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1.  Proceedings of the 2016 Childhood Arthritis and Rheumatology Research Alliance (CARRA) Scientific Meeting 
Fotis, Lampros | Shaikh, Nur | Baszis, Kevin | French, Anthony | Tarr, Phillip | Grevich, Sriharsha | Lee, Peggy | Ringold, Sarah | Leroux, Brian | Leahey, Hannah | Yuasa, Megan | Foster, Jessica | Sokolove, Jeremy | Lahey, Lauren | Robinson, William | Newsom, Joshua | Stevens, Anne | Karasawa, Rie | Tamaki, Mayumi | Tanaka, Megumi | Sato, Toshiko | Yudoh, Kazuo | Jarvis, James N. | Moncrieffe, Halima | Bennett, Mark F. | Tsoras, Monica | Luyrink, Lorie | Xu, Huan | Prahalad, Sampath | Morris, Paula | Dare, Jason | Nigrovic, Peter A. | Rosenkranz, Margalit | Becker, Mara | O’Neil, Kathleen M. | Griffin, Thomas | Lovell, Daniel J. | Grom, Alexei A. | Medvedovic, Mario | Thompson, Susan D. | Zhu, Lisha | Jiang, Kaiyu | Wong, Laiping | Buck, Michael J | Chen, Yanmin | Moncrieffe, Halima | Brungs, Laura | Liu, Tao | Wang, Ting | Jarvis, James N | Alsaeid, Khaled | Alfailakawi, Jasim | Alenezi, Hamid | Alsaeed, Hazim | Beukelman, Tim | Natter, Marc | Ilowite, Norm | Mieszkalski, Kelly | Burrell, Grendel | Best, Brian | Bristow, Helen | Carr, Shannon | Dennos, Anne | Kaufmann, Rachel | Kimura, Yukiko | Schanberg, Laura | Blier, Peter R. | Boneparth, Alexis | Wenderfer, Scott E. | Moorthy, L. Nandini | Radhakrishna, Suhas M. | Sagcal-Gironella, Anna Carmela P. | von Scheven, Emily | Gedik, Kader Cetin | Siddique, Salma | Aguiar, Cassyanne L. | Erkan, Doruk | Cohen, Ezra | Lee, Yvonne | Dossett, Michelle | Mehta, Darshan | Davis, Roger | Gilbert, Mileka | Goilav, Beatrice | Meidan, Esra | Hsu, Joyce | Boneparth, Alexis | Chua, Anabelle | Ardoin, Stacy | Wenderfer, Scott E. | Von Scheven, Emily | Ruth, Natasha M. | Hui-Yuen, Joyce | Gedik, Kader Cetin | Bermudez, Liza | Cook, Ashlea | Imundo, Lisa | Starr, Amy | Eichenfield, Andrew | Askanase, Anca | Janow, Ginger | Schanberg, Laura E. | Setoguchi, Soko | Hasselblad, Victor | Mellins, Elizabeth D. | Schneider, Rayfel | Kimura, Yukiko | Kimura, Yukiko | Grevich, Sriharsha | Beukelman, Timothy | Morgan, Esi | Graham, T. Brent | Ibarra, Maria | Ruas, Yonit Sterba | Klein-Gitelman, Marisa | Onel, Karen | Prahalad, Sampath | Punaro, Marilynn | Ringold, Sarah | Toib, Dana | Van Mater, Heather | Weiss, Jennifer E. | Weiss, Pamela F. | Mieszkalski, Kelly | Schanberg, Laura E. | Kwok, Timothy S. H. | Bisaillon, Jacinthe | Smith, Christine | Brosseau, Lucie | Stinson, Jennifer | Huber, Adam M. | Duffy, Ciaran M. | April, Karine Toupin | Lewandowski, Laura B. | Scott, Christiaan | Li, Suzanne C. | Torok, Kathryn S. | Rabinovich, C. Egla | Hong, Sandy D. | Becker, Mara L | Dedeoglu, Fatma | Ibarra, Maria F. | Ferguson, Polly J | Fuhbrigge, Rob C. | Stewart, Katie G. | Pope, Elena | Laxer, Ronald M. | Mason, Thomas G. | Higgins, Gloria C. | Li, Xiaohu | Punaro, Marilynn G. | Tomlinson, George | Pullenayegum, Eleanor | Matelski, John | Schanberg, Laura | Feldman, Brian M. | Manthiram, Kalpana | Correa, Hernan | Edwards, Kathryn | Oberle, Edward J. | Bayer, Michelle | Co, Dominic O. | Baris, Hatice Ezgi | Chiu, Yvonne | Huber, Adam | Kim, Susan | Oberle, Edward J. | Beukelman, Timothy | Orandi, Amir B. | Baszis, Kevin W. | Dharnidharka, Vikas | Hoeltzel, Mark F. | Reed, Ann | Huber, Adam | Tomlinson, George | Pullenayegum, Eleanor | Matelski, John | Goh, Y. Ingrid | Schanberg, Laura | Feldman, Brian M. | Schnabel, Anja | Range, Ursula | Hahn, Gabriele | Siepmann, Timo | Berner, Reinhard | Hedrich, Christian Michael | Stevens, Brandi | Torok, Kathryn S. | Li, Suzanne | Hershey, Nicole | Curran, Megan | Higgins, Gloria | Moore, Katharine | Rabinovich, Egla | Stevens, Anne M. | Stinson, Jennifer | Connelly, Mark | Huber, Adam | Luca, Nadia | Spiegel, Lynn | Tsimicalis, Argerie | Luca, Stephanie | Tajuddin, Naweed | Berard, Roberta | Barsalou, Julia | Campillo, Sarah | Dancey, Paul | Duffy, Ciaran | Feldman, Brian | Johnson, Nicole | McGrath, Patrick | Shiff, Natalie | Tse, Shirley | Tucker, Lori | Victor, Charles | Stinson, Jennifer | Lalloo, Chitra | Harris, Lauren | Cafazzo, Joseph | Spiegel, Lynn | Feldman, Brian | Luca, Nadia | Laxer, Ronald | Bullock, Danielle R. | Vehe, Richard K. | Zhang, Lei | Correll, Colleen K. | Ganguli, Suhas | Shenberger, Max | Korumilli, Ritesh | Gottlieb, Beth | Rodriguez, Martha | de Ranieri, Deirdre | Onel, Karen | Wagner-Weiner, Linda | Tesher, Melissa | Wojcicki, Elizabeth Roth | Maletta, Kristyn L. | Co, Dominic O. | Malloy, Marsha | Thomson, Sarah | Olson, Judyann C. | Wenderfer, Scott E. | Gilbert, Mileka | Hsu, Joyce | Sule, Sangeeta | Rubinstein, Tamar B. | Goilav, Beatrice | Okamura, Daryl M. | Chua, Annabelle | Greenbaum, Laurence A. | Lane, Jerome C. | von Scheven, Emily | Ardoin, Stacy P. | Ruth, Natasha M. | Woo, Jennifer M. P. | Malloy, Marsha M. | Jegers, James A. | Hahn, Dustin J. | Hintermeyer, Mary K. | Martinetti, Stacey M. | Heckel, Gretchen R. | Roth-Wojcicki, Elizabeth L. | Co, Dominic O.
