principles, multiple surgeons adopted the technique for samples with a minimal dimension of 5 mm spanning all cortical layers and subcortical white matter. Small samples (5-7 mm) were ideal for acute slice preparation and electrophysiology. No adverse events from sample resection were observed. CONCLUSION: The microdissection technique of human cortical access tissue is safe and easily adoptable into the routine of neurosurgical procedures. The standardized and reliable surgical extraction of human brain tissue lays the foundation for human-to-human translational research on human brain tissue.

Electro-optic sampling based characterization of broad-band high efficiency THz-FEL.

Extremely high beam-to-radiation energy conversion efficiencies can be obtained in a THz FEL using a strongly tapered helical undulator at the zero-slippage resonant condition, where a circular waveguide is used to match the radiation group velocity to the electron beam longitudinal velocity. In this paper we report on the first electro-optic sampling (EOS) based measurements of the broadband THz FEL radiation pulses emitted in this regime. The THz field waveforms are reconstructed in the spatial and temporal domains using multi-shot and single-shot EOS schemes respectively. The measurements are performed varying the input electron beam energy in the undulator providing insights on the complex dynamics in a waveguide FEL.

Helical plating - a novel technique to increase stiffness in defect fractures.

Single-plate fixation bridging bone defects provokes nonunion and risks plate-fatigue failure due to under- dimensioned implants. Adding a helical plate to bridge the fracture increases stiffness and balances load sharing. This study compares the stiffness and plate surface strain of different constructs in a transverse contact and gap femoral shaft fracture model. Eight groups of six synthetic femora each were formed: intact femora; intact femora with lateral locking plate; contact and gap transverse shaft osteotomies each with lateral locking plate, lateral locking plate and helical locking plate, and long proximal femoral nail. Constructs underwent non-destructive quasi-static axial and torsional loading. Plate surface strain evaluation was performed under 200 N axial loading. Constructs with both lateral and helical plates demonstrated similar axial and torsional stiffness- independent of the contact or gap situations - being significantly higher compared to lateral plating (p < 0.01). Torsional stiffness of the constructs, with both lateral and helical plates in the gap situation, was significantly higher compared to this situation stabilised by a nail (p < 0.01). Plate surface strain dropped from 0.3 % in the gap situation with a lateral plate to < 0.1 % in this situation with both a lateral and a helical plate. Additional helical plating increases axial and torsional construct stiffness in synthetic bone and seems to provide well-balanced load sharing. Its use should be considered in very demanding situations for gap or defect fractures, where single-plate osteosynthesis provides inadequate stiffness for fracture healing and induces nonunion.

NF-kB decoy oligodeoxynucleotide preserves disc height in a rabbit anular-puncture model and reduces pain induction in a rat xenograft-radiculopathy model.

While it is known that the degenerated intervertebral disc (IVD) is one of the primary reasons for low-back pain and subsequent need for medical care, there are currently no established effective methods for direct treatment. Nuclear factor-κB (NF-κB) is a transcription factor that regulates various genes' expression, among which are inflammatory cytokines, in many tissues including the IVD. NF-κB decoy is an oligodeoxynucleotide containing the NF-κB binding site that entraps NF-κB subunits, resulting in suppression of NF-κB activity. In the present preclinical study, NF-κB decoy was injected into degenerated IVDs using the rabbit anular-puncture model. In terms of distribution, NF-κB decoy persisted in the IVDs up to at least 4 weeks after injection. The remaining amount of NF-κB decoy indicated that it fit a double-exponential-decay equation. Investigation of puncture-caused degeneration of IVDs showed that NF-κB decoy injection recovered, dose-dependently, the reduced disc height that was associated with reparative cell cloning and morphological changes, as assessed through histology. Gene expression, by quantitative real-time polymerase chain reaction (qRT-PCR), showed that NF-κB decoy attenuated inflammatory gene expression, such as that of interleukin-1 and tumor necrosis factor-α, in rabbit degenerated IVDs. NF-κB decoy also reduced the pain response as seen using the "pain sensor" nude rat xenograft-radiculopathy model. This is the first report demonstrating that NF-κB decoy suppresses the inflammatory response in degenerated IVDs and restores IVD disc height loss. Therefore, the intradiscal injection of NF-κB decoy may have the potential as an effective therapeutic strategy for discogenic pain associated with degenerated IVDs.

