Genomic heterozygosity is associated with a lower risk of osteoarthritis.

BACKGROUND: Genomic heterozygosity has been shown to confer a health advantage in humans and play a protective role in complex diseases. Given osteoarthritis (OA) is a highly polygenic disease, we set out to determine if an association exists between OA and genomic heterozygosity. RESULTS: End-stage knee and hip OA patients and healthy controls were recruited from the Newfoundland and Labrador (NL) population. The Arthritis Research UK Osteoarthritis Genetics (arcOGEN) consortium database was utilized as a replication cohort. DNA was extracted from blood samples and genotyped. Individual rates of observed heterozygosity (HetRate) and heterozygosity excess (HetExcess) relative to the expected were mathematically derived, and standardized to a z-score. Logistic regression modeling was used to examine the association between OA and HetRate or HetExcess. A total of 559 knee and hip OA patients (mean age 66.5 years, body mass index (BMI) 33.7 kg/m2, and 55% females) and 118 healthy controls (mean age 56.4 years, BMI 29.5 kg/m2, and 59% female) were included in the NL cohort analysis. We found that OA had an inverse relationship with HetRate and HetExcess with odds ratios of 0.64 (95% CI: 0.45-0.91) and 0.65 (95% CI: 0.45-0.93) per standard deviation (SD), respectively. The arcOGEN data included 2,019 end-stage knee and hip OA patients and 2,029 healthy controls, validating our findings with HetRate and HetExcess odds ratios of 0.60 (95% CI: 0.56-0.64) and 0.44 (95% CI: 0.40-0.47) per SD, respectively. CONCLUSIONS: Our results are the first to clearly show evidence, from two separate cohorts, that reduced genomic heterozygosity confers a risk for the future development of OA.

Individual participant data meta-analysis of metabolomics on sustained knee pain in primary osteoarthritis patients.

OBJECTIVES: Knee pain is the major driver for OA patients to seek healthcare, but after pursuing both conservative and surgical pain interventions, ∼20% of patients continue to report long-term pain following total knee arthroplasty (TKA). This study aimed to identify a metabolomic signature for sustained knee pain after TKA to elucidate possible underlying mechanisms. METHODS: Two independent cohorts from St John's, NL, Canada (n = 430), and Toronto, ON, Canada (n = 495) were included in the study. Sustained knee pain was assessed using the WOMAC pain subscale (five questions) at least 1 year after TKA for primary OA. Those reporting any pain on all five questions were considered to have sustained knee pain. Metabolomic profiling was performed on fasted pre-operative plasma samples using the Biocrates Absolute IDQ p180 kit. Associations between metabolites and pair-wise metabolite ratios with sustained knee pain in each individual cohort were assessed using logistic regression with adjustment for age, sex and BMI. Random-effects meta-analysis using inverse variance as weights was performed on summary statistics from both cohorts. RESULTS: One metabolite, phosphatidylcholine (PC) diacyl (aa) C28:1 (odds ratio = 0.66, P = 0.00026), and three metabolite ratios, PC aa C32:0 to PC aa C28:1, PC aa C28:1 to PC aa C32:0, and tetradecadienylcarnitine (C14:2) to sphingomyelin C20:2 (odds ratios = 1.59, 0.60 and 1.59, respectively; all P < 2 × 10-5), were significantly associated with sustained knee pain. CONCLUSIONS: Though further investigations are needed, our results provide potential predictive biomarkers and drug targets that could serve as a marker for poor response and be modified pre-operatively to improve knee pain and surgical response to TKA.

Glutathione, polyamine, and lysophosphatidylcholine synthesis pathways are associated with circulating pro-inflammatory cytokines.

INTRODUCTION: Pro-inflammatory cytokines are responsible for initiating an effective defense against exogenous pathogens, and their regulation has a vital role in maintaining physiological homeostasis. The involvement of pro-inflammatory cytokines in pathological conditions have been explored in great detail, however, studies investigating metabolic pathways associated with these cytokines under normal homeostatic conditions are scarce. OBJECTIVES: The aim of the current study was to identify metabolites and metabolic pathways associated with circulating pro-inflammatory cytokines under homeostatic conditions using a metabolomics approach. METHODS: The study participants (n = 133) were derived from the Newfoundland Osteoarthritis Study (NFOAS) and the Complex Diseases in the Newfoundland population: Environment and Genetics (CODING) study. Plasma concentrations of cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1ß), and macrophage migration inhibitory factor (MIF) were assessed by enzyme-linked immunosorbent assay. Targeted metabolomic profiling on fasting plasma samples was performed using Biocrates MxP® Quant 500 kit which measures a total of 630 metabolites. Associations between natural log-transformed metabolite concentrations and metabolite sums/ratios and cytokine levels were assessed using linear regression with adjustment for age, sex, body mass index (BMI), and osteoarthritis status. RESULTS: Seven metabolites and 11 metabolite sums/ratios were found to be significantly associated with TNF-α, IL-1ß, and MIF (all p ≤ 5.13 × 10- 5) after controlling multiple testing with Bonferroni method, indicating the association between glutathione (GSH), polyamine, and lysophosphatidylcholine (lysoPC) synthesis pathways and these pro-inflammatory cytokines. CONCLUSION: GSH, polyamine, and lysoPC synthesis pathways were positively associated with circulating TNF-α, IL-1ß, and MIF levels under homeostatic conditions.

Endotypes of primary osteoarthritis identified by plasma metabolomics analysis.