Table of Contents
P1 Serologic evidence of gut-driven systemic inflammation in juvenile idiopathic arthritis
Lampros Fotis, Nur Shaikh, Kevin Baszis, Anthony French, Phillip Tarr
P2 Oral health and anti-citrullinated peptide antibodies (ACPA) in juvenile idiopathic arthritis
Sriharsha Grevich, Peggy Lee, Sarah Ringold, Brian Leroux, Hannah Leahey, Megan Yuasa, Jessica Foster, Jeremy Sokolove, Lauren Lahey, William Robinson, Joshua Newsom, Anne Stevens
P3 Novel autoantigens for endothelial cell antibodies in pediatric rheumatic diseases identified by proteomics
Rie Karasawa, Mayumi Tamaki, Megumi Tanaka, Toshiko Sato, Kazuo Yudoh, James N. Jarvis
P4 Transcriptional profiling reveals monocyte signature associated with JIA patient poor response to methotrexate
Halima Moncrieffe, Mark F. Bennett, Monica Tsoras, Lorie Luyrink, Huan Xu, Sampath Prahalad, Paula Morris, Jason Dare, Peter A. Nigrovic, Margalit Rosenkranz, Mara Becker, Kathleen M. O’Neil, Thomas Griffin, Daniel J. Lovell, Alexei A. Grom, Mario Medvedovic, Susan D. Thompson
P5 A multi-dimensional genomic map for polyarticular juvenile idiopathic arthritis
Lisha Zhu, Kaiyu Jiang, Laiping Wong, Michael J Buck, Yanmin Chen, Halima Moncrieffe, Laura Brungs, Tao Liu, Ting Wang, James N Jarvis
P6 Tocilizumab for treatment of children with refractory JIA
Khaled Alsaeid, Jasim Alfailakawi, Hamid Alenezi, Hazim Alsaeed
P7 Clinical characteristics of the initial patients enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry
Tim Beukelman, Marc Natter, Norm Ilowite, Kelly Mieszkalski, Grendel Burrell, Brian Best, Helen Bristow, Shannon Carr, Anne Dennos, Rachel Kaufmann, Yukiko Kimura, Laura Schanberg
P8 Comparative performance of small and large clinical centers in a comprehensive pediatric rheumatology disease registry
Peter R Blier
P9 Clinical characteristics of children with membranous lupus nephritis: The Childhood Arthritis and Rheumatology Research Alliance Legacy Registry
Alexis Boneparth, Scott E. Wenderfer, L. Nandini Moorthy, Suhas M. Radhakrishna, Anna Carmela P. Sagcal-Gironella, Emily von Scheven
P10 Rituximab use in pediatric lupus anticoagulant hypoprothrombinemia syndrome - a two center experience
Kader Cetin Gedik, Salma Siddique, Cassyanne L. Aguiar, Doruk Erkan
P11 Predictors of complementary and alternative medicine use and response in children with musculoskeletal conditions
Ezra Cohen, Yvonne Lee, Michelle Dossett, Darshan Mehta, Roger Davis
P12 Comparison of pediatric rheumatology and nephrology survey results for the treatment of refractory proliferative lupus nephritis and renal flare in juvenile SLE
Mileka Gilbert, Beatrice Goilav, Esra Meidan, Joyce Hsu, Alexis Boneparth, Anabelle Chua, Stacy Ardoin, Scott E. Wenderfer, Emily Von Scheven, Natasha M. Ruth
P13 Transitioning lupus patients from pediatric to adult rheumatology
Joyce Hui-Yuen, Kader Cetin Gedik, Liza Bermudez, Ashlea Cook, Lisa Imundo, Amy Starr, Andrew Eichenfield, Anca Askanase
P14 The systemic juvenile idiopathic arthritis cohort of the Childhood Arthritis & Rheumatology Research Alliance Registry
Ginger Janow, Laura E. Schanberg, Soko Setoguchi, Victor Hasselblad, Elizabeth D. Mellins, Rayfel Schneider, Yukiko Kimura, The CARRA Legacy Registry Investigators
P15 Results of the pilot study of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) consensus treatment plans for new-onset systemic juvenile idiopathic arthritis
Yukiko Kimura, Sriharsha Grevich, Timothy Beukelman, Esi Morgan, T Brent Graham, Maria Ibarra, Yonit Sterba Ruas, Marisa Klein-Gitelman, Karen Onel, Sampath Prahalad, Marilynn Punaro, Sarah Ringold, Dana Toib, Heather Van Mater, Jennifer E. Weiss, Pamela F. Weiss, Kelly Mieszkalski, Laura E. Schanberg
P16 A systemic review of pain relief modalities in juvenile idiopathic arthritis: First step in developing a novel decision support intervention
Timothy S. H. Kwok, Jacinthe Bisaillon, Christine Smith, Lucie Brosseau, Jennifer Stinson, Adam M. Huber, Ciaran M. Duffy, Karine Toupin April
P17 Barriers and facilitators to care retention for pediatric systemic lupus erythematous patients in South Africa: A qualitative study
Laura B Lewandowski, Christiaan Scott
P18 Evaluating the feasibility of conducting comparative effectiveness studies in juvenile Localized Scleroderma (jLS)
Suzanne C. Li, Kathryn S. Torok, C. Egla Rabinovich, Sandy D. Hong, Mara L Becker, Fatma Dedeoglu, Maria F. Ibarra, Polly J Ferguson, Rob C. Fuhbrigge, Katie G. Stewart, Elena Pope, Ronald M. Laxer, Thomas G. Mason, Gloria C. Higgins, Xiaohu Li, Marilynn G. Punaro, George Tomlinson, Eleanor Pullenayegum, John Matelski, Laura Schanberg, Brian M. Feldman
