The outcomes of Perthes' disease.

AIMS: To identify a suite of the key physical, emotional, and social outcomes to be employed in clinical practice and research concerning Perthes' disease in children. METHODS: The study follows the guidelines of the COMET-Initiative (Core Outcome Measures in Effectiveness Trials). A systematic review of the literature was performed to identify a list of outcomes reported in previous studies, which was supplemented by a qualitative study exploring the experiences of families affected by Perthes' disease. Collectively, these outcomes formed the basis of a Delphi survey (two rounds), where 18 patients with Perthes' disease, 46 parents, and 36 orthopaedic surgeons rated each outcome for importance. The International Perthes Study Group (IPSG) (Dallas, Texas, USA (October 2018)) discussed outcomes that failed to reach any consensus (either 'in' or 'out') before a final consensus meeting with representatives of surgeons, patients, and parents. RESULTS: In total, 23 different outcome domains were identified from the systematic review, and a further ten from qualitative interviews. After round one of the Delphi survey, participants suggested five further outcome domains. A total of 38 outcomes were scored in round two of the Delphi. Among these, 16 outcomes were scored over the prespecified 70% threshold for importance (divided into six main categories: adverse events; life impact; resource use; pathophysiological manifestations; death; and technical considerations). Following the final consensus meeting, 14 outcomes were included in the final Core Outcome Set (COS). CONCLUSION: Core Outcome Sets (COSs) are important to improve standardization of outcomes in clinical research and to aid communication between patients, clinicians, and funding bodies. The results of this study should be a catalyst to develop high-quality clinical research in order to determine the optimal treatments for children with Perthes' disease. Cite this article: Bone Joint J 2020;102-B(5):611-617

The Impact of Duty Hours on Resident Self Reports of Errors

BACKGROUND: Resident duty hour limitations aim, in part, to reduce medical errors. Residents’ perceptions of the impact of duty hours on errors are unknown. OBJECTIVE: To determine residents’ self-reported contributing factors, frequency, and impact of hours worked on suboptimal care practices and medical errors. DESIGN: Cross-sectional survey. SUBJECTS: 164 Internal Medicine Residents at the University of California, San Francisco. MEASUREMENTS AND RESULTS: Residents were asked to report the frequency and contributing factors of suboptimal care practices and medical errors, and how duty hours impacted these practices and aspects of resident work-life. One hundred twenty-five residents (76%) responded. The most common suboptimal care practices were working while impaired by fatigue and forgetting to transmit information during sign-out. In multivariable models, residents who felt overwhelmed with work (p = 0.02) and who reported spending >50% of their time in nonphysician tasks (p = 0.002) were more likely to report suboptimal care practices. Residents reported work-stress (a composite of fatigue, excessive workload, distractions, stress, and inadequate time) as the most frequent contributing factor to medical errors. In multivariable models, only engaging in suboptimal practices was associated with self-report of higher risk for medical errors (p < 0.001); working more than 80 hours per week was not associated with suboptimal care or errors. CONCLUSION: Our findings suggest that administrative load and work stressors are more closely associated with resident reports of medical errors than the number of hours work. Efforts to reduce resident duty hours may also need to address the nature of residents’ work to reduce errors

Intrinsically aggregation-prone proteins form amyloid-like aggregates and contribute to tissue aging in C. elegans

Reduced protein homeostasis leading to increased protein instability is a common molecular feature of aging, but it remains unclear whether this is a cause or consequence of the aging process. In neurodegenerative diseases and other amyloidoses, specific proteins self-assemble into amyloid fibrils and accumulate as pathological aggregates in different tissues. More recently, widespread protein aggregation has been described during normal aging. Until now, an extensive characterization of the nature of age-dependent protein aggregation has been lacking. Here, we show that age-dependent aggregates are rapidly formed by newly synthesized proteins and have an amyloid-like structure resembling that of protein aggregates observed in disease. We then demonstrate that age-dependent protein aggregation accelerates the functional decline of different tissues in C. elegans. Together, these findings imply that amyloid-like aggregates contribute to the aging process and therefore could be important targets for strategies designed to maintain physiological functions in the late stages of life

The Extended Learning Curve for Laparoscopic Fundoplication: A Cohort Analysis Of 400 Consecutive Cases

