tbuckley/cabot-search huggingface dataset:
Evaluation of Clinical Outcomes of Sutureless vs Sutured Closure Techniques in Gastroschisis Repair
Authors: Russell G. Witt, Michael Zobel, Benjamin Padilla, Hanmin Lee, Tippi C. MacKenzie, Lan Vu
Journal: JAMA Surgery (2018)

<h3>Importance</h3> Sutureless gastroschisis repair offers an alternative to the traditional sutured method and has been associated with decreased intubation time. Published study results are inconsistent regarding the advantages of sutureless closure. <h3>Objective</h3> To compare the clinical outcomes of sutureless and sutured gastroschisis repair. <h3>Design, Setting, and Participants</h3> A single-center cohort review was performed of all consecutive patients (n = 97) who underwent gastroschisis repair from February 1, 2007, to April 30, 2017, at the University of California, San Francisco. Patients' medical records were evaluated for clinical characteristics and outcomes. Cases with incomplete data during initial hospitalization were excluded. <h3>Main Outcomes and Measures</h3> Length of hospital stay, time to full enteral feeds, total parenteral nutrition duration, days requiring intravenous analgesia, days intubated, wound infection rate, antibiotic treatment duration, rate of umbilical hernias that required an operation, and readmission rate. <h3>Results</h3> In total, 97 patients (47 [48%] were female and 50 [52%] were male with a mean [SD] age of 2.8 [2.8] days) underwent gastroschisis repair, of which 7 were excluded for incomplete medical record. Of the 90 patients included in the study, 50 (56%) underwent sutured closure and 40 (44%) underwent sutureless closure. No statistical difference was found between the sutured and sutureless groups in length of hospital stay (mean [SD] days, 43.9 [40.4] vs 36.7 [21.2];<i>P</i> = .71), time to full enteral feeds (mean [SD] days, 31.4 [20.2] vs 27.9 [17.3];<i>P</i> = .22), total parenteral nutrition duration (mean [SD] days, 33.5 [29.8] vs 27.4 [18.2];<i>P</i> = .23), wound infection rates (14 [28%] vs 10 [25%];<i>P</i> = .81), and readmission rates (5 [10%] vs 7 [18%];<i>P</i> = .36). The sutureless group, compared with the sutured group, had substantially fewer days receiving antibiotics (mean [SD], 7.2 [6.4] vs 12.4 [13.2];<i>P</i> = .003), fewer days intubated (mean [SD], 2.8 [3.3] vs 6.8 [1.3];<i>P</i> = .001), fewer days receiving intravenous analgesia (mean [SD], 4.2 [4.0] vs 7.1 [4.5];<i>P</i> = .003), and fewer patients that required silo reduction (25 [63%] vs 48 [96%];<i>P</i> &lt; .001). Sutureless closures, compared with the sutured technique, had considerably more umbilical hernias requiring surgical repair (5 [13%] vs 0;<i>P</i> = .02). <h3>Conclusions and Relevance</h3> Sutureless repair of gastroschisis appears to be associated with a statistically significant reduction in mechanical ventilation duration and pain medication requirements but may increase umbilical hernia risk. Multicenter randomized clinical trials are necessary to determine the true advantages of the sutureless approach.
Multiregion Sequencing Reveals the Genetic Heterogeneity and Evolutionary History of Osteosarcoma and Matched Pulmonary Metastases
Authors: Di Wang, Xiaohui Niu, Zhijie Wang, Cheng-Li Song, Zhen Huang, Ke-Neng Chen, Jianchun Duan, Hua Bai, Jiachen Xu, Jun Zhao, Yu Wang, Minglei Zhuo, X. Sunney Xie, Xiaozheng Kang, Yanhua Tian, Liangliang Cai, Jie-Fei Han, Tongtong An, Yu Sun, Shugeng Gao, Jun Zhao, Jianming Ying, Luhua Wang, Jie He, Jie Wang
Journal: Cancer Research (2018)