P19 Tonsillar histology in patients with periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome
Kalpana Manthiram, Hernan Correa, Kathryn Edwards
P20 Clinical course of juvenile dermatomyositis presenting as skin predominant disease
Edward J. Oberle, Michelle Bayer, Dominic O. Co, Hatice Ezgi Baris, Yvonne Chiu, Adam Huber, Susan Kim
P21 A Survey of musculoskeletal ultrasound practices of pediatric rheumatologists in North America
Edward J Oberle, Timothy Beukelman
P22 Assessment, classification and treatment of calcinosis as a complication of juvenile dermatomyositis: A survey of pediatric rheumatologists by the Childhood Arthritis and Rheumatology Research Alliance
Amir B. Orandi, Kevin W. Baszis, Vikas Dharnidharka, Mark F. Hoeltzel, for the CARRA JDM Committee
P23 CARRA dermatomyositis CTP pilot study
Ann Reed, Adam Huber, George Tomlinson, Eleanor Pullenayegum, John Matelski, Y. Ingrid Goh, Laura Schanberg, Brian M. Feldman
P24 Unexpectedly high incidences and prolonged disease activity in children with chronic non-bacterial osteomyelitis (CNO) as compared to bacterial osteomyelitis
Anja Schnabel, Ursula Range, Gabriele Hahn, Timo Siepmann, Reinhard Berner, Christian Michael Hedrich
P25 Juvenile systemic sclerosis cohort within the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry: Follow up characteristics
Brandi Stevens, Kathryn S. Torok, Suzanne Li, Nicole Hershey, Megan Curran, Gloria Higgins, Katharine Moore, Egla Rabinovich, Anne M. Stevens, for the CARRA Registry Investigators
P26 Development and usability testing of an iPad and desktop psycho-educational game for children with Juvenile Idiopathic Arthritis and their parents
Jennifer Stinson, Mark Connelly, Adam Huber, Nadia Luca, Lynn Spiegel, Argerie Tsimicalis, Stephanie Luca, Naweed Tajuddin, Roberta Berard, Julia Barsalou, Sarah Campillo, Paul Dancey, Ciaran Duffy, Brian Feldman, Nicole Johnson, Patrick McGrath, Natalie Shiff, Shirley Tse, Lori Tucker, Charles Victor
P27 iCanCopeTM: User-centred design and development of a smartphone app to support self-management for youth with arthritis pain
Jennifer Stinson, Chitra Lalloo, Lauren Harris, Joseph Cafazzo, Lynn Spiegel, Brian Feldman, Nadia Luca, Ronald Laxer
P28 Accessing pediatric rheumatology care: Despite barriers, few parents prefer telemedicine
Danielle R. Bullock, Richard K. Vehe, Lei Zhang, Colleen K. Correll1
P29 Exploration of factors contributing to time to achieve clinically inactive disease (CID) in juvenile idiopathic arthritis (JIA): A preliminary report
Suhas Ganguli, Max Shenberger, Ritesh Korumilli, Beth Gottlieb
P30 Pediatric rheumatology referral patterns: Presenting complaints of new patients at a large, urban academic center
Martha Rodriguez, Deirdre de Ranieri, Karen Onel, Linda Wagner-Weiner, Melissa Tesher
P31 Quality improvement (QI) initiatives in childhood systemic lupus erythematosus (cSLE)
Elizabeth Roth Wojcicki, Kristyn L. Maletta, Dominic O. Co, Marsha Malloy, Sarah Thomson, Judyann C. Olson
P32 Proliferative lupus nephritis in juvenile SLE: Support from the pediatric nephrology community for the definitions of responsiveness and flare in the 2012 consensus treatment plans
Scott E. Wenderfer, Mileka Gilbert, Joyce Hsu, Sangeeta Sule, Tamar B. Rubinstein, Beatrice Goilav, Daryl M. Okamura, Annabelle Chua, Laurence A. Greenbaum, Jerome C. Lane, Emily von Scheven, Stacy P. Ardoin, Natasha M. Ruth
P33 The steroid taper app: Making of a mobile app
Jennifer M. P. Woo, Marsha M. Malloy, James A. Jegers, Dustin J. Hahn, Mary K. Hintermeyer, Stacey M. Martinetti, Gretchen R. Heckel, Elizabeth L. Roth-Wojcicki, Dominic O. Co
doi:10.1186/s12969-016-0098-0
PMCID: PMC4943514  PMID: 27409414
2.  Procedural pain and patient-reported side effects with weekly injections of subcutaneous Methotrexate in children with rheumatic disorders 
Background
Despite the widespread use of subcutaneous methotrexate in treating pediatric rheumatic disorders, the amount of pain associated with the injections has not been quantified. Our study aims 1) to quantify the amount of pain associated with subcutaneous injections of methotrexate, 2) to explore predictors of pain, 3) to determine the frequency of patient-reported clinical adverse effects of methotrexate, and 4) identify coping strategies of patients and caregivers.
