tbuckley/cabot-search huggingface dataset:
Should This Woman With Dense Breasts Receive Supplemental Breast Cancer Screening?
Authors: Gerald W. Smetana, Joann G. Elmore, Christoph I. Lee, Risa B. Burns
Journal: Annals of Internal Medicine (2018)

Breast cancer will develop in 12% of women during their lifetime and is the second leading cause of cancer death among U.S. women. Mammography is the most commonly used tool to screen for breast cancer. Considerable uncertainty exists regarding the age at which to begin screening and the optimal screening interval. Breast density is a risk factor for breast cancer. In addition, for women with dense breasts, small tumors may be missed on mammography and the sensitivity of screening is diminished. At the time of publication, 35 states had passed laws mandating that breast density be reported in the letters that radiologists send to women with their mammogram results. The mandated language may be challenging for patients to understand, and such reporting may increase worry for women who are told that their risk for breast cancer is higher than average on the basis of breast density alone. The U.S. Preventive Services Task Force and the American College of Radiology (ACR) have each issued guidelines that address breast cancer screening for women with dense breasts. Both organizations found insufficient evidence to recommend for or against magnetic resonance screening, whereas the ACR advises consideration of ultrasonography for supplemental screening. In this Beyond the Guidelines, 2 experts—a radiologist and a general internist—discuss these controversies. In particular, the discussants review the role of supplemental breast cancer screening, including breast ultrasonography or magnetic resonance imaging for women with dense breasts. Finally, the experts offer specific advice for a patient who finds her mammography reports confusing.
Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia
Authors: Elena J. Orlando, Xia Han, Catherine Tribouley, Patricia A. Wood, Rebecca J. Leary, Markus Riester, John E. Levine, Muna Qayed, Stephan A. Grupp, Michael Boyer, Barbara De Moerloose, Eneida R. Nemecek, Henrique Bittencourt, Hidefumi Hiramatsu, Jochen Buechner, Stella M. Davies, Michael R. Verneris, Kevin Nguyen, Jennifer L. Brogdon, Hans Bitter, Michael Morrissey, Piotr Pierog, Serafino Pantano, Jeffrey A. Engelman, Wendy Winckler
Journal: Nature Medicine (2018)
Patterns of Ancestral Animal Codon Usage Bias Revealed through Holozoan Protists
Authors: Jade Southworth, Paul Armitage, Brandon Fallon, Holly Dawson, Jarosław Bryk, Martin Carr
Journal: Molecular Biology and Evolution (2018)

Choanoflagellates and filastereans are the closest known single celled relatives of Metazoa within Holozoa and provide insight into how animals evolved from their unicellular ancestors. Codon usage bias has been extensively studied in metazoans, with both natural selection and mutation pressure playing important roles in different species. The disparate nature of metazoan codon usage patterns prevents the reconstruction of ancestral traits. However, traits conserved across holozoan protists highlight characteristics in the unicellular ancestors of Metazoa. Presented here are the patterns of codon usage in the choanoflagellates Monosiga brevicollis and Salpingoeca rosetta, as well as the filasterean Capsaspora owczarzaki. Codon usage is shown to be remarkably conserved. Highly biased genes preferentially use GC-ending codons, however there is limited evidence this is driven by local mutation pressure. The analyses presented provide strong evidence that natural selection, for both translational accuracy and efficiency, dominates codon usage bias in holozoan protists. In particular, the signature of selection for translational accuracy can be detected even in the most weakly biased genes. Biased codon usage is shown to have coevolved with the tRNA species, with optimal codons showing complementary binding to the highest copy number tRNA genes. Furthermore, tRNA modification is shown to be a common feature for amino acids with higher levels of degeneracy and highly biased genes show a strong preference for using modified tRNAs in translation. The translationally optimal codons defined here will be of benefit to future transgenics work in holozoan protists, as their use should maximise protein yields from edited transgenes.
Deploying end-of-life utilization measures for oncology patients to assess hospital care quality and value.
Authors: Kristen K. McNiff, Yichen Zhang, Belen Fraile, Michael J. Hassett
Journal: Journal of Clinical Oncology (2018)

