K48- and K63-linked ubiquitin chain interactome reveals branch- and length-specific ubiquitin interactors.

The ubiquitin (Ub) code denotes the complex Ub architectures, including Ub chains of different lengths, linkage types, and linkage combinations, which enable ubiquitination to control a wide range of protein fates. Although many linkage-specific interactors have been described, how interactors are able to decode more complex architectures is not fully understood. We conducted a Ub interactor screen, in humans and yeast, using Ub chains of varying lengths, as well as homotypic and heterotypic branched chains of the two most abundant linkage types-lysine 48-linked (K48) and lysine 63-linked (K63) Ub. We identified some of the first K48/K63-linked branch-specific Ub interactors, including histone ADP-ribosyltransferase PARP10/ARTD10, E3 ligase UBR4, and huntingtin-interacting protein HIP1. Furthermore, we revealed the importance of chain length by identifying interactors with a preference for Ub3 over Ub2 chains, including Ub-directed endoprotease DDI2, autophagy receptor CCDC50, and p97 adaptor FAF1. Crucially, we compared datasets collected using two common deubiquitinase inhibitors-chloroacetamide and N-ethylmaleimide. This revealed inhibitor-dependent interactors, highlighting the importance of inhibitor consideration during pulldown studies. This dataset is a key resource for understanding how the Ub code is read.

Back-pocket optimization of 2-aminopyrimidine-based macrocycles leads to potent dual EPHA2/GAK kinase inhibitors with antiviral activity.

Macrocyclization of acyclic compounds is a powerful strategy for improving inhibitor potency and selectivity. Here, we developed a 2-aminopyrimidine-based macrocyclic dual EPHA2/GAK kinase inhibitor as a chemical tool to study the role of these two kinases in viral entry and assembly. Starting with a promiscuous macrocyclic inhibitor, 6, we performed a structure-guided activity relationship and selectivity study using a panel of over 100 kinases. The crystal structure of EPHA2 in complex with the developed macrocycle 23 provided a basis for further optimization by specifically targeting the back pocket, resulting in compound 55 as a potent dual EPHA2/GAK inhibitor. Subsequent front-pocket derivatization resulted in an interesting in cellulo selectivity profile, favoring EPHA4 over the other ephrin receptor kinase family members. The dual EPHA2/GAK inhibitor 55 prevented dengue virus infection of Huh7 liver cells, mainly via its EPHA2 activity, and is therefore a promising candidate for further optimization of its activity against dengue virus.

Operative vs. conservative treatment of AC-Joint Dislocations Rockwood grade ≥ III -An economical and clinical evaluation.

INTRODUCTION: Acromioclavicular joint dislocations (ACD) are one of the most common shoulder injuries. There is no consensus in how to treat higher graded ACD ≥ Rockwood grade III. This study compares operative versus conservative treatment regarding costs and clinical outcome parameters. MATERIALS AND METHODS: This retrospective, consecutive case-control-study includes 14 patients. Seven operatively treated patients were matched, by Rockwood grade, with seven conservatively treated patients. The cost was extracted out of the clinical- and insurance-based cost sheets and furthermore these include the loss of earnings. Clinical examination, demographic data as well as different outcome-questionnaires were recorded. RESULTS: There were no significant differences between operative and conservative treated patients for outcome Questionnaires. Of note, there was a significantly higher incidence of tenderness over the AC-joint (p = 0.0038) postoperatively. As expected, economical evaluation showed various findings in favor of the conservative treatment. The costs for medical services (11012.39vs.1163.81USD; p = 0.0061), days of hospitalization (3.3vs.0days; p < 0.0001); total cost for medical treatment (30262.17 vs. 7833.82 USD; p = 0.0358) were significantly higher in the operative group. CONCLUSION: Even with a limited case number and a retrospective study design almost all clinical results were equal in both groups. Operative therapy of higher graded ACDs (Rockwood > III) compared to conservative is economically inefficient. Under consideration of clinical comparable results, indications for operative treatment should be set very carefully.

