Fractures are the most common large-organ, traumatic injuries to humans. The repair of bone fractures is a postnatal regenerative process that recapitulates many of the ontological events of embryonic skeletal development. Although fracture repair usually restores the damaged skeletal organ to its pre-injury cellular composition, structure and biomechanical function, about 10% of fractures will not heal normally. This article reviews the developmental progression of fracture healing at the tissue, cellular and molecular levels. Innate and adaptive immune processes are discussed as a component of the injury response, as are environmental factors, such as the extent of injury to the bone and surrounding tissue, fixation and the contribution of vascular tissues. We also present strategies for fracture treatment that have been tested in animal models and in clinical trials or case series. The biophysical and biological basis of the molecular actions of various therapeutic approaches, including recombinant human bone morphogenetic proteins and parathyroid hormone therapy, are also discussed.

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Fracture healing: mechanisms and interventions

GRADE guidelines: 12. Preparing summary of findings tables-binary outcomes.

Context Theory and simulation suggest that randomized controlled trials (RCTs) stopped early for benefit (truncated RCTs) systematically overestimate treatment effects for the outcome that precipitated early stopping. Objective To compare the treatment effect from truncated RCTs with that from meta-analyses of RCTs addressing the same question but not stopped early (nontruncated RCTs) and to explore factors associated with overestimates of effect. Data Sources Search of MEDLINE, EMBASE, Current Contents, and full-text journal content databases to identify truncated RCTs up to January 2007; search of MEDLINE, Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effects to identify systematic reviews from which individual RCTs were extracted up to January 2008. Study Selection Selected studies were RCTs reported as having stopped early for benefit and matching nontruncated RCTs from systematic reviews. Independent reviewers with medical content expertise, working blinded to trial results, judged the eligibility of the nontruncated RCTs based on their similarity to the truncated RCTs. Data Extraction Reviewers with methodological expertise conducted data extraction independently. Results The analysis included 91 truncated RCTs asking 63 different questions and 424 matching nontruncated RCTs. The pooled ratio of relative risks in truncated RCTs vs matching nontruncated RCTs was 0.71 (95% confidence interval, 0.65-0.77). This difference was independent of the presence of a statistical stopping rule and the methodological quality of the studies as assessed by allocation concealment and blinding. Large differences in treatment effect size between truncated and nontruncated RCTs (ratio of relative risks Conclusions Truncated RCTs were associated with greater effect sizes than RCTs not stopped early. This difference was independent of the presence of statistical stopping rules and was greatest in smaller studies.

https://jamanetwork.com/journals/jama/articlepdf/185591/jrv05001_1180_1187.pdf

Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis.

GRADE Evidence to Decision (EtD) frameworks for adoption, adaptation, and de novo development of trustworthy recommendations: GRADE-ADOLOPMENT.

Stimulation of bone repair with ultrasound: a review of the possible mechanic effects.

Objective To determine the efficacy of low intensity pulsed ultrasonography for healing of fractures. Design Systematic review of randomised controlled trials. Data sources Electronic literature search without language restrictions of CINAHL, Embase, Medline, HealthSTAR, and the Cochrane Central Registry of Controlled Trials, from inception of the database to 10 September 2008. Review methods Eligible studies were randomised controlled trials that enrolled patients with any kind of fracture and randomly assigned them to low intensity pulsed ultrasonography or to a control group. Two reviewers independently agreed on eligibility; three reviewers independently assessed methodological quality and extracted outcome data. All outcomes were included and meta-analyses done when possible. Results 13 randomised trials, of which five assessed outcomes of importance to patients, were included. Moderate quality evidence from one trial found no effect of low intensity pulsed ultrasonography on functional recovery from conservatively managed fresh clavicle fractures; whereas low quality evidence from three trials suggests benefit in non-operatively managed fresh fractures (faster radiographic healing time mean 36.9%, 95% confidence interval 25.6% to 46.0%). A single trial provided moderate quality evidence suggesting no effect of low intensity pulsed ultrasonography on return to function among non-operatively treated stress fractures. Three trials provided very low quality evidence for accelerated functional improvement after distraction osteogenesis. One trial provided low quality evidence for a benefit of low intensity pulsed ultrasonography in accelerating healing of established non-unions managed with bone graft. Four trials provided low quality evidence for acceleration of healing of operatively managed fresh fractures. Conclusion Evidence for the effect of low intensity pulsed ultrasonography on healing of fractures is moderate to very low in quality and provides conflicting results. Although overall results are promising, establishing the role of low intensity pulsed ultrasonography in the management of fractures requires large, blinded trials, directly addressing patient important outcomes such as return to function.

