Disruptive physician behavior may diminish productivity, lead to medical errors, and compromise patient safety. The purpose of this paper is to review how common psychological conditions such as ...depression, stress, and burnout may drive disruptive behavior in the workplace and result in impaired patterns of professional conduct similar to what is seen with substance abuse. Problems related to these psychological morbidities may be more effectively managed with improved understanding of the conditions and behaviors, their associated risk factors, and the barriers that exist to reporting them. Further research and educational programs are warranted to address how these conditions might affect radiology.
Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage ...variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme. For the latter, we introduce 'annotation principal components', multidimensional summaries of in silico variant annotations. STAAR accounts for population structure and relatedness and is scalable for analyzing very large cohort and biobank whole-genome sequencing studies of continuous and dichotomous traits. We applied STAAR to identify RVs associated with four lipid traits in 12,316 discovery and 17,822 replication samples from the Trans-Omics for Precision Medicine Program. We discovered and replicated new RV associations, including disruptive missense RVs of NPC1L1 and an intergenic region near APOC1P1 associated with low-density lipoprotein cholesterol.
Abstract
Background
Fatigue is one of the most important symptoms among patients receiving dialysis and is nominated as a core outcome to be reported in all clinical trials in this setting. However, ...few trials of interventions targeting fatigue have been conducted. Patients historically have rarely been involved in the design of interventions, which can limit acceptability and uptake. When asked, they have indicated a preference for lifestyle interventions, such as exercise, to improve fatigue. While some research has focussed on intradialytic exercise for patients receiving haemodialysis, patients have also indicated a preference for a convenient method of exercising with guidance, but on their own time outside of dialysis hours. In response to this, a mobile phone application was proposed as the method of delivery for a home-based exercise intervention targeting fatigue.
Methods
We convened a workshop with five breakout group sessions in Australia, with 24 patients on dialysis (16 haemodialysis and 8 peritoneal dialysis) and 8 caregivers to identify, prioritize and discuss exercise interventions for fatigue in patients receiving dialysis and the delivery of this through a mobile application.
Results
Of the 21 types of exercise identified, the top-ranked were walking outdoors, walking on a treadmill and cardio and resistance training. Six themes were identified: (i) ‘an expectation of tangible gains from exercise’, including strengthening and protecting against bodily deterioration related to dialysis; (ii) ‘overcoming physical limitations’, meaning that comorbidities, baseline fatigue and fluctuating health needed to be addressed to engage in exercise; (iii) ‘fear of risks’, which reinforced the importance of safety and compatibility of exercise with dialysis; (iv) ‘realistic and achievable’ exercise, which would ensure initial readiness for uptake; (v) ‘enhancing motivation and interest’ , which expected to support sustained use of the exercise intervention and (vi) ‘ensuring usability of the mobile application’ , which would require simplicity, convenience and comprehensibility.
Conclusion
Exercise interventions that are expected by patients to improve health outcomes and that are safe, realistic and easy to adopt may be more acceptable to patients on dialysis.
Eating Disorders Andersen, Arnold E; Mehler, Philip S
2022
eBook
A comprehensive guide on how to diagnose, treat, and care for those with eating disorders.Eating disorders, which include such conditions as anorexia, bulimia, binge eating, and pica, represent a ...challenge to both patients and health care providers alike. For more than 20 years, health care providers have turned to the expert advice found in Eating Disorders to keep up to date with the latest research in the field and to help them provide the best care available for their patients. In this new, thoroughly revised and expanded edition of their best-selling work, Drs. Philip S. Mehler and Arnold E. Andersen provide a user-friendly and comprehensive guide to treating and managing eating disorders for primary care physicians, mental health professionals, worried family members and friends, and nonmedical professionals (such as teachers and coaches). Mehler and Andersen • identify common medical complications faced by people who have eating disorders• answer questions about how to treat both physical and behavioral aspects of eating disorders• discuss serious complications, including cardiac arrhythmia, electrolyte abnormalities, and gastrointestinal problems• incorporate all-new information on avoidant restrictive food intake disorder (ARFID), binge eating disorder, and the role of social media in promoting disordered eating• offer targeted advice for working with specialists• include four new chapters on eating disorders in children and adolescents; atypical anorexia; eating disorders in transgender individuals; and family therapy• feature engaging clinical vignettes • answer a list of common questions practitioners may have in each chapterThe most comprehensive work on the market and the only book that covers eating disorders in transgender individuals, Eating Disorders is a compassionate, evidence-based, and essential guide.Contributors: Arnold E. Andersen, Ovidio Bermudez, Jeana Cost, Meghan Foley, Dennis Gibson, Neville Golden, Sacha Gorell, Jeffrey Hollis, Mori J. Krantz, Daniel Le Grange, Russell Marx, Jennifer McBride, Philip S. Mehler, Leah Puckett, Katherine Sachs, Michael Spaulding-Barclay, Anna Tanner, Nathalia Trees, Jessica Tse, Kenneth Weiner, Patricia Westmoreland
The most common mutation in human melanoma, BRAF(V600E), activates the serine/threonine kinase BRAF and causes excessive activity in the mitogen-activated protein kinase pathway. BRAF(V600E) ...mutations are also present in benign melanocytic naevi, highlighting the importance of additional genetic alterations in the genesis of malignant tumours. Such changes include recurrent copy number variations that result in the amplification of oncogenes. For certain amplifications, the large number of genes in the interval has precluded an understanding of the cooperating oncogenic events. Here we have used a zebrafish melanoma model to test genes in a recurrently amplified region of chromosome 1 for the ability to cooperate with BRAF(V600E) and accelerate melanoma. SETDB1, an enzyme that methylates histone H3 on lysine 9 (H3K9), was found to accelerate melanoma formation significantly in zebrafish. Chromatin immunoprecipitation coupled with massively parallel DNA sequencing and gene expression analyses uncovered genes, including HOX genes, that are transcriptionally dysregulated in response to increased levels of SETDB1. Our studies establish SETDB1 as an oncogene in melanoma and underscore the role of chromatin factors in regulating tumorigenesis.