OBJECTIVE: To identify endotypes of osteoarthritis (OA) by a metabolomics analysis. METHODS: Study participants included hip/knee OA patients and controls. Fasting plasma samples were metabolomically profiled. Common factor analysis and K-means clustering were applied to the metabolomics data to identify the endotypes of OA patients. Logistic regression was utilized to identify the most significant metabolites contributing to the endotypes. Clinical and epidemiological factors were examined in relation to the identified OA endotypes. RESULTS: Six hundred and fifteen primary OA patients and 237 controls were included. Among the 186 metabolites measured, 162 passed the quality control analysis. The 615 OA patients were classified in three clusters (A, 66; B, 200; and C, 349). Patients in cluster A had a significantly higher concentration of butyrylcarnitine (C4) than other clusters and controls (all P < 0.0002). Elevated C4 is thought to be related to muscle weakness and wasting. Patients in cluster B had a significantly lower arginine concentration than other clusters and controls (all P < 7.98 × 10-11). Cluster C patients had a significantly lower concentration of lysophosphatidylcholine (with palmitic acid), which is a pro-inflammatory bioactive compound, than other clusters and controls (P < 3.79 × 10-6). Further, cluster A had a higher BMI and prevalence of diabetes than other clusters (all P ≤ 0.0009), and also a higher prevalence of coronary heart disease than cluster C (P = 0.04). Cluster B had a higher prevalence of coronary heart disease than cluster C (P = 0.003) whereas cluster C had a higher prevalence of osteoporosis (P = 0.009). CONCLUSION: Our data suggest three possible clinically actionable endotypes in primary OA: muscle weakness, arginine deficit and low inflammatory OA.

Association Between Epidemiological Factors and Nonresponders to Total Joint Replacement Surgery in Primary Osteoarthritis Patients.

BACKGROUND: While total joint replacement (TJR) is the most effective treatment for end-stage osteoarthritis (OA), one-third of patients do not experience clinically important improvement in pain or function following the surgery. Thus, it is important to identify factors for nonresponders and develop strategies to improve TJR outcomes. METHODS: Study participants were patients who underwent TJR (hip/knee) due to OA and completed the WOMAC before and on average 4 years after surgery. Nonresponders (pain nonresponders, function nonresponders, pain and function nonresponders) were determined using the WOMAC change score from baseline to follow-up under two previously reported criteria. Eighty-eight self-reported factors collected by a general health questionnaire were examined for associations with nonresponders. RESULTS: A total of 601 patients (30.8% hip and 69.2% knee replacement) were included; 18% of them were found to be either pain or function nonresponders. Nine factors were identified in the univariable analyses to be associated with nonresponders, and 5 of them (clinical depression, multisite musculoskeletal pain [MSMP], younger age, golfer's elbow, and driving more than 4 hours on average per working day) remained significant in the multivariable analyses in at least one of six categories. Clinical depression, having MSMP, and younger age were the major factors to be independently associated with nonresponders across five categories. In addition, two factors (age at menopause and age at hysterectomy) were significantly associated with female nonresponders. CONCLUSION: Our data suggested potential roles of pain perception, widespread pain sensitization, patient expectations, and early menopause in females in TJR outcomes, warranting further investigation.

Differential correlation network analysis identified novel metabolomics signatures for non-responders to total joint replacement in primary osteoarthritis patients.

INTRODUCTION: Up to one third of total joint replacement patients (TJR) experience poor surgical outcome. OBJECTIVES: To identify metabolomic signatures for non-responders to TJR in primary osteoarthritis (OA) patients. METHODS: A newly developed differential correlation network analysis method was applied to our previously published metabolomic dataset to identify metabolomic network signatures for non-responders to TJR. RESULTS: Differential correlation networks involving 12 metabolites and 23 metabolites were identified for pain non-responders and function non-responders, respectively. CONCLUSION: The differential networks suggest that inflammation, muscle breakdown, wound healing, and metabolic syndrome may all play roles in TJR response, warranting further investigation.

An evolutionary learning and network approach to identifying key metabolites for osteoarthritis.

Metabolomics studies use quantitative analyses of metabolites from body fluids or tissues in order to investigate a sequence of cellular processes and biological systems in response to genetic and environmental influences. This promises an immense potential for a better understanding of the pathogenesis of complex diseases. Most conventional metabolomics analysis methods exam one metabolite at a time and may overlook the synergistic effect of combining multiple metabolites. In this article, we proposed a new bioinformatics framework that infers the non-linear synergy among multiple metabolites using a symbolic model and subsequently, identify key metabolites using network analysis. Such a symbolic model is able to represent a complex non-linear relationship among a set of metabolites associated with osteoarthritis (OA) and is automatically learned using an evolutionary algorithm. Applied to the Newfoundland Osteoarthritis Study (NFOAS) dataset, our methodology was able to identify nine key metabolites including some known osteoarthritis-associated metabolites and some novel metabolic markers that have never been reported before. The results demonstrate the effectiveness of our methodology and more importantly, with further investigations, propose new hypotheses that can help better understand the OA disease.

