Publications by authors named "James Hayes"

47 Publications

Considering the long-term respiratory effects of Covid-19.

Authors:
James P Hayes

Occup Med (Lond) 2021 Jan 22. Epub 2021 Jan 22.

Respiratory Unit, Cavan Monaghan Hospital, RCSI Group, Lisdaran, Cavan H12 Y7W1, Ireland.

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http://dx.doi.org/10.1093/occmed/kqaa224DOI Listing
January 2021

Validation of prostate cancer risk variants rs10993994 and rs7098889 by CRISPR/Cas9 mediated genome editing.

Gene 2021 Feb 26;768:145265. Epub 2020 Oct 26.

Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Program in Cancer Biology and Genetics and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, United States. Electronic address:

GWAS have identified numerous SNPs associated with prostate cancer risk. One such SNP is rs10993994. It is located in the β-microseminoprotein (MSMB) promoter region, mediates MSMB prostate secretion levels, and is linked to mRNA expression changes in both MSMB and the adjacent gene NCOA4. In addition, our previous work showed a second SNP, rs7098889, is in positive linkage disequilibrium with rs10993994 and associated with MSMB expression independent of rs10993994. Here, we generate a series of clones with single alleles removed by double guide RNA (gRNA) mediated CRISPR/Cas9 deletions, through which we demonstrate that each of these SNPs independently and greatly alters MSMB expression in an allele-specific manner. We further show that these SNPs have no substantial effect on the expression of NCOA4. These data demonstrate that a single SNP can have a large effect on gene expression and illustrate the importance of functional validation studies to deconvolute observed correlations. The method we have developed is generally applicable to test any SNP for which a relevant heterozygous cell line is available. AUTHOR SUMMARY: In pursuing the underlying biological mechanism of prostate cancer pathogenesis, scientists utilized the existence of common single nucleotide polymorphisms (SNPs) in the human genome as genetic markers to perform large scale genome wide association studies (GWAS) and have so far identified more than a hundred prostate cancer risk variants. Such variants provide an unbiased and systematic new venue to study the disease mechanism, and the next big challenge is to translate these genetic associations to the causal role of altered gene function in oncogenesis. The majority of these variants are waiting to be studied and lots of them may act in oncogenesis through gene expression regulation. To prove the concept, we took rs10993994 and its linked rs7098889 as an example and engineered single cell clones by allelic-specific CRISPR/Cas9 deletion to separate the effect of each allele. We observed that a single nucleotide difference would lead to surprisingly high level of MSMB gene expression change in a gene specific and cell-type specific manner. Our study strongly supports the notion that differential level of gene expression caused by risk variants and their associated genetic locus play a major role in oncogenesis and also highlights the importance of studying the function of MSMB encoded β-MSP in prostate cancer pathogenesis.
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http://dx.doi.org/10.1016/j.gene.2020.145265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796996PMC
February 2021

Tuning monoclonal antibody galactosylation using Raman spectroscopy-controlled lactic acid feeding.

Biotechnol Prog 2021 Jan 10;37(1):e3085. Epub 2020 Oct 10.

Microbial & Cell Culture Development, GlaxoSmithKline, King of Prussia, Pennsylvania, USA.

A key aspect of large-scale production of biotherapeutics is a well-designed and consistently-executed upstream cell culture process. Process analytical technology tools provide enhanced monitoring and control capabilities to support consistent process execution, and also have potential to aid in maintenance of product quality at desired levels. One such tool, Raman spectroscopy, has matured as a useful technique to achieve real-time monitoring and control of key cell culture process attributes. We developed a Raman spectroscopy-based nutrient control strategy to enable dual control of lactate and glucose levels for a fed-batch CHO cell culture process for monoclonal antibody (mAb) production. To achieve this, partial least squares-based chemometric models for real-time prediction of glucose and lactate concentrations were developed and deployed in feedback control loops. In particular, feeding of lactic acid post-metabolic shift was investigated based on previous work that has shown the impact of lactate levels on ammonium as well as mAb product quality. Three feeding strategies were assessed for impact on cell metabolism, productivity, and product quality: bolus-fed glucose, glucose control at 4 g/L, or simultaneous glucose control at 4 g/L and lactate control at 2 g/L. The third feeding strategy resulted in a significant reduction in ammonium levels (68%) while increasing mAb galactosylation levels by approximately 50%. This work demonstrated that when deployed in a cell culture process, Raman spectroscopy is an effective technique for simultaneous control of multiple nutrient feeds, and that lactic acid feeding can have a positive impact on both cell metabolism and mAb product quality.
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http://dx.doi.org/10.1002/btpr.3085DOI Listing
January 2021

Understanding the Experience of Cancer Pain From the Perspective of Patients and Family Caregivers to Inform Design of an In-Home Smart Health System: Multimethod Approach.

JMIR Form Res 2020 Aug 26;4(8):e20836. Epub 2020 Aug 26.

The George Washington University School of Engineering & Applied Science, Washington, DC, United States.

Background: Inadequately managed pain is a serious problem for patients with cancer and those who care for them. Smart health systems can help with remote symptom monitoring and management, but they must be designed with meaningful end-user input.

Objective: This study aims to understand the experience of managing cancer pain at home from the perspective of both patients and family caregivers to inform design of the Behavioral and Environmental Sensing and Intervention for Cancer (BESI-C) smart health system.

Methods: This was a descriptive pilot study using a multimethod approach. Dyads of patients with cancer and difficult pain and their primary family caregivers were recruited from an outpatient oncology clinic. The participant interviews consisted of (1) open-ended questions to explore the overall experience of cancer pain at home, (2) ranking of variables on a Likert-type scale (0, no impact; 5, most impact) that may influence cancer pain at home, and (3) feedback regarding BESI-C system prototypes. Qualitative data were analyzed using a descriptive approach to identity patterns and key themes. Quantitative data were analyzed using SPSS; basic descriptive statistics and independent sample t tests were run.

Results: Our sample (n=22; 10 patient-caregiver dyads and 2 patients) uniformly described the experience of managing cancer pain at home as stressful and difficult. Key themes included (1) unpredictability of pain episodes; (2) impact of pain on daily life, especially the negative impact on sleep, activity, and social interactions; and (3) concerns regarding medications. Overall, taking pain medication was rated as the category with the highest impact on a patient's pain (=4.79), followed by the categories of wellness (=3.60; sleep quality and quantity, physical activity, mood and oral intake) and interaction (=2.69; busyness of home, social or interpersonal interactions, physical closeness or proximity to others, and emotional closeness and connection to others). The category related to environmental factors (temperature, humidity, noise, and light) was rated with the lowest overall impact (=2.51). Patients and family caregivers expressed receptivity to the concept of BESI-C and reported a preference for using a wearable sensor (smart watch) to capture data related to the abrupt onset of difficult cancer pain.

Conclusions: Smart health systems to support cancer pain management should (1) account for the experience of both the patient and the caregiver, (2) prioritize passive monitoring of physiological and environmental variables to reduce burden, and (3) include functionality that can monitor and track medication intake and efficacy; wellness variables, such as sleep quality and quantity, physical activity, mood, and oral intake; and levels of social interaction and engagement. Systems must consider privacy and data sharing concerns and incorporate feasible strategies to capture and characterize rapid-onset symptoms.
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http://dx.doi.org/10.2196/20836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481872PMC
August 2020

An Ultra-Microporous Metal-Organic Framework with Exceptional Xe Capacity.

Chemistry 2020 Oct 16;26(55):12544-12548. Epub 2020 Sep 16.

