Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer.

Diabetes is a complex metabolic syndrome that is characterized by prolonged high blood glucose levels and frequently associated with life-threatening complications1,2. Epidemiological studies have suggested that diabetes is also linked to an increased risk of cancer3-5. High glucose levels may be a prevailing factor that contributes to the link between diabetes and cancer, but little is known about the molecular basis of this link and how the high glucose state may drive genetic and/or epigenetic alterations that result in a cancer phenotype. Here we show that hyperglycaemic conditions have an adverse effect on the DNA 5-hydroxymethylome. We identify the tumour suppressor TET2 as a substrate of the AMP-activated kinase (AMPK), which phosphorylates TET2 at serine 99, thereby stabilizing the tumour suppressor. Increased glucose levels impede AMPK-mediated phosphorylation at serine 99, which results in the destabilization of TET2 followed by dysregulation of both 5-hydroxymethylcytosine (5hmC) and the tumour suppressive function of TET2 in vitro and in vivo. Treatment with the anti-diabetic drug metformin protects AMPK-mediated phosphorylation of serine 99, thereby increasing TET2 stability and 5hmC levels. These findings define a novel 'phospho-switch' that regulates TET2 stability and a regulatory pathway that links glucose and AMPK to TET2 and 5hmC, which connects diabetes to cancer. Our data also unravel an epigenetic pathway by which metformin mediates tumour suppression. Thus, this study presents a new model for how a pernicious environment can directly reprogram the epigenome towards an oncogenic state, offering a potential strategy for cancer prevention and treatment.

Accuracy of radiographic techniques in detection of the calcaneofibular ligament calcaneal insertion for lateral ankle ligament complex surgery.

BACKGROUND: Grade III ankle sprains that fail conservative treatment can require surgical management. Anatomic procedures have been shown to properly restore joint mechanics, and precise localization of insertion sites of the lateral ankle complex ligaments can be determined through radiographic techniques. Ideally, radiographic techniques that are easily reproducible intraoperatively will lead to a consistently well-placed CFL reconstruction in lateral ankle ligament surgery. PURPOSE: To determine the most accurate method to locate the calcaneofibular ligament (CFL) insertion radiographically. METHODS: MRIs of 25 ankles were utilized to identify the "true" insertion of the CFL. Distances between the true insertion and three bony landmarks were measured. Three proposed methods (Best, Lopes, and Taser) for determining the CFL insertion were applied to lateral ankle radiographs. X and Y coordinate distances were measured from the insertion found on each proposed method to the three bony landmarks: the most superior point of the postero-superior surface of the calcaneus, the posterior most aspect of the sinus tarsi, and the distal tip of the fibula. X and Y distances were compared to the true insertion found on MRI. All measurements were made using a picture archiving and communication system. The average, standard deviation, minimum, and maximum were obtained. Statistical analysis was performed using repeated measures ANOVA, and a post hoc analysis was performed with the Bonferroni test. RESULTS: The Best and Taser techniques were found to be closest to the true CFL insertion when combining X and Y distances. For distance in the X direction, there was no significant difference between techniques (P = 0.264). For distance in the Y direction, there was a significant difference between techniques (P = 0.015). For distance in the combined XY direction, there was a significant difference between techniques (P = 0.001). The CFL insertion as determined by the Best method was significantly closer to the true insertion compared to the Lopes method in the Y (P = 0.042) and XY (P = 0.004) directions. The CFL insertion as determined by the Taser method was significantly closer to the true insertion compared to the Lopes method in the XY direction (P = 0.017). There was no significant difference between the Best and Taser methods. CONCLUSION: If the Best and Taser techniques can be readily used in the operating room, they would likely prove the most reliable for finding the true CFL insertion.

Stemless reverse total shoulder arthroplasty: a systematic review.