Methods
Patients aged 4–17 years with rheumatologic diseases who were receiving weekly subcutaneous methotrexate injections for at least 4 weeks were invited to participate in this prospective cohort study. They were trained to use the Faces Pain Scale – Revised (FPS-R) and Faces, Legs, Arms, Cry, Consolability (FLACC) tools to rate pain associated with the injections. All patients underwent focused interviews exploring their experiences with methotrexate injections.
Results
Forty-one patients consented to the study. The mean age was 11.2 years (SD = 3.9 years) and 68% were female. Most patients were diagnosed with JIA (73%). Mean duration of methotrexate therapy was 2.5 years (SD = 2.1 yrs). All but one of the patients used methotrexate 25 mg/ml solution for injection in 1 cc or 3 cc syringe with 30 gauge ½” needle. Median amount of pain was 2/10 on the FPS-R and 1/10 on the FLACC. Higher intensity of pain was significantly associated with presence of side effects (p = 0.004), but not duration of therapy (p = 0.20) or age (p = 0.24). Most participants (61%) experienced at least one adverse effect; nausea (56%) and vomiting (34%) were the most common symptoms reported. Patients and caregivers reported using ice (34%), comfort positions (51%), rewards (49%), reassurance (54%), distraction (51%), and analgesic medications (22%) to cope with the injections.
Conclusion
Subcutaneous injections of methotrexate are associated with a mild amount of pain. Presence of side effects may amplify the amount of perceived pain. Clinicians can apply this knowledge when counseling patients and family members about methotrexate therapy.
doi:10.1186/1546-0096-12-54
PMCID: PMC4290103  PMID: 25584042
5.  Galactorrhea associated with juvenile systemic lupus erythematosus: a review of the role of prolactin 
This case report is based on the clinical observation of a patient with juvenile systemic lupus erythematosus (SLE) who developed transient galactorrhea. The subsequent literature review documented an interesting association between prolactin and rheumatic diseases and in particular, hyperprolactinemia and SLE. The discussion that follows the case report explores this relationship and proposes a hypothesis regarding why this patient with juvenile SLE developed galactorrhea.
doi:10.1186/1546-0096-7-17
PMCID: PMC2770548  PMID: 19852783
6.  Inflammatory arthritis in children with osteochondrodysplasias 
Annals of the Rheumatic Diseases  2000;59(11):864-869.
Osteochondrodysplasias are a heterogeneous group of genetic skeletal dysplasias. Patients with these diseases commonly develop an early degenerative arthritis or osteoarthritis. Occasional observations of inflammatory arthritis have been made in this population but such observations are based on clinical grounds alone without confirmatory imaging studies. Four patients followed up in a paediatric rheumatology clinic with three different skeletal dysplasias, who had both clinical and radiological evidence of an inflammatory arthritis and coexistent degenerative arthritis, are described.


doi:10.1136/ard.59.11.864
PMCID: PMC1753032  PMID: 11053062
9.  Adjuvant and carrier protein-dependent T-cell priming promotes a robust antibody response against the Plasmodium falciparum Pfs25 vaccine candidate 
Scientific Reports  2017;7:40312.
Humoral immune responses have the potential to maintain protective antibody levels for years due to the immunoglobulin-secreting activity of long-lived plasma cells (LLPCs). However, many subunit vaccines under development fail to generate robust LLPC responses, and therefore a variety of strategies are being employed to overcome this limitation, including conjugation to carrier proteins and/or formulation with potent adjuvants. Pfs25, an antigen expressed on malaria zygotes and ookinetes, is a leading transmission blocking vaccine (TBV) candidate for Plasmodium falciparum. Currently, the conjugate vaccine Pfs25-EPA/Alhydrogel is in Phase 1 clinical trials in the USA and Africa. Thus far, it has proven to be safe and immunogenic, but it is expected that a more potent formulation will be required to establish antibody titers that persist for several malaria transmission seasons. We sought to determine the contribution of carrier determinants and adjuvants in promoting high-titer, long-lived antibody responses against Pfs25. We found that both adjuvants and carrier proteins influence the magnitude and capacity of Pfs25-specific humoral responses to remain above a protective level. Furthermore, a liposomal adjuvant with QS21 and a TLR4 agonist (GLA-LSQ) was especially effective at inducing T follicular helper (Tfh) and LLPC responses to Pfs25 when coupled to immunogenic carrier proteins.
doi:10.1038/srep40312
PMCID: PMC5238395  PMID: 28091576
10.  Dynamic Electrical Source Imaging (DESI) of Seizures and Interictal Epileptic Discharges Without Ensemble Averaging 
We propose an algorithm for electrical source imaging of epileptic discharges that takes a data-driven approach to regularizing the dynamics of solutions. The method is based on linear system identification on short time segments, combined with a classical inverse solution approach. Whereas ensemble averaging of segments or epochs discards inter-segment variations by averaging across them, our approach explicitly models them. Indeed, it may even be possible to avoid the need for the time-consuming process of marking epochs containing discharges altogether. We demonstrate that this approach can produce both stable and accurate inverse solutions in experiments using simulated data and real data from epilepsy patients. In an illustrative example, we show that we are able to image propagation using this approach. We show that when applied to imaging seizure data, our approach reproducibly localized frequent seizure activity to within the margins of surgeries that led to patients’ seizure freedom. The same approach could be used in the planning of epilepsy surgeries, as a way to localize potentially epileptogenic tissue that should be resected.
doi:10.1109/TMI.2016.2595329
PMCID: PMC5217759  PMID: 27479957
11.  Age-Related Sleep Disruption and Reduction in the Circadian Rhythm of Urine Output: Contribution to Nocturia? 
Current aging science  2016;9(1):34-43.