Pacific Northwest National Laboratory, Richland, Washington, 99354, United States.

Molecular confinement plays a significant effect on trapped gas and solvent molecules. A fundamental understanding of gas adsorption within the porous confinement provides information necessary to design a material with improved selectivity. In this regard, metal-organic framework (MOF) adsorbents are ideal candidate materials to study confinement effects for weakly interacting gas molecules, such as noble gases. Among the noble gases, xenon (Xe) has practical applications in the medical, automotive and aerospace industries. In this Communication, we report an ultra-microporous nickel-isonicotinate MOF with exceptional Xe uptake and selectivity compared to all benchmark MOF and porous organic cage materials. The selectivity arises because of the near perfect fit of the atomic Xe inside the porous confinement. Notably, at low partial pressure, the Ni-MOF interacts very strongly with Xe compared to the closely related Krypton gas (Kr) and more polarizable CO . Further Xe NMR suggests a broad isotropic chemical shift due to the reduced motion as a result of confinement.
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http://dx.doi.org/10.1002/chem.202002331DOI Listing
October 2020

Leveraging Smart Health Technology to Empower Patients and Family Caregivers in Managing Cancer Pain: Protocol for a Feasibility Study.

JMIR Res Protoc 2019 Dec 9;8(12):e16178. Epub 2019 Dec 9.

The George Washington University School of Engineering & Applied Science, Washington, DC, United States.

Background: An estimated 60%-90% of patients with cancer experience moderate to severe pain. Poorly managed cancer pain negatively affects the quality of life for both patients and their family caregivers and can be a particularly challenging symptom to manage at home. Mobile and wireless technology ("Smart Health") has significant potential to support patients with cancer and their family caregivers and empower them to safely and effectively manage cancer pain.

Objective: This study will deploy a package of sensing technologies, known as Behavioral and Environmental Sensing and Intervention for Cancer (BESI-C), and evaluate its feasibility and acceptability among patients with cancer-family caregiver dyads. Our primary aims are to explore the ability of BESI-C to reliably measure and describe variables relevant to cancer pain in the home setting and to better understand the dyadic effect of pain between patients and family caregivers. A secondary objective is to explore how to best share collected data among key stakeholders (patients, caregivers, and health care providers).

Methods: This descriptive two-year pilot study will include dyads of patients with advanced cancer and their primary family caregivers recruited from an academic medical center outpatient palliative care clinic. Physiological (eg, heart rate, activity) and room-level environmental variables (ambient temperature, humidity, barometric pressure, light, and noise) will be continuously monitored and collected. Behavioral and experiential variables will be actively collected when the caregiver or patient interacts with the custom BESI-C app on their respective smart watch to mark and describe pain events and answer brief, daily ecological momentary assessment surveys. Preliminary analysis will explore the ability of the sensing modalities to infer and detect pain events. Feasibility will be assessed by logistic barriers related to in-home deployment, technical failures related to data capture and fidelity, smart watch wearability issues, and patient recruitment and attrition rates. Acceptability will be measured by dyad perceptions and receptivity to BESI-C through a brief, structured interview and surveys conducted at deployment completion. We will also review summaries of dyad data with participants and health care providers to seek their input regarding data display and content.

Results: Recruitment began in July 2019 and is in progress. We anticipate the preliminary results to be available by summer 2021.

Conclusions: BESI-C has significant potential to monitor and predict pain while concurrently enhancing communication, self-efficacy, safety, and quality of life for patients and family caregivers coping with serious illness such as cancer. This exploratory research offers a novel approach to deliver personalized symptom management strategies, improve patient and caregiver outcomes, and reduce disparities in access to pain management and palliative care services.

International Registered Report Identifier (irrid): DERR1-10.2196/16178.
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http://dx.doi.org/10.2196/16178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928698PMC
December 2019

The burden of urological disease in Zomba, Malawi: A needs assessment in a sub-Saharan tertiary care center.

Can Urol Assoc J 2020 Jan 17;14(1):E6-E12. Epub 2019 Jun 17.

Division of Urology, Michael Garron Hospital, Toronto, ON, Canada.

Introduction: A large part of the developing world continues to lack access to surgical care. Urology remains one of the least represented surgical subspecialties in global health. To begin understanding the burden of urological illness in sub-Saharan Africa, we sought to characterize all patients presenting to a tertiary care hospital in Malawi with a urological diagnosis or related complaint in the past year.

Methods: Retrospective review of the surgical clinic and surgical theater record books at Zomba Central Hospital (ZCH) was performed over a one-year time span. Patients presenting with urological diagnoses or undergoing a urological procedure under local or general anesthetic in the operating theater were identified and entered into a database.

Results: We reviewed 440 clinical patients. The most common clinical presentations were for urinary retention (34.7%) and lower urinary tract symptoms (15.5%). A total of 182 surgical cases were reviewed. The most common diagnoses for surgical patients were urethral stricture disease (22%), bladder masses (17%), and benign prostatic hyperplasia (BPH) symptoms (14.8%). Urethral stricture-related procedures, including direct visual internal urethrotomy and urethral dilatation, were the most common (14.2% and 7.7%, respectively). BPH-related procedures, including simple prostatectomy and transurethral resection of the prostate were the second most common (6.7% and 8.2%, respectively).

Conclusions: Urethral stricture disease, BPH, and urinary retention represent the clinical diagnoses with the highest burden of visits. Despite these numbers, few definitive procedures are performed annually. Further focus on urological training in sub-Saharan Africa should focus on these conditions and their surgical management.
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http://dx.doi.org/10.5489/cuaj.5837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955180PMC
January 2020

Case report: Pulmonary amyloidosis in two patients with chronic obstructive lung disease (COPD).

Respir Med Case Rep 2019 9;28:100897. Epub 2019 Jul 9.

Cavan and Monaghan Hospital, Ireland RCSI Group.

We present two cases of patients with chronic obstructive lung disease (COPD) who developed different forms of pulmonary amyloidosis. In both cases malignancy was considered as primary diagnosis. Transthoracic biopsy confirmed pulmonary amyloidosis. In the first case the patient presented with progressive dyspnoea over a two years period. Initial assessment was consistent with a diagnosis of COPD but progressive changes in symptoms and lung functions and subsequently CT Thorax revealed possible airway obstruction. Bronchoscopy confirmed an obstructive lesion initially considered to be malignant but was found to be due to tracheobronchial amyloid (TBA). Our second case presented with symptoms and signs consistent with COPD. Follow up chest X-rays revealed a pulmonary nodule which on CT examination was considered to be malignant. Transthoracic biopsy confirmed pulmonary amyloidosis. Although it is a rare condition amyloid disease should to consider as the part of the differential diagnosis in COPD patients who present with signs and symptoms consistent with pulmonary malignancy.
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http://dx.doi.org/10.1016/j.rmcr.2019.100897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6630020PMC
July 2019

Investigation of non-community stakeholders regarding community engagement and environmental malodour.

Sci Total Environ 2019 May 11;665:546-556. Epub 2019 Feb 11.

UNSW Water Research Centre, School of Civil and Environmental Engineering, University of New South Wales, Sydney, NSW 2052, Australia.

