tbuckley/cabot-search huggingface dataset:
THU0139 Increased homocysteine level for 7 years in patients with rheumatoid arthritis: tomorrow study
Authors: K. Inui, T. Koike, Y. Sugioka, T. Okano, K. Mamoto, Y. Yamada, K. Mandai, M. Tada, H. Nakamura
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Osteoporosis is a disease in which not only bone density but also bone quality is low. Patients with rheumatoid arthritis (RA) are at higher proven risk of osteoporosis. Increased homocysteine (Hcy), one of the main markers of bone quality, is caused by insufficiency of folate or vitamin B. Elevation of Hcy inhibits physiological crosslink of collagen, which yields worse bone quality. <h3>Objectives</h3> In this study, we evaluated Hcy level as a bone quality marker in patients with RA for a period of 7 years and compared Hcy in RA patients with that in healthy volunteers (Vo). <h3>Methods</h3> We used the data for 7 years from a prospective cohort study (TOMORROW Study: UMIN000003876), which started in 2010 and compares data from RA patients with age- and sex-matched volunteer controls (Vo) recruited through mass media. Laboratory data were collected for all participants, including bone metabolic markers (urinary pentosidine, Hcy, collagen type 1 crosslinked N-telopeptide (NTX), and osteocalcin) and anthropometric parameters. Bone mineral density (BMD) of the lower leg was determined using whole-body dual-energy X-ray absorptiometry (DXA). Their parameters were compared with those of healthy controls, and multiple regression analysis was carried out only in the RA population. In RA patients, treatment regimen and Disease Activity Score 28 were recorded. <h3>Results</h3> There were 413 participants (208 RA patients and 205 in the Vo group; mean age, 58 years) enrolled in the study, 349 of whom were female. In RA patients (mean disease duration, 13 years), bone density was significantly lower (p&lt;0.001. repeated-measures ANOVA) and Hcy (p&lt;0.0001, repeated-measures ANOVA) was higher in comparison with the Vo group during the 7 year study period. In the analysis of change in Hcy level over 7 years, "RA" and "time" were found to interact with each other (p=2.58e-7, repeated-measures ANOVA) (figure 1). Multiple linear regression analysis in the RA population revealed a relationship between the level of Hcy and MTX dose at baseline (p=0.048), but no relationship between the level of Hcy and MCV (p=0.165). <h3>Conclusions</h3> MTX intake leads to folate deficiency, which is thought to cause elevation of the Hcy level. Ageing is another significant factor related to Hcy increase. <h3>Acknowledgements</h3> We thank Atsuko Kamiyama and Tomoko Nakatsuka for serving as research coordinators in terms of recruiting participants, collecting data and managing the quality of the data. <h3>Disclosure of Interest</h3> None declared
Therapeutic Inhibition of VEGF Signaling and Associated Nephrotoxicities
Authors: Chelsea C. Estrada, Alejandro Maldonado, Sandeep K. Mallipattu
Journal: Journal of the American Society of Nephrology (2019)

Inhibition of vascular endothelial growth factor A (VEGFA)/vascular endothelial growth factor receptor 2 (VEGFR2) signaling is a common therapeutic strategy in oncology, with new drugs continuously in development. In this review, we consider the experimental and clinical evidence behind the diverse nephrotoxicities associated with the inhibition of this pathway. We also review the renal effects of VEGF inhibition’s mediation of key downstream signaling pathways, specifically MAPK/ERK1/2, endothelial nitric oxide synthase, and mammalian target of rapamycin (mTOR). Direct VEGFA inhibition via antibody binding or VEGF trap (a soluble decoy receptor) is associated with renal-specific thrombotic microangiopathy (TMA). Reports also indicate that tyrosine kinase inhibition of the VEGF receptors is preferentially associated with glomerulopathies such as minimal change disease and FSGS. Inhibition of the downstream pathway RAF/MAPK/ERK has largely been associated with tubulointerstitial injury. Inhibition of mTOR is most commonly associated with albuminuria and podocyte injury, but has also been linked to renal-specific TMA. In all, we review the experimentally validated mechanisms by which VEGFA-VEGFR2 inhibitors contribute to nephrotoxicity, as well as the wide range of clinical manifestations that have been reported with their use. We also highlight potential avenues for future research to elucidate mechanisms for minimizing nephrotoxicity while maintaining therapeutic efficacy.