Summary Background Local excision is an organ-preserving treatment alternative to transabdominal resection for patients with stage I rectal cancer. However, local excision alone is associated with a ...high risk of local recurrence and inferior survival compared with transabdominal rectal resection. We investigated the oncological and functional outcomes of neoadjuvant chemoradiotherapy and local excision for patients with stage T2N0 rectal cancer. Methods We did a multi-institutional, single-arm, open-label, non-randomised, phase 2 trial of patients with clinically staged T2N0 distal rectal cancer treated with neoadjuvant chemoradiotherapy at 26 American College of Surgeons Oncology Group institutions. Patients with clinical T2N0 rectal adenocarcinoma staged by endorectal ultrasound or endorectal coil MRI, measuring less than 4 cm in greatest diameter, involving less than 40% of the circumference of the rectum, located within 8 cm of the anal verge, and with an Eastern Cooperative Oncology Group performance status of at least 2 were included in the study. Neoadjuvant chemoradiotherapy consisted of capecitabine (original dose 825 mg/m2 twice daily on days 1–14 and 22–35), oxaliplatin (50 mg/m2 on weeks 1, 2, 4, and 5), and radiation (5 days a week at 1·8 Gy per day for 5 weeks to a dose of 45 Gy, followed by a boost of 9 Gy, for a total dose of 54 Gy) followed by local excision. Because of adverse events during chemoradiotherapy, the dose of capecitabine was reduced to 725 mg/m2 twice-daily, 5 days per week, for 5 weeks, and the boost of radiation was reduced to 5·4 Gy, for a total dose of 50·4 Gy. The primary endpoint was 3-year disease-free survival for all eligible patients (intention-to-treat population) and for patients who completed chemotherapy and radiation, and had ypT0, ypT1, or ypT2 tumours, and negative resection margins (per-protocol group). This study is registered with ClinicalTrials.gov , number NCT00114231. Findings Between May 25, 2006, and Oct 22, 2009, 79 eligible patients were recruited to the trial and started neoadjuvant chemoradiotherapy. Two patients had no surgery and one had a total mesorectal excision. Four additional patients completed protocol treatment, but one had a positive margin and three had ypT3 tumours. Thus, the per-protocol population consisted of 72 patients. Median follow-up was 56 months (IQR 46–63) for all patients. The estimated 3-year disease-free survival for the intention-to-treat group was 88·2% (95% CI 81·3–95·8), and for the per-protocol group was 86·9% (79·3–95·3). Of 79 eligible patients, 23 (29%) had grade 3 gastrointestinal adverse events, 12 (15%) had grade 3–4 pain, and 12 (15%) had grade 3–4 haematological adverse events during chemoradiation. Of the 77 patients who had surgery, six (8%) had grade 3 pain, three (4%) had grade 3–4 haemorrhage, and three (4%) had gastrointestinal adverse events. Interpretation Although the observed 3-year disease free survival was not as high as anticipated, our data suggest that neoadjuvant chemoradiotherapy followed by local excision might be considered as an organ-preserving alternative in carefully selected patients with clinically staged T2N0 tumours who refuse, or are not candidates for, transabdominal resection. Funding National Cancer Institute and Sanofi-Aventis.
Polymer networks are complex systems consisting of molecular components. Whereas the properties of the individual components are typically well understood by most chemists, translating that chemical ...insight into polymer networks themselves is limited by the statistical and poorly defined nature of network structures. As a result, it is challenging, if not currently impossible, to extrapolate from the molecular behavior of components to the full range of performance and properties of the entire polymer network. Polymer networks therefore present an unrealized, important, and interdisciplinary opportunity to exert molecular-level, chemical control on material macroscopic properties. A barrier to sophisticated molecular approaches to polymer networks is that the techniques for characterizing the molecular structure of networks are often unfamiliar to many scientists. Here, we present a critical overview of the current characterization techniques available to understand the relation between the molecular properties and the resulting performance and behavior of polymer networks, in the absence of added fillers. We highlight the methods available to characterize the chemistry and molecular-level properties of individual polymer strands and junctions, the gelation process by which strands form networks, the structure of the resulting network, and the dynamics and mechanics of the final material. The purpose is not to serve as a detailed manual for conducting these measurements but rather to unify the underlying principles, point out remaining challenges, and provide a concise overview by which chemists can plan characterization strategies that suit their research objectives. Because polymer networks cannot often be sufficiently characterized with a single method, strategic combinations of multiple techniques are typically required for their molecular characterization.
