Citations

AbstractMotivationOne objective of human microbiome studies is to identify differentially abundant microbes across biological conditions. Previous statistical methods focus on detecting the shift in the abundance and/or prevalence of the microbes and treat the dispersion (spread of the data) as a nuisance. These methods also assume that the dispersion is the same across conditions, an assumption which may not hold in presence of sample heterogeneity. Moreover, the widespread outliers in the microbiome sequencing data make existing parametric models not overly robust. Therefore, a robust and powerful method that allows covariate-dependent dispersion and addresses outliers is still needed for differential abundance analysis.ResultsWe introduce a novel test for differential distribution analysis of microbiome sequencing data by jointly testing the abundance, prevalence and dispersion. The test is built on a zero-inflated negative binomial regression model and winsorized count data to account for zero-inflation and outliers. Using simulated data and real microbiome sequencing datasets, we show that our test is robust across various biological conditions and overall more powerful than previous methods.Availability and implementationR package is available at https://github.com/jchen1981/MicrobiomeDDA.Supplementary informationSupplementary data are available at Bioinformatics online.

Background: Isolated long thoracic nerve palsy results in scapular winging and destabilization. In this study, we review the surgical management of isolated long thoracic nerve palsy and suggest a surgical technique and treatment algorithm to simplify management. Methods: In total, 19 patients who required surgery for an isolated long thoracic nerve palsy were reviewed retrospectively. Preoperative demographics, electromyography (EMG), and physical examinations were reviewed. Intraoperative nerve stimulation, surgical decision making, and postoperative outcomes were reviewed. Results: In total, 19 patients with an average age of 32 were included in the study. All patients had an isolated long thoracic nerve palsy caused by either an injury (58%), Parsonage-Turner syndrome (32%), or shoulder surgery (10%); 18 patients (95%) underwent preoperative EMG; 10 with evidence of denervation (56%); and 13 patients had motor unit potentials in the serratus anterior (72%). The preoperative EMG did not correlate with intraoperative nerve stimulation in 13 patients (72%) and did correlate in 5 patients (28%); 3 patients had a nerve transfer (3 thoracodorsal to long thoracic at lateral chest, 1 pec to long thoracic at supraclavicular incision). In the 3 patients who had a nerve transfer, there was return of full forward flexion of the shoulder at an average of 2.5 months. Conclusions: A treatment algorithm based on intraoperative nerve stimulation will help guide surgeons in their clinical decision making in patients with isolated long thoracic nerve palsy. Intraoperative nerve stimulation is the gold standard in the management of isolated long thoracic nerve palsy.

* Preclinical animal studies have demonstrated that vascularized bone grafts increase blood flow, maintain patent pedicles, provide immediate structural integrity, hypertrophy in response to mechanical stress, and deliver proper environments for healing in challenging situations. * The absolute indications for vascularized bone graft as borne out by high-quality studies have yet to be defined. Currently, the literature suggests varying success rates for difficult reconstructive problems requiring additional biological and structural properties offered only by vascularized bone-grafting. * Orthopaedic reconstructive challenges can be met with a variety of options, including pedicled and free vascularized bone grafts.

Abstract Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system, and CB-5083, a first-in-class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematologic and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma cell lines and a number of in vivo multiple myeloma models. Treatment with CB-5083 is associated with accumulation of ubiquitinated proteins, induction of the unfolded protein response, and apoptosis. CB-5083 decreases viability in multiple myeloma cell lines and patient-derived multiple myeloma cells, including those with background proteasome inhibitor (PI) resistance. CB-5083 has a unique mechanism of action that combines well with PIs, which is likely owing to the p97-dependent retro-translocation of the transcription factor, Nrf1, which transcribes proteasome subunit genes following exposure to a PI. In vivo studies using clinically relevant multiple myeloma models demonstrate that single-agent CB-5083 inhibits tumor growth and combines well with multiple myeloma standard-of-care agents. Our preclinical data demonstrate the efficacy of CB-5083 in several multiple myeloma disease models and provide the rationale for clinical evaluation as monotherapy and in combination in multiple myeloma. Mol Cancer Ther; 16(11); 2375–86. ©2017 AACR.