A loss-of-function variant in ALOX15 protects against nasal polyps and chronic rhinosinusitis
Authors: Ragnar P. Kristjansson, Stefania Benonisdottir, Olafur B. Davidsson, Asmundur Oddsson, Vinicius Tragante, Jon K. Sigurdsson, Lilja Stefansdottir, Stefan Jonsson, Brynjar O. Jensson, Joseph G. Arthur, Gudny A. Arnadottir, Gerald Sulem, Bjarni V. Halldorsson, Bjarni Gunnarsson, Gisli H. Halldorsson, Olafur A. Stefansson, Gudjon R. Oskarsson, Aimee M. Deaton, Isleifur Olafsson, Gudmundur I. Eyjolfsson, Olof Sigurdardottir, Pall T. Onundarson, David Gislason, Thorarinn Gislason, Bjorn R. Ludviksson, Dora Ludviksdottir, Thorunn A. Olafsdottir, Thorunn Rafnar, Gisli Masson, Florian Zink, Gyda Bjornsdottir, Olafur Th. Magnusson, Unnur S. Bjornsdottir, Gudmar Thorleifsson, Gudmundur L. Norddahl, Daniel F. Gudbjartsson, Unnur Thorsteinsdottir, Ingileif Jonsdottir, Patrick Sulem, Kari Stefansson
Journal: Nature Genetics (2019)
AB0653 Prediction of relapses in autoimmune large-vessel vasculitis – towards personalised immunosuppressive treatment stewardship
Authors: P.S. Fuchs, M.B. Bigler, C. Küng, T. Manigold, M. Aschwanden, D. Staub, D. Kyburz, V. Greiff, T. Daikeler, C.T. Berger
Journal: Annals of the Rheumatic Diseases (2018)

p=0.3).The median SUVmax was 3.0 [1.8-8.6]without significative difference between GCA and TA: 3.4 (2.1-8.6)versus 2.6 (1.8-7.1)(p=0.4),respectively.Eleven PET (61%) were performed under treatment, which consisted of steroids with a median dose at 30 mg/day [3-240].Among 11 patients with active disease, 8 had inflammatory patterns and 3 had normal PET/MR, i.e a sensibility of 73%, and the sensibility increased to 100% in patients with active TA disease.Median SUVmax were 4.7 [2.1-8.6] in patients with active disease versus 2 [1.8-2.6] in patients with remission (p=0.003).Conclusions: PET/MR is a new hybrid modality of imaging which is interesting for the diagnosis and the follow-up of large-vessel vasculitis.
Non Invasive Evaluation of Hepatic Iron Concentration By Fibroscan in Transfusion-Dependent Egyptian Patients with Chronic Hemolytic Anemia
Authors: Amal El-Beshlawy, Dalia Omran, Hala Mohsen Abdullatif, Niveen Salama, Mohamed Ahmed Abdel Naeem, Mona El ghamrawy, Amina Abdel-Salam
Journal: Blood (2018)
Shared Molecular Targets Confer Resistance over Short and Long Evolutionary Timescales
Authors: Jing Li, Ignacio Vázquez-García, Karl Persson, Asier González, Jia-Xing Yue, Benjamin Barré, Michael N Hall, Anthony Long, Jonas Warringer, Ville Mustonen, Gianni Liti
Journal: Molecular Biology and Evolution (2019)

Pre-existing and de novo genetic variants can both drive adaptation to environmental changes, but their relative contributions and interplay remain poorly understood. Here we investigated the evolutionary dynamics in drug-treated yeast populations with different levels of pre-existing variation by experimental evolution coupled with time-resolved sequencing and phenotyping. We found a doubling of pre-existing variation alone boosts the adaptation by 64.1% and 51.5% in hydroxyurea and rapamycin, respectively. The causative pre-existing and de novo variants were selected on shared targets: RNR4 in hydroxyurea and TOR1, TOR2 in rapamycin. Interestingly, the pre-existing and de novo TOR variants map to different functional domains and act via distinct mechanisms. The pre-existing TOR variants from two domesticated strains exhibited opposite rapamycin resistance effects, reflecting lineage-specific functional divergence. This study provides a dynamic view on how pre-existing and de novo variants interactively drive adaptation and deepens our understanding of clonally evolving populations.