Research into industry-community relationships have focused almost exclusively on the ways in which communities responds to actions from industries. This has led to a paucity of understanding with regards to how community engagement and malodour amelioration practices have been adopted by industry personnel, as well as the attitudes and beliefs of non-community stakeholders in general. In this study, a survey to water industry personnel was distributed to three Australian water utilities in South-Eastern Australia and a semi-structured interview process was carried out with plant managers at six wastewater treatment plants. It was observed that best practice has not yet been established with regards to community engagement and odour amelioration, and that water industry personnel in general had a poor understanding of these concepts. Recommendations for how this situation could be improved, and how non-community stakeholders investigated, are discussed.
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http://dx.doi.org/10.1016/j.scitotenv.2019.02.137DOI Listing
May 2019

Framework for the use of odour wheels to manage odours throughout wastewater biosolids processing.

Sci Total Environ 2018 Sep 5;634:214-223. Epub 2018 Apr 5.

School of Civil and Environmental Engineering, UNSW Sydney, Sydney, Australia.

Odorous emissions from wastewater biosolids processing can cause nuisance impacts to the surrounding community. Odour Wheels are an effective tool for environmental odour management, but have yet to be provided for wastewater biosolids processing. Emissions throughout the biosolids processing from eight wastewater treatment plants, each with different unit operation configurations, were surveyed to identify odorants present and their olfactory properties. Chemical and olfactory methods identified a range of odorants and odours emitted throughout biosolids processing. Within the biosolids processing locations studied Sulfur type odours, described as rotten eggs or cabbage, were typically encountered. However, there was also a varying presence of Rancid/putrid and Faecal/manure type odours. Odour Wheels were generated to communicate both the olfactory and chemical components of emissions which were measured throughout biosolids processing. Examples based on the operation of the eight wastewater treatment plants were used to demonstrate how the Odour Wheels can be used as an onsite odour management aid. The paper demonstrates how Odour Wheels can be prepared using chemical and olfactory measurements and then used to communicate olfactory properties, as well as identify the causes of nuisance emissions throughout biosolids processing at wastewater treatment plants. The linking of odours and odorants to process conditions throughout biosolids processing facilitates effective abatement and management practices.
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http://dx.doi.org/10.1016/j.scitotenv.2018.03.352DOI Listing
September 2018

Intsy: a low-cost, open-source, wireless multi-channel bioamplifier system.

Physiol Meas 2018 03 29;39(3):035008. Epub 2018 Mar 29.

Department of Physics and Engineering, Washington and Lee University, Lexington, VA 24450, United States of America.

Objective: Multi-channel electrical recordings of physiologically generated signals are common to a wide range of biomedical fields. The aim of this work was to develop, validate, and demonstrate the practical utility of a high-quality, low-cost 32/64-channel bioamplifier system with real-time wireless data streaming capability.

Approach: The new 'Intsy' system integrates three main off-the-shelf hardware components: (1) Intan RHD2132 bioamplifier; (2) Teensy 3.2 microcontroller; and (3) RN-42 Bluetooth 2.1 module with a custom LabView interface for real-time data streaming and visualization. Practical utility was validated by measuring serosal gastric slow waves and surface EMG on the forearm with various contraction force levels. Quantitative comparisons were made to a gold-standard commercial system (Biosemi ActiveTwo).

Main Results: Intsy signal quality was quantitatively comparable to that of the ActiveTwo. Recorded slow wave signals had high SNR (24  ±  2.7 dB) and wavefront propagation was accurately mapped. EMG spike bursts were characterized by high SNR (⩾10 dB) and activation timing was readily identified. Stable data streaming rates achieved were 3.5 kS s for wireless and 64 kS s for USB-wired transmission.

Significance: Intsy has the highest channel count of any existing open-source, wireless-enabled module. The flexibility, portability and low cost ($1300 for the 32-channel version, or $2500 for 64 channels) of this new hardware module reduce the entry barrier for a range of electrophysiological experiments, as are typical in the gastrointestinal (EGG), cardiac (ECG), neural (EEG), and neuromuscular (EMG) domains.
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http://dx.doi.org/10.1088/1361-6579/aaad51DOI Listing
March 2018

Synthesis and Physicochemical Characterization of the One-Carbon Carrier 10-Formyltetrahydrofolate; A Reference Standard for Metabolomics.

Metabolomics 2017 Oct 31;13(10). Epub 2017 Aug 31.

Research Triangle Institute, P.O. Box 12194, Research Triangle Park, NC 27709.

Introduction: Metabolomics analysis depends on the identification and validation of specific metabolites. This task is significantly hampered by the absence of well-characterized reference standards. The one-carbon carrier 10-formyltetrahydrofolate acts as a donor of formyl groups in anabolism where it is a substrate in formyltransferase reactions in purine biosynthesis. It has been reported as an unstable substance and is currently unavailable as a reference standard for metabolomics analysis.

Objectives: The current study was undertaken to provide the metabolomics community thoroughly characterized 10-formyltetrahydrofolate along with analytical methodology and guidelines for its storage and handling.

Methods: Anaerobic base treatment of 5,10-methenyltetrahydrofolate chloride in the presence of anti-oxidant was utilized to prepare 10-formyltetrahydrofolate.

Results: Pure 10-formyltetrahydrofolate has been prepared and physicochemically characterized. Conditions toward maintaining the stability of a solution of the dipotassium salt of 10-formyltetrahydrofolate in solution have been determined.

Conclusion: This study describes the facile preparation of pure (>90%) 10-formyltetrahydrofolate, its qualitative physicochemical characterization, as well as conditions to enable its use as a reference standard in physiologic samples.
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http://dx.doi.org/10.1007/s11306-017-1256-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791523PMC
October 2017

Prediction of sub-surface Ar concentrations at locations in the Northwestern United States.

J Environ Radioact 2018 Jan 23;181:1-7. Epub 2017 Oct 23.

Pacific Northwest National Laboratory, 902 Battelle Blvd, Richland, WA 99454, USA.

The Comprehensive Nuclear-Test-Ban Treaty, which is intended to prevent nuclear weapon test explosions and any other nuclear explosions, includes a verification regime, which provides monitoring to identify potential nuclear explosions. The presence of elevated Ar is one way to identify subsurface nuclear explosive testing. However, the naturally occurring formation of Ar in the subsurface adds a complicating factor. Prediction of the naturally occurring concentration of Ar can help to determine if a measured Ar concentration is elevated relative to background. The naturally occurring Ar background concentration has been shown to vary between less than 1 mBq/m to greater than 100 mBq/m (Riedmann and Purtschert, 2011). The purpose of this work was to enhance the understanding of the naturally occurring background concentrations of Ar, allowing for better interpretation of results. To that end, we present and evaluate a computationally efficient model for predicting the average concentration of Ar at any depth under transient barometric pressures. Further, measurements of Ar concentrations in samples collected at multiple locations are provided as validation of the concentration prediction model. The model is shown to compare favorably with concentrations of Ar measured at multiple locations in the Northwestern United States.
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http://dx.doi.org/10.1016/j.jenvrad.2017.10.005DOI Listing
January 2018

Correction: Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults.