Morbidity and mortality following pelvic ramus fractures in an older Atlantic Canadian cohort

Background: Pelvic ramus fractures in older patients are associated with substantial morbidity and mortality. There is a paucity of literature on fractures of the pelvis in this age group. The purpose of this study was to report mortality rates following such injuries. In addition, we aimed to describe and quantify the important resultant morbidity in this vulnerable population. Methods: We performed a retrospective chart review of all low-energy pelvic ramus fractures in patients more than age 60 years that occurred between January 2000 and December 2005. Data on survival, hospital length of stay, ambulatory status and place of residence were recorded. For comparison, we calculated the mortality rate for a surrogate age- and sex-matched group using Statistics Canada survival data for use as an uninjured control group. Results: We identified 43 patients (32 women [74%]; mean age 79.4 yr) with isolated low-energy pelvic ramus fractures over the study period. The 1- and 5-year mortality rates were 16.3% (95% confidence interval [CI] 7.8%­30.3%) and 58.1% (95% CI 43.3%­71.6%), respectively, both significantly higher than the point estimates for the control group (6.6% and 31.3%, respectively). Following injury, 14/39 patients (36%) permanently required increased ambulatory aids, and 8 (20%) required a permanent increase in everyday level of care. Conclusion: The results suggest that there may be increased mortality and morbidity following low-energy pattern pelvic ramus fractures in an older population compared to age- and sex-matched uninjured control subjects.

Contexte: Les fractures du bassin chez les personnes âgées sont associées à une morbidité et une mortalité substantielles. La littérature sur les fractures du bassin dans ce groupe d'âge est peu abondante. Le but de cette étude était donc de faire état des taux de mortalité suite à de telles blessures. Nous avons aussi voulu décrire et quantifier l'importante morbidité qui en résulte chez cette population vulnérable. Méhodes: Nous avons effectué une revue rétrospective de tous les cas de fractures du bassin consécutives à un traumatisme de faible énergie chez des patients de plus de 60 ans survenues entre janvier 2000 et décembre 2005. Les données de survie, la durée de l'hospitalisation, le statut ambulatoire et le lieu de résidence ont été notées. À des fins de comparaison, nous avons calculé le taux de mortalité pour un groupe témoin indemme assorti selon l'âge et le sexe en nous servant des données de survie de Statistique Canada. Résultats: Nous avons recensé 43 patients (32 femmes [74 %]; âge moyen 79,4 ans) porteurs de fractures du bassin isolées consécutives à un traumatisme de faible énergie pour la période de l'étude. Les taux de mortalité à 1 an et à 5 ans ont été de 16,3 % (intervalle confiance [IC] de 95 % 7,8 %­30,3 %) et 58,1 % (IC de 95 % 43,3 %­71,6 %), respectivement, tous deux significativement plus élevés que les estimations ponctuelles pour le groupe témoin (6,6 % et 31,3 %, respectivement). Après le traumatisme, 14 patients sur 39 (36 %) ont eu besoin de façon permanente et croissante de dispositifs d'aide à la marche et 8 (20 %) ont eu besoin de façon permanente d'un niveau de soins quotidiens accru. Conclusion: Les résultats donnent à penser que la mortalité et la morbidité pourraient être plus marquées après une fracture de la hanche consécutive à un traumatisme de faible énergie chez la population âgée, comparativement à des témoins assortis selon l'âge et le sexe.

The Orthopedic Trauma Symposium: improving care of orthopedic injuries in Haiti.

BACKGROUND: Although single-trip volunteer medical teams can provide much-needed acute trauma care following natural disasters, their ability to leave a legacy of improved care in the region is often limited. One way to improve treatment of traumatic injuries is through conference-based teaching, such as the Orthopedic Trauma Symposium (OTS), which took place in Haiti in 2014. However, there is little research evaluating the effectiveness of such teaching tools. We evaluated the OTS and the potential benefits of future iterations of the course. METHODS: A survey consisting of 5-point Likert scale questions as well as qualitative open feedback assessed respondents' opinions regarding the value, content and delivery of the OTS. Respondents were classified dichotomously in terms of their role in the OTS (instructor v. participant) to measure any meaningful difference in feedback. RESULTS: In total, 84% of all participants agreed that course content was clearly communicated, and 98% agreed that instructors were knowledgeable in the topics covered. Moreover, 87% of all participants responded that they would apply the training in their medical practices going forward. CONCLUSION: Haitian physicians, residents and medical students responded favourably to the OTS. Open-ended questions offered concise, attainable improvements for future iterations of the course. Organizations committed to improving medical care in low- and middle-income countries should take note of these findings while continuing to develop the OTS and similar initiatives globally.

CONTEXTE: Les équipes médicales bénévoles qui font des interventions ponctuelles sont en mesure de prodiguer des soins essentiels en traumatologie aigüe après des désastres naturels, mais elles laissent souvent un héritage limité pour ce qui est de l'amélioration des soins dans la région touchée. Or, il est possible d'améliorer le traitement des blessures post-traumatismes par le biais de conférences didactiques, telles que le Symposium de traumatologie-orthopédie (STO) tenu en Haïti en 2014. Peu de recherches ont toutefois mesuré l'efficacité de ce type d'outil didactique. Nous avons voulu faire un bilan du STO et des avantages potentiels qu'il y aurait à répéter l'expérience. MÉTHODES: Un questionnaire prenant la forme d'une échelle de Likert en 5 points, ainsi que des questions qualitatives ouvertes, ont permis de recueillir l'opinion des répondeurs au sujet de l'utilité, du contenu et du déroulement du STO. Nous avons scindé les répondeurs en 2 groupes en fonction de leur rôle lors du STO (soit instructeurs, soit participants) pour mesurer les différences notables sur le plan des perceptions. RÉSULTATS: En tout, 84 % de l'ensemble des participants ont affirmé que le contenu du cours avait été clairement communiqué et 98 % ont affirmé que les instructeurs connaissaient les thèmes abordés. En outre, 87 % de tous les participants ont répondu avoir l'intention d'appliquer dorénavant la formation à leur pratique médicale. CONCLUSION: Les médecins, résidents et étudiants en médecine haïtiens ont répondu favorablement au STO. Les questions ouvertes ont suscité des suggestions concises et réalistes pour améliorer les futures éditions du cours. Les organisations vouées à l'amélioration des soins médicaux dans les pays à revenu faible et moyen devraient prendre note de ces observations tout en continuant d'exploiter la formule des STO et autres initiatives similaires ailleurs dans le monde.