FRI0017 An exploratory study on the role of vitamin d supplementation in improving pain and disease activity in rheumatoid arthritis
Authors: G. Adami, O. Viapiana, L. Bogliolo, F.P. Cantatore, M. Varenna, N. Malavolta, A. Del Puente, M. Muratore, G. Orsolini, D. Gatti, M. Rossini
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Lower serum vitamin D levels have been associated with various autoimmune disorders. Especially in patients affected by Rheumatoid Arthritis (RA), has been observed an inverse correlation between serum levels of 25-hydroxyvitamin D (25OHD), pain and disease activity, but the cause-effect relationship is not clear. <h3>Objectives</h3> The aim of this exploratory study is to investigate the effects of supplementation with cholecalciferol (vitD3) in improving pain and disease activity in RA patients with or without vitamin D deficiency (25OHD&lt;20 ng/ml). <h3>Methods</h3> In this prospective open-label intervention study, patients fulfilling the EULAR/ACR 2010 criteria for diagnosis of RA, in non-remission (DAS28-CRP&gt;2,6), on stable disease-modifying antirheumatic drugs, and whose treatment was not expected to be changed over a 3 month period following inclusion, were recruited. DAS28-CRP, VAS pain and serum levels of 25OHD, were evaluated at the baseline and after 3 months of supplementation with oral 100,000 IU/monthly of vitD3. <h3>Results</h3> A sample composed by 61 patients (47 females), with an average age (SD) of 5812 years within 26–86 years range were included. At baseline the mean (SD) 25OHD levels were 2210 ng/mL. 57% of the patients were found to have vitamin D deficiency (&lt;20 ng/mL). Mean serum 25OHD levels improved from 13±5 to 32±12 and from 29±7 to 41±10 ng/mL in patients with or without vitamin D deficiency, respectively. At baseline, mean VAS pain was significantly higher in patients with vitamin D deficiency. In the figure are shown DAS28-CRP and VAS pain at baseline and after 3 months of vitD3 supplementation both in patients with or without vitamin D deficiency. After large doses of VitD3, VAS pain significantly decreased in patients with vitamin D deficiency, while DAS28-CRP significantly improved only in patients without vitamin D deficiency at baseline. <h3>Conclusions</h3> VitD3 supplementation appears to be associated with significant and different effects on pain and disease activity in RA patients dependent on 25OHD serum levels. Vitamin D deficiency (&lt;20 ng/mL) seems to be mainly correlated with pain, while higher levels of 25OHD might have immunomodulatory effects. A randomised, double-blind, low versus high vitD3 dose, placebo-controlled trial is recommended. <h3>Disclosure of Interest</h3> None declared
The Projected Economic and Health Burden of Uncontrolled Asthma in the United States
Authors: Mohsen Yaghoubi, Amin Adibi, Abdollah Safari, J. Mark FitzGerald, Mohsen Sadatsafavi
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Despite effective treatments, a large proportion of patients with asthma do not achieve sustained asthma control. The "preventable" burden associated with lack of proper control is likely taking a high toll at the personal and population level.