Dynamic syndesmotic stabilisation and reinforcement of the antero-inferior tibiofibular ligament with internal brace.

PURPOSE: Syndesmotic injuries are associated with long recovery times and high morbidity. Systematic reviews show a trend toward better outcomes of suture buttons compared to screw fixation. The anteroinferior tibiofibular ligament (AITFL) confers the most significant component of translational and rotatory stability. Techniques have developed which reinforce the AITFL. This study aimed to assess results of syndesmotic stabilisation with dynamic stabilisation and reinforcement of the AITFL, with an early mobilisation program. MATERIALS AND METHODS: Retrospective case series of 30 patients (mean age 31 years). Syndesmotic instability was confirmed with clinical examination, MRI and weightbearing-CT. Dynamic syndesmotic stabilisation with a single suture button was performed followed by the placement of an Internal Brace over the AITFL. A standardised postoperative rehabilitation protocol was established. Foot and Ankle Ability Measure (FAAM) scores were collected postoperatively. RESULTS: The average follow-up was 13 months. The total FAAM score for ADL was 95 ± 4.9 % (range, 83 - 100 %) and for sport activities 87 ± 13.6 % (range, 50 - 100 %). The rating of mean postoperative function for ADL was 94 ± 5.5 % (range, 80 - 100 %) and 90 ± 13 % (range, 35 - 100 %) for sportv. The difference between acute and chronic injuries was statistically higher (p < 0.05) for daily activities and sport, but the rating of current level of sport activites as well as for daily activites did not show a significant difference (p = 0.9296 and p = 0.1615, respectively). Twenty-seven patients (90 %) rated their overall current level of function as normal or nearly normal. CONCLUSION: This technique aims to directly stabilise the AITFL and the interosseous components of the syndesmosis, and allow early mobilisation and return to sport at 10 weeks. Early results show the procedure is safe, with comparable results to the literature. Acute injuries showed better results of the FAAM score than chronic injuries.

Plantar Plating in the Modified Lapidus Procedure: Evaluation of Function and Impairment of the Tibialis Anterior Tendon.

The modified "Lapidus" procedure (MLP) describes the arthrodesis of the first tarsometatarsal joint. We investigate if there are detectable changes of the tendon or the function of the muscle and clinical outcome after MLP. We reviewed 22 feet. All patients underwent magnetic resonance imaging (MRI) at an average of 27 (range, 12-49) months. Clinical outcome was evaluated using the European Foot and Ankle Society score. Strength was measured and complications were assessed. MRI revealed signs of tendinopathy of the tibialis anterior tendon in 13 feet (59%). The mean total European Foot and Ankle Society score at final follow-up was 17 (range, 6-24) points. The mean postoperative Visual Analog Scale score was 1.4 (range, 0-5). Range of motion and force data were not significantly different to the contralateral side. In conclusion, MRI showed signs of tendinopathy in 59%, which does not seem to affect clinical outcome, but has to be considered when choosing the desired implant and placement. MLP leads to high patient satisfaction rates and significant improvement at midterm follow up.

Structural and Functional Results of Subscapularis and Conjoint Tendon After Latarjet Procedure at 8-Year Average Follow-up.