106 Background: Addressing utilization near the end of life (EOL) for cancer patients is critical to enhance the value of cancer care. Cancer EOL utilization measures have been widely endorsed, including by the National Quality Forum (chemotherapy in the last 14 days; ICU in the last 30 days; not admitted to hospice; admitted to hospice for &lt; 3 days). However, efforts to use these measures to assess hospital quality and value have been constrained, in part because currently endorsed specifications do not provide a claims-based approach to cohort identification, and do not include a hospital attribution methodology. Methods: Using Medicare fee-for-service claims for adults ≥65 years, and through an iterative process informed by an expert panel, we developed extensible claims-based algorithms to a) identify patients who were deceased from cancer; b) attribute each patient to a responsible hospital; and c) derive hospital-level performance measures. We sought to ensure that these algorithms had strong face validity and were consistent with standard practices for claims-based analyses. Results: We identified 347,452 cancer decedents as those who had a cancer diagnosis associated with ≥2 hospital inpatient (IP), hospital outpatient (OP), or hospice claims, and died between 2011-2014. A decedent’s care was attributed to a hospital if there were ≥2 claims from that institution during the 6 months before death (N = 221,102). If this identified multiple hospitals, one was selected using the following sequence: total majority of all claims; most OP claims; most IP claims; last IP claim before death. Measure performance reflected national published data: 6% received chemotherapy in the last 14 days; 28% admitted to ICU in the last 30 days; and 34% not admitted to hospice. There was significant variation in hospital performance for all measures. Conclusions: Claims-based EOL measures do not define ‘ideal’ performance, but they do provide hospitals with broad utilization data that can help inform value-based cancer care delivery. These methods addressed gaps hindering the application of endorsed cancer EOL measures to hospitals. Companion quality measures to assess goal-concordant care are also needed.
Abstract 18628: Atypical Symptoms and Results of Non-Invasive Tests Do Not Explain Poor Diagnostic Yield of Invasive Angiography in Women Suspected of Obstructive Coronary Artery Disease
Authors: Christina B Therming, Søren Galatius, Merete Heitmann, Helena Dominguez, Dorte Husum, Jan Bech, Thomas Hermann, Thomas Sehestedt, Søren Højberg, Charlotte Sørum, Jacob Reeh, Lene Rørdam, Eva Prescott
Journal: Circulation (2016)

Background: Angina pectoris is the most common symptom of coronary artery disease (CAD) among women but large studies have indicated low diagnostic yield of invasive coronary angiography (ICA). It is well accepted that women have more atypical symptoms and that some tests perform less well in women. Purpose: To examine whether symptoms and non-invasive test result (NIT) are less predictive of obstructive CAD in women compared to men in a large city hospital. Methods: Patients referred for assessment of stable CAD in 2012-2014 in a single center were included. Information on symptoms, risk factors, results of NIT and ICA was gathered from registries and patient records. Ability of symptoms and NIT result to predict obstructive CAD in men and women was compared in multiple adjusted logistic regression models by testing for statistical interaction. Results: A total of 2763 patients were included, 1462 (53%) women. Women were older (59.1 vs 56.4 years, p<0.0001), more likely to have non-anginal chest pain and...
Automated quality control process for tracking appropriateness of antiemesis.
Authors: Naveed R. Cheema, Samip R. Master, Richard P. Mansour
Journal: Journal of Clinical Oncology (2018)