[Extensor tendon injuries of the thumb]. / Strecksehnenverletzungen des Daumens.

Extensor tendon injuries of the thumb include lesions of the tendons of the extensor pollicis longus, extensor pollicis brevis and abductor pollicis longus muscles. The latter is practically only affected in open injuries. Open injuries require a tendon reconstruction by suture followed by immobilization in the distal and an adequate aftercare depending on the zone of injury. In distal injuries static splinting is applied, whereas proximal injuries from T4 on require a dynamic after-treatment. Different courses of the tendon of the extensor pollicis brevis muscle exist distal to the metacarpophalangeal joint and must be considered. The rare ruptures of the extensor hood at the metacarpophalangeal joint provoke an ulnar displacement of the extensor pollicis longus or both extensor tendons with concomitant lack of active extension in the metacarpophalangeal and interphalangeal joints. This injury is often misdiagnosed as a rupture of the ulnar collateral ligament of the metacarpophalangeal joint. It should be treated by refixation of the ruptured structures. Closed chronic ruptures of the extensor pollicis longus tendon go along with a defect that requires a tendon transfer or a tendon autograft.

Effects of barium on the pathways of anaerobic digestion.

The sufficient presence of trace elements (TE) is essential for anaerobic digestion. Barium (Ba) is considered a non-essential trace element that can be collaterally added to digesters as part of low-cost trace element sources or because of its presence in some feedstocks, such as crude glycerol. In the present study, the impact of Ba supplementation (2-2000 mg/L) on each stage of the anaerobic digestion (AD) process was evaluated using pure substrates (i.e., cellulose, glucose, a mixture of volatile fatty acids, sodium acetate and hydrogen) as well as a complex substrate (i.e., dried green fodder). Hydrolytic activity was affected at dosages higher than 200 mg Ba/L, whereas cellulose degradation was completely inhibited at 2000 mg Ba/L. The negative effects of the addition of Ba to methane production were observed only in the hydrolytic activity, and no effects were detected at any barium dosage in the subsequent anaerobic steps. Because Ba does not have a reported role as a cofactor of enzymes, this response could have been due to a direct inhibitory effect, a variation in the bioavailability of other trace elements, or even the availability of CO2/SO4 through precipitation as Ba-carbonates and sulphates. The results showed that the addition of Ba modified the chemical equilibrium of the studied system by varying the soluble concentration of some TEs and therefore their bioavailability. The highest variation was detected in the soluble concentration of zinc, which increased as the amount of Ba increased. Although little research has shown that Ba has some utility in anaerobic processes, its addition must be carefully monitored to avoid an undesirable modification of the chemical equilibrium in the system.

Cure SMA and our patient community celebrate the first approved drug for SMA.

Cure SMA is dedicated to the treatment and cure of spinal muscular atrophy (SMA)-a disease affecting motor neurons, that robs patients of their ability to walk, eat and even breathe. Since 1984, we have directed and invested in comprehensive research that has shaped the scientific community's understanding of SMA. On 23 December, 2016, the Food and Drug Administration (FDA) announced approval of Spinraza, a treatment developed by Biogen and Ionis, making it the first-ever approved therapy for SMA. Cure SMA provided early research funding in 2003 leading to the discovery of ISS-N1 sequence, now targeted by Spinraza. We are pleased that our strategy of providing seed funding for research to either identify new therapeutic strategies or de-risk early stage ones, has proven successful with Spinraza's approval. The approval of Spinraza provides great hope to the SMA community and represents decades of hard work and perseverance by families, researchers, pharmaceutical companies and the FDA. Our hope is that Spinraza is the leading edge of a robust drug pipeline, and with our deep expertise in every aspect of SMA, we remain committed to do everything we can to support research and drug development to achieve the greatest possible effect for each and every SMA patient.

International field trials of pyrethroid-treated wood exposed to Coptotermes acinaciformis in Australia and Coptotermes formosanus (Isoptera: Rhinotermitidae) in China and the United States.

