关键词： Caper   Fmr1   Locomotor behavior   Neuromuscular junction  

摘要： RNA-binding proteins play an important role in the regulation of post-transcriptional gene expression throughout the nervous system. This is underscored by the prevalence of mutations in genes encoding RNA splicing factors and other RNA-binding proteins in a number of neurodegenerative and neurodevelopmental disorders. The highly conserved alternative splicing factor Caper is widely expressed throughout the developing embryo and functions in the development of various sensory neural subtypes in the Drosophila peripheral nervous system. Here we find that caper dysfunction leads to aberrant neuromuscular junction morphogenesis, as well as aberrant locomotor behavior during larval and adult stages. Despite its widespread expression, our results indicate that caper function is required to a greater extent within the nervous system, as opposed to muscle, for neuromuscular junction development and for the regulation of adult locomotor behavior. Moreover, we find that Caper interacts with the RNA-binding protein Fmrp to regulate adult locomotor behavior. Finally, we show that caper dysfunction leads to various phenotypes that have both a sex and age bias, both of which are commonly seen in neurodegenerative disorders in humans.

关键词： time study   EMR   burnout  

摘要： Background: The purpose of this study is to quantify how pediatric orthopaedic surgeons spend time in clinic. Methods: Two pediatric orthopaedic surgeons were individually observed and activities were timed during 3 clinic sessions. One medical student observed and recorded the time using a data collection sheet and a watch. The duration of each clinic session was 4 hours and a new patient was seen every 20 minutes. Data was collected in 7 categories including: time with the patient;time with staff;time listening to the resident presentations, time teaching, time multitasking, time dictating, and time on the electronic medical record (EMR). The number of computer mouse clicks needed to complete each patient encounter was also recorded. The Cerner EMR system was used (Cerner Inc. North Kansas City, MO). Results: Thirty-six percent of the physician's time was spent on the EMR. Thirty-five percent of time was spent with the patient, 7% was spent dictating, 7% teaching, 5% multitasking, 6% with staff, and 4% listening to resident presentations. Overall, during a 20-minute patient visit, 7.2 minutes was spent on the EMR. During a 4-hour clinic, 87 minutes was spent on the EMR. During a full day of clinic-two 4-hour sessions-173 minutes were spent on the EMR. The average number of computer mouse clicks to complete a patient encounter was 70 (range: 42 to 110). A total of 1680 clicks were needed to see 24 patients in a typical 2 session clinic. Conclusion: Pediatric orthopaedic surgeons spend more time on the EMR than with patients. About 70 computer mouse clicks are needed per patient encounter. The excessive computer time can diminish the patient-physician relationship. Click fatigue in physicians is real and needs to be resolved by improved EMR technology, utilization of medical scribes, or a return to partial use of paper.

关键词： clubfoot   Ponseti method   casting   semirigid fiberglass   Softcast  

摘要： Background: Synthetic casting materials have been used as alternatives to plaster of Paris (POP) in the treatment of clubfoot using the Ponseti method. The aim of this study was to evaluate the clinical outcome of children with idiopathic clubfoot managed by the Ponseti method using POP versus semirigid fiberglass (SRF). Methods: Medical records were retrospectively reviewed for all newborns with idiopathic clubfoot who underwent manipulation and casting by the Ponseti technique between January 2013 and December 2016 at 2 different institutions. In all, 136 consecutive clubfeet were included, of which 68 underwent casting with POP (Group A), and 68 were casted using SRF (Group B). Statistical analysis was performed using the Fisher exact test for categorical variables, and the unpaired t test for quantitative parameters. Results: Mean age at time of first cast was 10 days (range, 3 to 21 d). Mean Pirani score at start of treatment was 4.6 and 4.5 in Groups A and B, respectively. Mean number of casts for each patient in Group A was 5.2 against 4.2 in patients in Group B. Mean follow-up was 63.8 months (range, 42 to 88 mo). In each group, 4 cases of relapse were reported (2.9%). No complications related to cast phase or brace phase were recorded. Shorter duration of cast treatment was recorded in Group B. Conclusions: Despite its higher cost and slightly lower moldability, the use of SRF in experienced hands showed comparable results in idiopathic clubfeet treated by the Ponseti technique.