Aging is associated with a marked increase in sleep complaints, and one factor causing sleep disruption is waking to void (nocturia). Urological surveys have found that few young adults report nocturia symptoms, but about half of those in their 60’s and nearly 80% of older age groups are affected. Sleep surveys have found nocturia is a major cause of sleep disruption, with a majority of older adults with sleep disruption citing the need to void as the cause of their awakening. While much of the urological literature implies that nocturia causes sleep disruption, age-related changes in sleep depth and continuity may make it more likely that an older adult will wake in response to a filling bladder, or that an older adult will wake for another reason and then decide to void. There is also evidence that age-related changes in the amplitude of circadian rhythms contribute to nocturia. There is a well-described circadian rhythm in urine output, and evidence of circadian rhythmicity in some diuretic and anti-diuretic hormones. In this article we describe how age-related changes in sleep depth and continuity and age-related changes in circadian rhythm amplitude may contribute to nocturia, and how nocturia in turn leads to sleep disruption. Better understanding of how changes in sleep and circadian rhythmicity impact nocturia may lead to improved treatments and better quality of life for older adults.
PMCID: PMC4713267  PMID: 26632430
Aldosterone; circadian; nocturia; obstructive sleep apnea; sleep; vasopressin
12.  Prevalence and Risk Factors of Self-Reported Smell and Taste Alterations: Results from the 2011–2012 US National Health and Nutrition Examination Survey (NHANES) 
Chemical Senses  2015;41(1):69-76.
Chemosensory problems challenge health through diminished ability to detect warning odors, consume a healthy diet, and maintain quality of life. We examined the prevalence and associated risk factors of self-reported chemosensory alterations in 3603 community-dwelling adults (aged 40+ years), from the nationally representative, US National Health and Nutrition Examination Survey (NHANES) 2011–2012. In this new NHANES component, technicians surveyed adults in the home about perceived smell and taste problems, distortions, and diminished abilities since age 25 (termed “alterations”), and chemosensory-related health risks and behaviors. The prevalence of self-reported smell alteration was 23%, including phantosmia at 6%; taste was 19%, including dysgeusia at 5%. Prevalence rates increased progressively with age, highest in those aged 80+ years (smell, 32%; taste, 27%). In multivariable logistic regression, controlling for sociodemographics, health behaviors, and chemosensory-related conditions, the strongest independent risk factor for smell alteration was sinonasal symptoms (odds ratio [OR] = 2.06; 95% confidence interval [CI]: 1.63–2.61), followed by heavy drinking, loss of consciousness from head injury, family income ≤110% poverty threshold, and xerostomia. For taste, the strongest risk factor was xerostomia (OR = 2.65; 95% CI: 1.97–3.56), followed by nose/facial injury, lower educational attainment, and fair/poor health. Self-reported chemosensory alterations are prevalent in US adults, supporting increased attention to decreasing their modifiable risks, managing safety/health consequences, and expanding chemosensory screening/testing and treatments.
doi:10.1093/chemse/bjv057
PMCID: PMC4715252  PMID: 26487703
dry mouth; dysgeusia; head injury; health status; phantosmia
13.  Using vignettes to rethink Latino-white disparities in self-rated health 
Researchers often rely on respondents’ self-rated health (SRH) to measure social disparities in health, but recent studies suggest that systematically different reporting styles across groups can yield misleading conclusions about disparities in SRH. In this study, we test whether this finding extends to ethnic differences in self-assessments of health in particular domains. We document differences between US-born whites and four Latino subgroups in respondents’ assessments of health in six health domains using data from the second wave of the Los Angeles Family and Neighborhood Study (N=1468). We use both conventional methods and an approach that uses vignettes to adjust for differential reporting styles.
Our results suggest that despite consistent evidence from the literature that Latinos tend to rate their overall health more poorly than whites, and that Latino immigrants report worse SRH than US-born Latinos, this pattern is not true of self-reports in individual health domains. We find that at the bivariate level, US-born whites (and often US-born Mexicans) have significantly more pessimistic reporting styles than Latino immigrants. After adding controls, we find evidence of significantly different reporting styles for only one domain: US-born Mexicans and whites consistently interpret head pain more severely than the other Latino subgroups. Finally, we find that both before and after adjusting for differences in rating styles across groups, non-Mexican Latino immigrants report better social and physical functioning and less pain than other groups.
Our findings underscore the advantages of domain-specific ratings when evaluating ethnic differences in self-assessments of health. We encourage researchers studying social disparities in health to consider respondents’ self-assessments in a variety of domains, and to also investigate (when possible) potential biases in their findings due to different reporting styles. The anchoring vignettes approach we use is one potential method for overcoming biases due to different rating styles across groups.
doi:10.1016/j.socscimed.2015.11.031
PMCID: PMC5146984  PMID: 26706402
Self-rated health; health disparities; vignettes; racial/ethnic disparities
14.  Clinical Use of Cancer Biomarkers in Epithelial Ovarian Cancer: Updated Guidelines from the European Group on Tumor Markers (EGTM) 
Objective
To present an update of the European Group on Tumor Markers (EGTM) guidelines for serum markers in epithelial ovarian cancer.