Lysophosphatidylcholines to phosphatidylcholines ratio predicts advanced knee osteoarthritis.

OBJECTIVE: To identify novel biomarker(s) for predicting advanced knee OA. METHODS: Study participants were derived from the Newfoundland Osteoarthritis Study and the Tasmania Older Adult Cohort Study. All knee OA cases were patients who underwent total knee replacement (TKR) due to primary OA. Metabolic profiling was performed on fasting plasma. Four thousand and eighteen plasma metabolite ratios that were highly correlated with that in SF in our previous study were generated as surrogates for joint metabolism. RESULTS: The discovery cohort included 64 TKR cases and 45 controls and the replication cohorts included a cross-sectional cohort of 72 TKR cases and 76 controls and a longitudinal cohort of 158 subjects, of whom 36 underwent TKR during the 10-year follow-up period. We confirmed the previously reported association of the branched chain amino acids to histidine ratio with advanced knee OA (P = 9.3 × 10(-7)) and identified a novel metabolic marker-the lysophosphatidylcholines (lysoPCs) to phosphatidylcholines (PCs) ratio-that was associated with advanced knee OA (P = 1.5 × 10(-7)) after adjustment for age, sex and BMI. When the subjects of the longitudinal cohort were categorized into two groups based on the optimal cut-off of the ratio of 0.09, we found the subjects with the ratio ⩾0.09 were 2.3 times more likely to undergo TKR than those with the ratio <0.09 during the 10-year follow-up (95% CI: 1.2, 4.3, P = 0.02). CONCLUSION: We identified the ratio of lysoPCs to PCs as a novel metabolic marker for predicting advanced knee OA. Further studies are required to examine whether this ratio can predict early OA change.

Does Open Reduction and Internal Fixation versus Primary Arthrodesis Improve Patient Outcomes for Lisfranc Trauma? A Systematic Review and Meta-analysis.

BACKGROUND: Although Lisfranc injuries are uncommon, representing approximately 0.2% of all fractures, they are complex and can result in persistent pain, degenerative arthritis, and loss of function. Both open reduction and internal fixation (ORIF) and primary fusion have been proposed as treatment options for these injuries, but debate remains as to which approach is better. QUESTIONS/PURPOSES: We asked whether ORIF or primary fusion led to (1) fewer reoperations for hardware removal; (2) less frequent revision surgery; (3) higher patient outcome scores; and (4) more frequent anatomic reduction. METHODS: A systematic review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Three trials met the criteria for inclusion within the meta-analysis. Qualifying articles for the meta-analysis had data extracted independently by two authors (NS, AF). The quality of each study was assessed using the Center for Evidence Based Medicine's evaluation strategy; data were extracted from articles rated as good and fair: two and one article, respectively. RESULTS: The risk ratio for hardware removal was 0.23 (95% confidence interval [CI], 0.11-0.45; p < 0.001) indicating more hardware removal for ORIF than fusion. For other revision surgery, the risk ratio for ORIF was 0.36 (95% CI, 0.08-1.59; p = 0.18) favoring neither. Similarly, neither was favored using patient-reported outcomes; the standard mean difference was calculated to be 0.50 (95% CI, -2.13 to 3.12; p = 0.71). When considering the risk of nonanatomic alignment, neither was favored (risk ratio, 1.48; 95% CI, 0.34-6.38; p = 0.60). CONCLUSIONS: The surgeon should consider the increased risk of hardware removal along with its associated morbidity and discuss this with the patient preoperatively when considering ORIF of Lisfranc injuries. Because no new trials have been performed since 2012, further randomized controlled trials will be needed improve our understanding of these interventions. LEVEL OF EVIDENCE: Level I, therapeutic study.

Plain film measurement error in acute displaced midshaft clavicle fractures.

BACKGROUND: Clavicle fractures are common and optimal treatment remains controversial. Recent literature suggests operative fixation of acute displaced mid-shaft clavicle fractures (DMCFs) shortened more than 2 cm improves outcomes. We aimed to identify correlation between plain film and computed tomography (CT) measurement of displacement and the inter- and intraobserver reliability of repeated radiographic measurements. METHODS: We obtained radiographs and CT scans of patients with acute DMCFs. Three orthopedic staff and 3 residents measured radiographic displacement at time zero and 2 weeks later. The CT measurements identified absolute shortening in 3 dimensions (by subtracting the length of the fractured from the intact clavicle). We then compared shortening measured on radiographs and shortening measured in 3 dimensions on CT. Interobserver and intraobserver reliability were calculated. RESULTS: We reviewed the fractures of 22 patients. Bland-Altman repeatability coefficient calculations indicated that radiograph and CT measurements of shortening could not be correlated owing to an unacceptable amount of measurement error (6 cm). Interobserver reliability for plain radiograph measurements was excellent (Cronbach α = 0.90). Likewise, intraobserver reliabilities for plain radiograph measurements as calculated with paired t tests indicated excellent correlation (p > 0.05 in all but 1 observer [p = 0.04]). CONCLUSION: To establish shortening as an indication for DMCF fixation, reliable measurement tools are required. The low correlation between plain film and CT measurements we observed suggests further research is necessary to establish what imaging modality reliably predicts shortening. Our results indicate weak correlation between radiograph and CT measurement of acute DMCF shortening.