Coptotermes Wasmann is one of the most important genera of wood-destroying insect pests, both in its native and introduced countries. Pyrethroids are among the most widely used insecticides in wood preservation around the world. Consequently, they have often been evaluated against different species of Coptotermes. However, because various test methods have been used between countries, comparing results is problematic. These field trials, using a single aboveground method of exposure, assessed a range of retentions of two pyrethroids (bifenthrin and permethrin) in Pinus radiata D. Don sapwood against two species of Coptotermes in three countries to provide directly comparable results. Coptotermes acinaciformis (Froggatt) in Australia consumed the most nontreated wood, followed by Coptotermes formosanus Shiraki in China, then C. formosanus in the United States, although these data were not significantly different. Both termite species demonstrated a dose-response to wood treated with the two pyrethroids; less wood was consumed as retention increased. Overall, C. acinaciformis consumed relatively little of the treated wood. In comparison, C. formosanus consumed 20-90% of the wood treated at the lowest retentions of the pyrethroids evaluated. Results indicated that C. acinaciformis was more sensitive to pyrethroid toxicity/repellency compared with C. formosanus. Factors that may have influenced the results are discussed. However, using a single aboveground method of exposure across three countries, that suited both species of Coptotermes, made it possible to determine unambiguously the actual differences between the species in their tolerances to the two pyrethroid insecticides.

[Diagnosis and treatment of periprosthetic infections]. / Diagnose und Therapie periprothetischer Infektionen.

The differentiation of periprosthetic infections into early onset and late onset infections is the determining factor fores the therapeutic strategy. The diagnosis of chronic unapparent infections is sometimes difficult. The therapeutic success, especially in early onset infections, is essentially influenced by a well-timed diagnosis and an immediate therapy. Surgical wound debridement with preservation of the prosthesis, one-stage replacement and two-stage replacement all with concomitant appropriate systemically administered double combined antibiotics are therapeutic options depending on factors, such as the duration of the infection. Prosthesis replacement is currently the only option to treat biofilm colonization of endoprosthetic surfaces. The bacterial adhesion on polyethylene can be extremely resistant. Due to the therapeutic consequences, periprosthetic infections remain one of the worst complications in endoprosthetic joint replacement.

[Traumatic dissection of the internal carotid artery following whiplash injury. Diagnostic workup and therapy of an often overlooked but potentially dangerous additional vascular lesion]. / Traumatische Dissektion der A. carotis interna nach HWS-Beschleunigungstrauma. Diagnostik und Therapie einer häufig übersehenen aber potenziell gefährlichen Begleitverletzung.

We report on the case of a 33-year-old male patient who was brought to the emergency room of our hospital after suffering a high-energy trauma due to an automobile accident. Besides a scaphoid fracture there were no signs of any neurological deficits. After several hours without clinical symptoms the patient developed dysarthria as the first manifestation of local cerebral ischemia based on a traumatic dissection of the internal carotid artery. Under systemic high-dose heparin therapy, fast and complete remission of all neurological disorders could be achieved. In the course of time a dissecting aneurysm developed. Temporary anticoagulation with phenprocoumon was started in the meantime and no further complications have appeared up to now. Besides presenting this absorbing case, this article highlights the diagnostic and therapeutic regime in cases of a traumatic dissection of supra-aortal arteries for rapid and adequate management of this rare but potentially dangerous complication.

Cerclage, evolution and potential of a Cinderella technology. An overview with reference to periprosthetic fractures.

Periprosthetic fractures are increasingly frequent. The fracture may be located over the shaft of the prosthesis, at its tip or below. The treatment of explosion fractures is difficult because the shaft blocks the application of implants, like screws, which need to penetrate the medullary cavity. The cerclage, as a simple periosteal loop, made of wire or more recently cable, does not only avoid the medullary cavity. Its centripetal mode of action is well suited for reducing and maintaining radially displaced fractures. Furthermore, the cerclage lends itself well for minimally invasive internal fixation. New insight challenges the disrepute of which the cerclage technology suffered for decades. The outcome of cerclage fixation benefits from an improved understanding of its technology, mechano-biology and periosteal blood supply. Preconceived and generally accepted opinions like "strangulation of blood supply" need to be re-examined. Recent mechanical evaluations demonstrate that the wire application may be improved but cable is superior in hand- ling, maintenance of tension and strength. Beside the classical concepts of absolute and relative stability a defined stability condition needs consideration. It is typical for cerclage. Called "loose-lock stability" it specifies the situation where a loosened implant allows first unimpeded displacement changing abruptly into a locked fixation preventing further dislocation.