关键词： health technology assessment   indirect comparison   method of moments   population adjustment   propensity score model   weight adjustment  

摘要： Methods for indirect comparisons and network meta-analysis use aggregate level data from multiple studies. A very common, and closely related, scenario is where a company has individual patient data (IPD) from its own trial, but only has published aggregate data from a competitor's trial, and an indirect comparison of the treatments evaluated in these two trials is required. Matching-Adjusted Indirect Comparison (MAIC) has been developed for this situation, where we use the available IPD to adjust for between-trial imbalances in the distributions of observed baseline covariates between the two trials. We extend the current MAIC methodology, where we compute the weights that satisfy the conventional method of moments and result in the largest possible effective sample size (ESS). We show that the approach proposed by Zubizarreta in a previous study can be used for this purpose. We derive a new analytical result that shows why this alternative approach provides a larger ESS than a conventional MAIC. We also derive a new formula for the maximum ESS that can be achieved, even when permitting negative weights, when adjusting for one covariate. This can be used as an easily computed new metric that quantifies the difficulty in adjusting for covariates. What is already known: MAIC is an established way to perform population adjustment in the situation where IPD is available from one trial but only aggregate level data is available from another trial, and an indirect comparison is required. However the effective sample size (ESS) can be small after making the adjustment. What is new: We show that an alternative method can result in a larger ESS. We provide new analytical results showing why this is the case. We derive a new descriptive statistic that is based on maximising the ESS that quantifies the difficulties in adjusting for particular covariates. Potential impact for RSM readers outside the authors' field: Reweighting methods for population adjustment are becoming mor

关键词： Targeted proteomics   Mass spectrometry   Parallel reaction monitoring   Alternative splicing   Protein isoforms   Proteoforms   Machine learning   Heart  

摘要： Alternative splicing is prevalent in the heart and implicated in many cardiovascular diseases, but not every alternative transcript is translated and detecting non-canonical isoforms at the protein level remains challenging. Here we show the use of a computation-assisted targeted proteomics workflow to detect protein alternative isoforms in the human heart. We build on a recent strategy to integrate deep RNA-seq and large-scale mass spectrometry data to identify candidate translated isoform peptides. A machine learning approach is then applied to predict their fragmentation patterns and design protein isoform-specific parallel reaction monitoring detection (PRM) assays. As proof-of-principle, we built PRM assays for 29 non-canonical isoform peptides and detected 22 peptides in a human heart lysate. The predictions-aided PRM assays closely mirrored synthetic peptide standards for non-canonical sequences. This approach may be useful for validating non-canonical protein identification and discovering functionally relevant isoforms in the heart.

关键词： Pancreaticoduodenectomy   Pancreatico-jejunal anastomosis   Total pancreatectomy   FRS  

摘要： Purpose Patients with fistula risk score (FRS) >= 7 are at the highest risk of developing clinically relevant post-operative pancreatic fistula (CR-POPF). There is no agreement on the management of this subpopulation. The primary outcome of the study was the definition of the role of intraoperative completion pancreatectomy (ICP) in patients at high risk for CR-POPF, as an alternative to high-risk pancreaticoduodenectomy (PD). Methods This is an observational study set in a single tertiary referral center. Patients scheduled for PD in our center between 2010 and 2019 with FRS >= 7 were included in the study. Data were prospectively collected. Results A total of 738 patients were scheduled for between 2010 and 2019, and 62 had FRS >= 7. Thirty-five patients were managed with PD and pancreatico-jejunal anastomosis (group A), and 27 with ICP (group B). Overall complication rate was significantly higher in group A than group B (95 versus 59%;p=0.005) and there was a not significantly higher rate of major complications (Clavien-Dindo >= 3) (43 versus 26%;p=0.192). In group A, 49% of patients had a CR-POPF. Median post-operative length of stay was 15 days in group A and 12 in group B (p=0.043). Readmission was observed only in group A (26%). In multivariate analysis, PD was an independent predictive factor of major post-operative morbidity (RR 9.27;CI 1.74-49.31). No patients in either group suffered major adverse events related to endocrine and exocrine insufficiency. Conclusion In high-FRS patients, ICP has good short-term outcomes relative to PD without major long-term events related to endocrine and exocrine insufficiency. ICP could be considered as a feasible alternative in selected cases.