Many studies have looked at the learning curve associated with laparoscopic Nissen fundoplication (LNF) in a given institution. This study looks at the learning curve of a single surgeon with a large cohort of patients over a 10-year period. Prospective data were collected on 400 patients undergoing laparoscopic fundoplication for over 10 years. The patients were grouped consecutively into cohorts of 50 patients. The operating time, the length of postoperative hospital stay, the conversion rate to open operation, the postoperative dilatation rate, and the reoperation rate were analyzed. Results showed that the mean length of operative time decreased from 143 min in the first 50 patients to 86 min in the last 50 patients. The mean postoperative length of hospital stay decreased from 3.7 days initially to 1.2 days latterly. There was a 14% conversion to open operation rate in the first cohort compared with a 2% rate in the last cohort. Fourteen percent of patients required reoperation in the first cohort and 6% in the last cohort. Sixteen percent required postoperative dilatation in the first cohort. None of the last 150 patients required dilatation. In conclusion, laparoscopic fundoplication is a safe and effective operation for patients with gastroesophageal reflux disease. New techniques and better instrumentation were introduced in the early era of LNF. The learning curve, however, continues well beyond the first 20 patients

High-definition tDCS of the temporo-parietal cortex enhances access to newly learned words

Learning associations between words and their referents is crucial for language learning in the developing and adult brain and for language re-learning after neurological injury. Non-invasive transcranial direct current stimulation (tDCS) to the posterior temporo-parietal cortex has been suggested to enhance this process. However, previous studies employed standard tDCS set-ups that induce diffuse current flow in the brain, preventing the attribution of stimulation effects to the target region. This study employed high-definition tDCS (HD-tDCS) that allowed the current flow to be constrained to the temporo-parietal cortex, to clarify its role in novel word learning. In a sham-controlled, double-blind, between-subjects design, 50 healthy adults learned associations between legal non-words and unfamiliar object pictures. Participants were stratified by baseline learning ability on a short version of the learning paradigm and pairwise randomized to active (20 mins; N = 25) or sham (40 seconds; N = 25) HD-tDCS. Accuracy was comparable during the baseline and experimental phases in both HD-tDCS conditions. However, active HD-tDCS resulted in faster retrieval of correct word-picture pairs. Our findings corroborate the critical role of the temporo-parietal cortex in novel word learning, which has implications for current theories of language acquisition

CIP2A expression predicts recurrences of tamoxifen-treated breast cancer

CIP2A is emerging as an oncoprotein overexpressed commonly across many tumours and generally correlated with higher tumour grade and therapeutic resistance. CIP2A drives an oncogenic potential through inhibiting protein phosphatase 2A, stabilizing MYC, and promoting epithelial-to-mesenchymal transition, although further biological mechanisms for CIP2A are yet to be defined. CIP2A protein expression was studied by immunohistochemistry in oestrogen receptor–positive primary breast cancers (n = 250) obtained from the Leeds Tissue Bank. In total, 51 cases presented with a relapse or metastasis during adjuvant treatment with tamoxifen and were regarded as tamoxifen resistant. CIP2A expression was scored separately for cytoplasmic, nuclear, or membranous staining, and scores were tested for statistically significant relationships with clinicopathological features. Membranous CIP2A was preferentially expressed in cases who experienced a recurrence during tamoxifen treatment thus predicting a worse overall survival (log rank = 8.357, p = 0.004) and disease-free survival (log rank = 21.766, p < 0.001). Cox multivariate analysis indicates that it is an independent prognostic indicator for overall survival (hazard ratio = 4.310, p = 0.013) and disease-free survival (hazard ratio = 5.449, p = 0.002). In this study, we propose the assessment of membranous CIP2A expression as a potential novel prognostic and predictive indicator for tamoxifen resistance and recurrence within oestrogen receptor–positive breast cancer

Ezrin Ubiquitylation by the E3 Ubiquitin Ligase, WWP1, and Consequent Regulation of Hepatocyte Growth Factor Receptor Activity

The membrane cytoskeleton linker ezrin participates in several functions downstream of the receptor Met in response to Hepatocyte Growth Factor (HGF) stimulation. Here we report a novel interaction of ezrin with a HECT E3 ubiquitin ligase, WWP1/Aip5/Tiul1, a potential oncogene that undergoes genomic amplification and overexpression in human breast and prostate cancers. We show that ezrin binds to the WW domains of WWP1 via the consensus motif PPVY477 present in ezrin’s C-terminus. This association results in the ubiquitylation of ezrin, a process that requires an intact PPVY477 motif. Interestingly ezrin ubiquitylation does not target the protein for degradation by the proteasome. We find that ezrin ubiquitylation by WWP1 in epithelial cells leads to the upregulation of Met level in absence of HGF stimulation and increases the response of Met to HGF stimulation as measured by the ability of the cells to heal a wound. Interestingly this effect requires ubiquitylated ezrin since it can be rescued, after depletion of endogenous ezrin, by wild type ezrin but not by a mutant of ezrin that cannot be ubiquitylated. Taken together our data reveal a new role for ezrin in Met receptor stability and activity through its association with the E3 ubiquitin ligase WWP1. Given the role of Met in cell proliferation and tumorigenesis, our results may provide a mechanistic basis for understanding the role of ezrin in tumor progression