Crowd Intelligence for the Classification of Fractures and Beyond

Medical diagnosis, like all products of human cognition, is subject to error. We tested the hypothesis that errors of diagnosis in the realm of fracture classification can be reduced by a consensus (group) diagnosis; and that digital imaging and Internet access makes feasible the compilation of a diagnostic consensus in real time.Twelve orthopaedic surgeons were asked to evaluate 20 hip radiographs demonstrating a femoral neck fracture. The surgeons were asked to determine if the fractures were displaced or not. Because no reference standard is available, the maximal accuracy of the diagnosis of displacement can be inferred from inter-observer reliability: if two readers disagree about displacement, one of them must be wrong. That method was employed here. Additionally, virtual reader groups of 3 and 5 individual members were amalgamated, with the response of those groups defined by majority vote. The purpose of this step was to see if increasing the number of readers would improve accuracy. In a second experiment, to study the feasibility of amassing a reader group on the Internet in real time, 40 volunteers were sent 10 periodic email requests to answer questions and their response times were assessed.The mean kappa coefficient for individual inter-observer reliability for the diagnosis of displacement was 0.69, comparable to prior published values. For 3-member virtual reader groups, inter-observer reliability was 0.77; and for 5-member groups, it was 0.80. In the experiment studying the feasibility of amassing a reader group in real time, the mean response time was 594 minutes. For all cases, a 9-member group (theoretically 99% accurate) was amassed in 135.8 minutes or less.Consensus may improve diagnosis. Amassing a group for this purpose on the Internet is feasible

Bone healing in an aged murine fracture model is characterized by sustained callus inflammation and decreased cell proliferation

Geriatric fractures take longer to heal and heal with more complications than those of younger patients; however, the mechanistic basis for this difference in healing is not well understood. To improve this understanding, we investigated cell and molecular differences in fracture healing between 5‐month‐old (young adult) and 25‐month‐old (geriatric) mice healing utilizing high‐throughput analysis of gene expression. Mice underwent bilateral tibial fractures and fracture calluses were harvested at 5, 10, and 20 days post‐fracture (DPF) for analysis. Global gene expression analysis was performed using Affymetrix MoGene 1.0 ST microarrays. After normalization, data were compared using ANOVA and evaluated using Principal Component Analysis (PCA), CTen, heatmap, and Incromaps analysis. PCA and cross‐sectional heatmap analysis demonstrated that DPF followed by age had pronounced effects on changes in gene expression. Both un‐fractured and 20 DPF aged mice showed increased expression of immune‐associated genes (CXCL8, CCL8, and CCL5) and at 10 DPF, aged mice showed increased expression of matrix‐associated genes, (Matn1, Ucma, Scube1, Col9a1, and Col9a3). Cten analysis suggested an enrichment of CD8+ cells and macrophages in old mice relative to young adult mice and, conversely, a greater prevalence of mast cells in young adult mice relative to old. Finally, consistent with the PCA data, the classic bone healing pathways of BMP, Indian Hedgehog, Notch and Wnt clustered according to the time post‐fracture first and age second. Clinical Significance: Greater understanding of age‐dependent molecular changes with healing will help form a mechanistic basis for therapies to improve patient outcomes. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:149–158, 2018.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142531/1/jor23652.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142531/2/jor23652_am.pd

Suppression of Notch Signaling in Osteoclasts Improves Bone Regeneration and Healing

Owing to the central role of osteoclasts in bone physiology and remodeling, manipulation of their maturation process provides a potential therapeutic strategy for treating bone diseases. To investigate this, we genetically inhibited the Notch signaling pathway in the myeloid lineage, which includes osteoclast precursors, using a dominant negative form of MAML (dnMAML) that inhibits the transcriptional complex required for downstream Notch signaling. Osteoclasts derived from dnMAML mice showed no significant differences in early osteoclastic gene expression compared to the wild type. Further, these demonstrated significantly lowered resorption activity using bone surfaces while retaining their osteoblast stimulating ability using ex vivo techniques. Using in vivo approaches, we detected significantly higher bone formation rates and osteoblast gene expression in dnMAML cohorts. Further, these mice exhibited increased bone/tissue mineral density compared to wild type and larger bony calluses in later stages of fracture healing. These observations suggest that therapeutic suppression of osteoclast Notch signaling could reduce, but not eliminate, osteoclastic resorption without suppression of restorative bone remodeling and, therefore, presents a balanced paradigm for increasing bone formation, regeneration, and healing. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2089–2103, 2019Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151846/1/jor24384.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151846/2/jor24384_am.pd

Use of Novel Strategies to Develop Guidelines for Management of Pyogenic Osteomyelitis in Adults: A WikiGuidelines Group Consensus Statement.