Methods
Systematic literature survey from 2008 to 2013. The articles were evaluated by Level Of Evidence and Strength Of Recommendation.
Results
Due to its low sensitivity (50-62% for early stage epithelial ovarian cancer) and limited specificity (94-98.5%), CA125 is not recommended as a screening test in asymptomatic women. The Risk of Malignancy Index which includes CA125, transvaginal ultrasound and menopausal status is recommended for the differential diagnosis of a pelvic mass. As HE4 has been reported to have superior specificity to CA 125, especially in premenopausal women, it may be considered either alone or as part of the Risk of Ovarian Malignancy Algorithm, in the differential diagnosis of pelvic masses, especially in such women. CA 125 should be used to monitor response to first-line chemotherapy using the previously published criteria of The Gynecological Cancer Intergroup, i.e., at least a 50% reduction of a pre-treatment sample ≥70 kU/L. The value of CA 125 in post-therapy surveillance is less clear. Although a prospective randomized trial concluded that early administration of chemotherapy based on increasing CA 125 levels had no effect on survival, EGTM state that monitoring with CA 125 in this situation should occur, especially if the patient is a candidate for secondary cytoreductive surgery.
Conclusion
At present, CA125 remains the most important biomarker for epithelial ovarian cancer, excluding tumors of mucinous origin.
doi:10.1097/IGC.0000000000000586
PMCID: PMC4679342  PMID: 26588231
16.  Large screen approaches to identify novel malaria vaccine candidates 
Vaccine  2015;33(52):7496-7505.
Until recently, malaria vaccine development efforts have focused almost exclusively on a handful of well characterized Plasmodium falciparum antigens. Despite dedicated work by many researchers on different continents spanning more than half a century, a successful malaria vaccine remains elusive. Sequencing of the P. falciparum genome has revealed more than five thousand genes, providing the foundation for systematic approaches to discover candidate vaccine antigens. We are taking advantage of this wealth of information to discover new antigens that may be more effective vaccine targets. Herein, we describe different approaches to large-scale screening of the P. falciparum genome to identify targets of either antibody responses or T cell responses using human specimens collected in Controlled Human Malaria Infections (CHMI) or under conditions of natural exposure in the field. These genome, proteome and transcriptome based approaches offer enormous potential for the development of an efficacious malaria vaccine.
doi:10.1016/j.vaccine.2015.09.059
PMCID: PMC4729565  PMID: 26428458
Antigen discovery; large-scale screen; immunomics; reverse vaccinology; protein microarrays; T cell antigens
17.  Protocol for developing, disseminating and implementing a core outcome set for endometriosis 
BMJ Open  2016;6(12):e013998.
Introduction
Endometriosis is a common gynaecological disease characterised by pain and subfertility. Randomised controlled trials evaluating treatments for endometriosis have reported many different outcomes and outcome measures. This variation restricts effective data synthesis limiting the usefulness of research to inform clinical practice. To address these methodological concerns, we aim to develop, disseminate and implement a core outcome set for endometriosis engaging with key stakeholders, including healthcare professionals, researchers and women with endometriosis.
Methods and analysis
An international steering group has been established, including healthcare professionals, researchers and patient representatives. Potential outcomes identified from a systematic review of the literature will be entered into a modified Delphi method. Key stakeholders will be invited to participate including healthcare professionals, researchers and women with endometriosis. Participants will be invited to score individual outcomes on a nine-point Likert scale anchored between 1 (not important) and 9 (critical). Repeated reflection and rescoring should promote whole and individual stakeholder group converge towards consensus, ‘core’, outcomes. High-quality outcome measures will be associated with core outcomes.
Ethics and dissemination
The implementation of a core outcome set for endometriosis within future clinical trials, systematic reviews and clinical guidelines will enhance the availability of comparable data to facilitate evidence-based patient care. This study was prospectively registered with Core Outcome Measures in Effectiveness Trials Initiative; number: 691.
doi:10.1136/bmjopen-2016-013998
PMCID: PMC5223702  PMID: 28003300
Core outcome sets; Consensus methodology; Endometriosis; outcome harmonization; Outcome variation
18.  Effect of peripheral arterial disease on the onset of lactate threshold during cardiopulmonary exercise test: study protocol 
BMJ Open  2016;6(12):e012763.
Introduction
Cardiopulmonary exercise test (CPET) is widely used in preoperative assessment and cardiopulmonary rehabilitation. The effect of peripheral arterial disease (PAD) on oxygen delivery (VO2) measured by CPET is not known. The aim of this study was to investigate the effect of PAD on VO2 measurements during CPET.
Methods and analysis
We designed a prospective cohort study, which will recruit 30 patients with PAD, who will undergo CPET before and after treatment of iliofemoral occlusive arterial disease. The main outcome measure is the difference in VO2 at the lactate threshold (LT) between the 2 CPETs. The secondary outcome measure is the relationship between change in VO2 at the LT and peak exercise pretreatment and post-treatment and haemodynamic measures of PAD improvement (ankle–brachial index differential). For VO2 changes, only simple paired bivariate comparisons, not multivariate analyses, are planned, due to the small sample size. The correlation between ABI and VO2 rise will be tested by linear regression.
Ethics and dissemination
The study was approved by the North West-Lancaster Research and Ethics committee (reference 15/NW/0801). Results will be disseminated through scientific journal and scientific conference presentation. Completion of recruitment is expected by the end of 2016, and submission for publication by March 2017.
