Citations

ABSTRACTThere is a clear discrepancy between the growth of cell therapy and tissue engineering research in orthopaedics over the last two decades and the number of approved clinical therapies and products available to patients. At the 2015 annual meeting of the Orthopaedic Research Society, a workshop was held to highlight important considerations from the perspectives of an academic scientist, clinical researcher, and industry representative with the aim of helping researchers to successfully translate their ideas into clinical and commercial reality. Survey data acquired from workshop participants indicated an overall positive opinion on the future potential of cell‐based therapies to make a significant contribution to orthopaedic medicine. The survey also indicated an agreement on areas requiring improvement in the development of new therapies, specifically; increased support for fundamental research and education and improved transparency of regulatory processes. This perspectives article summarises the content and conclusions of the workshop and puts forward suggestions on how translational success of cell‐based therapies in orthopaedics may be achieved. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:17–21, 2016.

ABSTRACTEpithelial‐mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single‐nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome‐wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT‐related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive‐cancer patients and 23,447 controls. A P‐value <0.05 and a false discovery rate (FDR) <0.2 were considered statistically significant. In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (odds ratio (OR) = 1.16, 95% CI = 1.07–1.25, P = 0.0003, FDR = 0.19), whereas F8 rs7053448 (OR = 1.69, 95% CI = 1.27–2.24, P = 0.0003, FDR = 0.12), F8 rs7058826 (OR = 1.69, 95% CI = 1.27–2.24, P = 0.0003, FDR = 0.12), and CAPN13 rs1983383 (OR = 0.79, 95% CI = 0.69–0.90, P = 0.0005, FDR = 0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC.

The effect of fish consumption on blood pressure is controversial. The authors measured blood pressure and calculated oily fish servings per week in 677 community‐dwellers aged 40 years and older living in rural coastal Ecuador. Using regression models with linear splines, the authors evaluated whether dietary fish intake was related to blood pressure levels, after adjusting for relevant confounders. Mean oily fish consumption was 9.1±5.6 servings per week. There was a nonlinear relationship between systolic pressure and fish servings. In the group of individuals consuming up to five servings per week, each serving significantly reduced systolic pressure by 2.3 mm Hg (P=.020). Any extra serving provided no further effects. The study shows an inverse relationship between oily fish consumption and systolic pressure. Currently recommended amounts of dietary oily fish intake per week (1–2 servings) might be insufficient to exert beneficial effects of fish in the control of blood pressure.

Introduction E-consultations are asynchronous, text-based consultations. The specialist e-consultant answers clinical questions in a similar way to a standard consultation but the questions and answers are sent electronically. The e-consultant has access to some or all of the medical record but does not have contact with the patient. Although e-consultations are meant to substitute for face-to-face (F2F) consultations, a significant proportion of e-consultations are converted to F2F consultations. Methods We examined e-consultation content from a sample of e-consultations that had subsequent F2F visits in the same specialty as the e-consultation within 28 days of the e-consultation. Results Out of 5115 e-consultations, there were a total of 547 (10.7%) early F2F conversions. One hundred and fifty-one e-consultations with subsequent early F2F conversions were reviewed in eight specialties. In 64% of the F2F conversions, specialists recommended the F2F consultations. In 75% there were complex diagnostic or treatment considerations. In only 1% was there a sense of medical urgency or a stated need for physical examination. Discussion E-consultations convert to F2F consultations primarily at the request of the specialist. Diagnostic and treatment complexity appear to be the main reasons. We found little evidence that patients decided independently to get a F2F visit or that specialists needed a F2F visit to perform a physical examination. Although e-consultations might not be a complete substitute for F2F consultations, they may serve as an entry level consultation that could be supplemented by a video consultation as needed for cases with more diagnostic and treatment complexity.

Histone deacetylases (Hdacs) are conserved enzymes that remove acetyl groups from lysine side chains in histones and other proteins. Eleven of the 18 Hdacs encoded by the human and mouse genomes depend on Zn2+for enzymatic activity, while the other 7, the sirtuins (Sirts), require NAD2+. Collectively, Hdacs and Sirts regulate numerous cellular and mitochondrial processes including gene transcription, DNA repair, protein stability, cytoskeletal dynamics, and signaling pathways to affect both development and aging. Of clinical relevance, Hdacs inhibitors are United States Food and Drug Administration-approved cancer therapeutics and are candidate therapies for other common diseases including arthritis, diabetes, epilepsy, heart disease, HIV infection, neurodegeneration, and numerous aging-related disorders. Hdacs and Sirts influence skeletal development, maintenance of mineral density and bone strength by affecting intramembranous and endochondral ossification, as well as bone resorption. With few exceptions, inhibition of Hdac or Sirt activity though either loss-of-function mutations or prolonged chemical inhibition has negative and/or toxic effects on skeletal development and bone mineral density. Specifically, Hdac/Sirt suppression causes abnormalities in physiological development such as craniofacial dimorphisms, short stature, and bone fragility that are associated with several human syndromes or diseases. In contrast, activation of Sirts may protect the skeleton from aging and immobilization-related bone loss. This knowledge may prolong healthspan and prevent adverse events caused by epigenetic therapies that are entering the clinical realm at an unprecedented rate. In this review, we summarize the general properties of Hdacs/Sirts and the research that has revealed their essential functions in bone forming cells (e.g., osteoblasts and chondrocytes) and bone resorbing osteoclasts. Finally, we offer predictions on future research in this area and the utility of this knowledge for orthopedic applications and bone tissue engineering.

