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Abstract Recent successes in developing small molecule degraders that act through the ubiquitin system have spurred efforts to extend this technology to other mechanisms, including the autophagosomal-lysosomal pathway. Therefore, reports of autophagosome tethering compounds (ATTECs) have received considerable attention from the drug development community. ATTECs are based on the recruitment of targets to LC3/GABARAP, a family of ubiquitin-like proteins that presumably bind to the autophagosome membrane and tether cargo-loaded autophagy receptors into the autophagosome. In this work, we rigorously tested the target engagement of the reported ATTECs to validate the existing LC3/GABARAP ligands. Surprisingly, we were unable to detect interaction with their designated target LC3 using a diversity of biophysical methods. Intrigued by the idea of developing ATTECs, we evaluated the ligandability of LC3/GABARAP by in silico docking and large-scale crystallographic fragment screening. Data based on approximately 1000 crystal structures revealed that most fragments bound to the HP2 but not to the HP1 pocket within the LIR docking site, suggesting a favorable ligandability of HP2. Through this study, we identified diverse validated LC3/GABARAP ligands and fragments as starting points for chemical probe and ATTEC development.

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.

Abstract 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.

Category: Bunion Introduction/Purpose: In hallux valgus deformity less weight can be borne by the first ray which may lead to transfer metatarsalgia and lesser toe deformities. Depending on the exact configuration of the bone cuts during the scarf procedure, an iatrogenic shortening of the first metatarsal may occur which may diminish weightbearing ability of the first ray as well, causing transfer metatarsalgia. The aim of the present study was therefore to determine preoperative and postoperative changes in length of the first metatarsal by using different methods of measuring metatarsal length. Methods: A consecutive series of 118 feet in 106 patients (89% female, 11% male) was enrolled, who underwent correctional osteotomy (Scarf-with/without Akin-Osteotomy) from May 2015 to July 2017 at a single institution. Patients, who underwent additional shortening osteotomy of the metatarsals, were excluded. Average age at the time of surgery was 51 years (range, 14 to 83 years). Pre- and postoperative angle measurement of hallux valgus- and intermetatarsal angle was assessed at between six weeks and three months postoperatively on standardized weight-bearing radiographs in dorsoplantar plane. We also identified early complications in hallux valgus surgery. An assessment and comparison of different methods of measuring metatarsal length (length of first metatarsal, ratio first to second metatarsal, Coughlin method) postoperatively was performed to identify the amount of shortening with this technique. Results: Hallux valgus angle was statistically significant reduced by an average of 18.6° (28.3° preoperatively to 9.7° postoperatively, p < 0.001), intermetatarsal angle by 7.7° (12.8° to 5.1°, p < 0.001). Measuring the length of the first metatarsal, in all three methods a statistically significant reduction of the first metatarsal length could be detected. Mean absolute shortening of 1.8 mm was measured (p < 0.001). The ratio of the first metatarsal to the second metatarsal averaged -0.03 (p = 0.02). The mean relative lengthening of the second metatarsal, using the method described by Coughlin, was 0.42 mm (from 4.51 to 4.89 mm, p < 0.001) on average. Of those three methods, the Coughlin method showed the highest correlation. 6 minor complications were observed (5%). Conclusion: In the current study we could demonstrate a significant reduction of hallux valgus angle and intermetatarsal angle with hallux valgus correction using Scarf-/Akin-Osteotomy, with a low complication rate. However, statistically significant shortening of the first metatarsal could be detected as well. Further research is required to improve and establish a hallux valgus correction technique without shortening of the first metatarsal.

Lung cancer is a common malignancy which is frequently found to metastasize to distant sites including bone, liver, and adrenal glands. There are rare reports of metastases to the gastrointestinal (GI) tract, with the duodenum being the most uncommon. We present a rare case of a poorly differentiated lung carcinoma metastasizing to the duodenum. This case enhances the medical literature as it provides additional distinct features to the clinical and histological presentation of metastatic lung carcinoma to the GI tract. A 61-year-old male with a history of poorly differentiated lung carcinoma presented with worsening dizziness, fatigue, and early satiety. He had extensive workup done in the past for hemoptysis including a computerized tomography scan of the chest which showed a new lobulated, apical lesion and hilar lymphadenopathy. He ultimately had a transthoracic fine-needle aspiration (FNA) of the mass and was later diagnosed with poorly differentiated lung carcinoma. On examination, the patient was noted to be pale, tachycardic, and hypotensive. The patient was noted to have an acute drop in his hemoglobin requiring fluid resuscitation, multiple blood transfusions, and evaluation with an esophagogastroduodenoscopy. He was found to have an oozing ulcer in the third portion of the duodenum whose biopsies showed poorly differentiated carcinoma with areas of neuroendocrine differentiation, similar to his lung biopsy results, which was consistent with metastatic lung carcinoma.