Osteosarcoma is the most common primary bone malignancy, and the lung is the most frequent site of metastasis. The limited understanding of the tumoral heterogeneity and evolutionary process of genomic alterations in pulmonary metastatic osteosarcoma impedes development of novel therapeutic strategies. Here we systematically illustrate the genomic disparities between primary tumors and corresponding pulmonary metastatic tumors by multiregional whole-exome and whole-genome sequencing in 86 tumor regions from 10 patients with osteosarcoma. Metastatic tumors exhibited a significantly higher mutational burden and genomic instability compared with primary tumors, possibly due to accumulation of mutations caused by a greater number of alterations in DNA damage response genes in metastatic tumors. Integrated analysis of the architecture and relationships of subclones revealed a dynamic mutational process and diverse dissemination patterns of osteosarcoma during pulmonary metastasis (6/10 with linear and 4/10 with parallel evolutionary patterns). All patients demonstrated more significant intertumoral rather than intratumoral heterogeneity between primary tumors and metastatic tumors. Mutated genes were enriched in the PI3K-Akt pathway at both the early and late stages of tumor evolution and in the MAPK pathway at the metastatic stage. Conversely, metastatic tumors showed improved immunogenicity, including higher neoantigen load, elevated PD-L1 expression, and tumor-infiltrating lymphocytes than the corresponding primary tumors. Our study is the first to report the dynamic evolutionary process and temporospatial tumor heterogeneity of pulmonary metastatic osteosarcoma, providing new insights for diagnosis and potential therapeutic strategies for pulmonary metastasis. SIGNIFICANCE: High-throughput sequencing of primary and metastatic osteosarcoma provides new insights into the diagnosis of and potential clinical therapeutic strategies for pulmonary metastasis.
Abstract 17820: Overexpression of Nos1ap Alters Qtc Intervals and Risk of Arrhythmias in Mice
Authors: Tatjana Williams, Daniel Oppelt, Paula Anahi Arias-Loza, Marco Abesser, Joachim Schmitt, Kai Schuh, Oliver Ritter
Journal: Circulation (2015)

Rationale: The QT interval duration (QTc) reflects cardiac depolarization. It may predispose individuals to ventricular tachycardia and sudden cardiac death if prolonged (long QTc), shortened (short QTc) or otherwise unregularly. Whole-genome association studies have linked genetic variations in the neuronal nitric oxide synthase adapter protein NOS1AP to variations in QTc intervals and sudden cardiac death. Hypothesis: We hypothesize NOS1AP functions as an L-type-Ca2+ channel modulator via its interaction with the neuronal nitric oxide synthase NOS1. Therefore, alterations in myocardial NOS1AP expression should temper with QTc intervals and increase susceptibility to rhythm disorders. Methods and results: We generated conditional double transgenic mice by crossbreeding pTRE-6xHN-Nos1AP animals with α-MHC-tTA mice; NOS1AP expression is therefore restricted to cardiomyocytes and under control of doxycycline (Tet-Off system). NOS1AP overexpressing animals were investigated with the main focus upon electrophysiology. Heart rates were similar in induced and non-induced animals. NOS1AP overexpression resulted in arrhythmia already under basal conditions; we observed ventricular fibrillation and tachycardia. There was a clear decrease of QTc intervals in NOS1AP overexpressing mice paralleled by a significantly reduced survival (only 56% after 12 weeks vs 100% in non-induced mice. QTc alterations and accompanied deaths subsided upon readministration of doxycycline. We also investigated the functional effect of the human SNP rs16847548 (T/C). We found that this SNP decreased NOS1AP transcriptional activity in vitro and therefore suggest this leads to a decrease in NOS1AP expression in humans. Conclusion: Myocardial overexpression of NOS1AP leads to short QTc syndrome with increased susceptibility to atrial and ventricular rhythm disorders and cardiac death. SNP rs16847548 in NOS1AP resulted in less NOS1AP promoter activity in vitro which could explain the alteration in QTc intervals. In summary, not only mutations in ion channels themselves but also genetic alterations in the expression of ion channel modulators such as NOS1AP, have an impact on QTc intervals.
Author Correction: The digital scribe
Authors: Enrico Coiera, Baki Kocaballi, John Halamka, Liliana Laranjo
Journal: npj Digital Medicine (2018)

The original version of the published Article contained an error in the spelling of the third Author’s name. “John Halamaka” has been changed to “John Halamka”. This has been corrected in the HTML and PDF version of the Article.
Targeting Mitochondrial Dysfunction and Oxidative Stress in Activated Microglia using Dendrimer-Based Therapeutics
Authors: Anjali Sharma, Kevin Liaw, Rishi Sharma, Zhi Zhang, Sujatha Kannan, Rangaramanujam M. Kannan
Journal: Theranostics (2018)