Ferroelectric absorbers, which promote carrier separation and exhibit above-gap photovoltages, are attractive candidates for constructing efficient solar cells. Using the ferroelectric insulator ...BaTiO sub(3) we show how photogeneration and the collection of hot, non-equilibrium electrons through the bulk photovoltaic effect (BPVE) yields a greater-than-unity quantum efficiency. Despite absorbing less than a tenth of the solar spectrum, the power conversion efficiency of the BPVE device under 1 sun illumination exceeds the Shockley-Queisser limit for a material of this bandgap. We present data for devices that feature a single-tip electrode contact and an array with 24 tips (total planar area of 11 mu m super(2)) capable of generating a current density of 17mAcm super(-2) under illumination of AM1.5G. In summary, the BPVE at the nanoscale provides an exciting new route for obtaining high-efficiency photovoltaic solar energy conversion.
ICU-acquired muscle atrophy occurs commonly and worsens outcomes in adults. The incidence and severity of muscle atrophy in critically ill children are poorly characterized.
To determine incidence, ...severity and risk factors for muscle atrophy in critically ill children.
A single-center, prospective cohort study of 34 children receiving invasive mechanical ventilation for ≥48 hours. Patients 1 week- 18 years old with respiratory failure and without preexisting neuromuscular disease or skeletal trauma were recruited from a tertiary Pediatric Intensive Care Unit (PICU) between June 2015 and May 2016. We used serial bedside ultrasound to assess thickness of the diaphragm, biceps brachii/brachialis, quadriceps femoris and tibialis anterior. Serial electrical impedance myography (EIM) was assessed in children >1 year old. Medical records were abstracted from an electronic database.
Respiratory failure requiring endotracheal intubation for ≥48 hours.
The primary outcome was percent change in muscle thickness. Secondary outcomes were changes in EIM-derived fat percentage and "quality".
Of 34 enrolled patients, 30 completed ≥2 ultrasound assessments with a median interval of 6 (IQR 6-7) days. Mean age was 5.42 years, with 12 infants <1 year (40%) and 18 children >1 year old (60%). In the entire cohort, diaphragm thickness decreased 11.1% (95%CI, -19.7% to -2.52%) between the first two assessments or 2.2%/day. Quadriceps thickness decreased 8.62% (95%CI, -15.7% to -1.54%) or 1.5%/day. Biceps (-1.71%; 95%CI, -8.15% to 4.73%) and tibialis (0.52%; 95%CI, -5.81% to 3.40%) thicknesses did not change. Among the entire cohort, 47% (14/30) experienced diaphragm atrophy (defined a priori as ≥10% decrease in thickness). Eighty three percent of patients (25/30) experienced atrophy in ≥1 muscle group, and 47% (14/30)-in ≥2 muscle groups. On multivariate linear regression, increasing age and traumatic brain injury (TBI) were associated with greater muscle loss. EIM revealed increased fat percentage and decreased muscle "quality".
In children receiving invasive mechanical ventilation, diaphragm and other skeletal muscle atrophy is common and rapid. Increasing age and TBI may increase severity of limb muscle atrophy. Prospective studies are required to link muscle atrophy to functional outcomes in critically ill children.
Inhibition of Bruton’s tyrosine kinase (BTK) with the irreversible inhibitor ibrutinib has emerged as a transformative treatment option for patients with chronic lymphocytic leukemia (CLL) and other ...B-cell malignancies, yet >80% of CLL patients develop resistance due to a cysteine to serine mutation at the site covalently bound by ibrutinib (C481S). Currently, an effective treatment option for C481S patients exhibiting relapse to ibrutinib does not exist, and these patients have poor outcomes. To address this, we have developed a PROteolysis TArgeting Chimera (PROTAC) that induces degradation of both wild-type and C481S mutant BTK. We selected a lead PROTAC, MT-802, from several candidates on the basis of its potency to induce BTK knockdown. MT-802 recruits BTK to the cereblon E3 ubiquitin ligase complex to trigger BTK ubiquitination and degradation via the proteasome. MT-802 binds fewer off-target kinases than ibrutinib does and retains an equivalent potency (>99% degradation at nanomolar concentrations) against wild-type and C481S BTK. In cells isolated from CLL patients with the C481S mutation, MT-802 is able to reduce the pool of active, phosphorylated BTK whereas ibrutinib cannot. Collectively, these data provide a basis for further preclinical study of BTK PROTACs as a novel strategy for treatment of C481S mutant CLL.
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