Authors:
Mariaelisa Graff Robert A Scott Anne E Justice Kristin L Young Mary F Feitosa Llilda Barata Thomas W Winkler Audrey Y Chu Anubha Mahajan David Hadley Luting Xue Tsegaselassie Workalemahu Nancy L Heard-Costa Marcel den Hoed Tarunveer S Ahluwalia Qibin Qi Julius S Ngwa Frida Renström Lydia Quaye John D Eicher James E Hayes Marilyn Cornelis Zoltan Kutalik Elise Lim Jian'an Luan Jennifer E Huffman Weihua Zhang Wei Zhao Paula J Griffin Toomas Haller Shafqat Ahmad Pedro M Marques-Vidal Stephanie Bien Loic Yengo Alexander Teumer Albert Vernon Smith Meena Kumari Marie Neergaard Harder Johanne Marie Justesen Marcus E Kleber Mette Hollensted Kurt Lohman Natalia V Rivera John B Whitfield Jing Hua Zhao Heather M Stringham Leo-Pekka Lyytikäinen Charlotte Huppertz Gonneke Willemsen Wouter J Peyrot Ying Wu Kati Kristiansson Ayse Demirkan Myriam Fornage Maija Hassinen Lawrence F Bielak Gemma Cadby Toshiko Tanaka Reedik Mägi Peter J van der Most Anne U Jackson Jennifer L Bragg-Gresham Veronique Vitart Jonathan Marten Pau Navarro Claire Bellis Dorota Pasko Åsa Johansson Søren Snitker Yu-Ching Cheng Joel Eriksson Unhee Lim Mette Aadahl Linda S Adair Najaf Amin Beverley Balkau Juha Auvinen John Beilby Richard N Bergman Sven Bergmann Alain G Bertoni John Blangero Amélie Bonnefond Lori L Bonnycastle Judith B Borja Søren Brage Fabio Busonero Steve Buyske Harry Campbell Peter S Chines Francis S Collins Tanguy Corre George Davey Smith Graciela E Delgado Nicole Dueker Marcus Dörr Tapani Ebeling Gudny Eiriksdottir Tõnu Esko Jessica D Faul Mao Fu Kristine Færch Christian Gieger Sven Gläser Jian Gong Penny Gordon-Larsen Harald Grallert Tanja B Grammer Niels Grarup Gerard van Grootheest Kennet Harald Nicholas D Hastie Aki S Havulinna Dena Hernandez Lucia Hindorff Lynne J Hocking Oddgeir L Holmens Christina Holzapfel Jouke Jan Hottenga Jie Huang Tao Huang Jennie Hui Cornelia Huth Nina Hutri-Kähönen Alan L James John-Olov Jansson Min A Jhun Markus Juonala Leena Kinnunen Heikki A Koistinen Ivana Kolcic Pirjo Komulainen Johanna Kuusisto Kirsti Kvaløy Mika Kähönen Timo A Lakka Lenore J Launer Benjamin Lehne Cecilia M Lindgren Mattias Lorentzon Robert Luben Michel Marre Yuri Milaneschi Keri L Monda Grant W Montgomery Marleen H M De Moor Antonella Mulas Martina Müller-Nurasyid A W Musk Reija Männikkö Satu Männistö Narisu Narisu Matthias Nauck Jennifer A Nettleton Ilja M Nolte Albertine J Oldehinkel Matthias Olden Ken K Ong Sandosh Padmanabhan Lavinia Paternoster Jeremiah Perez Markus Perola Annette Peters Ulrike Peters Patricia A Peyser Inga Prokopenko Hannu Puolijoki Olli T Raitakari Tuomo Rankinen Laura J Rasmussen-Torvik Rajesh Rawal Paul M Ridker Lynda M Rose Igor Rudan Cinzia Sarti Mark A Sarzynski Kai Savonen William R Scott Serena Sanna Alan R Shuldiner Steve Sidney Günther Silbernagel Blair H Smith Jennifer A Smith Harold Snieder Alena Stančáková Barbara Sternfeld Amy J Swift Tuija Tammelin Sian-Tsung Tan Barbara Thorand Dorothée Thuillier Liesbeth Vandenput Henrik Vestergaard Jana V van Vliet-Ostaptchouk Marie-Claude Vohl Uwe Völker Gérard Waeber Mark Walker Sarah Wild Andrew Wong Alan F Wright M Carola Zillikens Niha Zubair Christopher A Haiman Loic Lemarchand Ulf Gyllensten Claes Ohlsson Albert Hofman Fernando Rivadeneira André G Uitterlinden Louis Pérusse James F Wilson Caroline Hayward Ozren Polasek Francesco Cucca Kristian Hveem Catharina A Hartman Anke Tönjes Stefania Bandinelli Lyle J Palmer Sharon L R Kardia Rainer Rauramaa Thorkild I A Sørensen Jaakko Tuomilehto Veikko Salomaa Brenda W J H Penninx Eco J C de Geus Dorret I Boomsma Terho Lehtimäki Massimo Mangino Markku Laakso Claude Bouchard Nicholas G Martin Diana Kuh Yongmei Liu Allan Linneberg Winfried März Konstantin Strauch Mika Kivimäki Tamara B Harris Vilmundur Gudnason Henry Völzke Lu Qi Marjo-Riitta Järvelin John C Chambers Jaspal S Kooner Philippe Froguel Charles Kooperberg Peter Vollenweider Göran Hallmans Torben Hansen Oluf Pedersen Andres Metspalu Nicholas J Wareham Claudia Langenberg David R Weir David J Porteous Eric Boerwinkle Daniel I Chasman Gonçalo R Abecasis Inês Barroso Mark I McCarthy Timothy M Frayling Jeffrey R O'Connell Cornelia M van Duijn Michael Boehnke Iris M Heid Karen L Mohlke David P Strachan Caroline S Fox Ching-Ti Liu Joel N Hirschhorn Robert J Klein Andrew D Johnson Ingrid B Borecki Paul W Franks Kari E North L Adrienne Cupples Ruth J F Loos Tuomas O Kilpeläinen

PLoS Genet 2017 Aug 23;13(8):e1006972. Epub 2017 Aug 23.

[This corrects the article DOI: 10.1371/journal.pgen.1006528.].
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http://dx.doi.org/10.1371/journal.pgen.1006972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567921PMC
August 2017

Improved performance comparisons of radioxenon systems for low level releases in nuclear explosion monitoring.

J Environ Radioact 2017 Nov 14;178-179:127-135. Epub 2017 Aug 14.

Pacific Northwest National Laboratory, 902 Battelle Blvd., Richland, WA, 99354, USA. Electronic address:

The Comprehensive Nuclear-Test-Ban Treaty bans all nuclear tests and mandates development of verification measures to detect treaty violations. One verification measure is detection of radioactive xenon isotopes produced in the fission of actinides. The International Monitoring System (IMS) currently deploys automated radioxenon systems that can detect four radioxenon isotopes. Radioxenon systems with lower detection limits are currently in development. Historically, the sensitivity of radioxenon systems was measured by the minimum detectable concentration for each isotope. In this paper we analyze the response of radioxenon systems using rigorous metrics in conjunction with hypothetical representative releases indicative of an underground nuclear explosion instead of using only minimum detectable concentrations. Our analyses incorporate the impact of potential spectral interferences on detection limits and the importance of measuring isotopic ratios of the relevant radioxenon isotopes in order to improve discrimination from background sources particularly for low-level releases. To provide a sufficient data set for analysis, hypothetical representative releases are simulated every day from the same location for an entire year. The performance of three types of samplers are evaluated assuming they are located at 15 IMS radionuclide stations in the region of the release point. The performance of two IMS-deployed samplers and a next-generation system is compared with proposed metrics for detection and discrimination using representative releases from the nuclear test site used by the Democratic People's Republic of Korea.
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http://dx.doi.org/10.1016/j.jenvrad.2017.08.005DOI Listing
November 2017

Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults.