Importance Traditional approaches to practice guidelines frequently result in dissociation between strength of recommendation and quality of evidence. Objective To construct a clinical guideline for pyogenic osteomyelitis management, with a new standard of evidence to resolve the gap between strength of recommendation and quality of evidence, through the use of a novel open access approach utilizing social media tools. Evidence Review This consensus statement and systematic review study used a novel approach from the WikiGuidelines Group, an open access collaborative research project, to construct clinical guidelines for pyogenic osteomyelitis. In June 2021 and February 2022, authors recruited via social media conducted multiple PubMed literature searches, including all years and languages, regarding osteomyelitis management; criteria for article quality and inclusion were specified in the group's charter. The GRADE system for evaluating evidence was not used based on previously published concerns regarding the potential dissociation between strength of recommendation and quality of evidence. Instead, the charter required that clear recommendations be made only when reproducible, prospective, controlled studies provided hypothesis-confirming evidence. In the absence of such data, clinical reviews were drafted to discuss pros and cons of care choices. Both clear recommendations and clinical reviews were planned with the intention to be regularly updated as new data become available. Findings Sixty-three participants with diverse expertise from 8 countries developed the group's charter and its first guideline on pyogenic osteomyelitis. These participants included both nonacademic and academic physicians and pharmacists specializing in general internal medicine or hospital medicine, infectious diseases, orthopedic surgery, pharmacology, and medical microbiology. Of the 7 questions addressed in the guideline, 2 clear recommendations were offered for the use of oral antibiotic therapy and the duration of therapy. In addition, 5 clinical reviews were authored addressing diagnosis, approaches to osteomyelitis underlying a pressure ulcer, timing for the administration of empirical therapy, specific antimicrobial options (including empirical regimens, use of antimicrobials targeting resistant pathogens, the role of bone penetration, and the use of rifampin as adjunctive therapy), and the role of biomarkers and imaging to assess responses to therapy. Conclusions and Relevance The WikiGuidelines approach offers a novel methodology for clinical guideline development that precludes recommendations based on low-quality data or opinion. The primary limitation is the need for more rigorous clinical investigations, enabling additional clear recommendations for clinical questions currently unresolved by high-quality data

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

p53-mediated transcriptional repression: Targets and mechanisms

The p53 tumor-suppressor gene is an important factor in the ability of a cell to maintain genomic integrity and control growth in response to a variety of stresses. The ability of p53 to transcriptionally activate an array of genes in response to damage has been well characterized. However, there is growing evidence that p53 can also function as a transcriptional repressor and that this function may be involved in apoptosis. Currently, only a handful of down-regulated genes have been identified and the mechanism by which p53 transrepresses remains unclear. To add to our understanding of this potentially important function of p53, we have identified two novel targets, stathmin and FKBP25. Upon induction of p53, both genes display decreased levels of endogenous expression in a p53-dependent and specific manner in a number of human and murine cell lines. Furthermore, stathmin was utilized as a molecular marker to investigate a possible mechanism of this down-regulation. We have found that repression of stathmin is mostly relieved by treatment with trichostatin A, an inhibitor of histone deacetylases. This observation provides a functional link between p53-mediated repression and a bona fide repression complex which includes HDAC1 and mSin3a. In support of this potential link, we have shown that p53 associates in vivo with HDAC1 indirectly through mSin3a. In addition, the regions responsible for p53-mSin3a interaction have been initially mapped in vitro to the PAH2-3 region of mSin3a and two regions of p53 previously shown to be involved in repression—the tetramerization and proline domains. Interestingly, the proline domain has been recently shown to be an important component of p53-dependent apoptosis. Finally, we provide evidence that p53 and mSin3a are inducibly targeted to the stathmin promotor and may affect the acetylation status of the region. In conclusion, our data strongly suggest that p53 may repress transcription by recruitment of a repression complex to the promotors of target genes