关键词： long noncoding RNAs   cancer   alternative splicing   single-cell RNA sequencing   database  

摘要： Accumulating studies demonstrated that the roles of lncRNAs for tumorigenesis were isoform-dependent and their aberrant splicing patterns in cancers contributed to function specificity. However, there is no existing database focusing on cancer-related alternative splicing of lncRNAs. Here, we developed a comprehensive database called LncAS2Cancer, which collected 5335 bulk RNA sequencing and 1826 single-cell RNA sequencing samples, covering over 30 cancer types. By applying six state-of-the-art splicing algorithms, 50 859 alternative splicing events for 8 splicing types were identified and deposited in the database. In addition, the database contained the following information: (i) splicing patterns of lncRNAs under seven different conditions, such as gene interference, which facilitated to infer potential regulators;(ii) annotation information derived from eight sources and manual curation, to understand the functional impact of affected sequences;(iii) survival analysis to explore potential biomarkers;as well as (iv) a suite of tools to browse, search, visualize and download interesting information. LncAS2Cancer could not only confirm the known cancer-associated lncRNA isoforms but also indicate novel ones. Using the data deposited in LncAS2Cancer, we compared gene model and transcript overlap between lncRNAs and protein-coding genes and discusses how these factors, along with sequencing depth, affected the interpretation of splicing signals. Based on recurrent signals and potential confounders, we proposed a reliable score to prioritize splicing events for further elucidation. Together, with the broad collection of lncRNA splicing patterns and annotation, LncAS2Cancer will provide important new insights into the diverse functional roles of lncRNA isoforms in human cancers. LncAS2Cancer is freely available at https://***/.

关键词： Esophageal atresia   Long gap esophageal atresia   Left-sided approach   Foker procedure   Internal traction  

摘要： Purpose: : We describe a left-sided approach for long gap esophageal atresia (LGEA) repair in patients who have a large leftward upper pouch and no significant tracheomalacia, or as a salvage strategy after prior failed right-sided repairs. Methods: : Retrospective review of patients who underwent repair via traction induced growth (Foker procedure [FP]) from 2014 to 2019 was performed. Surgical technique and post-operative outcomes were evaluated. Results: : Of 47 LGEA patients, 18 (38%) were approached via the left side-94% had a left aortic arch, and 22% had prior attempts at a right-sided anastomosis. More left-sided patients underwent minimally invasive repair (39% vs 7%, p = 0.007) and internal traction (50% vs 10%, p = 0.002) compared to right-sided patients. On multivariate analysis, internal traction was associated with a decreased length of paralysis ( p < 0.01);length of intubation and hospital stay were similar between groups. Anastomotic leak (17% vs 20%, p = 0.80) and stricture resection (6% vs 24%, p = 0.12) rates were similar. No left-sided FP patient required additional surgery for tracheomalacia, while six right-sided patients required intervention. Conclusion: : Left-sided FP can be considered for LGEA patients with a large leftward upper pouch or as a salvage pathway after a failed right chest approach, with similar outcomes to the right-sided approach. (c) 2020 Elsevier Inc. All rights reserved.

关键词： Indoor dust   Legacy flame retardants   Alternative flame retardants   Human exposure  

摘要： Flame retardants (FRs) are additives used in consumer products to reduce flammability, even though they can easily contaminate the indoor environment. Since it is common for people in modern cities to spend up to 85% of time indoors, the quality of the indoor environment is critical for human health. In this study, polybrominated diphenyl ethers (PBDEs), organophosphorus flame retardants (OPFRs), emerging brominated flame retardants (EBFRs), and dechlorane-related compounds (DRCs) were measured in household dust samples (n = 34) from Latvia, followed by human exposure assessment. Among all studied compounds, OPFRs showed the highest concentrations (1380-133,000 ng g(-1)). Despite the phase-out of PBDEs, they were the second most significant flame retardants in the studied dust samples (468-25,500 ng g(-1)) and the predominant compound was BDE-209. The concentrations of EBFRs were in the range of 120-7295 ng g(-1), with the most abundant contaminant being DBDPE, which is widely used as a substitute for the deca-BDE formulation. DRCs were the least common flame retardants in the Latvian indoor environments, with concentrations ranging 22.4-192 ng g(-1). Although the concentrations of specific FRs are known to vary between different countries, the levels and patterns observed in dust samples from Latvia were similar to those reported from Central Europe. Human exposure was evaluated as the estimated daily intake (EDI). The calculated exposure to most of the FRs was several orders of magnitude lower than the available reference dose (RfD) values.