Authors:
Mariaelisa Graff Robert A Scott Anne E Justice Kristin L Young Mary F Feitosa Llilda Barata Thomas W Winkler Audrey Y Chu Anubha Mahajan David Hadley Luting Xue Tsegaselassie Workalemahu Nancy L Heard-Costa Marcel den Hoed Tarunveer S Ahluwalia Qibin Qi Julius S Ngwa Frida Renström Lydia Quaye John D Eicher James E Hayes Marilyn Cornelis Zoltan Kutalik Elise Lim Jian'an Luan Jennifer E Huffman Weihua Zhang Wei Zhao Paula J Griffin Toomas Haller Shafqat Ahmad Pedro M Marques-Vidal Stephanie Bien Loic Yengo Alexander Teumer Albert Vernon Smith Meena Kumari Marie Neergaard Harder Johanne Marie Justesen Marcus E Kleber Mette Hollensted Kurt Lohman Natalia V Rivera John B Whitfield Jing Hua Zhao Heather M Stringham Leo-Pekka Lyytikäinen Charlotte Huppertz Gonneke Willemsen Wouter J Peyrot Ying Wu Kati Kristiansson Ayse Demirkan Myriam Fornage Maija Hassinen Lawrence F Bielak Gemma Cadby Toshiko Tanaka Reedik Mägi Peter J van der Most Anne U Jackson Jennifer L Bragg-Gresham Veronique Vitart Jonathan Marten Pau Navarro Claire Bellis Dorota Pasko Åsa Johansson Søren Snitker Yu-Ching Cheng Joel Eriksson Unhee Lim Mette Aadahl Linda S Adair Najaf Amin Beverley Balkau Juha Auvinen John Beilby Richard N Bergman Sven Bergmann Alain G Bertoni John Blangero Amélie Bonnefond Lori L Bonnycastle Judith B Borja Søren Brage Fabio Busonero Steve Buyske Harry Campbell Peter S Chines Francis S Collins Tanguy Corre George Davey Smith Graciela E Delgado Nicole Dueker Marcus Dörr Tapani Ebeling Gudny Eiriksdottir Tõnu Esko Jessica D Faul Mao Fu Kristine Færch Christian Gieger Sven Gläser Jian Gong Penny Gordon-Larsen Harald Grallert Tanja B Grammer Niels Grarup Gerard van Grootheest Kennet Harald Nicholas D Hastie Aki S Havulinna Dena Hernandez Lucia Hindorff Lynne J Hocking Oddgeir L Holmens Christina Holzapfel Jouke Jan Hottenga Jie Huang Tao Huang Jennie Hui Cornelia Huth Nina Hutri-Kähönen Alan L James John-Olov Jansson Min A Jhun Markus Juonala Leena Kinnunen Heikki A Koistinen Ivana Kolcic Pirjo Komulainen Johanna Kuusisto Kirsti Kvaløy Mika Kähönen Timo A Lakka Lenore J Launer Benjamin Lehne Cecilia M Lindgren Mattias Lorentzon Robert Luben Michel Marre Yuri Milaneschi Keri L Monda Grant W Montgomery Marleen H M De Moor Antonella Mulas Martina Müller-Nurasyid A W Musk Reija Männikkö Satu Männistö Narisu Narisu Matthias Nauck Jennifer A Nettleton Ilja M Nolte Albertine J Oldehinkel Matthias Olden Ken K Ong Sandosh Padmanabhan Lavinia Paternoster Jeremiah Perez Markus Perola Annette Peters Ulrike Peters Patricia A Peyser Inga Prokopenko Hannu Puolijoki Olli T Raitakari Tuomo Rankinen Laura J Rasmussen-Torvik Rajesh Rawal Paul M Ridker Lynda M Rose Igor Rudan Cinzia Sarti Mark A Sarzynski Kai Savonen William R Scott Serena Sanna Alan R Shuldiner Steve Sidney Günther Silbernagel Blair H Smith Jennifer A Smith Harold Snieder Alena Stančáková Barbara Sternfeld Amy J Swift Tuija Tammelin Sian-Tsung Tan Barbara Thorand Dorothée Thuillier Liesbeth Vandenput Henrik Vestergaard Jana V van Vliet-Ostaptchouk Marie-Claude Vohl Uwe Völker Gérard Waeber Mark Walker Sarah Wild Andrew Wong Alan F Wright M Carola Zillikens Niha Zubair Christopher A Haiman Loic Lemarchand Ulf Gyllensten Claes Ohlsson Albert Hofman Fernando Rivadeneira André G Uitterlinden Louis Pérusse James F Wilson Caroline Hayward Ozren Polasek Francesco Cucca Kristian Hveem Catharina A Hartman Anke Tönjes Stefania Bandinelli Lyle J Palmer Sharon L R Kardia Rainer Rauramaa Thorkild I A Sørensen Jaakko Tuomilehto Veikko Salomaa Brenda W J H Penninx Eco J C de Geus Dorret I Boomsma Terho Lehtimäki Massimo Mangino Markku Laakso Claude Bouchard Nicholas G Martin Diana Kuh Yongmei Liu Allan Linneberg Winfried März Konstantin Strauch Mika Kivimäki Tamara B Harris Vilmundur Gudnason Henry Völzke Lu Qi Marjo-Riitta Järvelin John C Chambers Jaspal S Kooner Philippe Froguel Charles Kooperberg Peter Vollenweider Göran Hallmans Torben Hansen Oluf Pedersen Andres Metspalu Nicholas J Wareham Claudia Langenberg David R Weir David J Porteous Eric Boerwinkle Daniel I Chasman Gonçalo R Abecasis Inês Barroso Mark I McCarthy Timothy M Frayling Jeffrey R O'Connell Cornelia M van Duijn Michael Boehnke Iris M Heid Karen L Mohlke David P Strachan Caroline S Fox Ching-Ti Liu Joel N Hirschhorn Robert J Klein Andrew D Johnson Ingrid B Borecki Paul W Franks Kari E North L Adrienne Cupples Ruth J F Loos Tuomas O Kilpeläinen

PLoS Genet 2017 Apr 27;13(4):e1006528. Epub 2017 Apr 27.

MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.

Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
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http://dx.doi.org/10.1371/journal.pgen.1006528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407576PMC
April 2017

Exposure to Inhalable Dust, Endotoxin, and Total Volatile Organic Carbons on Dairy Farms Using Manual and Automated Feeding Systems.

Ann Work Expo Health 2017 Apr;61(3):344-355

School of Physics, National University of Ireland, Univeristy Road, Galway H91TK33, Ireland.

Introduction: Agricultural workers tend to have high exposures to organic dusts which may induce or exacerbate respiratory disorders. Studies investigating the effect of work tasks and farm characteristics on organic dust exposures among farm workers suggest that handling of animal feed is an important exposure determinant; however, the effect of the animal feeding system has not been explored in any detail.

Objectives: To measure the exposure of Irish dairy farmers to inhalable dust, endotoxin, and total volatile organic compounds (TVOCs) during parlour work and to explore whether levels of exposure to these agents depend on the applied feeding system in the farms.

Methods: Thirty-eight personal exposure measurements were collected from farmers across seven dairy farms. The farms used manual, loft, or semi-automated feeding systems. Information on worker tasks and farm characteristics was collected during the surveys. Associations between exposure concentrations and feeding systems, worker tasks, and other farm characteristics were explored in linear mixed-effect regression models with farmer identity treated as a random effect.

