From evidence to best practice in the management of fractures of the distal radius in adults: working towards a research agenda

BACKGROUND: Fracture of the distal radius is a common clinical problem, particularly in older white women with osteoporosis. We report our work towards evidence-based and patient-centred care for adults with these injuries. METHODS: We developed a systematic programme of research that built on our systematic review of the evidence of effectiveness of treatment interventions for these fractures. We devised schemata showing 'typical' care pathways and identified over 100 patient management questions. These depicted the more important decisions taken when progressing along each care pathway. We compiled a comprehensive document summarising the evidence available for each decision point from our reviews of randomised trials of treatment interventions. Using these documents, we undertook a formal and structured consultation process involving key players, including a patient representative, to obtain their views on the available evidence and to establish a research agenda. The resulting feedback was then processed and interpreted, using systematic methods. RESULTS: Some evidence from 114 randomised trials was available for 31 of the 117 patient management questions. However, there was sufficient evidence to base some conclusions of effectiveness for particular interventions in only five of these. Though only 60% of those approached responded, the responses received from the consultation group were often comprehensive and provided important insights into treatment practice and policy. There was a clear acceptance of the aims of the project and, aside from some suggestions for the more explicit inclusion of secondary prevention and management of complications, of the care pathways scheme. Though some respondents stressed that randomised trials were not always appropriate, there was no direct overall criticism of the evidence document and underlying processes. We were able to identify important core themes that underpin management decisions and research from the feedback of the consultation exercise. CONCLUSIONS: Overall, this project is an important advance towards evidence-based and patient-centred management of adults with distal radial fractures. It exposes the serious deficiency in the available evidence but also provides a template for further action. As well as being a valuable basis for viewing and informing current practice, the insights gained from this project should inform a future research agenda

Overview of systematic reviews of therapeutic ranges : methodologies and recommendations for practice

BACKGROUND: Many medicines are dosed to achieve a particular therapeutic range, and monitored using therapeutic drug monitoring (TDM). The evidence base for a therapeutic range can be evaluated using systematic reviews, to ensure it continues to reflect current indications, doses, routes and formulations, as well as updated adverse effect data. There is no consensus on the optimal methodology for systematic reviews of therapeutic ranges. METHODS: An overview of systematic reviews of therapeutic ranges was undertaken. The following databases were used: Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts and Reviews of Effects (DARE) and MEDLINE. The published methodologies used when systematically reviewing the therapeutic range of a drug were analyzed. Step by step recommendations to optimize such systematic reviews are proposed. RESULTS: Ten systematic reviews that investigated the correlation between serum concentrations and clinical outcomes encompassing a variety of medicines and indications were assessed. There were significant variations in the methodologies used (including the search terms used, data extraction methods, assessment of bias, and statistical analyses undertaken). Therapeutic ranges should be population and indication specific and based on clinically relevant outcomes. Recommendations for future systematic reviews based on these findings have been developed. CONCLUSION: Evidence based therapeutic ranges have the potential to improve TDM practice. Current systematic reviews investigating therapeutic ranges have highly variable methodologies and there is no consensus of best practice when undertaking systematic reviews in this field. These recommendations meet a need not addressed by standard protocols

Altering crystal growth and annealing in ice-templated scaffolds.

The potential applications of ice-templating porous materials are constantly expanding, especially as scaffolds for tissue engineering. Ice-templating, a process utilizing ice nucleation and growth within an aqueous solution, consists of a cooling stage (before ice nucleation) and a freezing stage (during ice formation). While heat release during cooling can change scaffold isotropy, the freezing stage, where ice crystals grow and anneal, determines the final size of scaffold features. To investigate the path of heat flow within collagen slurries during solidification, a series of ice-templating molds were designed with varying the contact area with the heat sink, in the form of the freeze drier shelf. Contact with the heat sink was found to be critical in determining the efficiency of the release of latent heat within the perspex molds. Isotropic collagen scaffolds were produced with pores which ranged from 90 μm up to 180 μm as the contact area decreased. In addition, low-temperature ice annealing was observed within the structures. After 20 h at -30 °C, conditions which mimic storage prior to lyophilization, scaffold architecture was observed to coarsen significantly. In future, ice-templating molds should consider not only heat conduction during the cooling phase of solidification, but the effects of heat flow during ice growth and annealing.The authors gratefully acknowledge the financial support of the Gates Cambridge Trust, the Newton Trust, and ERC Advanced Grant 320598 3D-E. A.H. held a Daphne Jackson Fellowship funded by the University of Cambridge.This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s10853-015-9343-