BACKGROUND: The use of reverse total shoulder arthroplasty and stemless anatomic total shoulder replacement has been increasing in the United States every year. Stemless humeral components in reverse total shoulder arthroplasty are only approved for clinical trials in the United States with an investigational device exception with limited data. METHODS: A systematic review on stemless reverse total shoulder arthroplasty was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A search was conducted on November 25, 2020, using the MEDLINE/PubMed, Cochrane, and Embase databases. All articles were reviewed by 2 independent evaluators, with any conflicts or issues resolved by consensus or a final decision by the senior author. The primary outcomes extracted were complications, radiographic results, and outcome scores. RESULTS: We evaluated 10 studies that used either the Total Evolutive Shoulder System (TESS) or Verso implant. There were 430 total patients and 437 total procedures; 266 patients in the TESS group underwent a total of 272 procedures, and 164 patients in the Verso group underwent a total of 165 procedures. The mean age at the time of surgery was 73.8 years (range, 38-93 years). The mean follow-up period ranged from 6.4 to 101.6 months per study. There was an overall trend of improved clinical outcome scores, a 0.2% humeral component loosening rate, and an 11.2% complication rate. CONCLUSIONS: This review shows that the clinical and functional outcomes following stemless or metaphyseal reverse total shoulder arthroplasty are quite promising, especially with the low rate of humeral-sided complications. There continues to be a need for additional long-term studies and randomized clinical trials.

The Effects of the COVID-19 Pandemic on Pediatric Orthopedic Injuries: A Single-Center Retrospective Study.

OBJECTIVES: The COVID-19 pandemic has had a profound effect on the pediatric population worldwide. The consequences of the lockdown and the reallocation of hospital resources have caused notable changes in the presentation of pediatric orthopedic injuries. Through our use of patient records, we were able to display the epidemiological trends, as well as analyze the changes in the type and mechanism of various injuries. Our purpose is to further understand the considerable effects of the COVID-19 pandemic on pediatric orthopedic trauma and help guide the allocation of future healthcare resources. METHODS: We conducted a retrospective cohort study on pediatric patients admitted for any orthopedic injury over a 3-year period (September 2018 to August 2021) at a Midwest level 1 trauma center. Cases were stratified into two groups based on the United States' COVID-19 lockdown (19 March 2020): Pre-COVID-19 cases were any cases prior to the lockdown and Intra-COVID-19 which are cases following the lockdown. Numerical data and categorical variables were summarized and differences between the case groups were examined using either two-Proportion Z-Test, Independent Two-Sample t-test, Pearson's chi-squared, or Fisher's exact tests. RESULTS: A total of 3179 pediatric orthopedic referrals occurred between the Pre-COVID-19 and Intra-COVID-19 study periods. We observed a general decrease in orthopedic injuries following the COVID-19 lockdowns with 1235 injuries compared to 1606 Pre-COVID-19. Patterns in the locations of injuries changed; notably, fractures of the humerus, tibia, and fibula decreased significantly (p < 0.05). Several mechanisms of injuries decreased significantly following the onset of COVID-19 including injuries caused by monkey bars, basketball, and automobiles (p < 0.01). There was a significant increase in the overall injury severity during the Intra-COVID-19 period (p < 0.05). CONCLUSIONS: Although there was a reduction in acute orthopedic trauma referrals, many injury mechanisms displayed similar trends regardless of restrictions. We clinically observed an overall increase in the severity of pediatric orthopedic injuries during the COVID-19 pandemic.

Soft Tissue Lengthening for Flexion Dislocation of Patella.