Trial registration number
NCT02657278.
doi:10.1136/bmjopen-2016-012763
PMCID: PMC5168619  PMID: 27993904
OXYGEN DELIVERY; PREOPERATIVE ASSESSMENT; VASCULAR SURGERY; REHABILITATION MEDICINE
19.  Randomised clinical trial: exploratory phase 2 study of ONO‐2952 in diarrhoea‐predominant irritable bowel syndrome 
Summary
Background
ONO‐2952 is a novel and selective inhibitor of translocator protein 18 kDa that reduces stress‐induced defecation and visceral hyperalgesia in rat models.
Aim
To evaluate the efficacy and safety of ONO‐2952 in females with irritable bowel syndrome with diarrhoea in an exploratory proof‐of‐concept study.
Methods
A randomised, double‐blind, placebo‐controlled study was conducted at 49 US centres. Two hundred subjects with irritable bowel syndrome with diarrhoea (Rome III criteria) were randomised to ONO‐2952 20 mg, or 60 mg, or placebo. Subjects recorded irritable bowel syndrome symptoms daily during a 2‐week baseline period, the 4‐week treatment period and for 4 weeks post‐treatment. The co‐primary endpoints were change from baseline to week 4 in abdominal pain, stool consistency and stool frequency.
Results
Improvements in irritable bowel syndrome symptoms were seen with ONO‐2952 over placebo in per‐protocol analyses for all three co‐primary endpoints, but these did not reach statistical significance at the 5% level. The largest improvement was seen with ONO‐2952 60 mg. ONO‐2952 was well tolerated with a safety profile similar to that of placebo. Most adverse events were mild or moderate in severity and not treatment related.
Conclusion
ONO‐2952 showed evidence of clinical efficacy in reducing irritable bowel syndrome‐related symptoms in female subjects with irritable bowel syndrome with diarrhoea, and further evaluation is, therefore, warranted to assess its potential as a treatment for irritable bowel syndrome with diarrhoea (NCT01844180).
doi:10.1111/apt.13839
PMCID: PMC5157770  PMID: 27910150
20.  Toward real-time remote processing of laparoscopic video 
Journal of Medical Imaging  2015;2(4):045002.
Abstract.
Laparoscopic surgery is a minimally invasive surgical technique where surgeons insert a small video camera into the patient’s body to visualize internal organs and use small tools to perform surgical procedures. However, the benefit of small incisions has a drawback of limited visualization of subsurface tissues, which can lead to navigational challenges in the delivering of therapy. Image-guided surgery uses the images to map subsurface structures and can reduce the limitations of laparoscopic surgery. One particular laparoscopic camera system of interest is the vision system of the daVinci-Si robotic surgical system (Intuitive Surgical, Sunnyvale, California). The video streams generate approximately 360 MB of data per second, demonstrating a trend toward increased data sizes in medicine, primarily due to higher-resolution video cameras and imaging equipment. Processing this data on a bedside PC has become challenging and a high-performance computing (HPC) environment may not always be available at the point of care. To process this data on remote HPC clusters at the typical 30 frames per second (fps) rate, it is required that each 11.9 MB video frame be processed by a server and returned within 1/30th of a second. The ability to acquire, process, and visualize data in real time is essential for the performance of complex tasks as well as minimizing risk to the patient. As a result, utilizing high-speed networks to access computing clusters will lead to real-time medical image processing and improve surgical experiences by providing real-time augmented laparoscopic data. We have performed image processing algorithms on a high-definition head phantom video (1920 × 1080 pixels) and transferred the video using a message passing interface. The total transfer time is around 53 ms or 19 fps. We will optimize and parallelize these algorithms to reduce the total time to 30 ms.
doi:10.1117/1.JMI.2.4.045002
PMCID: PMC4676794  PMID: 26668817
laparoscopy; image-guided surgery; medical imaging; high-performance computing; high-throughput networking
21.  Biodiversity and human well-being: an essential link for sustainable development 
As society strives to transition towards more sustainable development pathways, it is important to properly conceptualize the link between biodiversity (i.e. genes, traits, species and other dimensions) and human well-being (HWB; i.e. health, wealth, security and other dimensions). Here, we explore how published conceptual frameworks consider the extent to which the biodiversity–HWB links are being integrated into public discourse and scientific research and the implications of our findings for sustainable development. We find that our understanding has gradually evolved from seeing the value of biodiversity as an external commodity that may influence HWB to biodiversity as fundamental to HWB. Analysis of the literature trends indicates increasing engagement with the terms biodiversity, HWB and sustainable development in the public, science and policy spheres, but largely as independent rather than linked terms. We suggest that a consensus framework for sustainable development should include biodiversity explicitly as a suite of internal variables that both influence and are influenced by HWB. Doing so will enhance clarity and help shape coherent research and policy priorities. We further suggest that the absence of this link in development can inadvertently lead to a ratcheting down of biodiversity by otherwise well-meaning policies. Such biotic impoverishment could lock HWB at minimum levels or lead to its decline and halt or reverse progress in achieving sustainable development.
doi:10.1098/rspb.2016.2091
PMCID: PMC5204155  PMID: 27928039
biodiversity; sustainable development; human well-being; ecosystem services
22.  Ethical considerations in hibernation research 
Lab animal  2013;42(7):248-252.