Treatment of reducible unstable fractures of the distal radius in adults: a randomised controlled trial of De Palma percutaneous pinning versus bridging external fixation

Background: At present, there is no conclusive evidence regarding the best treatment method for reducible unstable fractures of the distal radius. This study compared the effectiveness of two methods used in surgical treatment of such fractures: percutaneous pinning and external fixation.Methods: We randomly allocated 100 patients into two groups treated surgically with modified de Palma percutaneous pinning and bridging external fixation. Independent but not blinded evaluators administered the DASH quality-of-life questionnaire at postoperative months 6 and 24, performed functional assessment of pain, range of motion, and palm grip strength, and radiographic examinations (volar and radial angle, and height of the radius) before the operation, immediately afterwards, and at 6 and 24 months postoperative. Modified de Palma percutaneous pinning patients used an above-elbow cast whereas external fixation group had unrestricted elbow motion after surgery. Patients who for any reason demonstrated treatment failure or required additional interventions were followed up and their results were included in the group into which these patients had initially been randomised according to the intention-to-treat principle. A significance level of 5% (alpha = 0.05). was used for all statistical tests, such that tests presenting a p-value less than 0.05 were considered statistically significant.Results: Ninety one (58.8 mean age and 66 participants were female) were included in the final assessment at 24 months. the DASH questionnaire evaluation showed a statistically significant result favouring the de Palma group (mean difference = -7.1 p = 0.044) after six months, but this was not maintained at 24 months. There were no statistically differences between the groups with respect to palm grip strength. Analysis of the range-of-motion limitation index (uninjured side minus affected side motion of) showed a statistical difference (mean difference = 2.4 p = 0.043) favoring the external fixator group with regard to the supination movement 6 months after the operation; however, this was not maintained at 24 months. the final results of the radiographic evaluation were similar for the two groups. Overall, five patients developed complications: two with de Palma pinning and three with external fixation.Conclusion: There was a small statistically significant difference favouring the de Palma method in early functional at 6 months according to the DASH questionnaire, and for supination movement favouring the fixator group. However, both were not clinical relevant. By 24 months the groups were similar for all outcome

IMRT in oral cavity cancer

BACKGROUND: Except for early T1,2 N0 stages, the prognosis for patients with oral cavity cancer (OCC) is reported to be worse than for carcinoma in other sites of the head and neck (HNC). The aim of this work was to assess disease outcome in OCC following IMRT. Between January 2002 and January 2007, 346 HNC patients have been treated with curative intensity modulated radiation therapy (IMRT) at the Department of Radiation Oncology, University Hospital Zurich. Fifty eight of these (16%) were referred for postoperative (28) or definitive (30) radiation therapy of OCC. 40 of the 58 OCC patients (69%) presented with locally advanced T3/4 or recurred lesions. Doses between 60 and 70 Gy were applied, combined with simultaneous cisplatin based chemotherapy in 78%. Outcome analyses were performed using Kaplan Meier curves. In addition, comparisons were performed between this IMRT OCC cohort and historic in-house cohorts of 33 conventionally irradiated (3DCRT) and 30 surgery only patients treated over the last 10 years. RESULTS: OCC patients treated with postoperative IMRT showed the highest local control (LC) rate of all assessed treatment sequence subgroups (92% LC at 2 years). Historic postoperative 3DCRT patients and patients treated with surgery alone reached LC rates of ~70–80%. Definitively irradiated patients revealed poorest LC rates with ~30 and 40% following 3DCRT and IMRT, respectively. T1 stage resulted in an expectedly significantly higher LC rate (95%, n = 19, p < 0.05) than T2-4 and recurred stages (LC ~50–60%, n = 102). Analyses according to the diagnosis revealed significantly lower LC in OCC following definitive IMRT than that in pharyngeal tumors treated with definitive IMRT in the same time period (43% vs 82% at 2 years, p < 0.0001), while the LC rate of OCC following postoperative IMRT was as high as in pharyngeal tumors treated with postoperative IMRT (>90% at 2 years). CONCLUSION: Postoperative IMRT of OCC resulted in the highest local control rate of the assessed treatment subgroups. In conclusion, generous indication for IMRT following surgical treatment is recommended in OCC cases with unfavourable features like tight surgical margin, nodal involvement, primary tumor stage >T1N0, or already recurred disease, respectively. Loco-regional outcome of OCC following definitive IMRT remained unsatisfactory, comparable to that following definitive 3DCRT