Abstract Therapy for polymyalgia rheumatica (PMR) varies widely in clinical practice as international recommendations for PMR treatment are not currently available. In this paper, we report the 2015 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) recommendations for the management of PMR. We used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology as a framework for the project. Accordingly, the direction and strength of the recommendations are based on the quality of evidence, the balance between desirable and undesirable effects, patients’ and clinicians’ values and preferences, and resource use. Eight overarching principles and nine specific recommendations were developed covering several aspects of PMR, including basic and follow‐up investigations of patients under treatment, risk factor assessment, medical access for patients and specialist referral, treatment strategies such as initial glucocorticoid (GC) doses and subsequent tapering regimens, use of intramuscular GCs and disease modifying anti‐rheumatic drugs (DMARDs), as well as the roles of non‐steroidal anti‐rheumatic drugs and non‐pharmacological interventions. These recommendations will inform primary, secondary and tertiary care physicians about an international consensus on the management of PMR. These recommendations should serve to inform clinicians about best practices in the care of patients with PMR.

AbstractBackground Electronic health records (EHRs) are increasingly used for clinical and translational research through the creation of phenotype algorithms. Currently, phenotype algorithms are most commonly represented as noncomputable descriptive documents and knowledge artifacts that detail the protocols for querying diagnoses, symptoms, procedures, medications, and/or text-driven medical concepts, and are primarily meant for human comprehension. We present desiderata for developing a computable phenotype representation model (PheRM).Methods A team of clinicians and informaticians reviewed common features for multisite phenotype algorithms published in PheKB.org and existing phenotype representation platforms. We also evaluated well-known diagnostic criteria and clinical decision-making guidelines to encompass a broader category of algorithms.Results We propose 10 desired characteristics for a flexible, computable PheRM: (1) structure clinical data into queryable forms; (2) recommend use of a common data model, but also support customization for the variability and availability of EHR data among sites; (3) support both human-readable and computable representations of phenotype algorithms; (4) implement set operations and relational algebra for modeling phenotype algorithms; (5) represent phenotype criteria with structured rules; (6) support defining temporal relations between events; (7) use standardized terminologies and ontologies, and facilitate reuse of value sets; (8) define representations for text searching and natural language processing; (9) provide interfaces for external software algorithms; and (10) maintain backward compatibility.Conclusion A computable PheRM is needed for true phenotype portability and reliability across different EHR products and healthcare systems. These desiderata are a guide to inform the establishment and evolution of EHR phenotype algorithm authoring platforms and languages.

ObjectivesTo examine the independent effects of sex on the risk of rapid cycling and other indicators of adverse illness course in patients with bipolar I disorder (BP‐I) or bipolar II disorder (BP‐II).MethodsWe analyzed data from the first 1,225 patients enrolled in the Mayo Clinic Individualized Medicine Biobank for Bipolar Disorder. Demographic and clinical variables were ascertained using standardized questionnaires; height and weight were assessed to determine body mass index (BMI). Rates of rapid cycling, cycle acceleration, and increased severity of mood episodes over time were compared between women and men overall and within subgroups defined by bipolar disorder subtype (BP‐I or BP‐II). Multiple logistic regression analysis was used to assess the independent effect of sex on the risk of these indicators of adverse illness course.ResultsWomen had significantly higher rates of rapid cycling than men. Overall rates of rapid cycling were higher in patients with BP‐II than BP‐I; and sex differences in the rate of rapid cycling were more pronounced in patients with BP‐II than BP‐I, although the power to detect statistically significant differences was reduced due to the lower sample size of subjects with BP‐II. Female sex was a significant predictor of rapid cycling, cycle acceleration, and increased severity of mood episodes over time after adjusting for age, bipolar disorder subtype, BMI, having any comorbid psychiatric disorder, and current antidepressant use.ConclusionsFemale sex was associated with significantly higher risk of rapid cycling, cycle acceleration, and increased severity of mood episodes over time in a sample of 1,225 patients with bipolar disorders.

ObjectivesBrain‐derived neurotrophic factor (BDNF) Val66Met (rs6265) functional polymorphism has been implicated in early‐onset bipolar disorder. However, results of studies are inconsistent. We aimed to further explore this association.MethodsDNA samples from the Treatment of Early Age Mania (TEAM) and Mayo Clinic Bipolar Disorder Biobank were investigated for association of rs6265 with early‐onset bipolar disorder. Bipolar cases were classified as early onset if the first manic or depressive episode occurred at age ≤19 years (versus adult‐onset cases at age >19 years). After quality control, 69 TEAM early‐onset bipolar disorder cases, 725 Mayo Clinic bipolar disorder cases (including 189 early‐onset cases), and 764 controls were included in the analysis of association, assessed with logistic regression assuming log‐additive allele effects.ResultsComparison of TEAM cases with controls suggested association of early‐onset bipolar disorder with the rs6265 minor allele [odds ratio (OR) = 1.55, p = 0.04]. Although comparison of early‐onset adult bipolar disorder cases from the Mayo Clinic versus controls was not statistically significant, the OR estimate indicated the same direction of effect (OR = 1.21, p = 0.19). When the early‐onset TEAM and Mayo Clinic early‐onset adult groups were combined and compared with the control group, the association of the minor allele rs6265 was statistically significant (OR = 1.30, p = 0.04).ConclusionsThese preliminary analyses of a relatively small sample with early‐onset bipolar disorder are suggestive that functional variation in BDNF is implicated in bipolar disorder risk and may have a more significant role in early‐onset expression of the disorder.