BACKGROUND: The Latarjet procedure involves initial dissection through a longitudinal split of the subscapularis tendon with only a final partial closure to accommodate the transferred coracoid bone. Furthermore, by transferring the coracoid bone block to the anterior glenoid, the surgeon completely alters the resting and dynamic route of the attached conjoint tendon. The eventual structural and functional integrity of the subscapularis and conjoint tendons is currently unknown. PURPOSE: To examine the structural and functional integrity of the subscapularis and the conjoint tendon after the Latarjet procedure at an 8-year average follow-up. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Twenty patients with anterior shoulder instability at a mean age of 30 years (range, 19-50 years) underwent the open Latarjet procedure. Clinical examination at the final follow-up included quantitative isometric measurement of abduction and internal rotation strength compared with the nonoperative side. Patients were assessed via radiograph examination and preoperative computed tomography. Final position and healing of the transferred coracoid bone block were evaluated using standard radiographs. At follow-up, the subscapularis and conjoint tendon were evaluated via magnetic resonance imaging (MRI) with metal artifact reduction techniques and via ultrasound. RESULTS: Nineteen of the 20 shoulders remained stable at the final follow-up; there was 1 redislocation (5%) after 14 months. The mean Rowe score was 83 points (SD, 17.9 points), the mean Constant score was 85 points (SD, 8.1 points), and the Subjective Shoulder Value was 80% (SD, 18%). The mean abduction strength of the operative shoulder was 7.41 ± 2.06 kg compared with 8.33 ± 2.53 kg for the nonoperative side (P = .02). The mean internal rotation strength at 0° for the operative shoulder was 8.82 ± 3.47 kg compared with 9.06 ± 3.01 kg for the nonoperative side (P = .36). The mean internal rotation strength in the belly-press position for the operative shoulder was 8.12 ± 2.89 kg compared with 8.50 ± 3.03 kg (P = .13). Four of 20 shoulders showed mild tendinopathic changes of the subscapularis tendon but no partial or complete tear. One patient exhibited fatty degeneration Goutallier stage 1. Conjoint tendon was in continuity in all 20 shoulders on MRI scans. CONCLUSION: Abduction, but not internal rotation strength, was slightly reduced after the Latarjet procedure at a mean of 8 years of follow-up. The subscapularis tendon was intact based on ultrasound examination, and the conjoint tendon was intact based on MRI scans. Subscapularis muscle girth relative to the supraspinatus muscle remained intact from preoperative measurements based on MRI scans.

The Metatarsal Cortical Index as an Indicator of Insufficiency Fracture of the Foot.

The diagnosis of metatarsal stress fractures is challenging. Standard imaging often shows false-negative results. The aim of this study was to create reliable radiologic outcome parameters to predict insufficiency fractures of the metatarsals. We performed an age- and sex-matched case-control study of patients with (n = 18) and without insufficiency fracture (n = 18) of the foot. The metatarsal cortical index (MCI) for each metatarsal was developed to predict an insufficiency fracture. The MCI of each metatarsal was significantly decreased in the insufficiency fracture group compared with the control group (p < .01). The MCI of the fourth ray yielded the highest area under the curve among the analyzed MCI values (area under the curve, 0.79; 95% confidence interval, 0.61-0.90). A cut-off value of 1.62 for the MCI of the fourth ray yielded a sensitivity of 78% and a specificity of 78% to predict insufficiency fracture of the foot (odds ratio, 12.25; 95% confidence interval, 2.54-58.97), and enabled accurate allocation to the insufficiency fracture group versus the control group in 74% of cases. In conclusion, a decreased MCI is associated with metatarsal insufficiency fractures and enables an accurate diagnosis in 3 out of 4 cases. The MCI might aid clinicians in identifying insufficiency fracture, and raise the suspicion of the diagnosis without additional imaging studies.

How Should We Grade Cervical Disk Degeneration? A Comparison of Two Popular Classification Systems.