Scaphoid Waist Internal Fixation for Fractures Trial (SWIFFT) protocol : a pragmatic multi-centre randomised controlled trial of cast treatment versus surgical fixation for the treatment of bi-cortical, minimally displaced fractures of the scaphoid waist in adults

BACKGROUND: A scaphoid fracture is the most common type of carpal fracture affecting young active people. The optimal management of this fracture is uncertain. When treated with a cast, 88 to 90 % of these fractures unite; however, for the remaining 10-12 % the non-union almost invariably leads to arthritis. The alternative is surgery to fix the scaphoid with a screw at the outset. METHODS/DESIGN: We will conduct a randomised controlled trial (RCT) of 438 adult patients with a "clear" and "bicortical" scaphoid waist fracture on plain radiographs to evaluate the clinical effectiveness and cost-effectiveness of plaster cast treatment (with fixation of those that fail to unite) versus early surgical fixation. The plaster cast treatment will be immobilisation in a below elbow cast for 6 to 10 weeks followed by mobilisation. If non-union is confirmed on plain radiographs and/or Computerised Tomogram at 6 to 12 weeks, then urgent surgical fixation will be performed. This is being compared with immediate surgical fixation with surgeons using their preferred technique and implant. These treatments will be undertaken in trauma units across the United Kingdom. The primary outcome and end-point will be the Patient Rated Wrist Evaluation (a patient self-reported assessment of wrist pain and function) at 52 weeks and also measured at 6, 12, 26 weeks and 5 years. Secondary outcomes include an assessment of radiological union of the fracture; quality of life; recovery of wrist range and strength; and complications. We will also qualitatively investigate patient experiences of their treatment. DISCUSSION: Scaphoid fractures are an important public health problem as they predominantly affect young active individuals in the more productive working years of their lives. Non-union, if untreated, can lead to arthritis which can disable patients at a very young age. There is a rapidly increasing trend for immediate surgical fixation of these fractures but there is insufficient evidence from existing RCTs to support this. The SWIFFT Trial is a rigorously designed and adequately powered study which aims to contribute to the evidence-base to inform clinical decisions for the treatment of this common fracture in adults. TRIAL REGISTRATION: The trial is registered with the International Standard Randomised Controlled Trial Register ( ISRCTN67901257 ). Date registration assigned was 13/02/2013

Differential effects of glucagon-like peptide-1 receptor agonists on heart rate

Abstract While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are known to increase heart rate (HR), it is insufficiently recognized that the extent varies greatly between the various agonists and is affected by the assessment methods employed. Here we review published data from 24-h time-averaged HR monitoring in healthy individuals and subjects with type 2 diabetes mellitus (T2DM) treated with either short-acting GLP-1 RAs, lixisenatide or exenatide, or long-acting GLP-1 RAs, exenatide LAR, liraglutide, albiglutide, or dulaglutide (N\ua0=\ua01112; active-treatment arms). HR effects observed in two independent head-to-head trials of lixisenatide and liraglutide (N\ua0=\ua0202; active-treatment arms) are also reviewed. Short-acting GLP-1 RAs, exenatide and lixisenatide, are associated with a transient (1\u201312\ua0h) mean placebo- and baseline-adjusted 24-h HR increase of 1\u20133\ua0beats per minute (bpm). Conversely, long-acting GLP-1 RAs are associated with more pronounced increases in mean 24-h HR; the highest seen with liraglutide and albiglutide at 6\u201310\ua0bpm compared with dulaglutide and exenatide LAR at 3\u20134\ua0bpm. For both liraglutide and dulaglutide, HR increases were recorded during both the day and at night. In two head-to-head comparisons, a small, transient mean increase in HR from baseline was observed with lixisenatide; liraglutide induced a substantially greater increase that remained significantly elevated over 24\ua0h. The underlying mechanism for increased HR remains to be elucidated; however, it could be related to a direct effect at the sinus node and/or stimulation of the sympathetic nervous system, with this effect related to the duration of action of the respective GLP-1 RAs. In conclusion, this review indicates that the effects on HR differ within the class of GLP-1 RAs: short-acting GLP-1 RAs are associated with a modest and transient HR increase before returning to baseline levels, while some long-acting GLP-1 RAs are associated with a more pronounced and sustained increase during the day and night. Findings from recently completed trials indicate that a GLP-1 RA-induced increase in HR, regardless of magnitude, does not present an increased cardiovascular risk for subjects with T2DM, although a pronounced increase in HR may be associated with adverse clinical outcomes in those with advanced heart failure