317 Background: Quality tracking and improvement are areas of importance for delivery of high value patient care. Quality Oncology Practice Initiatives (QOPI) are tools designed by ASCO to help oncology practices deliver high quality care. Specifically, QOPI measure 29 tracks whether antiemetics are administered appropriately with moderate/high emetic risk chemotherapy. In this study, we attempted to automate this quality measure using an adapted Microsoft Structured Query Language (SQL) procedure. Our primary aim was to develop an efficient and cost effective system to track appropriate anti emesis that is adaptable to other cancer centers. A secondary aim was to quantify any degree of over treatment in anti emesis in our center. Methods: We created an SQL procedure which accessed the EPIC CLARITY database and used 9 steps to identify how many chemotherapy administrations in our center for the year 2017 were given sufficient, over, or under anti emesis. We adapted our center’s antiemesis guidelines from 2017 ASCO Clinical Practice Guideline Update for antiemetics. The program identified “pass”/”fail”/”pass(-)” for appropriate/insufficient/over treatment of anti emesis, respectively. Results: 1490 patient/chemotherapy encounters were found for 2017. 862/118/510 were high/intermediate/low emetic risk, respectively. 1314/14/162 chemotherapy administrations received “pass”/”fail”/”pass (-)”, respectively. The reason for 13 of 14 “fails” was lack of steroid in high emetic risk regimens. The primary reason for “pass (-)” was use of fosaprepitant in low/intermediate risk regimens. The time required to execute the program for all 1490 encounters was 40 seconds; the average time for manual review was 3 minutes per encounter. There was no discordance between “pass/fail” status in comparing automated and manual reviews. Conclusions: We have created an automated process which rapidly and accurately verifies adherence to QOPI measure 29. It eliminates time and costs associated with manual review. Further, this program saves costs by identifying areas of over treatment in anti emesis. We have demonstrated on a large scale an adaptable and shareable process for other centers using similar EMR databases.
Brief Report: Monosodium Urate Monohydrate Crystal Deposits Are Common in Asymptomatic Sons of Patients With Gout: The Sons of Gout Study
Authors: Abhishek Abhishek, Philip Courtney, Wendy Jenkins, Gabriela Sandoval‐Plata, Adrian C. Jones, Weiya Zhang, Michael Doherty
Journal: Arthritis & Rheumatology (2018)

Objective To estimate the prevalence and distribution of asymptomatic monosodium urate monohydrate ( MSU ) crystal deposition in sons of patients with gout. Methods Patients with gout were mailed an explanatory letter with an enclosed postage‐paid study packet to mail to their son(s) age ≥20 years old. Sons interested in participating returned a reply form and underwent telephone screening. Subsequently, they attended a study visit at which blood and urine samples were obtained and musculoskeletal ultrasonography was performed, with the sonographer blinded with regard to the subject's serum urate level. Images were assessed for double contour sign, intraarticular or intratendinous aggregates/tophi, effusion, and power Doppler signal. Logistic regression was used to examine associations. Adjusted odds ratios ( OR adj ) and 95% confidence intervals (95% CI s) were calculated. Results One hundred thirty‐one sons (mean age 43.8 years, mean body mass index 27.1 kg/m 2 ) completed assessments. The serum urate level was ≥6 mg/dl in 64.1%, and 29.8% had either a double contour sign or intraarticular aggregates/tophi in ≥1 joint. All participants with MSU deposition had involvement of 1 or both first metatarsophalangeal joints. Intratendinous aggregates were present in 21.4% and were associated with intraarticular MSU crystal deposits ( OR adj 2.96 [95% CI 1.17–7.49]). No participant with a serum urate level of ≤5 mg/dl had MSU crystal deposition seen on ultrasonography, and 24.2% of those with serum urate levels between 5 and 6 mg/dl had ultrasonographic MSU deposition. MSU crystal deposition was associated with increasing serum urate levels ( OR adj 1.61 [95% CI 1.10–2.36] for each increase of 1 mg/dl). Conclusion Asymptomatic sons of patients with gout frequently have hyperuricemia and MSU crystal deposits. In this study MSU crystal deposits were present in participants with serum urate levels of ≥5 mg/dl. Evaluation of subjects without a family history of gout is needed to determine whether the threshold for MSU crystal deposition is also lower in the general population.
SUMOylation Negatively Regulates Angiogenesis by Targeting Endothelial NOTCH Signaling
Authors: Xiaolong Zhu, Sha Ding, Cong Qiu, Yanna Shi, Lin Song, Yueyue Wang, Yuewen Wang, Jinying Li, Yiran Wang, Yi Sun, Lingfeng Qin, Jun Chen, Michael Simons, Wang Min, Luyang Yu
Journal: Circulation Research (2017)