PURPOSE OF REVIEW: Obligatory dislocation of the patella (also known as habitual dislocation) is a rare subset of patellofemoral instability in which the patella dislocates every time the knee is flexed. The problem arises due to contracture of the quadriceps muscles. Soft tissue lengthening procedures such as quadriceps tendon lengthening are the mainstay of treatment, in contrast to medial patellofemoral reconstruction (MPFL-R) for the more common recurrent lateral patellar dislocation. The current review explores the existing literature surrounding the pathophysiology and treatment strategies for this unique cause of knee instability. RECENT FINDINGS: Flexion dislocation of the knee often presents in children when they begin to walk. It is also termed obligatory or habitual because the patella dislocates laterally with each flexion and extension cycle of the knee. In contrast to other forms of patellar dislocation, the displacement is painless in obligatory dislocation. Likewise, the underlying biomechanical cause of this issue is related to contracture of tissues lateral to the patella rather than disruption of medial soft tissues as seen in recurrent/traumatic dislocation or subluxation of the patella. A number of procedures have been described for management of obligatory dislocation of the patella, with the general consensus that a combination of procedures including release/lengthening of the proximal lateral soft tissues as a critical component for a successful outcome. Soft tissue release/lengthening has been performed for over 50 years to treat obligatory dislocation of the patella. This procedure must be used in combination with other proximal and distal reconstructive with careful intraoperative assessment of knee flexion and patellar tracking for satisfactory outcomes. Further research using standardized outcome measures is needed to identify the optimal step-wise approach in treatment of obligatory patellar dislocation.

Pediatric Distal Tibia Physeal Injury Presenting with Acute In-toeing: A Case Report and Literature Review.

Ankle fractures are among the most common fractures sustained in the pediatric population. Given the frequency of physeal involvement of the distal fragment, complications including growth arrest, overgrowth, and rotational deformities are not uncommon. This case report describes a 12-year-old adolescent boy who presented after an acute right ankle injury sustained while playing. He noted right ankle pain, swelling, and in-toeing of his foot. Radiographs of the ankle demonstrated a distal tibia Salter-Harris type II fracture that appeared nondisplaced. However, a CT scan of the ankle demonstrated a 60° difference in the rotational profile between the injured and noninjured tibias. The patient's acute rotational deformity was corrected with closed reduction and percutaneous pinning. Pediatric distal tibia physis fractures presenting with in-toeing are rare and difficult to diagnose accurately with radiographs alone. Accordingly, a detailed history, physical examination, comparison radiographs, and CT scans are imperative in making the correct diagnosis and determining the appropriate treatment.

Successful Return to Sport and Daily Activities After Suture Augmentation of Both the Anterior Talofibular Ligament and Calcaneofibular Ligament.

Purpose: To evaluate the return to sport and daily activities in addition to clinical outcomes after modification of the Brostöm repair, specifically using suture augmentation for concomitant fixation of both the anterior talofibular ligament and calcaneofibular ligament. Methods: Patients who had grade III ankle sprains and lateral ankle instability, all of whom failed supervised conservative management, were included. Patients underwent a modified Broström procedure consisting of suture augmentation for both the anterior talofibular ligament and calcaneofibular ligament. For clinical outcome evaluation, Foot and Ankle Ability Measure (FAAM) and Karlsson-Peterson Scoring System for Ankle Function questionnaires coupled with questions regarding time of return to sport and level of sports activity were used. Results: Thirty-one patients were included. The differences in preoperative and postoperative FAAM scores for both the Activities of Daily Living subscale and Sports subscale were significant (P < .001). The FAAM Activities of Daily Living score improved from an average of 46.06 preoperatively to 77.49 postoperatively (P < .001, 99% confidence interval, 26.4-36.4). The FAAM Sports score improved from an average of 4 preoperatively to 19.31 postoperatively (P < .001, 99% confidence interval, 11.6-19.0). For the Karlsson-Peterson Scoring System for Ankle Function, the surveyed population reported a mean of 82.74 points out of 100 post-op (standard deviation 20.14). The mean time to return to sport activity was 5.72 months. Mean follow-up time was 24.12 months. Conclusions: This variant Broström procedure with suture anchors and augmentation of both the anterior talofibular ligament and calcaneofibular ligament was effective in helping patients return to their preinjury functionality level in both daily life and sports activity. Level of Clinical Evidence: Level IV, therapeutic case series.

Outcomes and Complications After Primary Arthroscopic Suprapectoral Versus Open Subpectoral Biceps Tenodesis for Superior Labral Anterior-Posterior Tears or Biceps Abnormalities: A Systematic Review and Meta-analysis.