Purpose To analyze failure rate in 2‐year increments to determine if graft choice changed over time and graft failure rate. Methods A prospective 2002‐2008 database was used to identify risk factors for anterior cruciate ligament (ACL) retear. Subjects who had primary ACL retear with no history of contralateral surgery and 2‐year follow‐up were included. Subjects who underwent a multiligament reconstruction were excluded. Graft type, age, sex, smoking status, body mass index, Marx activity level at index surgery, medial and lateral meniscus status at time of ACL retear, sport played after ACL reconstruction, and clinical site were evaluated. Analysis was repeated using 2002‐2003 (early) and 2007‐2008 (late) 2‐year databases. Analysis of variance with post hoc analysis was performed to detect significant differences in age and Marx score by graft type over time. Results Two‐year follow‐up for graft failure was obtained on 2,497 of 2,692 (93%) subjects. There were 112 of 2,497 (4.5%) ACL retears identified at 2‐year follow‐up. The only predictor that changed between early/late periods was allograft use. Allograft odds ratio decreased from 13.1 to 9.5 ( P < .01). Allografts were used in older patients (31‐40 years) and with lower Marx scores (10‐8) from early to late periods. The mean age of subjects who received bone–patellar tendon–bone autografts did not significantly change over time (22.8‐23.5). The mean age of subjects who received hamstring autografts fell (27.9‐25.5). The mean age of subjects who received allografts rose significantly (31.3‐39.8, P < .01). The mean Marx score of subjects who received bone–patellar tendon–bone and hamstring autografts did not significantly change over time. The mean Marx score of subjects who received allografts decreased significantly ( P < .01). Conclusions After early recognition, allograft use in young active patients was a risk factor for retear; graft choice by surgeons changed in the late period to use of allografts in older and less‐active patients, which correlated with a significant decrease in retear risk. Level of Evidence Level III, case control study.

AbstractThe clinical significance of the c.427G>A (p.A143T) variant in GLA is a topic of debate within the lysosomal storage disease community. A review of the literature and published case reports found the clinical impact of the variant to range from classic Fabry symptoms to healthy unaffected males with normal alpha‐ galactosidase enzyme levels, leaving clinicians unsure of how to manage these individuals. As the number of states testing for Fabry disease on their newborn screening panel has increased, more people with this variant are being identified. The goal of this project was to learn how the uncertainty surrounding the clinical significance of the p.A143T variant affects those with this change. A self‐response questionnaire was developed to explore this topic. In addition to evaluating participant feelings, the questionnaire explored individuals’ beliefs regarding the pathogenicity of the variant. Results suggest that people have diverse feelings regarding reclassification of the p.A143T variant. Around half of those surveyed reported feeling frustrated by the lack of clear information. Despite the ambiguity regarding the health consequences of this variant, many participants felt that knowing this result helps guide medical management.

Objective To describe self-reported disease understanding for newly diagnosed patients with atrial fibrillation (AF) and assess (1) how disease understanding changes over the first 6 months after diagnosis and (2) the relationship between patient understanding of therapies at baseline and treatment receipt at 6 months among treatment-naïve patients. Methods We analysed survey data from SATELLITE (Survey of Patient Knowledge and Personal Priorities for Treatment), a substudy of patients with new-onset AF enrolled in the national Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT) II registry across 56 US sites. Patients were surveyed at the baseline and 6-month follow-up clinic visits using Likert scales. Results Among 1004 baseline survey responses, patients’ confidence in their understanding of rhythm control, ablation, anticoagulation and cardioversion was suboptimal, with ‘high’ understanding ranging from 8.5% for left atrial appendage closure to 71.3% for rhythm therapy. Of medical history and demographic factors, education level was the strongest predictor of reporting ‘high’ disease understanding. Among the 786 patients with 6-month survey data, significant increases in the proportion reporting high understanding were observed (p<0.05) only for warfarin and direct oral anticoagulants (DOACs). With the exception of ablation, high understanding for a given therapeutic option was not associated with increased use of that therapy at 6 months. Conclusions About half of patients with new-onset AF understood the benefits of oral anticoagulant at the time of diagnosis and understanding improved over the first 6 months. However, understanding of AF treatment remains suboptimal at 6 months. Our results suggest a need for ongoing patient education. Clinical trial registration Clinicaltrials.gov. Identifier: NCT01701817.