The highly conserved NOTCH (neurogenic locus notch homolog protein) signaling pathway functions as a key cell-cell interaction mechanism controlling cell fate and tissue patterning, whereas its dysregulation is implicated in a variety of developmental disorders and cancers. The pivotal role of endothelial NOTCH in regulation of angiogenesis is widely appreciated; however, little is known about what controls its signal transduction. Our previous study indicated the potential role of post-translational SUMO (small ubiquitin-like modifier) modification (SUMOylation) in vascular disorders. The aim of this study was to investigate the role of SUMOylation in endothelial NOTCH signaling and angiogenesis. Endothelial SENP1 (sentrin-specific protease 1) deletion, in newly generated endothelial SENP1 (the major protease of the SUMO system)-deficient mice, significantly delayed retinal vascularization by maintaining prolonged NOTCH1 signaling, as confirmed in cultured endothelial cells. An in vitro SUMOylation assay and immunoprecipitation revealed that when SENP1 associated with N1ICD (NOTCH1 intracellular domain), it functions as a deSUMOylase of N1ICD SUMOylation on conserved lysines. Immunoblot and immunoprecipitation analyses and dual-luciferase assays of natural and SUMO-conjugated/nonconjugated NOTCH1 forms demonstrated that SUMO conjugation facilitated NOTCH1 cleavage. This released N1ICD from the membrane and stabilized it for translocation to the nucleus where it functions as a cotranscriptional factor. Functionally, SENP1-mediated NOTCH1 deSUMOylation was required for NOTCH signal activation in response to DLL4 (Delta-like 4) stimulation. This in turn suppressed VEGF (vascular endothelial growth factor) receptor signaling and angiogenesis, as evidenced by immunoblotted signaling molecules and in vitro angiogenesis assays. These results establish reversible NOTCH1 SUMOylation as a regulatory mechanism in coordinating endothelial angiogenic signaling; SENP1 acts as a critical intrinsic mediator of this process. These findings may apply to NOTCH-regulated biological events in nonvascular tissues and provide a novel therapeutic strategy for vascular diseases and tumors.
Evaluation of Artificial Intelligence–Based Grading of Diabetic Retinopathy in Primary Care
Authors: Yogesan Kanagasingam, Di Xiao, Janardhan Vignarajan, Amita Preetham, Mei-Ling Tay-Kearney, Ateev Mehrotra
Journal: JAMA Network Open (2018)

<h3>Importance</h3> There has been wide interest in using artificial intelligence (AI)–based grading of retinal images to identify diabetic retinopathy, but such a system has never been deployed and evaluated in clinical practice. <h3>Objective</h3> To describe the performance of an AI system for diabetic retinopathy deployed in a primary care practice. <h3>Design, Setting, and Participants</h3> Diagnostic study of patients with diabetes seen at a primary care practice with 4 physicians in Western Australia between December 1, 2016, and May 31, 2017. A total of 193 patients consented for the study and had retinal photographs taken of their eyes. Three hundred eighty-six images were evaluated by both the AI-based system and an ophthalmologist. <h3>Main Outcomes and Measures</h3> Sensitivity and specificity of the AI system compared with the gold standard of ophthalmologist evaluation. <h3>Results</h3> Of the 193 patients (93 [48%] female; mean [SD] age, 55 [17] years [range, 18-87 years]), the AI system judged 17 as having diabetic retinopathy of sufficient severity to require referral. The system correctly identified 2 patients with true disease and misclassified 15 as having disease (false-positives). The resulting specificity was 92% (95% CI, 87%-96%), and the positive predictive value was 12% (95% CI, 8%-18%). Many false-positives were driven by inadequate image quality (eg, dirty lens) and sheen reflections. <h3>Conclusions and Relevance</h3> The results demonstrate both the potential and the challenges of using AI systems to identify diabetic retinopathy in clinical practice. Key challenges include the low incidence rate of disease and the related high false-positive rate as well as poor image quality. Further evaluations of AI systems in primary care are needed.
An ATM/TRIM37/NEMO Axis Counteracts Genotoxicity by Activating Nuclear-to-Cytoplasmic NF-κB Signaling
Authors: Geyan Wu, Libing Song, Jinrong Zhu, Yameng Hu, Lixue Cao, Zhanyao Tan, Shuxia Zhang, Ziwen Li, Jun Li
Journal: Cancer Research (2018)