CONTEXTE: Les fractures de la clavicule sont fréquentes, et le choix du traitement optimal ne fait pas l'unanimité. Selon la littérature récente, la fixation chirurgicale des fractures du tiers médial déplacées (FTMD) aiguës raccourcies de plus de 2 cm donnerait de meilleurs résultats. Nous avons voulu établir une corrélation entre la mesure du déplacement obtenue par radiographie simple et par tomodensitométrie (TDM) et la fiabilité inter- et intra-observateur des mesures radiographiques répétées. MÉTHODES: Nous avons obtenu les radiographies et les TDM de patients ayant subi une FTMD aiguë. Trois orthopédistes et 3 résidents ont mesuré le déplacement radiographique au temps zéro et 2 semaines plus tard. Les mesures par TDM ont permis d'identifier un raccourcissement absolu en 3 dimensions (en soustrayant de la longueur de la clavicule intacte celle de la clavicule brisée). Nous avons ensuite comparé le raccourcissement mesuré par radiographie au raccourcissement en 3 dimensions mesuré par TDM. La fiabilité inter- et intra-observateur a ensuite été calculée. RÉSULTATS: Nous avons ainsi analysé les fractures de 22 patients. Les calculs du coefficient de répétabilité de Bland et Altman ont indiqué qu'il était impossible d'établir des corrélations entre les mesures obtenues par radiographie et par TDM compte tenu de l'ampleur inacceptable de l'erreur de mesure (6 cm). La fiabilité inter-observateur a été excellente pour les mesures radiographiques (coefficient α de Cronbach = 0,90). De même, la fiabilité intra-observateur pour les mesures radiographiques calculée par test t pour échantillons appariés a indiqué une excellente corrélation (p > 0,05 chez tous les observateurs, sauf 1 [p = 0,04]). CONCLUSION: Pour que le raccourcissement devienne une indication de la FTMD, il faut disposer d'outils de mesure fiables. La faible corrélation que nous avons observée entre les mesures obtenues par radiographie et par TDM montre qu'il faut approfondir la recherche afin de déterminer quelle modalité permet de prédire de manière fiable le raccourcissement. Nos résultats démontrent une faible corrélation entre les mesures du raccourcissement obtenues par radiographie et par TDM dans la FTMD aiguë.

Genome-wide DNA methylation study of hip and knee cartilage reveals embryonic organ and skeletal system morphogenesis as major pathways involved in osteoarthritis.

BACKGROUND: Evidence suggests that epigenetics plays a role in osteoarthrits (OA). The aim of the study was to describe the genome wide DNA methylation changes in hip and knee OA and identify novel genes and pathways involved in OA by comparing the DNA methylome of the hip and knee osteoarthritic cartilage tissues with those of OA-free individuals. METHODS: Cartilage samples were collected from hip or knee joint replacement patients either due to primary OA or hip fractures as controls. DNA was extracted from the collected cartilage and assayed by Illumina Infinium HumanMethylation450 BeadChip array, which allows for the analysis of >480,000 CpG sites. Student T-test was conducted for each CpG site and those sites with at least 10 % methylation difference and a p value <0.0005 were defined as differentially methylated regions (DMRs) for OA. A sub-analysis was also done for hip and knee OA separately. DAVID v6.7 was used for the functional annotation clustering of the DMR genes. Clustering analysis was done using multiple dimensional scaling and hierarchical clustering methods. RESULTS: The study included 5 patients with hip OA, 6 patients with knee OA and 7 hip cartilage samples from OA-free individuals. The comparisons of hip, knee and combined hip/knee OA patients with controls resulted in 26, 72, and 103 DMRs, respectively. The comparison between hip and knee OA revealed 67 DMRs. The overall number of the sites after considering the overlaps was 239, among which 151 sites were annotated to 145 genes. One-fifth of these genes were reported in previous studies. The functional annotation clustering of the identified genes revealed clusters significantly enriched in skeletal system morphogenesis and development. The analysis revealed significant difference among OA and OA-free cartilage, but less different between hip OA and knee OA. CONCLUSIONS: We found that a number of CpG sites and genes across the genome were differentially methylated in OA patients, a remarkable portion of which seem to be involved in potential etiologic mechanisms of OA. Genes involved in skeletal developmental pathways and embryonic organ morphogenesis may be a potential area for further OA studies.

Evaluating the reliability of surgical assessment methods in an orthopedic residency program.