INTRODUCTION: Despite being originally developed for the evaluation of lumbar disk degeneration, the Pfirrmann classification has emerged as the most popular classification system for cervical disk degeneration. However, with the Suzuki classification, a new classification system that is specifically tailored for the evaluation of cervical disk disease was introduced. In this study, we aim to evaluate differences in inter- and intraobserver reliability of both classifications in a head-to-head comparison. METHODS: In total, we have evaluated 120 cervical disks within 40 patients via magnetic resonance imaging according to the Pfirrmann and Suzuki classification. The degree of disk degeneration was evaluated by two independent musculoskeletal radiologists. After 6 months, the classification was reassessed to evaluate the intraobserver reliability. The inter- and intraobserver reliabilities were then calculated using Cohen's kappa. RESULTS: The inter- and intraobserver reliability provided a significant agreement between all ratings in Pfirrmann as well as the Suzuki classification (p>0.001). The interobserver reliability was determined to be fair in both the Suzuki classification (κ=0.290) and the Pfirrmann classification (κ=0.265). The intraobserver reliability was substantial in the Suzuki classification (κ=0.798), while it was almost perfect in the Pfirrmann classification (κ=0.858). CONCLUSIONS: Although not designed for the evaluation of cervical disk degeneration, the Pfirrmann classification yielded equal inter- and higher intraobserver reliability. Both classification systems are viable options for the grading of cervical disk degeneration. While the Pfirrmann classification has the advantage of being better established, the Suzuki classification may be clinically superior due to a better representation of cervical disk degeneration and the consideration of disk bulging for the classification of cervical disk degeneration.

Non-Adherence to Pain Medication Increases Risk of Postoperative Frozen Shoulder.

BACKGROUND: Postoperative frozen shoulder (FS) or adhesive capsulitis is a relatively frequent complication (5-20%), even after simple arthroscopic shoulder surgeries. The pathophysiology is still unclear, but psychological factors may play a pivotal role. From clinical experience, we hypothesized that patients, who are reluctant to take medications, particularly "pain-killers," have an increased incidence of postoperative FS. METHODS: We identified twenty patients who underwent limited arthroscopic operations of the shoulder and developed postoperative FS. Twenty patients with matching type of surgery, age, and gender served as control group (n = 20). All patients were at least one year postoperative and asymptomatic at the time of examination. Demographic data, the patient's adherence to self-medication (including self-medicating scale, SMS), development the Quality of life (QoL), and depression scale (PHQ-4-questionnaire) were assessed. RESULTS: Patients with FS had a 2-fold longer rehabilitation and 3-fold longer work inability compared to the patients without FS (P < 0.009 and P < 0.003, respectively). Subjective shoulder value SSV (P = 0.075) and post-operative improvement of QoL (P = 0.292) did not differ among the groups. There was a trend-but not significant-toward less coherence to self-medication in the FS-group (26.50 vs. 29.50; P = 0.094). Patients with postoperative FS significantly more often stated not to have "taken pain-killers as prescribed" (P = 0.003). CONCLUSIONS: Patients reporting unwillingness to take the prescribed pain medications had a significantly higher incidence of postoperative FS. It remains unclear whether the increased risk of developing FS is due to reduced postoperative analgesia or a critical attitude toward taking medication. However, patients who are reluctant to take painkillers should strongly be encouraged to take medications as prescribed.

Scarf osteotomy for hallux valgus deformity: Radiological outcome, metatarsal length and early complications in 118 feet.

BACKGROUND: Scarf osteotomy has been widely used to restore axial orientation of the first ray in the treatment of hallux valgus deformity. The aim of the study was to present our radiological outcomes of bunion reconstruction, identify surgical complications in early follow-up, and assess to what extent a shortening of the first metatarsal is present after surgery as a possible cause of postoperative metatarsalgia. METHODS: We enrolled 106 patients (118 feet) and assessed patients' pre- and postoperative measurements of hallux valgus and intermetatarsal angles on weightbearing X-ray images. Three different methods of measuring metatarsal length were compared and early postoperative complications noted. RESULTS: Hallux valgus angle decreased significantly by an average of 18.7 degrees and the intermetatarsal angle by 7.8 degrees. Using three methods of measuring metatarsal length, all showed significant shortening of the first metatarsal. Mean relative lengthening of the second metatarsal averaged 0.45mm. The Coughlin method showed the highest interrater reliability (ICC=0.96). CONCLUSIONS: Significant reduction of the hallux valgus angle and intermetatarsal angle was demonstrated with a low complication rate. There was significant shortening of the first metatarsal. The Coughlin method clearly demonstrated an excellent interrater reliability. LEVEL OF EVIDENCE: Level IV.