Cerclage handling for improved fracture treatment. A biomechanical study on the twisting procedure.

PURPOSE OF THE STUDY: Twisting is clinically the most frequently applied method for tightening and maintaining cerclage fixation. The twisting procedure is controversially discussed. Several factors during twisting affect the mechanical behaviour of the cerclage. This in vitro study investigated the influence of different parameters of the twisting procedure on the fixation strength of the cerclage in an experimental setup with centripetal force application. MATERIAL AND METHODS: Cortical half shells of the femoral shaft were mounted on a testing fixture. 1.0 mm, 1.25 mm and 1.5 mm stainless ste- el wire cerclages as well as a 1.0mm cable cerclage were applied to the bone. Pretension of the cerclage during the installation was measured during the locking procedure. Subsequently, cyclic testing was performed up to failure. RESULTS: Higher pretension could be achieved with increasing wire diameter. However, with larger wire diameter the drop of pre- tension due to the bending and cutting the twist also increased. The cable cerclage showed the highest pretension after locking. Cerclages twisted under traction revealed significantly higher initial cerclage tension. Plastically deformed twists offered higher cerclage pretension compared to twists which were deformed in the elastic region of the material. Cutting the wire within the twist caused the highest loss of cerclage tension (44% initial tension) whereas only 11 % was lost when cutting the wire ends separately. The bending direction of the twist significantly influenced the cerclage pretension. 45% pretension was lost in forward bending of the twist, 53% in perpendicular bending and 90% in backward bending. CONCLUSION: Several parameters affect the quality of a cerclage fixation. Adequate installation of cerclage wires could markedly improve the clinical outcome of cerclage.

High-throughput, accurate Monte Carlo simulation on CPU hardware for PET applications.

Monte Carlo simulations (MCS) represent a fundamental approach to modelling the photon interactions in positron emission tomography (PET). A variety of PET-dedicated MCS tools are available to assist and improve PET imaging applications. Of these, GATE has evolved into one of the most popular software for PET MCS because of its accuracy and flexibility. However, simulations are extremely time-consuming. The use of graphics processing units (GPU) has been proposed as a solution to this, with reported acceleration factors about 400-800. These factors refer to GATE benchmarks performed on a single CPU core. Consequently, CPU-based MCS can also be easily accelerated by one order of magnitude or beyond when exploiting multi-threading on powerful CPUs. Thus, CPU-based implementations become competitive when further optimisations can be achieved. In this context, we have developed a novel, CPU-based software called the PET physics simulator (PPS), which combines several efficient methods to significantly boost the performance. PPS flexibly applies GEANT4 cross-sections as a pre-calculated database, thus obtaining results equivalent to GATE. This is demonstrated for an elaborated PET scanner with 3-layer block detectors. All code optimisations yield an acceleration factor of ≈20 (single core). Multi-threading on a high-end CPU workstation (96 cores) further accelerates the PPS by a factor of 80. This results in a total speed-up factor of ≈1600, which outperforms comparable GPU-based MCS by a factor of ≳2. Optionally, the proposed method of coincidence multiplexing can further enhance the throughput by an additional factor of ≈15. The combination of all optimisations corresponds to an acceleration factor of ≈24 000. In this way, the PPS can simulate complex PET detector systems with an effective throughput of 106photon pairs in less than 10 milliseconds.

Are psychoeducational smoking cessation interventions for coronary heart disease patients effective? Meta-analysis of interventions.