BACKGROUND: Orthopedic surgical education in Canada has seen major change in the last 15 years. Work hour restrictions and external influence have led to new approaches for surgical training. With a change toward competency-based educational models under the CanMEDS headings there is a need to ensure the validity of modern assessment methods. Our objective was to evaluate the reliability of a currently used surgical skill assessment tool within an orthopedic residency program, as measured by the Surgical Encounters Form. METHODS: A surgical assessment tool has previously been created at our institution that comprises 15 items spanning 4 of the CanMEDS competencies. Results were blinded to the primary investigator and coded by a third party. The assessments were collected, and we measured percent agreement using Cronbach's α and Fleiss κ. RESULTS: Over a 5-month period 11 staff members assessed 10 residents. Eighty-eight assessments were completed in total. Weighted percent agreement was 90.9%. Cronbach's α averaged 0.865 for the medical expert role, 0.920 for technical skills, 0.934 for the communicator role, 1.00 for the collaborator role and 1.00 for the health advocate role. The mean Fleiss κ score was 0.147 (95% confidence interval -0.071 to 0.364), demonstrating low interrater reliability. CONCLUSION: Despite the development of a validated assessment tool to evaluate surgical skills acquisition, interrater reliability results suggest low levels of agreement among assessors.

CONTEXTE: L'enseignement de la chirurgie orthopédique au Canada a beaucoup évolué ces 15 dernières années. La diminution des heures de travail et les influences extérieures sont à l'origine des nouvelles approches pour la formation en chirurgie. Avec l'avènement des modèles de formation fondés sur les compétences et les rôles CanMEDS, il faut s'assurer de la validité des méthodes d'évaluation modernes. Notre objectif était d'évaluer la fiabilité d'un outil de vérification des habiletés chirurgicales actuellement utilisé par un programme de résidence en orthopédie, au moyen du Formulaire de rencontres chirurgicales. MÉTHODES: Un outil d'évaluation chirurgicale existe déjà dans notre établissement et comporte 15 éléments qui se rattachent à 4 des rôles CanMEDS. Sur une période de 5 mois, 11 membres du personnel ont évalué 10 résidents. Les résultats étaient à l'insu de l'investigateur principal et encodés par une tierce partie. Les évaluations ont été colligées et nous avons mesuré le pourcentage de concordance à l'aide du coefficient α de Cronbach et du score κ de Fleiss. RÉSULTANTS: Quatre-vingt-huit évaluations ont été effectuées au total. Le pourcentage de concordance pondéré a été de 90,9 %. Le coefficient α de Cronbach a été en moyenne de 0,865 pour le rôle d'expert médical, de 0,920 pour les habiletés techniques, de 0,934 pour le rôle de communicateur, de 1,00 pour le rôle de collaborateur et de 1,00 pour le rôle de promoteur de la santé. Le score κ de Fleiss moyen a été de 0,147 (intervalle de confiance de 95 % ­0,071 à 0,364), témoignant d'une faible fiabilité inter-évaluateurs. CONCLUSION: Malgré la mise au point d'un outil d'évaluation validé pour mesurer l'acquisition des habiletés en chirurgie, les résultats au plan de la fiabilité inter-évaluateurs indiquent un faible degré de concordance entre les examinateurs.

Radiographic evaluation of the ankle syndesmosis.

BACKGROUND: Radiographic measurements to document ankle anatomy have been suggested in recent literature to be inadequate. Focus has been put on stress views and computed tomography; however, there are also issues with these modalities. An orthogonal view that could be used both statically and dynamically could help determine syndesmotic stability. The purpose of this study was to determine a parameter on a normal lateral ankle radiograph that will increase the reliability of standard radiography in diagnosing syndesmotic integrity. METHODS: Three orthopedic surgeons reviewed 80 lateral ankle radiographs. Thirty of those radiographs were reviewed on a second occasion. Rotation of the radiographs was determined by evaluating the overlap of the talar dome. Four radiographic parameters were measured 1 cm above the tibial plafond: fibular width, tibial width, and anterior and posterior tibiofibular intervals. RESULTS: Seventy-two radiographs were determined by consensus to be adequate. Means and ratios were documented to determine the relationship of the fibula to the tibia. Interrater reliability ranged from moderate to near-perfect, and the intrarater reliability was documented for each ratio. The anterior tibiofibular ratio was shown to be strong to near-perfect. It demonstrates that 40% of the tibia should be seen anterior to the fibula at 1cm above the tibial plafond. CONCLUSION: The anterior tibiofibular ratio provides an orthogonal measure for the syndesmosis that, in conjunction with those parameters previously documented, could clinically and economically improve the diagnosis of syndesmotic disruptions.

CONTEXTE: Selon la littérature récente, les mesures radiographiques utilisées pour documenter l'anatomie de la cheville seraient inadéquates. L'accent a été placé sur les clichés de cheville en position de stress et sur la tomodensitométrie, mais ces modalités présentent également des inconvénients. Une vue orthogonale utilisée en position statique et en position dynamique pourrait aider à évaluer la stabilité syndesmotique. Le but de cette étude était de déterminer quel paramètre de la radiographie latérale normale de la cheville accroîtrait la fiabilité de la radiographie standard pour le diagnostic de l'intégrité syndesmotique. MÉTHODES: Trois chirurgiens orthopédistes ont passé en revue 80 radiographies latérales de la cheville. Trente de ces radiographies ont été interprétées une deuxième fois. La rotation des radiographies a été déterminée par l'évaluation du chevauchement du dôme talien. Quatre paramètres radiographiques ont été mesurés à 1 cm audessus du plafond tibial : la largeur du péroné, la largeur du tibia et les intervalles tibiofibulaires antérieur et postérieur. RÉSULTATS: Soixante-douze radiographies ont consensuellement été jugées adéquates. Les moyennes et les ratios ont été notés pour établir le rapport péroné-tibia. La fiabilité inter-examinateur a varié de modérée à quasi-parfaite et la fiabilité intra-examinateur a été documentée pour chaque ratio. Le ratio tibiofibulaire antérieur s'est révélé être un paramètre solide à quasi-parfait. Il démontre que 40 % du tibia devrait être visible à l'avant du péroné à 1 cm au-dessus du plafond tibial. CONCLUSION: Le ratio tibiofibulaire antérieur constitue une mesure orthogonale pour la syndesmose qui, en conjonction avec les paramètres précédemment documentés, permettrait d'améliorer le diagnostic des troubles syndesmotiques aux plans clinique et économique.

