Identification of regions critical for the integrity of the TSC1-TSC2-TBC1D7 complex

The TSC1-TSC2-TBC1D7 complex is an important negative regulator of the mechanistic target of rapamycin complex 1 that controls cell growth in response to environmental cues. Inactivating TSC1 and TSC2 mutations cause tuberous sclerosis complex (TSC), an autosomal dominant disorder characterised by the occurrence of benign tumours in various organs and tissues, notably the brain, skin and kidneys. TBC1D7 mutations have not been reported in TSC patients but homozygous inactivation of TBC1D7 causes megaencephaly and intellectual disability. Here, using an exon-specific deletion strategy, we demonstrate that some regions of TSC1 are not necessary for the core function of the TSC1-TSC2 complex. Furthermore, we show that the TBC1D7 binding site is encoded by TSC1 exon 22 and identify amino acid residues involved in the TSC1-TBC1D7 interaction

Survival after resection of malignant peripheral nerve sheath tumors: Introducing and validating a novel type-specific prognostic model

BACKGROUND: This study aimed to assess the performance of currently available risk calculators in a cohort of patients with malignant peripheral nerve sheath tumors (MPNST) and to create an MPNST-specific prognostic model including type-specific predictors for overall survival (OS). METHODS: This is a retrospective multicenter cohort study of patients with MPNST from 11 secondary or tertiary centers in The Netherlands, Italy and the United States of America. All patients diagnosed with primary MPNST who underwent macroscopically complete surgical resection from 2000 to 2019 were included in this study. A multivariable Cox proportional hazard model for OS was estimated with prespecified predictors (age, grade, size, NF-1 status, triton status, depth, tumor location, and surgical margin). Model performance was assessed for the Sarculator and PERSARC calculators by examining discrimination (C-index) and calibration (calibration plots and observed-expected statistic; O/E-statistic). Internal-external cross-validation by different regions was performed to evaluate the generalizability of the model. RESULTS: A total of 507 patients with primary MPNSTs were included from 11 centers in 7 regions. During follow-up (median 8.7 years), 211 patients died. The C-index was 0.60 (95% CI 0.53-0.67) for both Sarculator and PERSARC. The MPNST-specific model had a pooled C-index of 0.69 (95%CI 0.65-0.73) at validation, with adequate discrimination and calibration across regions. CONCLUSIONS: The MPNST-specific MONACO model can be used to predict 3-, 5-, and 10-year OS in patients with primary MPNST who underwent macroscopically complete surgical resection. Further validation may refine the model to inform patients and physicians on prognosis and support them in shared decision-making

A cross-sectional study comparing the rates of osteoarthritis, laxity, and quality of life in primary and revision anterior cruciate ligament reconstructions

The purpose of this study was to assess the degree of osteoarthritis, degree of laxity, and quality-of-life (QOL) scores in primary and revision anterior cruciate ligament (ACL) reconstruction. This was a cross-sectional study; 25 patients who had undergone revision ACL reconstruction with allografts were identified and compared with 27 randomly selected primary ACL reconstruction patients operated on in the same hospital in the same period with the same technique. The main outcome measure was the International Knee Documentation Committee (IKDC) radiographic osteoarthritis sum score, and secondary outcome measures were Knee injury and Osteoarthritis Outcome Score, IKDC functional outcome measures, anterior laxity, and QOL at follow-up. The median follow-up was 5.3 years for revision reconstruction patients and 5.1 years for primary reconstruction patients. Radiographic IKDC sum scores for osteoarthritis were found to be significantly worse in revision patients, with a median of 4, compared with primary patients, with a median of 1 (P = .016). Differences were found in meniscal injury (P = .02) and cartilage status (P < .001) before or at the index operation. Significantly worse outcomes were found in the following subscores of the Knee injury and Osteoarthritis Outcome Score: pain (median, 92 v 97; P = .032), symptom (median, 86 v 96; P = .015), activities of daily living (median, 94 v 100; P = .020), sport (median, 50 v 85; P = .006), and QOL (median, 56 v 81; P = .001). IKDC functional outcome measures were the same in both groups except for the pivot-shift test (P = .007). No differences were found in anterior drawer, Lachman, or KT-1000 arthrometer (MEDmetric, San Diego, CA) testing. Present-day health scores on the EQ-5D were worse for revision reconstruction patients (median, 70 v 80; P = .009). Revision reconstruction patients have more signs of osteoarthritis and worse QOL than primary reconstruction patients, even though they have comparable IKDC success rates and KT-1000 arthrometer laxity test results. Level III, retrospective comparative stud