Mitochondrial oxidative stress is associated with many neurodegenerative diseases, such as traumatic brain injury (TBI). Targeted delivery of antioxidants to mitochondria has failed to translate into clinical success due to their nonspecific cellular localization, poor transport properties across multiple biological barriers, and associated side effects. These challenges, coupled with the complex function of the mitochondria, create the need for innovative delivery strategies. Methods: Neutral hydroxyl-terminated polyamidoamine (PAMAM) dendrimers have shown significant potential as nanocarriers in multiple brain injury models. N-acetyl cysteine (NAC) is a clinically used antioxidant and anti-inflammatory agent which has shown significant potency when delivered in a targeted manner. Here we present a mitochondrial targeting hydroxyl PAMAM dendrimer-drug construct (TPP-D-NAC) with triphenyl-phosphonium (TPP) for mitochondrial targeting and NAC for targeted delivery to mitochondria in injured glia. Co-localization and mitochondrial content of mitochondria-targeted and unmodified dendrimer were assessed in microglia and macrophages in vitro via immunohistochemistry and fluorescence quantification. Therapeutic improvements of TPP-D-NAC over dendrimer-NAC conjugate (D-NAC) and free NAC were evaluated in vitro in microglia under oxidative stress challenge. In vivo neuroinflammation targeting was confirmed in a rabbit model of TBI. Results: TPP-conjugated dendrimer co-localized significantly more with mitochondria than unmodified dendrimer without altering overall levels of cellular internalization. This targeting capability translated to significant improvements in the attenuation of oxidative stress by TPP-D-NAC compared to D-NAC and free NAC. Upon systemic administration in a rabbit TBI model, TPP-conjugated dendrimer co-localized specifically with mitochondria in activated microglia and macrophages in the white matter of the ipsilateral/injured hemisphere, confirming its BBB penetration and glial targeting capabilities. Conclusion: D-NAC has shown promising efficacy in many animal models of neurodegeneration, and this work provides evidence that modification for mitochondrial targeting can further enhance its therapeutic efficacy, particularly in diseases where oxidative stress-induced glial cell death plays a significant role in disease progression.
Impact of Peer Support on Acute Care Visits and Hospitalizations for Individuals With Diabetes and Depressive Symptoms: A Cluster-Randomized Controlled Trial
Authors: Andrea L. Cherrington, Yulia Khodneva, Joshua S. Richman, Susan J. Andreae, Christopher Gamboa, Monika M. Safford
Journal: Diabetes Care (2018)

OBJECTIVE Comorbid depression is associated with increased health care utilization and cost. We examined the effects of peer support on acute care (AC) and hospital utilization in individuals with diabetes with or without depressive symptoms. RESEARCH DESIGN AND METHODS This was a cluster-randomized controlled trial conducted in 2010–2012, with the clusters being practices and their surrounding communities. Adults with type 2 diabetes who wanted help with self-management were eligible to participate. Those without a doctor, with limited life expectancy, with plans to move within the next year, and with an unwillingness to work with a peer advisor were excluded. Intervention participants received 1 year of peer support. Control participants received usual care. The Patient Health Questionnaire (PHQ-8) (range 0–24; 5 indicates mild and 10 indicates moderate depressive symptoms) assessed depressive symptoms. AC and hospital utilization were measured by self-report. Data were collected at baseline, 6 months, and 12 months. Quasi-Poisson regression using generalized estimating equations examined differences in utilization per year attributable to the intervention for those with and without mild depressive symptoms (and separately, moderate depressive symptoms), controlling for imbalance across treatment arms. RESULTS At baseline, half of the sample reported mild depressive symptoms (52% intervention and 48% control, P = 0.37), a quarter reported moderate depressive symptoms (25% intervention and 26% control, P = 1.0), and there were no significant differences in utilization. A total of 168 intervention (six clusters) and 187 control (five clusters) participants had follow-up data. In individuals with mild depressive symptoms, the incident rate ratio (IRR) for hospitalization among intervention compared with control was 0.26 (95% CI 0.08–0.84) per 10 patient-years. The IRR for AC was 0.55 (95% CI 0.28–1.07) per 10 person-years. Findings were similar for individuals with moderate depressive symptoms. CONCLUSIONS Peer support lowered AC visits and hospitalizations for individuals with depressive symptoms but not for those without depressive symptoms; these findings can guide resource allocation for population health management.
Murine Norovirus Infection Induces TH1 Inflammatory Responses to Dietary Antigens
Authors: Romain Bouziat, Scott B. Biering, Elaine Kouame, Kishan A. Sangani, Soowon Kang, Jordan D. Ernest, Mukund Varma, Judy J. Brown, Kelly Urbanek, Terence S. Dermody, Aylwin Ng, Reinhard Hinterleitner, Seungmin Hwang, Bana Jabri
Journal: Cell Host & Microbe (2018)
Impact of the Diabetes Canada Guideline Dissemination Strategy on the Prescription of Vascular Protective Medications: A Retrospective Cohort Study, 2010–2015
Authors: Alanna V. Rigobon, Sumeet Kalia, Jennica Nichols, Babak Aliarzadeh, Michelle Greiver, Rahim Moineddin, Frank Sullivan, Catherine Yu
Journal: Diabetes Care (2018)