Blocking genotoxic stress-induced NF-κB activation would substantially enhance the anticancer efficiency of genotoxic chemotherapy. Unlike the well-established classical NF-κB pathway, the genotoxic agents-induced "nuclear-to-cytoplasmic" NF-κB pathway is initiated from the nucleus and transferred to the cytoplasm. However, the mechanism linking nuclear DNA damage signaling to cytoplasmic IKK activation remains unclear. Here, we report that TRIM37, a novel E3 ligase, plays a vital role in genotoxic activation of NF-κB via monoubiquitination of NEMO at K309 in the nucleus, consequently resulting in nuclear export of NEMO and IKK/NF-κB activation. Clinically, TRIM37 levels correlated positively with levels of activated NF-κB and expression of Bcl-xl and XIAP in esophageal cancer specimens, which also associated positively with clinical stage and tumor-node-metastasis classification and associated inversely with overall and relapse-free survival in patients with esophageal cancer. Overexpression of TRIM37 conferred resistance to the DNA-damaging anticancer drug cisplatin in vitro and in vivo through activation of the NF-κB pathway. Genotoxic stress-activated ATM kinase directly interacted with and phosphorylated TRIM37 in the cytoplasm, which induced translocation of TRIM37 into the nucleus, where it formed a complex with NEMO and TRAF6 via a TRAF6-binding motif (TBM). Importantly, blocking the ATM/TRIM37/NEMO axis via cell-penetrating TAT-TBM peptide abrogated genotoxic agent-induced NEMO monoubiquitination and NF-κB activity, resulting in hypersensitivity of cancer cells to genotoxic drugs. Collectively, our results unveil a pivotal role for TRIM37 in genotoxic stress and shed light on mechanisms of inducible chemotherapy resistance in cancer.Significance: In response to genotoxic stress, TRIM37 activates NF-κB signaling via monoubiquitination of NEMO, which subsequently promotes cisplatin chemoresistance and tumor relapse in cancer. Cancer Res; 78(22); 6399-412. ©2018 AACR.
Creation and implementation of a chief fellow of quality improvement in an oncology fellowship program.
Authors: Amy Little Jones, Joshua Michael Gulvin, Catherin Butler-Gunn, Robert A. Wolff, Alyssa G. Rieber
Journal: Journal of Clinical Oncology (2018)

152 Background: Educating oncology trainees in methods and practical applications of quality improvement (QI) is essential. QI is a key component of the ACGME core competency of systems based practice. Formal QI training helps oncologists deliver safe and effective cancer care. Creating a QI chief fellow position allows for patient safety and QI initiatives to be fellow-driven and focused on building lifelong, oncology specific, QI skills. Methods: Feedback was solicited from the fellowship’s executive committee and divisional leadership to establish the job description and funding. Nominations were sought from peer fellows, focusing on a fellow who has expressed interest in QI, patient safety, and/or value based healthcare. The chief fellow was tasked with implementing a QI educational curriculum, developing a fellowship-wide QI project, and representing the fellowship on institution-wide QI and patient safety committees. Results: 100% (14/14) graduating fellows completed the requirements for an institutional clinical QI certificate by the end of the second year of the QI chief implementation, compared to 0% before the start of the implementation. 100% (27/27) of 1 st and 2 nd year fellows completed online training modules in QI. Biannual root cause analyses for patient safety events were initiated as a standard part of educational curriculum. 4 separate fellow-initiated QI projects were completed: oral chemotherapy patient education, opioid use and documentation, survivorship care plans, and infusion center usage. Fellows’ selection to the institutional clinical safety and effectiveness course increased from 4.8% (2/42) to 9.8% (4/41) in since implementation of the QI chief fellow. Fellowship representation on institution-wide patient safety committee increased from 0 to 2. Conclusions: Implementing a QI chief fellow role in an oncology fellowship is a feasible way to integrate a QI curriculum and provide structure for fellows to obtain further certification in QI or patient safety during fellowship. Ongoing challenges include encouraging enthusiasm from the entire fellowship for QI projects, finding appropriate QI mentorship from faculty, and translating QI initiatives into academic products.