PURPOSE: This systematic review aimed to assess the effectiveness of psychoeducational smoking cessation interventions for coronary heart disease (CHD) patients; and to examine behaviour change techniques used in interventions and their suitability to change behavioural determinants. METHODS: Multiple bibliographic databases and references of retrieved articles were searched for relevant randomized controlled studies. One reviewer extracted and a second reviewer checked data from included trials. Random effects meta-analyses were conducted to estimate pooled relative risks for smoking cessation and mortality outcomes. Behaviour change techniques used and their suitability to change behavioural determinants were evaluated using a framework by Michie, Johnston, Francis, Hardeman, and Eccles. RESULTS: A total of 14 studies were included. Psychoeducational interventions statistically significantly increased point prevalent (RR 1.44, 95% CI, 1.20-1.73) and continuous (RR 1.51, 95% CI, 1.18-1.93) smoking cessation, and statistically non-significantly decreased total mortality (RR 0.73, 95% CI, 0.46-1.15). Included studies used a mixture of theories in intervention planning. Despite superficial differences, interventions appear to deploy similar behaviour change techniques, targeted mainly at motivation and goals, beliefs about capacity, knowledge, and skills. CONCLUSIONS: Psychoeducational smoking cessation interventions appear effective for patients with CHD. Although questions remain about what characteristics distinguish an effective intervention, analysis indicates similarities between the behaviour change techniques used in such interventions.

[Clinical trials with advanced therapy medicinal products]. / Klinische Prüfung mit Arzneimitteln für Neuartige Therapien.

For advanced therapies, the same basic principles for assessment apply as for any other biotechnological medicinal product. Nevertheless, the extent of data for quality, safety, and efficacy can be highly specific. Until recently, advanced therapies were not uniformly regulated across Europe, e.g., tissue engineered products were regulated either as medicinal products or medical devices. Thus, for some products no data from clinical studies are available, e.g., for autologous chondrocyte products. The draft guideline on Good Clinical Practice for clinical trials with advanced therapies describes specific additional requirements, e.g., ensuring traceability. Most clinical studies with advanced therapies in Germany are still in early phase I or II trials with highly divergent types of products and clinical indications. The Committee for Advanced Therapies (CAT) at the European Medicines Agency (EMEA) has been established to meet the scientific and regulatory challenges with advanced therapies.

Actin modulates shape and mechanics of tubular membranes.

The actin cytoskeleton shapes cells and also organizes internal membranous compartments. In particular, it interacts with membranes for intracellular transport of material in mammalian cells, yeast, or plant cells. Tubular membrane intermediates, pulled along microtubule tracks, are formed during this process and destabilize into vesicles. While the role of actin in tubule destabilization through scission is suggested, literature also provides examples of actin-mediated stabilization of membranous structures. To directly address this apparent contradiction, we mimic the geometry of tubular intermediates with preformed membrane tubes. The growth of an actin sleeve at the tube surface is monitored spatiotemporally. Depending on network cohesiveness, actin is able to entirely stabilize or locally maintain membrane tubes under pulling. On a single tube, thicker portions correlate with the presence of actin. These structures relax over several minutes and may provide enough time and curvature geometries for other proteins to act on tube stability.

Does vancomycin resistance increase mortality in Enterococcus faecium bacteraemia after orthotopic liver transplantation? A retrospective study.

BACKGROUND: The relevance of vancomycin resistance in enterococcal blood stream infections (BSI) is still controversial. Aim of this study was to outline the effect of vancomycin resistance of Enterococcus faecium on the outcome of patients with BSI after orthotopic liver transplantation (OLT). METHODS: The outcome of OLT recipients developing BSI with vancomycin-resistant (VRE) versus vancomycin-susceptible Enterococcus faecium (VSE) was compared based on data extraction from medical records. Multivariate regression analyses identified risk factors for mortality and unfavourable outcomes (defined as death or prolonged intensive care stay) after 30 and 90 days. RESULTS: Mortality was similar between VRE- (n = 39) and VSE- (n = 138) group after 30 (p = 0.44) or 90 days (p = 0.39). Comparable results occurred regarding unfavourable outcomes. Mean SOFANon-GCS score during the 7-day-period before BSI onset was the independent predictor for mortality at both timepoints (HR 1.32; CI 1.14-1.53; and HR 1.18; CI 1.08-1.28). Timely appropriate antibiotic therapy, recent ICU stay and vancomycin resistance did not affect outcome after adjusting for confounders. CONCLUSION: Vancomycin resistance did not influence outcome among patients with Enterococcus faecium bacteraemia after OLT. Only underlying severity of disease predicted poor outcome among this homogenous patient population. TRIAL REGISTRATION: This study was registered at the German clinical trials register (DRKS-ID: DRKS00013285).