Functional outcome of supracondylar elbow fractures in children: a 3- to 5-year follow-up.

BACKGROUND: Long-term functional outcomes of supracondylar elbow fractures (SCEF) have not been well documented in the literature. We retrospectively evaluated functional outcomes of pediatric SCEF using the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire. METHODS: We retrospectively reviewed the outcomes of patients who presented to our tertiary care pediatric emergency department with SCEF between January 2005 and December 2009. We reviewed their charts to assess several clinical parameters, including age, sex, Gartland classification of SCEF, weight, comorbidities, treatment intervention, physiotherapy and the extremity involved. The DASH questionnaire was administered in 2012. We performed a multiple linear regression analysis to determine the significance of these clinical parameters as they related to the DASH score for functional outcome. RESULTS: We included 94 patients with SCEF in our review. Pediatric SCEF had good functional outcomes based on the DASH questionnaire (mean score 0.77 ± 2.10). We obtained the following DASH scores: 0.45 ± 2.20 for type I, 1.09 ± 1.70 for type II and 1.43 ± 2.40 for type III fractures. There was no statistical difference in functional outcome, regardless of sex (p = 0.07), age at injury (p = 0.96), fracture type (p = 0.14), weight (p = 0.59), right/left extremity (p = 0.26) or surgery (p = 0.52). CONCLUSION: Our results demonstrate that good functional outcomes can be expected with pediatric SCEF based on the DASH questionnaire, regardless of age at injury, sex, weight, right/left extremity or surgical/nonsurgical intervention, provided satisfactory reduction is achieved and maintained.

CONTEXTE: Les répercussions fonctionnelles à long terme des fractures du coude supracondyliennes (FCSC) n'ont pas été bien documentées dans la littérature. Nous avons évalué de manière rétrospective les résultats fonctionnels des FCSC pédiatriques à l'aide du questionnaire DASH (Disabilities of the Arm, Shoulder and Hand). MÉTHODES: Nous avons passé en revue rétrospectivement les résultats chez les patients amenés pour une FCSC au service d'urgence pédiatrique de notre établissement de soins tertiaires entre janvier 2005 et décembre 2009. Nous avons examiné leurs dossiers pour évaluer plusieurs paramètres cliniques, dont l'âge, le sexe, la classification de Gartland pour les FCSC, le poids, les comorbidités, l'intervention thérapeutique, la physiothérapie et la latéralité du membre affecté. Le questionnaire DASH a été administré en 2012. Nous avons procédé à une analyse de régression linéaire multiple pour déterminer la signification de ces paramètres cliniques en regard du score DASH d'évaluation fonctionnelle. RÉSULTATS: Nous avons inclus 94 patients ayant subi une FCSC dans notre analyse. La FCSC pédiatrique évolue bien au plan fonctionnel selon le questionnaire DASH (score moyen 0,77 ± 2,10). Nous avons obtenu les scores DASH suivants : 0,45 ± 2,20 pour les fractures de type I, 1,09 ± 1,70 pour les fractures de type II et 1,43 ± 2,40 pour les fractures de type III. On n'a noté aucune différence statistique quant aux résultats fonctionnels, indépendamment du sexe (p = 0,07), de l'âge au moment de la fracture (p = 0,96), du type de fracture (p = 0,14), du poids (p = 0,59), de la latéralité (p = 0,26) ou de la chirurgie (p = 0,52). CONCLUSION: Nos observations démontrent qu'on peut s'attendre à de bons résultats fonctionnels dans les cas de FCSC en se fondant sur le questionnaire DASH, indépendamment de l'âge au moment de la fracture, du sexe, du poids, de la latéralité ou de l'intervention chirurgicale ou non chirurgicale, à la condition d'obtenir et de maintenir une réduction satisfaisante.

The queen bee phenomenon in Canadian surgical subspecialties: An evaluation of gender biases in the resident training environment.

BACKGROUND: The queen bee phenomenon (QBP) describes the behavioural response that occurs when women achieve success in a male-dominated environment, and in this position of authority, treat their female subordinates more critically. It has been demonstrated in business, academia, the military, and police force. The goal of this study was to determine whether the QBP occurs in surgical specialties. We hypothesized that female surgeons, fellows, and senior surgical residents would be more critical in their assessment of junior female residents than their male counterparts. METHODS: A scenario-based survey was distributed via email to all Canadian surgical programs between February and March 2021. Scenarios were designed to assess either female or male learners. Centers distributed surveys to attending surgeons, surgical fellows, resident physicians, and affiliate surgeons. Respondents average Likert score for female-based and male-based questions were calculated. Subgroup analyses were performed based on gender, age, seniority, and surgical specialty. RESULTS: 716 survey responses were collected, with 387 respondents identifying as male (54%) and 321 identifying as female (45%). 385 attending surgeons (54%), 66 fellows (9%), and 263 residents (37%) responded. The mean Likert scores for female respondents assessing female learners was significantly lower than male learners (p = 0·008, CI = 95%). During subgroup analysis, some specialties demonstrated significant scoring differences. DISCUSSION: The QBP was shown to be present among surgical specialties. Female respondents assessed female learners more critically than their male counterparts. CONCLUSION: These findings highlight the importance of tackling organizational biases to create more equitable educational and work environment in surgery.