BACKGROUND: Biceps tenodesis is a surgical treatment for both superior labral anterior-posterior (SLAP) tears and long head of the biceps tendon (LHBT) abnormalities. Biceps tenodesis can be performed either above or below the pectoralis major tendon with arthroscopic or open techniques. PURPOSE: To analyze the outcomes and complications comparing primary arthroscopic suprapectoral versus open subpectoral biceps tenodesis for either SLAP tears or LHBT disorders. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: A search strategy based on the PRISMA (Preferred Reporting Items for Systematic Meta-Analyses) protocol was used to include 18 articles (471 patients) from a total of 974 articles identified. Overall exclusion criteria included the following: non-English language, non-full text, biceps tenodesis with concomitant rotator cuff repair, review articles, meta-analyses, and case reports. Data were extracted and analyzed according to procedure type and tenodesis location: arthroscopic suprapectoral biceps tenodesis (295 patients) versus open subpectoral bicepts tenodesis (176 patients). RESULTS: For arthroscopic suprapectoral biceps tenodesis, the weighted mean American Shoulder and Elbow Surgeons (ASES) score was 90.0 (97 patients) and the weighted mean Constant score was 88.7 (108 patients); for open subpectoral biceps tenodesis, the mean ASES score was 91.1 (199 patients) and mean Constant score was 84.7 (65 patients). Among the 176 patients who underwent arthroscopic biceps tenodesis, there was an overall complication rate of 9.1%. Among the 295 patients who underwent open biceps tenodesis, there was an overall complication rate of 13.5%. Both residual pain (5.7% vs 4.7%, respectively) and Popeye deformity (1.7% vs 1.0%, respectively) rates were similar between the groups. Open subpectoral biceps tenodesis had higher reoperation (3.0% vs 0.0%, respectively), wound complication (1.0% vs 0.0%, respectively), and nerve injury (0.7% vs 0.0%, respectively) rates postoperatively. A meta-analysis of 3 studies demonstrated that both methods had similar ASES scores (P = .36) as well as all-cause complication rates (odds ratio, 0.76 [95% CI, 0.13-4.48]; P = .26). CONCLUSION: Patients undergoing arthroscopic suprapectoral biceps tenodesis for either SLAP tears or LHBT abnormalities had similar outcome scores and complication rates compared with those undergoing open subpectoral biceps tenodesis. Additionally, both residual pain and Popeye deformity rates were similar between the 2 groups.

The Effect of Race on Early Perioperative Outcomes After Shoulder Arthroplasty: A Propensity Score Matched Analysis.

There is a paucity of data on how racial disparities may affect early outcomes following shoulder arthroplasty. The purpose of this study was to evaluate differences in 30-day complications and readmission rates after shoulder arthroplasty based on race. White and black patients who underwent hemiarthroplasty, anatomic or reverse total shoulder arthroplasty (Current Procedural Terminology codes 23470 and 23472) between 2006 and 2015 were identified in the American College of Surgeons National Surgical Quality Improvement Program database. Black patients were propensity score matched 1:4 based on preoperative demographics and comorbidities to white patients. Multivariable analysis was performed to assess postoperative complications based on race. Of the 12,663 patients with shoulder arthroplasty identified, 10,717 (84.6%) were white and 559 (4.4%) were black. Overall, 557 black patients were matched to 2228 white patients, for a total cohort of 2785 patients (mean age, 63.9±11.7 years; female, 61.0%). Surgical indications were similar between black and white patients. The 2 races had similar rates of overall complications, major complications, minor complications, readmissions, and discharge to facility. Mortality was significantly higher among black patients compared with white patients (0.6% vs 0.05%; P=.033). Black patients also experienced longer operative time (mean, 126.4 vs 112.5 minutes; P<.001) and length of stay (mean, 2.4 vs 2.1 days; P<.001). There was a significant disparity with underutilization of shoulder arthroplasty for black patients in the American College of Surgeons National Surgical Quality Improvement Program database. Black and white patients undergoing shoulder arthroplasty experienced similar rates of 30-day complications, readmissions, and discharge to facility. However, black patients experienced greater operative time, total length of stay, and mortality compared with white patients. [Orthopedics. 2019; 42(2):95-102.].