Results: Exposure concentrations were variable and had a geometric mean (GM; geometric standard deviation) of 1.5 mg m-3 (1.8) for inhalable dust and 128 EU m-3 (2.5) for endotoxin. More than 50% of the exposure measurements for endotoxin, and organic dust exceeded recommended health-based occupational exposure limits. Endotoxin levels were somewhat lower in farms using semi-automatic feeding systems when compared to those using manual feeding systems but in multivariate regression analysis associations were not statistically significant (β = -0.54, P = 0.4). Performance of activities related to handling and spreading of hay or straw was the strongest determinant for both inhalable dust and endotoxin exposure (β = 0.78, P ≤ 0.001; β = 0.72, P = 0.02, respectively). The level of dust exposure increased also as a consequence of a lower outdoor temperature, and higher ratio of distributed feed per cow (P = 0.01). Stationary measurements of TVOC and CO2 concentrations inside the dairy parlours had a GM of 180 ppb (1.9) and 589 ppb (1.3), respectively. The use of cow teat disinfectants and building ventilation were both strong predictors of TVOC concentrations within parlours.

Conclusions: Dairy farm workers can be exposed to high and variable levels of inhalable dust and endotoxin and may be at risk of respiratory disease. Results from this study suggest that exposure control strategies for organic dusts and TVOCs exposures should consider building ventilation and work tasks such as spreading of bedding material, using spray disinfectants and animal feeding. Until effective permanent engineering controls are established farm workers should be encouraged to wear respiratory protective equipment during these tasks.
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http://dx.doi.org/10.1093/annweh/wxw023DOI Listing
April 2017

28-year late spermatic cord relapse of a testicular non-seminomatous germ cell tumour, managed robotically.

Can Urol Assoc J 2016 Jul-Aug;10(7-8):E257-E260. Epub 2016 Jul 12.

Department of Surgical Oncology (Urology), Princess Margaret Cancer Centre, Toronto, ON, Canada.

We present a patient who relapsed symptomatically 28 years post-orchiectomy, initially followed by active surveillance for clinical stage I non-seminomatous germ cell tumour (CSI NSGCT). His relapse was localized to the pelvis, managed with robotic surgery, and achieved a complete resection with tumour markers normalized. We highlight the current Princess Margaret guidelines for followup of CSI NSGCT and discuss the trade-off between lifelong radiographic surveillance to detect the very small risk of late relapse. We discuss the incidence and presentation of late relapse, treatment options, and outcomes, highlighting that these tumours are typically refractory to chemotherapy and can often be managed with surgery alone.
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http://dx.doi.org/10.5489/cuaj.3492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325756PMC
July 2016

Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis.

Authors:
Frank J A van Rooij Rehan Qayyum Albert V Smith Yi Zhou Stella Trompet Toshiko Tanaka Margaux F Keller Li-Ching Chang Helena Schmidt Min-Lee Yang Ming-Huei Chen James Hayes Andrew D Johnson Lisa R Yanek Christian Mueller Leslie Lange James S Floyd Mohsen Ghanbari Alan B Zonderman J Wouter Jukema Albert Hofman Cornelia M van Duijn Karl C Desch Yasaman Saba Ayse B Ozel Beverly M Snively Jer-Yuarn Wu Reinhold Schmidt Myriam Fornage Robert J Klein Caroline S Fox Koichi Matsuda Naoyuki Kamatani Philipp S Wild David J Stott Ian Ford P Eline Slagboom Jaden Yang Audrey Y Chu Amy J Lambert André G Uitterlinden Oscar H Franco Edith Hofer David Ginsburg Bella Hu Brendan Keating Ursula M Schick Jennifer A Brody Jun Z Li Zhao Chen Tanja Zeller Jack M Guralnik Daniel I Chasman Luanne L Peters Michiaki Kubo Diane M Becker Jin Li Gudny Eiriksdottir Jerome I Rotter Daniel Levy Vera Grossmann Kushang V Patel Chien-Hsiun Chen Paul M Ridker Hua Tang Lenore J Launer Kenneth M Rice Ruifang Li-Gao Luigi Ferrucci Michelle K Evans Avik Choudhuri Eirini Trompouki Brian J Abraham Song Yang Atsushi Takahashi Yoichiro Kamatani Charles Kooperberg Tamara B Harris Sun Ha Jee Josef Coresh Fuu-Jen Tsai Dan L Longo Yuan-Tsong Chen Janine F Felix Qiong Yang Bruce M Psaty Eric Boerwinkle Lewis C Becker Dennis O Mook-Kanamori James G Wilson Vilmundur Gudnason Christopher J O'Donnell Abbas Dehghan L Adrienne Cupples Michael A Nalls Andrew P Morris Yukinori Okada Alexander P Reiner Leonard I Zon Santhi K Ganesh

Am J Hum Genet 2017 Jan 22;100(1):51-63. Epub 2016 Dec 22.

Division of Cardiovascular Medicine, Department of Internal Medicine, Department of Human Genetics, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA. Electronic address:

Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits.
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http://dx.doi.org/10.1016/j.ajhg.2016.11.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223059PMC
January 2017

Suppression of LPS-induced NF-κB activity in macrophages by the synthetic aurone, (Z)-2-((5-(hydroxymethyl) furan-2-yl) methylene) benzofuran-3(2H)-one.

Int Immunopharmacol 2017 Feb 16;43:116-128. Epub 2016 Dec 16.

Middle Tennessee State University, Department of Biology, 1301 East Main Street, Murfreesboro, TN 37132, USA. Electronic address:

Suppressing cytokine responses has frequently been shown to have promising therapeutic effects for many chronic inflammatory and autoimmune diseases. However, the severe side effects associated with the long-term use of current treatments, such as allergic reactions and increased risk of stroke, have focused attention towards the targeting of intracellular signaling mechanisms, such as NF-κB, that regulate inflammation. We synthesized a series of non-natural aurone derivatives and investigated their ability to suppress pro-inflammatory signaling in human monocyte (THP-1) and murine macrophage-like (RAW 267.4) cell lines. One of these derivatives, (Z)-2-((5-(hydroxymethyl) furan-2-yl) methylene) benzofuran-3(2H)-one (aurone 1), was found to inhibit LPS-induced secretion of the pro-inflammatory cytokines, tumor-necrosis factor α (TNFα), interleukin 1β (IL-1β), and IL-8 by THP-1 cells. To investigate the mechanism, we probed the effect of aurone 1 on LPS-induced MAPK and NF-κB signaling in both THP-1 and RAW264.7. While aurone 1 pre-treatment had no effect on the phosphorylation of ERK, JNK, or p38 MAPK, it strongly suppressed activation of IKK-β, as indicated by attenuation of Ser176/180 phosphorylation, resulting in decreased phosphorylation of p65 (ser536) as well as phosphorylation (ser32) and degradation of IκBα. Consistent with this, aurone 1 significantly reduced LPS-stimulated nuclear translocation of p65-containing NF-κB transcription factors and expression of an mCherry reporter of TNFα gene transactivation in RAW264.7 cells. Inhibition of TNFα expression at the transcription level was also demonstrated in THP-1 by qRT-PCR. In addition to its effects on cytokine expression, aurone 1 pre-treatment decreased expression of iNOS, a bona fide NF-κB target gene and marker of macrophage M1 polarization, resulting in decreased NO production in RAW264.7 cells. Together, these data indicate that aurone 1 may have the potential to function as a pharmacological agent for the treatment of chronic inflammation disorders.
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http://dx.doi.org/10.1016/j.intimp.2016.12.004DOI Listing
February 2017

Modifiable lifestyle factors that could reduce the incidence of colorectal cancer in New Zealand.

N Z Med J 2016 Dec 16;129(1447):13-20. Epub 2016 Dec 16.

Chief Science Advisor, Ministry of Health, Wellington, Adjunct Professor, School of Health Sciences, University of Canterbury, Christchurch, Professorial Fellow, Centre for Public Health Research, Massey University, Wellington, Senior Advisor, Fred Hutchinson Cancer Research Center, Seattle, USA.