Ethical research practices are a key component of scientific integrity and of public support for research. Hibernation research presents specific ethical issues in regard to animal welfare. In this article, the authors apply the ‘3Rs’ principles of humane experimental technique (replacement, reduction and refinement) to hibernation research. They provide recommendations for hibernation researchers and suggest future directions for addressing issues specific to hibernation research. They discuss the use of appropriate behavioral and physiological monitoring procedures, the development of species-specific brain atlases for placement of brain probes, the provision of environmental enrichment and the management of studies involving pharmacological induction of torpor. Addressing these issues in hibernation research will lead to improvements in research outcomes and in welfare of hibernating species.
doi:10.1038/laban.253
PMCID: PMC5148123  PMID: 23783315
23.  Malaria in HIV-Infected Children Receiving HIV Protease-Inhibitor- Compared with Non-Nucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy, IMPAACT P1068s, Substudy to P1060 
PLoS ONE  2016;11(12):e0165140.
Background
HIV and malaria geographically overlap. HIV protease inhibitors kill malaria parasites in vitro and in vivo, but further evaluation in clinical studies is needed.
Methods
Thirty-one children from Malawi aged 4–62 months were followed every 3 months and at intercurrent illness visits for ≤47 months (September 2009-December 2011). We compared malaria parasite carriage by blood smear microscopy (BS) and confirmed clinical malaria incidence (CCM, or positive BS with malaria symptoms) in children initiated on HIV antiretroviral therapy (ART) with zidovudine, lamivudine, and either nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor, or lopinavir-ritonavir (LPV-rtv), a protease inhibitor.
Results
We found an association between increased time to recurrent positive BS, but not CCM, when anti-malarial treatment and LPV-rtv based ART were used concurrently and when accounting for a LPV-rtv and antimalarial treatment interaction (adjusted HR 0.39; 95% CI (0.17,0.89); p = 0.03).
Conclusions
LPV-rtv in combination with malaria treatment was associated with lower risk of recurrent positive BS, but not CCM, in HIV-infected children. Larger, randomized studies are needed to confirm these findings which may permit ART optimization for malaria-endemic settings.
Trial Registration
ClinicalTrials.gov NCT00719602
doi:10.1371/journal.pone.0165140
PMCID: PMC5147802  PMID: 27936233
24.  Engaging Students in Science Courses: Lessons of Change from the Arctic 
Where you live should have something to do with what you teach. In the Arctic, this idea of place-based education—teaching and sharing knowledge that is needed to live well— is central to the UARCTIC consortium and the 4th International Polar Year educational reform effort. A place-based issue oriented context can engage students in chemistry concepts when it intersects with their experience and lives. This article examines the rationale and means of integrating local concerns such as world view, culture, traditional knowledge and policy into both general and specialized chemistry courses. More broadly, capacious place-based issues should be widely adapted by all curriculum reform efforts to demonstrate the connectivity between science and societal understanding of technological options. A case in point is the inclusion of indigenous perspectives in a non-majors general chemistry course when the concepts of scientific method, ice and water resources, genetic engineering, etc. are discussed. In a specialized course on radioactivity in the north, topics connected nuclear chemistry and radioactivity to people and energy. The local landscape should be central to science courses and involve issues relevant to stewardship, a component of the indigenous world view. The historical issues can be connected to current nuclear energy and uranium mining as they relate to the risks and benefits for the local community. This article will make the case that curriculum reform that focuses on real-world topics will not only engage students so that they perform well in class but also spark their interest so that they continue learning after the course is over.
doi:10.1007/s10780-011-9151-6
PMCID: PMC5148167  PMID: 27976754
Place-based Science Education; Environment; Climate Change; Arctic Science; UARCTIC; Culture and Stewardship; Civic Issue Engagement
25.  Inflammasome-Independent NLRP3 Restriction of a Protective Early Neutrophil Response to Pulmonary Tularemia 
PLoS Pathogens  2016;12(12):e1006059.
Francisella tularensis (Ft) causes a frequently fatal, acute necrotic pneumonia in humans and animals. Following lethal Ft infection in mice, infiltration of the lungs by predominantly immature myeloid cells and subsequent myeloid cell death drive pathogenesis and host mortality. However, following sub-lethal Ft challenge, more mature myeloid cells are elicited and are protective. In addition, inflammasome-dependent IL-1β and IL-18 are important for protection. As Nlrp3 appears dispensable for resistance to infection with Francisella novicida, we considered its role during infection with the virulent Type A strain SchuS4 and the attenuated Type B live vaccine strain LVS. Here we show that both in vitro macrophage and in vivo IL-1β and IL-18 responses to Ft LVS and SchuS4 involve both the Aim2 and Nlrp3 inflammasomes. However, following lethal infection with Francisella, IL-1r-, Caspase-1/11-, Asc- and Aim2-deficient mice exhibited increased susceptibility as expected, while Nlrp3-deficient mice were more resistant. Despite reduced levels of IL-1β and IL-18, in the absence of Nlrp3, Ft infected mice have dramatically reduced lung pathology, diminished recruitment and death of immature myeloid cells, and reduced bacterial burden in comparison to wildtype and inflammasome-deficient mice. Further, increased numbers of mature neutrophil appear in the lung early during lethal Ft infection in Nlrp3-deficient mice. Finally, Ft infection induces myeloid and lung stromal cell death that in part requires Nlrp3, is necrotic/necroptotic in nature, and drives host mortality. Thus, Nlrp3 mediates an inflammasome-independent process that restricts the appearance of protective mature neutrophils and promotes lethal necrotic lung pathology.
Author Summary
The Nlrp3 inflammasome is critical for various innate and adaptive immune responses through elaboration of IL-1β and IL-18. In contrast to the anticipated minimal, or perhaps absent, role of Nlrp3 in the pathogenesis of pulmonary tularemia, we find that Nlrp3 is a host susceptibility factor. Likely through promoting necrotic/necroptotic cell death, Nlrp3 contributes to the immature myeloid response and necrotic pathology that characterize lethal infection with Francisella tularensis.
doi:10.1371/journal.ppat.1006059
PMCID: PMC5142794  PMID: 27926940

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