OBJECTIVE The 2013 Diabetes Canada guidelines launched targeted dissemination tools and a simple assessment for vascular protection. We aimed to 1) examine changes associated with the launch of the 2013 guidelines and additional dissemination efforts in the rates of vascular protective medications prescribed in primary care for older patients with diabetes and 2) examine differences in the rates of prescriptions of vascular protective medications by patient and provider characteristics. RESEARCH DESIGN AND METHODS The study population included patients (≥40 years of age) from the Canadian Primary Care Sentinel Surveillance Network (CPCSSN) with type 2 diabetes and at least one clinic visit from April 2010 to December 2015. An interrupted time series analysis was used to assess the proportion of eligible patients prescribed a statin, ACE inhibitor (ACEI)/angiotensin receptor blocker (ARB), or antiplatelet prescription in each quarter. Proton pump inhibitor (PPI) prescriptions were the reference control. RESULTS A dynamic cohort was used where participants were enrolled each quarter using a prespecified set of conditions (range 25,985–70,693 per quarter). There were no significant changes in statin (P = 0.43), ACEI/ARB (P = 0.42), antiplatelet (P = 0.39), or PPI (P = 0.16) prescriptions at baseline (guideline intervention). After guideline publication, there was a significant change in slope for statin (−0.52% per quarter, SE 0.15, P &amp;lt; 0.05), ACEI/ARB (−0.38% per quarter, SE 0.13, P &amp;lt; 0.05), and reference PPI (−0.18% per quarter, SE 0.05, P &amp;lt; 0.05) prescriptions. CONCLUSIONS There was a decrease in prescribing trends over time that was not specific to vascular protective medications. More effective knowledge translation strategies are needed to improve vascular protection in diabetes in order for patients to receive the most effective interventions.
Increasing lean muscle mass in mice via nanoparticle-mediated hepatic delivery of follistatin mRNA
Authors: Canan Schumann, Duc X. Nguyen, Mason Norgard, Yulia Bortnyak, Tetiana Korzun, Stephanie Chan, Anna St. Lorenz, Abraham S. Moses, Hassan A. Albarqi, Leon Wong, Katherine Michaelis, Xinxia Zhu, Adam W. G. Alani, Olena R. Taratula, Stephanie Krasnow, Daniel L. Marks, Oleh Taratula
Journal: Theranostics (2018)

Muscle atrophy occurs during chronic diseases, resulting in diminished quality of life and compromised treatment outcomes.There is a high demand for therapeutics that increase muscle mass while abrogating the need for special dietary and exercise requirements.Therefore, we developed an efficient nanomedicine approach capable of increasing muscle mass.Methods: The therapy is based on nanoparticle-mediated delivery of follistatin messenger RNA (mRNA) to the liver after subcutaneous administration.The delivered mRNA directs hepatic cellular machinery to produce follistatin, a glycoprotein that increases lean mass through inhibition of negative regulators of muscle mass (myostatin and activin A).These factors are elevated in numerous disease states, thereby providing a target for therapeutic intervention.Results: Animal studies validated that mRNA-loaded nanoparticles enter systemic circulation following subcutaneous injection, accumulate and internalize in the liver, where the mRNA is translated into follistatin.Follistatin serum levels were elevated for 72 h post injection and efficiently reduced activin A and myostatin serum concentrations.After eight weeks of repeated injections, the lean mass of mice in the treatment group was ~10% higher when compared to that of the controls. Conclusion:Based on the obtained results demonstrating an increased muscle mass as well as restricted fat accumulation, this nanoplatform might be a milestone in the development of mRNA technologies and the treatment of muscle wasting disorders.
RNAi Rollercoaster Begins to Reap Therapies
Authors: Bridget M. Kuehn
Journal: JAMA (2018)