Aim: To estimate population attributable fractions for modifiable lifestyle factors and colorectal cancer in New Zealand.

Method: Relative risks for lifestyle risk factors for colorectal cancer, and population data on the prevalence of exposure in New Zealand, were used to estimate the population attributable fraction (PAF) for each risk factor.

Results: Six modifiable lifestyle risk factors were identified. The PAFs for these risk factors were 9% for obesity, 7% for alcohol, 4% for physical inactivity, 3% for smoking, 5% for consumption of red meat and 3% for processed meat. PAFs differed by ethnic group and sex. In women, the highest PAFs were 19% for obesity in Pacific women, 14% for obesity in Māori women, 7% for physical inactivity in Asian women, and 8% for obesity in European/other women. In men, the highest PAFs were 17% for obesity in Pacific men, 14% for high alcohol consumption in Māori men, 5% for physical inactivity in Asian men and 9% for high alcohol consumption in European/other men.

Conclusion: If obesity, alcohol consumption, smoking and consumption of red and processed meats could be reduced, and physical activity could be increased among New Zealanders, it would reduce the risk of colorectal cancer considerably.
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December 2016

Detection in subsurface air of radioxenon released from medical isotope production.

J Environ Radioact 2017 Feb 11;167:160-165. Epub 2016 Nov 11.

Pacific Northwest National Laboratory, Richland, WA 99354, USA.

In order to better understand potential backgrounds of Comprehensive-Nuclear Test-Ban Treaty on-site inspection relevant gases, a sampling campaign was performed near Canadian Nuclear Laboratories in the Ottawa River Valley, a major source of environmental radioxenon. First of their kind measurements of atmospheric radioxenon imprinted into the shallow subsurface from an atmospheric pressure driven force were made using current on-site inspection techniques. Both atmospheric and subsurface gas samples were measured and analyzed to determine radioxenon concentrations. These measurements indicate that under specific sampling conditions, on the order of ten percent of the atmospheric radioxenon concentration may be measured via subsurface sampling.
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http://dx.doi.org/10.1016/j.jenvrad.2016.10.021DOI Listing
February 2017

Identifying a robust design space for glycosylation during monoclonal antibody production.

Biotechnol Prog 2016 09 1;32(5):1149-1162. Epub 2016 Jul 1.

Dept. of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE, 19716.

Glycan distribution has been identified as a "critical quality attribute" for many biopharmaceutical products, including monoclonal antibodies. Consequently, determining quantitatively how process variables affect glycan distribution is important during process development to control antibody glycosylation. In this work, we assess the effect of six bioreactor process variables on the glycan distribution of an IgG1 produced in CHO cells. Our analysis established that glucose and glutamine media concentration, temperature, pH, agitation rate, and dissolved oxygen (DO) had small but significant effects on the relative percentage of various glycans. In addition, we assessed glycosylation enzyme transcript levels and intracellular sugar nucleotide concentrations within the CHO cells to provide a biological explanation for the observed effects on glycan distributions. From these results we identified a robust operating region, or design space, in which the IgG1 could be produced with a consistent glycan distribution. Since our results indicate that perturbations to bioreactor process variables will cause only small (even if significant) changes to the relative percentage of various glycans (<±1.5%)-changes that are too small to affect the bioactivity and efficacy of this IgG1 significantly-it follows that the glycan distribution obtained will be consistent even with relatively large variations in bioreactor process variables. However, for therapeutic proteins where bioactivity and efficacy are affected by small changes to the relative percentage of glycans, the same analysis would identify the manipulated variables capable of changing glycan distribution, and hence can be used to implement a glycosylation control strategy. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1149-1162, 2016.
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http://dx.doi.org/10.1002/btpr.2316DOI Listing
September 2016

Unmanned vehicles for maritime spill response case study: Exercise Cathach.

Mar Pollut Bull 2016 Sep 20;110(1):528-538. Epub 2016 Jun 20.

Mobile & Marine Robotics Research Centre, University of Limerick, Limerick, Ireland.

This paper deals with two aspects, namely a historical analysis of the use of unmanned vehicles (UAVs ROVs, AUVs) in maritime spill incidents and a detailed description of a multi-agency oil and HNS incident response exercise involving the integration and analysis of unmanned vehicles environmental sensing equipment. The exercise was a first in terms of the level of robotic systems deployed to assist in survey, surveillance and inspection roles for oil spills and harmful and noxious substances.
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http://dx.doi.org/10.1016/j.marpolbul.2016.02.072DOI Listing
September 2016

Modulation of Macrophage Inflammatory Nuclear Factor κB (NF-κB) Signaling by Intracellular Cryptococcus neoformans.

J Biol Chem 2016 07 26;291(30):15614-27. Epub 2016 May 26.

From the Departments of Biology and

Cryptococcus neoformans (Cn) is a common facultative intracellular pathogen that can cause life-threatening fungal meningitis in immunocompromised individuals. Shortly after infection, Cn is detectable as both extra- and intracellular yeast particles, with Cn being capable of establishing long-lasting latent infections within host macrophages. Although recent studies have shown that shed capsular polysaccharides and intact extracellular Cn can compromise macrophage function through modulation of NF-κB signaling, it is currently unclear whether intracellular Cn also affects NF-κB signaling. Utilizing live cell imaging and computational modeling, we find that extra- and intracellular Cn support distinct modes of NF-κB signaling in cultured murine macrophages. Specifically, in RAW 264.7 murine macrophages treated with extracellular glucuronoxylomannan (GXM), the major Cn capsular polysaccharide, LPS-induced nuclear translocation of p65 is inhibited, whereas in cells with intracellular Cn, LPS-induced nuclear translocation of p65 is both amplified and sustained. Mathematical simulations and quantification of nascent protein expression indicate that this is a possible consequence of Cn-induced "translational interference," impeding IκBα resynthesis. We also show that long term Cn infection induces stable nuclear localization of p65 and IκBα proteins in the absence of additional pro-inflammatory stimuli. In this case, nuclear localization of p65 is not accompanied by TNFα or inducible NOS (iNOS) expression. These results demonstrate that capsular polysaccharides and intact intracellular yeast manipulate NF-κB via multiple distinct mechanisms and provide new insights into how Cn might modulate cellular signaling at different stages of an infection.
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http://dx.doi.org/10.1074/jbc.M116.738187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4957046PMC
July 2016

Redox-Active Metal-Organic Composites for Highly Selective Oxygen Separation Applications.

Adv Mater 2016 05 8;28(18):3572-7. Epub 2016 Mar 8.

Physical & Computational Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA, 99352, USA.

A redox-active metal-organic composite material shows improved and selective O2 adsorption over N2 with respect to individual components (MIL-101 and ferrocene). The O2 sensitivity of the composite material arises due to the formation of maghemite nanoparticles with the pore of the metal-organic framework material.
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http://dx.doi.org/10.1002/adma.201600259DOI Listing
May 2016

Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.

