Investigator-Driven
Intra-articular injection is a common way to deliver biologics to joints, but their effectiveness is limited by rapid clearance from the joint space. This barrier can be overcome by genetically modifying cells within the joint such that they produce anti-arthritic gene products endogenously, thereby achieving sustained, therapeutic, intra-articular concentrations of the transgene products without re-dosing. A variety of non-viral and viral vectors have been subjected to preclinical testing to evaluate their suitability for delivering genes to joints. The first transfer of a gene to a human joint used an
We have undertaken a series of clinical trials over the last 20 years to look at different bearing surface combinations in young adults. We continue to follow these patients well beyond the planned duration of the trials and new information is constantly becoming available. The first trial compared ceramic-on-ceramic with ceramic-on-standard-polyethylene. These patients have now been followed for 20 years with significant wear in the polyethylene group but virtually identical revision rates. The second trial ceramic-on-ceramic, cobalt-chrome-on-standard-polyethylene and cobalt-chrome-on-cross-linked-polyethylene. In this group the ceramic-on-ceramic patients have the lowest revision rate; the ceramic-on-polyethylene group demonstrates a lower wear rate than cobalt-chrome-on-polyethylene. The third trial looks at cobalt-chrome versus zirconium on either cross-linked polyethylene or conventional polyethylene. At 10 years there remains no evidence of improved performance from the zirconium surface as compared to cobalt-chrome. The cross-linked polyethylene group is clearly outperforming the conventional polyethylene in terms of wear rate but at 10 years the revision rates remain the same in all groups. Cross liked polyethylene appears to be the major determining factor in prosthetic longevity and appears to be more important than the counter face material.
Although non-unions being one of the most common complication after long-bone fracture fixation, the definition of this entity remains controversial and varies widely among authors. A clear definition is crucial, not only for the evaluation of published research data but also for the establishment of uniform treatment concepts. The aim of this systematic review was to identify the definitions and different criteria used in the scientific literature to describe non-unions after long bone fractures. A comprehensive literature search was performed in PubMed, Cochrane Library, Web of Science, and Embase. according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Prospective therapeutic and diagnostic clinical studies in which adult long-bone fracture non-unions were investigated as main subject were included in this analysis.Aim
Method
Mesenchymal Stromal Cells (MSC) have been proposed as a potential therapy for a broad range of diseases including those affecting the musculoskeletal system. MSCs have received market authorization for treatment of graft versus host disease and fistulizing Crohn's disease. In addition, there are clinical trials underway for diseases affecting all organ systems. GMP manufactured cells are required for these clinical trials and suitable facilities with regulatory approval are thus crucial for the translational process. In this presentation I will review the process whereby such a facility has been constructed at NUI Galway and discuss challenges in operations and sustainability. Researchers at REMEDI and spin out company Orbsen Therapeutics are currently involved in 7 clinical trials using MSCs, 4 of which are EU wide consortia funded by the EU Commission. The presentation will also discuss issues such as source of MSCs, cell sorting, use of bioreactors and xeno-free processes.
Shoulder impingement is one of the most common non-traumatic upper limb causes of disability in adults. Often resulting in pain and disability, management remains highly debated. This meta-analysis of randomized trials aims to evaluate the efficacy of surgical intervention in the setting of shoulder impingement in comparison to non-operative or sham treatments. Two reviewers independently screened MEDLINE, EMBASE, PUBMED and Cochrane databases for randomized control trials published from 1946 through to May 19th, 2018. A risk of bias assessment was conducted for all included studies and outcomes were pooled using a random effects model. The primary outcome was improvement in pain up to two years. Secondary outcomes included functional outcome scores reported at the short term (/=2 years). Heterogeneity was assessed using the I2statistic. Functional outcome scores were presented along with minimal clinically important differences to provide clinical context to findings. Twelve RCT's (n=1062 patients) were included in this review. Eligible patients were a mean age of 48 (SD +/− 4) years with 45% being male gender. The pooled treatment effect of surgical intervention for shoulder impingement did not demonstrate any benefit to surgery with respect to pain relief (mean difference [MD] −0.07, 95% CI −0.40 to 0.26) or short-term functional outcomes (standardized mean difference [SMD] −0.09, 95% confidence interval [CI] −0.27 to 0.08). Surgical intervention did result in a small statistically significant but clinically unimportant improvement in long term functional outcomes (SMD 0.23, 95% CI 0.06 to 0.41). Evidence suggests surgical intervention has little, if any, benefit for impingement pathology in the middle-aged patient.