A Reliable, Valid and Responsive Questionnaire to Score the Impact of Knee Complaints on Work Following Total Knee Arthroplasty: The WORQ

The Work, Osteoarthritis or joint-Replacement Questionnaire (WORQ) was developed to assess physical difficulty experienced in work before or following total knee arthroplasty (TKA). Thirteen questions were designed. The WORQ was tested for internal consistency by factor analysis, internal reliability (Crohnbach's alpha), and construct validity. A test-retest reproducibility was performed for analyzing standard error of measurement (SEM agreement), reliability (ICC) and smallest detectable change (SDC) in individuals and groups. Lastly responsiveness (standardized response means [SRM]), floor and ceiling effects and interpretability (minimal important change [MIC]) were analyzed. It is shown that the WORQ is a reliable, valid and responsive questionnaire that can be used to evaluate the impact of knee complaints following TKA on patients' ability to work. (C) 2014 Elsevier Inc. All rights reserve

Occupational Exposure to Knee Loading and the Risk of Osteoarthritis of the Knee: A Systematic Review and a Dose-Response Meta-Analysis

Osteoarthritis of the knee is considered to be related to knee straining activities at work. The objective of this review is to assess the exposure dose-response relation between kneeling or squatting, lifting, and climbing stairs at work, and knee osteoarthritis. We included cohort and case-control studies. For each study that reported enough data, we calculated the odds ratio (OR) per 5,000 hours of cumulative kneeling and per 100,000 kg of cumulative lifting. We pooled these incremental ORs in a random effects meta-analysis. We included 15 studies (2 cohort and 13 case-control studies) of which nine assessed risks in more than two exposure categories. We considered all but one study at high risk of bias. The incremental OR per 5,000 hours of kneeling was 1.26 (95% confidence interval 1.17-1.35, 5 studies, moderate quality evidence) for a log-linear exposure dose-response model. For lifting, there was no exposure dose-response per 100,000 kg of lifetime lifting (OR 1.00, 95% confidence interval 1.00-1.01). For climbing, an exposure dose-response could not be calculated. There is moderate quality evidence that longer cumulative exposure to kneeling or squatting at work leads to a higher risk of osteoarthritis of the knee. For other exposure, there was no exposure dose-response or there were insufficient data to establish this. More reliable exposure measurements would increase the quality of the evidenc

Needle arthroscopy in the treatment of bacterial arthritis of the hip in a neonate and two infants

Bacterial arthritis in paediatrics is a potentially devastating disease. It can cause permanent damage to the joint leading to degenerative changes, possible growth deformities or failure, and might even result in death. An arthrotomy allows for sufficient irrigation. It might however lead to increased iatrogenic damage and unesthetic scarring. A new technical innovation, so-called needle arthroscopy, might reduce these side effects. The purpose of this case series is to show the safety and efficacy of the use of the 1.9-mm needle arthroscopic lavage in the management of neonates and infants with bacterial arthritis. All three cases are successfully managed using needle arthroscopy

Accuracy of cup placement in total hip arthroplasty by means of a mechanical positioning device: a comprehensive cadaveric 3d analysis of 16 specimens

Introduction: We tested whether a mechanical device (such as Hipsecure) to pinpoint the anterior pelvic plane (APP) as a guide can improve acetabular cup placement. To assess accuracy we asked: (1) is the APP an effective guide to position acetabular cup placement within acceptable ° of divergence from the optimal 40° inclination and 15° anteversion; (2) could a mechanical device increase the number of acetabular cup placements within Lewinnek’s safe zone (i.e. inclination 30° to 50°; anteversion 5° to 25°)? Methods: 16 cadaveric specimens were used to assess the 3D surgical success of using a mechanical device APP to guide acetabular cup placement along the APP. We used the Hipsecure mechanical device to implant acetabular cups at 40° inclination and 15° anteversion. Subequently, all cadaveric specimens with implants were scanned with a CT and 3D models were created of the pelvis and acetabular cups to assess the outcome in terms of Lewinnek’s safe zones. Results: The mean inclination of the 16 implants was 40.6° (95% CI, 37.7–43.4) and the mean anteversion angle was 13.4° (95% CI, 10.7–16.1). All 16 cup placements were within Lewinnek’s safe zone for inclination (between 30° and 50°) and all but 2 were within Lewinnek’s safe zone for anteversion (between 5° and 25°). Conclusion: In cadaveric specimens, the use of a mechanical device and the APP as a guide for acetabular cup placement resulted in good positioning with respect to both of Lewinnek’s safe zones