Authors:
Tuomas O Kilpeläinen Jayne F Martin Carli Alicja A Skowronski Qi Sun Jennifer Kriebel Mary F Feitosa Åsa K Hedman Alexander W Drong James E Hayes Jinghua Zhao Tune H Pers Ursula Schick Niels Grarup Zoltán Kutalik Stella Trompet Massimo Mangino Kati Kristiansson Marian Beekman Leo-Pekka Lyytikäinen Joel Eriksson Peter Henneman Jari Lahti Toshiko Tanaka Jian'an Luan Fabiola Del Greco M Dorota Pasko Frida Renström Sara M Willems Anubha Mahajan Lynda M Rose Xiuqing Guo Yongmei Liu Marcus E Kleber Louis Pérusse Tom Gaunt Tarunveer S Ahluwalia Yun Ju Sung Yolande F Ramos Najaf Amin Antoinette Amuzu Inês Barroso Claire Bellis John Blangero Brendan M Buckley Stefan Böhringer Yii-Der I Chen Anton J N de Craen David R Crosslin Caroline E Dale Zari Dastani Felix R Day Joris Deelen Graciela E Delgado Ayse Demirkan Francis M Finucane Ian Ford Melissa E Garcia Christian Gieger Stefan Gustafsson Göran Hallmans Susan E Hankinson Aki S Havulinna Christian Herder Dena Hernandez Andrew A Hicks David J Hunter Thomas Illig Erik Ingelsson Andreea Ioan-Facsinay John-Olov Jansson Nancy S Jenny Marit E Jørgensen Torben Jørgensen Magnus Karlsson Wolfgang Koenig Peter Kraft Joanneke Kwekkeboom Tiina Laatikainen Karl-Heinz Ladwig Charles A LeDuc Gordon Lowe Yingchang Lu Pedro Marques-Vidal Christa Meisinger Cristina Menni Andrew P Morris Richard H Myers Satu Männistö Mike A Nalls Lavinia Paternoster Annette Peters Aruna D Pradhan Tuomo Rankinen Laura J Rasmussen-Torvik Wolfgang Rathmann Treva K Rice J Brent Richards Paul M Ridker Naveed Sattar David B Savage Stefan Söderberg Nicholas J Timpson Liesbeth Vandenput Diana van Heemst Hae-Won Uh Marie-Claude Vohl Mark Walker Heinz-Erich Wichmann Elisabeth Widén Andrew R Wood Jie Yao Tanja Zeller Yiying Zhang Ingrid Meulenbelt Margreet Kloppenburg Arne Astrup Thorkild I A Sørensen Mark A Sarzynski D C Rao Pekka Jousilahti Erkki Vartiainen Albert Hofman Fernando Rivadeneira André G Uitterlinden Eero Kajantie Clive Osmond Aarno Palotie Johan G Eriksson Markku Heliövaara Paul B Knekt Seppo Koskinen Antti Jula Markus Perola Risto K Huupponen Jorma S Viikari Mika Kähönen Terho Lehtimäki Olli T Raitakari Dan Mellström Mattias Lorentzon Juan P Casas Stefanie Bandinelli Winfried März Aaron Isaacs Ko W van Dijk Cornelia M van Duijn Tamara B Harris Claude Bouchard Matthew A Allison Daniel I Chasman Claes Ohlsson Lars Lind Robert A Scott Claudia Langenberg Nicholas J Wareham Luigi Ferrucci Timothy M Frayling Peter P Pramstaller Ingrid B Borecki Dawn M Waterworth Sven Bergmann Gérard Waeber Peter Vollenweider Henrik Vestergaard Torben Hansen Oluf Pedersen Frank B Hu P Eline Slagboom Harald Grallert Tim D Spector J W Jukema Robert J Klein Erik E Schadt Paul W Franks Cecilia M Lindgren Rudolph L Leibel Ruth J F Loos

Nat Commun 2016 Feb 1;7:10494. Epub 2016 Feb 1.

MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK.

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
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http://dx.doi.org/10.1038/ncomms10494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740377PMC
February 2016

Assessment of penile erection methods in rhesus macaques to model pharmacokinetics of antiretroviral drugs and penile infection with simian immunodeficiency virus.

J Med Primatol 2016 Feb 18;45(1):34-41. Epub 2016 Jan 18.

Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA.

Background: An established macaque model to assess HIV interventions against penile transmission is currently not available. Physiological changes during penile erections may affect susceptibility to infection and drug pharmacokinetics (PK). Here, we identify methods to establish erections in macaques to evaluate penile transmission, PK, and efficacy under physiologic conditions.

Methods: Penile rigidity and length were evaluated in eight rhesus macaques following rectal electrostimulation (RES), vibratory stimulation (VS), or pharmacological treatment with Sildenafil Citrate (Viagra) or Alprostadil.

Results: Rectal electrostimulation treatment increased penile rigidity (>82%) and length (2.5 ± 0.58 cm), albeit the response was transient. In contrast, VS alone or coupled with Viagra or Alprostadil failed to elicit an erection response.

Conclusion: Rectal electrostimulation treatment elicits transient but consistent penile erections in macaques. High rigidity following RES treatment demonstrates increased blood flow and may provide a functional model for penile PK evaluations and possibly simian immunodeficiency virus (SIV) transmission under erect conditions.
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http://dx.doi.org/10.1111/jmp.12207DOI Listing
February 2016

Tissue-Specific Enrichment of Lymphoma Risk Loci in Regulatory Elements.

PLoS One 2015 30;10(9):e0139360. Epub 2015 Sep 30.

Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.

Though numerous polymorphisms have been associated with risk of developing lymphoma, how these variants function to promote tumorigenesis is poorly understood. Here, we report that lymphoma risk SNPs, especially in the non-Hodgkin's lymphoma subtype chronic lymphocytic leukemia, are significantly enriched for co-localization with epigenetic marks of active gene regulation. These enrichments were seen in a lymphoid-specific manner for numerous ENCODE datasets, including DNase-hypersensitivity as well as multiple segmentation-defined enhancer regions. Furthermore, we identify putatively functional SNPs that are both in regulatory elements in lymphocytes and are associated with gene expression changes in blood. We developed an algorithm, UES, that uses a Monte Carlo simulation approach to calculate the enrichment of previously identified risk SNPs in various functional elements. This multiscale approach integrating multiple datasets helps disentangle the underlying biology of lymphoma, and more broadly, is generally applicable to GWAS results from other diseases as well.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0139360PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589387PMC
June 2016

Atmospheric plume progression as a function of time and distance from the release point for radioactive isotopes.

J Environ Radioact 2015 Oct 4;148:123-9. Epub 2015 Jul 4.

Pacific Northwest National Laboratory, 902 Battelle Blvd., Richland, WA, USA. Electronic address:

The radionuclide network of the International Monitoring System comprises up to 80 stations around the world that have aerosol and xenon monitoring systems designed to detect releases of radioactive materials to the atmosphere from nuclear explosions. A rule of thumb description of plume concentration and duration versus time and distance from the release point is useful when designing and deploying new sample collection systems. This paper uses plume development from atmospheric transport modeling to provide a power-law rule describing atmospheric dilution factors as a function of distance from the release point. Consider the plume center-line concentration seen by a ground-level sampler as a function of time based on a short-duration ground-level release of a nondepositing radioactive tracer. The concentration C (Bq m(-3)) near the ground varies with distance from the source with the relationship C=R×A(D,C) ×e (-λ(-1.552+0.0405×D)) × 5.37×10(-8) × D(-2.35) where R is the release magnitude (Bq), D is the separation distance (km) from the ground level release to the measurement location, λ is the decay constant (h(-1)) for the radionuclide of interest and AD,C is an attenuation factor that depends on the length of the sample collection period. This relationship is based on the median concentration for 10 release locations with different geographic characteristics and 365 days of releases at each location, and it has an R(2) of 0.99 for 32 distances from 100 to 3000 km. In addition, 90 percent of the modeled plumes fall within approximately one order of magnitude of this curve for all distances.
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http://dx.doi.org/10.1016/j.jenvrad.2015.06.022DOI Listing
October 2015