Poor access to timely pain reduction interventions for pediatric patients with supracondylar humerus fracture.

OBJECTIVE: The purpose of this study was to describe the use of analgesic interventions in children with acute supracondylar fractures presenting to a pediatric emergency department (ED) and to explore the relationship between timely interventions and severity of injury. METHODS: This was a retrospective cohort study. Structured chart reviews were conducted on all eligible cases of acute supracondylar humerus fracture presenting to a single pediatric ED over a 5-year period ending in December 2009. Two interventions were studied: administration of a systemic analgesic and placement of an immobilizing backslab. Criteria for timeliness were administration of an analgesic within 30 minutes from triage and placement of a backslab before radiography. Cases were dichotomized as nonsevere or severe based on whether the fracture was treated with casting alone or with another orthopedic intervention (closed reduction in the ED or any procedure in the operating room). RESULTS: Of 160 eligible cases, 116 were classified as nonsevere and 44 as severe. The proportions receiving a timely analgesic were 3% and 11%, respectively, in these groups (P = 0.04 for difference). For backslab application, 16% and 61% received timely treatment in the nonsevere and severe groups, respectively (P = 0.000 for difference). CONCLUSIONS: Children presenting to a pediatric ED with a painful injury had low access to early systemic analgesics and backslab immobilization. Many factors may have played a role, including lack of mandated documentation of a formal pain score and lack of a medical directive allowing triage nurses to administer analgesics in the institution studied.

Radiographic Evaluation of Carpal Mechanics and the Scapholunate Angle in a Clenched Fist with Dynamic Computed Tomography Imaging.

Purpose: The long-term consequences of injuries to the scapholunate joint can severely limit hand function, and the potential for posttraumatic deformity makes early recognition of these injuries important. The purpose of this study was to evaluate the motion of the scapholunate joint in normal wrists through the radial and ulnar deviation using novel dynamic computed tomography (CT) imaging. Methods: Fifteen participants consented to have their uninjured wrists scanned. A protocol was designed to ensure adequate time, yet limited exposure, for volunteers. Participants began with the hand in a relaxed fist position and then proceeded to clench the hand in a full fist and relax. Once relaxed again, the wrist was maximally ulnarly deviated and then maximally radially deviated in a fluid motion. Dynamic CT imaging was captured throughout the range of motion. Results: The scapholunate angle was measured on dynamic wrist images. The mean range of the scapholunate angle that the wrists moved through was 37.2°-45.9°, and the mean midpoint angle was 41.2° ± 0.4°. All wrists had small, measurable differences in the scapholunate angle when moving from the maximum ulnar deviation to the maximal radial deviation. The average maximum angle change through the range is 11.7°, whereas the average minimum angle change was 0.9°. Conclusions: In this study, scapholunate angle calculations using dynamic wrist CT scans were within the range of accepted normal for the angle in uninjured wrists. With the increased focus on dynamic imaging for wrist motion, it may be possible to derive a standardized protocol for mapping the carpal motion that is clinically applicable and reproducible. Type of study/level of evidence: Diagnostic IV.

Restricting Branched-Chain Amino Acids within a High-Fat Diet Prevents Obesity.

Obesity is a global pandemic, but there is yet no effective measure to control it. Recent metabolomics studies have identified a signature of altered amino acid profiles to be associated with obesity, but it is unclear whether these findings have actionable clinical potential. The aims of this study were to reveal the metabolic alterations of obesity and to explore potential strategies to mitigate obesity. We performed targeted metabolomic profiling of the plasma/serum samples collected from six independent cohorts and conducted an individual data meta-analysis of metabolomics for body mass index (BMI) and obesity. Based on the findings, we hypothesized that restriction of branched-chain amino acids (BCAAs), phenylalanine, or tryptophan may prevent obesity and tested our hypothesis in a dietary restriction trial with eight groups of 4-week-old male C57BL/6J mice (n = 5/group) on eight different types of diets, respectively, for 16 weeks. A total of 3397 individuals were included in the meta-analysis. The mean BMI was 30.7 ± 6.1 kg/m2, and 49% of participants were obese. Fifty-eight metabolites were associated with BMI and obesity (all p ≤ 2.58 × 10-4), linked to alterations of the BCAA, phenylalanine, tryptophan, and phospholipid metabolic pathways. The restriction of BCAAs within a high-fat diet (HFD) maintained the mice's weight, fat and lean volume, subcutaneous and visceral adipose tissue weight, and serum glucose and insulin at levels similar to those in the standard chow group, and prevented obesity, adipocyte hypertrophy, adipose inflammation, and insulin resistance induced by HFD. Our data suggest that four metabolic pathways, BCAA, phenylalanine, tryptophan, and phospholipid metabolic pathways, are altered in obesity and restriction of BCAAs within a HFD can prevent the development of obesity and insulin resistance in mice, providing a promising strategy to potentially mitigate diet-induced obesity.