Cervical disc degeneration reduces distance between vertebral artery and surgical landmarks.

PURPOSE: Anterior cervical decompression surgery exposes the vertebral artery to the risk of injury. This risk can increase if the natural course of the vertebral artery is altered. Therefore, this study evaluated if the distance between surgical landmarks and the vertebral artery decrease with the progression of cervical disc degeneration. METHODS: This study analyzed 40 patients with cervical magnetic resonance imaging. We evaluated the distance between the uncinate process and the vertebral artery in axial-plane T2 weighted sequences of the cervical levels C3-C6. The cervical disc degeneration was graded according to the Pfirrmann- and Suzuki classification. The decrease of the distance was evaluated using a one-way ANOVA. RESULTS: The distance between the uncinate process and the vertebral artery decreased with increasing disc degeneration (p ≤ 0.015). ROC analysis provided an acceptable area under the curve in both classifications for the detection of a vertebral artery to the uncinate process distance of zero. The presence of Pfirrmann grade V had a positive predictive value of 69% for the presence of contact between the uncinate process and the vertebral artery. CONCLUSION: High-grade cervical disc degeneration according to the Pfirrmann- and the Suzuki classification decrease the distance between the uncinate process and the vertebral artery. High-grade disc degeneration therefore should raise the awareness of the surgeon for the loss of the distance between surgical landmarks and the vertebral artery. However, screening for high-grade disc degeneration alone cannot substitute the thorough evaluation of the anatomical course of the vertebral artery before surgery.

Matrix-Induced Autologous Chondrocyte Implantation (MACI) Grafting for Osteochondral Lesions of the Talus.

BACKGROUND: Matrix-induced autologous chondrocyte implantation (MACI) is an established treatment method for larger joints and has shown promising results in the ankle as well. We present a series of patients after ankle MACI with long-term follow-up of clinical and radiological outcomes. METHODS: We present the follow-up of 15 patients who underwent MACI grafting from August 2003 to February 2006. The mean follow-up was 12.9 years. Clinical evaluations were conducted using the American Orthopaedic Foot & Ankle Society (AOFAS), Foot and Ankle Activity Measurement (FAAM), and visual analog scale (VAS) scoring systems and the magnetic resonance observation of cartilage repair tissue (MOCART) scoring system for radiological evaluation. RESULTS: The mean size of the talar osteochondral defects was 204 mm2. We found a significant improvement in mean AOFAS score from 60 preoperatively to a mean of 84 at 12 years postoperatively. The 12-year FAAM score for Activities of Daily Living was 89% (range, 62%-99%). The mean 12-year MOCART score was 65 points (range, 30-100 points) with significant agreement between assessors (P < .001). However, the MOCART scores did not correlate with the FAAM scores (P = .86). CONCLUSION: Considering our long-term follow-up, we believe MACI is a reliable treatment method for talar osteochondral defects providing lasting pain relief and satisfying clinical results. However, with an equivalent outcome, but at higher costs, and the requirement for 2 operative procedures, the results do not seem to be superior to other established methods. The clinical utility of the MOCART score requires further scrutiny since we were not able to show any correlation between the score and clinical outcome. LEVEL OF EVIDENCE: Level IV, case series.

Do osteoarthritic subchondral bone cysts spontaneously consolidate after total hip replacement?