A prospective cohort study to identify and evaluate endotypes of venous thromboembolism: Rationale and design of the Genotyping and Molecular Phenotyping in Venous ThromboEmbolism project (GMP-VTE).

Several clinical, genetic and acquired risk factors for venous thromboembolism (VTE) have been identified. However, the molecular pathophysiology and mechanisms of disease progression remain poorly understood. This is reflected by uncertainties regarding the primary and secondary prevention of VTE and the optimal duration of antithrombotic therapy. A growing body of literature points to clinically relevant differences between VTE phenotypes (e.g. deep vein thrombosis (DVT) versus pulmonary embolism (PE), unprovoked versus provoked VTE). Extensive links to cardiovascular, inflammatory and immune-related morbidities are testament to the complexity of the disease. The GMP-VTE project is a prospective, multi-center cohort study on individuals with objectively confirmed VTE. Sequential data sampling was performed at the time of the acute event and during serial follow-up investigations. Various data levels (e.g. clinical, genetic, proteomic and platelet data) are available for multi-dimensional data analyses by means of advanced statistical, bioinformatic and machine learning methods. The GMP-VTE project comprises n = 663 individuals with acute VTE (mean age: 60.3 ±â€¯15.9 years; female sex: 42.8%). In detail, 28.4% individuals (n = 188) had acute isolated DVT, whereas 71.6% subjects (n = 475) had PE with or without concomitant DVT. In the study sample, 28.9% (n = 129) of individuals with PE and 30.1% (n = 55) of individuals with isolated DVT had a recurrent VTE event at the time of study enrolment. The systems-oriented approach for the comprehensive dataset of the GMP-VTE project may generate new biological insights into the pathophysiology of VTE and refine our current understanding and management of VTE.

Effect of an exercise and dietary intervention on serum biomarkers in overweight and obese adults with osteoarthritis of the knee.

OBJECTIVE: To determine the effects of exercise and weight loss interventions on serum levels of four biomarkers and to examine if changes in biomarker levels correlate with clinical outcome measures in obese and overweight adults with knee osteoarthritis (OA). METHODS: Serum was obtained at baseline, 6 and 18 months from 193 participants in Arthritis, Diet and Activity Promotion Trial. This was a single-blind 18-month trial with subjects randomized to four groups: healthy-lifestyle (HL), diet (D), exercise (E) and diet plus exercise (D+E). Serum levels of cartilage oligomeric matrix protein (COMP), hyaluronan (HA), antigenic keratan sulfate (AgKS), and transforming growth factor-beta1 (TGF-beta1) were measured by enzyme linked immunosorbent assay. RESULTS: At baseline there were no significant differences in biomarker levels between intervention groups. When results for all the intervention groups were combined, the levels of HA were found to be negatively correlated with medial joint space width and positively correlated with Kellgren-Lawrence scores (K-L scores) while TGF-beta1 levels negatively correlated with K-L scores. When biomarker levels measured at 6 and 18 months were adjusted for baseline values, age, gender, and body mass index, weak but significant differences between intervention groups were present for mean levels of COMP and TGF-beta1. Furthermore, AgKS levels averaged over all groups tended to decrease over time. There were no significant associations of baseline biomarkers and the follow-up outcomes. Weak associations were noted between change in the biomarkers at 18 months and change in outcome measures that included change in weight with AgKS and COMP and change in Western Ontario and McMaster Universities Osteoarthritis Index pain with AgKS. CONCLUSION: Overall, the E and D interventions did not show a consistent effect on levels of potential OA biomarkers. The four biomarkers showed differences in correlations with outcome measures suggesting that they may measure different aspects of disease activity in OA. The strongest correlations were between serum HA and radiographic measures of OA at baseline.