Measurement inconsistency across clinical trials is tackled by the development of a core outcome measurement set. Four core outcome domains were recommended for clinical trials in patients with non-specific LBP (nsLBP): physical functioning, pain intensity, health-related quality of life (HRQoL), and number of deaths. This study aimed to reach consensus on core instruments to measure the first three domains. The Steering Committee overseeing this project selected 17 potential core instruments for physical functioning, three for pain intensity, and five for HRQoL. Evidence on their measurement properties in nsLBP was synthesized in three systematic reviews using COSMIN methodology. Researchers, clinicians, and patients (n = 208) were invited in a Delphi survey to seek consensus on which instruments to endorse as core. Consensus was Background & purpose
Methods & Results
Aims. This systematic review places a recently completed multicentre randomized controlled trial (RCT), UK FROST, in the context of existing randomized evidence for the management of primary frozen shoulder. UK FROST compared the effectiveness of pre-specified physiotherapy techniques with a steroid injection (PTSI), manipulation under anaesthesia (MUA) with a steroid injection, and arthroscopic capsular release (ACR). This review updates a 2012 review focusing on the effectiveness of MUA, ACR, hydrodilatation, and PTSI. Methods. MEDLINE, Embase, PEDro, Science Citation Index, Clinicaltrials.gov, CENTRAL, and the World Health Organization (WHO) International
Lower limb fractures are commonly treated with cast immobilization, and as a main consequence of strict immobilization this typically leads to loss in muscle mass, decrease of bone density and decline in functional abilities. Body-worn sensors are increasingly used to assess outcome in clinical trials by providing objective mobility parameters in a real-world environment. The aim of this study is to investigate the usability aspects and potential changes in mobility parameters in partial-immobilization patients in real-world conditions. Six healthy young males (age 22.2 ± 1.2 years; weight 76.5 ± 6.7 kg, height 185.8 ± 6.1 cm. Mean ± standard deviation) wore a leg cylinder cast with walker boot to immobilize their dominant leg for two consecutive weeks. Subjects were asked to continuously wear a tri-axial accelerometer on the waist (actibelt) during waking hours for 6 weeks including 2 weeks before, during and after cast immobilisation. The total amount of days of continuous recording was 339 days with a total wearing time of 120 days. Software packages which allow to detect steps and to estimate real-world walking speed were used to analyse the accelerometry data. It was suspected that knee immobilization would affect strongly the wave form of the signal with an impact on the accuracy of the speed algorithm, whereas the step detection should be more robust. This effect was confirmed in a preliminary study performed to quantify the accuracy under immobilization conditions. On the other hand, step numbers are known to be sensitive to fluctuations in wearing time which was not uniform throughout the entire study. We concluded that in this setting step frequency is the most reliable parameter. Step frequency showed a systematic decrease in the values during the immobilization period which recovered to pre-immobilisation values after cast removal. This confirms the usability of accelerometry and sensitivity of its mobility parameters for clinical outcome assessment.
Randomised controlled clinical trials (RCTs) produce the most reliable evidence about the effects of clinical care. In surgical trials, lack of surgeons’ individual equipoise (state of genuine uncertainty about treatment arms) appears to be one of the greatest obstacles. Collective equipoise based on present or imminent controversy in the expert medical community has been proposed as a solution (Freedman, 1987), but could be applied only at the beginning of a trial to a general trial question. We developed a system that quantifies collective uncertainty among a group of surgeons for an individual clinical case. After a successful pilot study the system was introduced as an independent project within the UK Heel Fracture Trial. The expert panel included 10 surgeons from 8 hospitals. Anonymous clinical data of potentially eligible consecutive cases including CT and X-ray images was published on a secure online forum after 6 weeks follow up clinic to avoid interference with clinical course. Surgeons registered in the panel estimated the probability that the patient would be better or worse by various degrees with operative treatment. 30 clinical cases have been analysed, including 6 bilateral fractures (otherwise excluded). 86.7% could be recommended for inclusion in the trial, compared to 43.3% recruited out of this series in the actual trial. Lack of individual uncertainty within the panel was present in every case. The system not only has a potential to improve recruitment in surgical RCTs, but provides ethically sound grounds to offer or otherwise a patient participation in a trial. Surgeon’s individual equipoise dilemma and responsibility is shared with colleagues. Cases that otherwise will be excluded can be evaluated with broader inclusion criteria. The system is easy to use, cheap and reliable. Limitations include surgeons’ compliance and time lapse (at least 48 hours) for voting to be completed.
Inconsistent outcome reporting is a problematic issue in systematic reviews of clinical trials in non-specific LBP (NSLBP). To facilitate statistical pooling and improve reliability of reviews, the development of a core outcome set (COS) is recommended. In 1998, Deyo et al. proposed a standardized set of domains and measurement instruments for LBP clinical research. An international steering committee (ISC) was formed to update 1998 recommendations, and to determine, at first, which outcome domains should be included in a COS for clinical trials in NSLBP. The ISC used the OMERACT framework 2.0 to draw a list of potential core domains. This list was presented in a 3-round Delphi survey, in which researchers, clinicians and patients were invited to participate. Criteria for consensus were established a-Background and purpose:
Methods:
The Acrobot®, an active constraint “hands-on” robotic system, gives navigation cues to the surgeon, and also assists him in the surgery, using active software constraints if he tries to depart from the preoperative plan. It has just entered clinical trials. We report the first 5 cases. The Acrobot® system for precision total knee arthroplasty comprises the following components:
1. A CT-based planning system 2. The limb positioning system 3. The Acrobot’s hardware components:
a gross positioning device with separate brakes and encoders, locked off for safety during the procedure, a fully back-driveable low force robot, and a force control handle on the robot close to the high-speed milling tool.