https://www.bmj.com/content/bmj/338/bmj.b351.full.pdf

Low intensity pulsed ultrasonography for fractures: systematic review of randomised controlled trials

Randomized clinical trials (RCTs) stopped early for benefit often receive great attention and affect clinical practice, but pose interpretational challenges for clinicians, researchers, and policy makers. Because the decision to stop the trial may arise from catching the treatment effect at a random high, truncated RCTs (tRCTs) may overestimate the true treatment effect. The St udy O f Trial P olicy Of I nterim T runcation (STOPIT-1), which systematically reviewed the epidemiology and reporting quality of tRCTs, found that such trials are becoming more common, but that reporting of stopping rules and decisions were often deficient. Most importantly, treatment effects were often implausibly large and inversely related to the number of the events accrued. The aim of STOPIT-2 is to determine the magnitude and determinants of possible bias introduced by stopping RCTs early for benefit. We will use sensitive strategies to search for systematic reviews addressing the same clinical question as each of the tRCTs identified in STOPIT-1 and in a subsequent literature search. We will check all RCTs included in each systematic review to determine their similarity to the index tRCT in terms of participants, interventions, and outcome definition, and conduct new meta-analyses addressing the outcome that led to early termination of the tRCT. For each pair of tRCT and systematic review of corresponding non-tRCTs we will estimate the ratio of relative risks, and hence estimate the degree of bias. We will use hierarchical multivariable regression to determine the factors associated with the magnitude of this ratio. Factors explored will include the presence and quality of a stopping rule, the methodological quality of the trials, and the number of total events that had occurred at the time of truncation. Finally, we will evaluate whether Bayesian methods using conservative informative priors to "regress to the mean" overoptimistic tRCTs can correct observed biases. A better understanding of the extent to which tRCTs exaggerate treatment effects and of the factors associated with the magnitude of this bias can optimize trial design and data monitoring charters, and may aid in the interpretation of the results from trials stopped early for benefit.

/pdf/stopping-randomized-trials-early-for-benefit-a-protocol-of-2v7ghchrn7.pdf

Stopping randomized trials early for benefit: a protocol of the Study Of Trial Policy Of Interim Truncation-2 (STOPIT-2).

The seamless transition from hospital to home is essential for patient safety and continuity of care. This transition is challenged when primary care physicians receive incomplete, delayed, and inaccurate information about their patients' hospital stay. The discharge summary is the major vehicle for communicating post-discharge patient information from the hospital to primary care physicians. Considered the most comprehensive document in the health record, and despite numerous efforts to automate and computerize it, a complete, timely, and accurate discharge summary remains elusive in practice. From hand-written and delivered to collaborative generation, we trace the journey of the discharge summary through three decades of evolving information and communication technologies. In an attempt to narrow the divide between hospital and primary care physicians we discuss the evidence needed to improve the quality of patient care and to support more significant physician adoption of electronic discharge summaries.

Jagdeep Kaur

Papers

Low intensity pulsed ultrasonography for fractures: systematic review of randomised controlled trials

Stopping randomized trials early for benefit: a protocol of the Study Of Trial Policy Of Interim Truncation-2 (STOPIT-2).

The Discharge Summary Divide: A Review of Electronic Solutions, Obstacles and Benefits