BACKGROUND: During total hip replacement (THR), subchondral acetabular bone cysts are either left alone or treated by filling with autologous bone graft. We hypothesized that subchondral cysts would consolidate spontaneously over time without compromising the midterm survival of the implant. METHODS: We retrospectively screened the anteroposterior hip radiographs of 731 consecutive patients who underwent primary THR between January 2006 and April 2009. Patients were included in the current study if they had acetabular subchondral bone cysts visible radiographically that had been left alone during THR. RESULTS: 52 patients (54 hips) matched the inclusion criteria, with mean age of 66 ± 11 years at surgery, and a mean follow-up of 6.3 years (range 5-9 years). Among the 52 patients, there were 88 cysts, with 1.6 ± 0.83 cysts per patient and a mean cyst size of 9.3 ± 10 mm2 (range 0.9-57 mm2). Among the 88 cysts, 71 cysts (38 hips) had disappeared by the final follow-up, whereas 17 cysts (16 hips) were still visible. Most of these persistent cysts were located in Charnley zone I and were significantly smaller at the follow-up than before surgery (p = 0.015). Overall, most cysts decreased in size (p = 0.04). All cups survived and none showed radiological signs of loosening. CONCLUSIONS: After THR, most neglected subchondral cysts spontaneously consolidate or decrease in size. Larger cysts may persist without affecting the surgical outcome. No radiological signs of loosening or other adverse effects were observed when acetabular bone cysts are neglected during primary THR.

Postoperative alignment of TKA in patients with severe preoperative varus or valgus deformity: is there a difference between surgical techniques?

BACKGROUND: There have been conflicting studies published regarding the ability of various total knee arthroplasty (TKA) techniques to correct preoperative deformity. The purpose of this study was to compare the postoperative radiographic alignment in patients with severe preoperative coronal deformity (≥10° varus/valgus) who underwent three different TKA techniques; manual instrumentation (MAN), computer navigated instrumentation (NAV) and patient specific instrumentation (PSI). METHODS: Patients, who received a TKA with a preoperative coronal deformity of ≥10° with available radiographs were included in this retrospective study. The groups were: MAN; n = 54, NAV; n = 52 and PSI; n = 53. The mechanical axis (varus / valgus) and the posterior tibial slope were measured and analysed using standing long leg- and lateral radiographs. RESULTS: The overall mean postoperative varus / valgus deformity was 2.8° (range, 0 to 9.9; SD 2.3) and 2.5° (range, 0 to 14.7; SD 2.3), respectively. The overall outliers (>3°) represented 30.2% (48 /159) of cases and were distributed as followed: MAN group: 31.5%, NAV group: 34.6%, PSI group: 24.4%. No significant statistical differences were found between these groups. The distribution of the severe outliers (>5°) was 14.8% in the MAN group, 23% in the NAV group and 5.6% in the PSI group. The PSI group had significantly (p = 0.0108) fewer severe outliers compared to the NAV group while all other pairs were not statistically significant. CONCLUSIONS: In severe varus / valgus deformity the three surgical techniques demonstrated similar postoperative radiographic alignment. However, in reducing severe outliers (> 5°) and in achieving the planned posterior tibial slope the PSI technique for TKA may be superior to computer navigation and the conventional technique. Further prospective studies are needed to determine which technique is the best regarding reducing outliers in patients with severe preoperative coronal deformity.

Arthroscopic suture retrievers and shuttles: a biomechanical investigation of the force required for tendon penetration and defect size.

BACKGROUND: To compare instruments designed for arthroscopic suture handling during arthroscopic rotator cuff repair, to assess the force needed to penetrate the tendon, and to evaluate the residual defect size. METHODS: Twenty-one instruments were each tested ten times on thawed sheep infraspinatus tendons. The force needed to pierce the tendon with each instrument was measured using a custom setup. Bone wax plates were used to make the perforation marks visible and to quantify the lesions each instrument created. RESULTS: The force to pierce a tendon had a range of 5.6-18.5 N/mm. Within the group of suture retrievers, the angled instruments required in average 85 % higher forces than straight instruments. The lesion area had a range of 2-7 mm(2). Suture retrievers produced significantly larger lesion sizes compared with suture shuttles. CONCLUSION: For the identical task of passing a suture through a tendon, differences exist regarding the ease of tendon penetration and potential damage to the tendon for different tools. The design, function, and resulting lesion size may be relevant and important for surgical handling and to avoid excess structural damage to the tendon. These results suggest that choosing the most appropriate tools for arthroscopic suture stitching influences the ease of handling and final integrity of the tissue.