4. The Acrobot’s software which:
imports the preoperative plan, allows anatomic registration provides navigation, physically assists the surgeon perform his plan Each patient’s knee scores were monitored and postoperative CT scan was compared with the preoperative plan. Seven robot assisted arthroplasties have been performed. No significant complications have been encountered. The Knee and Womac Scores show that the procedure is safe and comparable to conventional surgery in the early postoperative period. The envelope of error on postoperative CT scans has been within the accuracy of the method of measurement, at <
1 mm and <
10 without the outliers which haunt every clinical series. The Acrobot® system for total knee arthroplasty has completed its preliminary trial satisfactorily. It provides a handson operation but with robotic levels of accuracy. It is suitable for conventional open surgery, but its real place will be in the arena of minimally invasive unicondylar knee arthroplasty, hip arthroplasty and resurfacing, and in the spine, where active constraint will prevent potentially dangerous surgical errors.
Clinical trials for common health conditions are constantly being designed and implemented in our institution, often with some urgency to meet funding deadlines. The scope and complexity of these trials has resulted in the need for databased computer management systems typically tailored to each project. Even with current advanced software resources, development, testing and implementation can take months for each new project. This presentation describes a new approach to this problem involving an adaptive table-driven software system using project-specific recruitment and screening data which we have developed using visual basic. The chief design criterion was that the software be reconfigurable by the user based on data tables that contain the parameters of the project design. Essentially, each new project would be implemented by generating new input to the tables, but without the need for reprogramming. The first system implemented was a branching phone screen application that presents questions in an interview format and records participant responses in a data table which can be judged against inclusion/exclusion criteria contained in another table as well as for status reports.Purpose
Methods
Displaced midshaft clavicular fractures are a common injury with a high occurrence rate in young, active individuals. Non-operative care has traditionally been the standard of care for such fractures, but more recent studies have suggested benefits following primary operative fixation. The purpose of this study was to review the literature on displaced midshaft clavicle fractures, identify randomized controlled trials of operative versus non-operative treatment, and pool the functional outcome and complication rates (including nonunion and symptomatic malunion), to arrive at summary estimates of these outcomes. A systematic review of the literature was performed to identify studies of randomized controlled trials comparing operative versus non-operative care for displaced midshaft clavicle fractures. Meeting abstracts were also searched and included in this study.Purpose
Method
Improvement in survival for teenagers and young adults (TYAs) has lagged behind those of children and adults, (Stiller et al 2006). In seeking explanations investigators have focused on two main factors. Firstly, the low accrual of TYAs into clinical trials (Newburger et al, 2002), and secondly the lack of appropriate multidisciplinary care (Stevens, 2005). Data from the UK Office of National Statistics confirms this with 70% of paediatric patients being entered into a clinical trial compared to only 20% of 15–24 year olds. In 2007 the Teenage Cancer Trust (TCT) asked over 200 14–25 year olds with cancer if they had been offered a clinical trial (TCT survey results, 2008). Of the total cohort only 30% reported that they had been given the opportunity to enter a clinical trial. The National Cancer Research Institute (NCRI) established a Teenage and Young Adult Clinical Studies Development Group in 2005 to address the issues surrounding the accrual of TYAs into clinical trials. At a specialist Teenage Cancer Trust Unit in the UK a TYA Clinical Research Nurse was appointed in May 2008; in order to improve TYA accrual into clinical trials. An audit is currently been undertaken to examine present data of clinical trial entry and retrospective data from 2006 and 2007. The focus of the audit is on patients aged 16–24 years with a bone or soft tissue sarcoma being treated in one TCT unit in the UK. The audit will examine whether the appointment of a TYA research nurse has influenced the accrual of TYA patients into clinical trials. The paper will focus on the particular difficulties and challenges with recruiting TYA patients and the developing role of the TYA Research Nurse in influencing practice. It is essential that improvements are made with regard to trial entry for this unique age group and the TYA Research Nurse may play a vital role in this in the future.
While there is a desperate need for effective treatments for acute spinal cord injury (SCI), the clinical validation of novel therapeutic interventions is severely hampered by the need to recruit relatively large numbers of patients into clinical trials for sufficient statistical power. While a centre might annually admit 100 acute SCI patients, only a fraction may satisfy the basic inclusion criteria for an acute clinical trial, which typically requires patients of a certain injury severity (eg ASIA A), within a specific time window (eg. 12 hours from injury), and without other major injuries or conditions that would cloud the baseline neurologic assessment. This study was conducted to define that “fraction” of SCI patients that would theoretically satisfy standard inclusion criteria of an acute clinical trial. Using a local database, we reviewed patients admitted to our Level 1 trauma center with a complete (ASIA A) or an incomplete (ASIA B, C and D) acute SCI involving bony spinal levels between C0 and sacrum. All patients admitted over the 4 year period from 2005 to 2009 were reviewed. Demographic information and data about the patients' SCI and other injuries were reviewed. We then determined how many of the total number of SCI patients would be eligible for enrolment into a hypothetical acute clinical trial that required a valid baseline assessment of neurologic impairment, and an enrolment window of either 12 hours, 24 hours, or 48 hours.Introduction
Methods