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Genebank genomics highlights the diversity of a global barley collection
Authors: Sara G. Milner, Matthias Jost, Shin Taketa, Elena Rey Mazón, Axel Himmelbach, Markus Oppermann, Stephan Weise, Helmut Knüpffer, Martín Basterrechea, Patrick König, Danuta Schüler, Rajiv Sharma, Raj K. Pasam, Twan Rutten, Ganggang Guo, Dongdong Xu, Jing Zhang, Gerhard Herren, Thomas Müller, Simon G. Krattinger, Beat Keller, Yong Jiang, Maria Y. González, Yusheng Zhao, Antje Habekuß, Sandra Färber, Frank Ordon, Matthias Lange, Andreas Börner, Andreas Graner, Jochen C. Reif, Uwe Scholz, Martin Mascher, Nils Stein
Journal: Nature Genetics (2018)
Older Patients (pts) with Previously Untreated Classical Hodgkin Lymphoma (cHL): A Detailed Analysis from the Phase 3 ECHELON-1 Study
Authors: Andrew M. Evens, Joseph M. Connors, Anas Younes, Stephen M. Ansell, Won Seog Kim, John Radford, Tatyana A. Feldman, Joseph Tuscano, Kerry J Savage, Yasuhiro Oki, Andrew P. Grigg, Christopher Pocock, Monika Dlugosz-Danecka, Keenan Fenton, Gerald Engley, Rachael Liu, Harry Miao, Hina Jolin, Ashish Gautam, Andrea Gallamini
Journal: Blood (2018)
Cognitive, Neurological, and Behavioral Features in Adults With <i>KCNJ11</i> Neonatal Diabetes
Authors: Pamela Bowman, Jacob Day, Lorna Torrens, Maggie H. Shepherd, Bridget A. Knight, Tamsin J. Ford, Sarah E. Flanagan, Ali Chakera, Andrew T. Hattersley, Adam Zeman
Journal: Diabetes Care (2018)

OBJECTIVE Central nervous system (CNS) features in children with permanent neonatal diabetes (PNDM) due to KCNJ11 mutations have a major impact on affected families. Sulfonylurea therapy achieves outstanding metabolic control but only partial improvement in CNS features. The effects of KCNJ11 mutations on the adult brain and their functional impact are not well understood. We aimed to characterize the CNS features in adults with KCNJ11 PNDM compared with adults with INS PNDM. RESEARCH DESIGN AND METHODS Adults with PNDM due to KCNJ11 mutations (n = 8) or INS mutations (n = 4) underwent a neurological examination and completed standardized neuropsychological tests/questionnaires about development/behavior. Four individuals in each group underwent a brain MRI scan. Test scores were converted to Z scores using normative data, and outcomes were compared between groups. RESULTS In individuals with KCNJ11 mutations, neurological examination was abnormal in seven of eight; predominant features were subtle deficits in coordination/motor sequencing. All had delayed developmental milestones and/or required learning support/special schooling. Half had features and/or a clinical diagnosis of autism spectrum disorder. KCNJ11 mutations were also associated with impaired attention, working memory, and perceptual reasoning and reduced intelligence quotient (IQ) (median IQ KCNJ11 vs. INS mutations 76 vs. 111, respectively; P = 0.02). However, no structural brain abnormalities were noted on MRI. The severity of these features was related to the specific mutation, and they were absent in individuals with INS mutations. CONCLUSIONS KCNJ11 PNDM is associated with specific CNS features that are not due to long-standing diabetes, persist into adulthood despite sulfonylurea therapy, and represent the major burden from KCNJ11 mutations.
Abstract 14154: Sacubitril/Valsartan/ Improves Left Ventricular Mitochondrial Function in Dogs With Experimentally-Induced Cardiorenal Syndrome
Authors: Ramesh Gupta, Vinita Singh-Gupta, Kefei Zhang, Jiang Xu, Hani N Sabbah
Journal: Circulation (2017)

Introduction: Sacubitril/Valsartan (S/Val) is a combined angiotensin-II receptor blocker (Val) and neprilysin inhibitor (S) and was shown to reduce the risk of cardiovascular death or heart failure...
A Subset of Mesotheliomas With Improved Survival Occurring in Carriers of<i>BAP1</i>and Other Germline Mutations
Authors: Sandra Pastorino, Yoshie Yoshikawa, Harvey I. Pass, Mitsuru Emi, Masaki Nasu, Ian Pagano, Yasutaka Takinishi, Ryuji Yamamoto, Michael Minaai, Tomoko Hashimoto-Tamaoki, Masaki Ohmuraya, Keisuke Goto, Chandra Goparaju, Kavita Y. Sarin, Mika Tanji, Angela Bononi, Andrea Napolitano, Giovanni Gaudino, Mary Hesdorffer, Haining Yang, Michele Carbone
Journal: Journal of Clinical Oncology (2018)

We hypothesized that four criteria could help identify malignant mesotheliomas (MMs) most likely linked to germline mutations of BAP1 or of other genes: family history of MM, BAP1-associated cancers, or multiple malignancies; or age younger than 50 years.