Evaluation of State-Mandated Reporting of Neonatal Abstinence Syndrome — Six States, 2013–2017
Authors: Shahla M. Jilani, Meghan T. Frey, Dawn Pepin, Tracey Jewell, Melissa Jordan,, Angela M. Miller, Meagan Robinson, Tomi St. Mars, Michael Bryan, Jean Y. Ko, Elizabeth C. Ailes, Russell F. McCord, Julie Gilchrist, Sarah Foster, Jennifer N. Lind, Lindsay Culp, Matthew S. Penn, Jennita Reefhuis
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

From 2004 to 2014, the incidence of neonatal abstinence syndrome (NAS) in the United States increased 433%, from 1.5 to 8.0 per 1,000 hospital births. The latest national data from 2014 indicate that one baby was born with signs of NAS every 15 minutes in the United States (1). NAS is a drug withdrawal syndrome that most commonly occurs among infants after in utero exposure to opioids, although other substances have also been associated with NAS. Prenatal opioid exposure has also been associated with poor fetal growth, preterm birth, stillbirth, and possible specific birth defects (2-5). NAS surveillance has often depended on hospital discharge data, which historically underestimate the incidence of NAS and are not available in real time, thus limiting states' ability to quickly direct public health resources (6,7). This evaluation focused on six states with state laws implementing required NAS case reporting for public health surveillance during 2013-2017 and reviews implementation of the laws, state officials' reports of data quality before and after laws were passed, and advantages and challenges of legally mandating NAS reporting for public health surveillance in the absence of a national case definition. Using standardized search terms in an online legal research database, laws in six states mandating reporting of NAS from medical facilities to state health departments (SHDs) or from SHDs to a state legislative body were identified. SHD officials in these six states completed a questionnaire followed by a semistructured telephone interview to clarify open-text responses from the questionnaire. Variability was found in the type and number of surveillance data elements reported and in how states used NAS surveillance data. Following implementation, five states with identified laws reported receiving NAS case reports within 30 days of diagnosis. Mandated NAS case reporting allowed SHDs to quantify the incidence of NAS in their states and to inform programs and services. This information might be useful to states considering implementing mandatory NAS surveillance.
AB1259 Is dose banding of infliximab cost effective – results from real world implementation
Authors: M.K. Nisar
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Infliximab dose is based on the patient's body weight (3–5 mg/kg) and requires the use of multiple 100 mg vials to reconstitute the individualised dose. As the product is expensive, there is a significant cost associated with unused and wasted infliximab in any part-used vials. "Dose banding" is one solution so that patients receive a pre-prepared dose produced in advance in batches where wastage from part vials is minimised. There is some encouraging data that reconstituted infliximab is stable for long enough to allow batch production of pre-prepared doses. The theoretical risk of course is over or under treatment while respectively rounding up or down the administered dose. <h3>Objectives</h3> We undertook a retrospective analysis of our experience of dose banding in rheumatology unit. <h3>Methods</h3> All patients prescribed infliximab for rheumatic indication at our centre were included in the analysis. Case notes were retrospectively reviewed to look at dose variance following implementation of this initiative, resultant disease control and the consequent cost savings. <h3>Results</h3> 10 patients prescribed infliximab biosimilar and two bio-originator were identified for the analysis. Median age was 55.5 years (range 25–80 years). Nine had the drug for RA, two for AS and one for myositis. Three had no change in dose as a result of implementing dose banding program. Three had dose increased by 3%–5%. Remaining six had dose reduced by range of 4%–6%. Their disease scores before and after dose banding remained largely unchanged (table 1). This equated to £1,184.58 annual savings in addition to the economic benefit of successfully switching the ten patients to biosimilar. No patient suffered loss of efficacy or adverse events in any of the three groups. <h3>Conclusions</h3> Our data confirms the utility of dose banding program for infliximab in rheumatology practice with no concerns about efficacy or safety of the initiative. There are potential opportunities to achieve considerable reductions in medicines discarded and improving finances by adopting dose banding for infliximab. It also helped curb over £10 000 expense to our Trust in infliximab waste cost alone. There are some important caveats to consider as well. True savings will depend on list price of each product and varies with originator versus biosimilar. The variance increases as the width of the dose bands increases i.e. the variance is greater at lower body weights. Consequently, depending on patient population both clinical and cost considerations could alter. Finally, assurance of the product integrity and stability is reliant on efficient pharmacy processes necessary to accommodate the use of new formulations for dose banding. <h3>Disclosure of Interest</h3> None declared
Antiaging effects of bioactive molecules isolated from plants and fungi
Authors: Jan Martel, David M. Ojcius, Yun‐Fei Ko, Chih‐Jung Chang, John D. Young
Journal: Medicinal Research Reviews (2019)

Abstract Aging is influenced by many lifestyle choices that are under human control, including nutrition and exercise. The most effective known antiaging intervention consists of calorie restriction (CR), which increases lifespan in yeasts, worms, fruit flies, mice, and nonhuman primates. CR also improves healthspan by preventing the development of various aging‐related diseases such as cancer, cardiovascular disease, diabetes, and neurodegeneration. Many compounds isolated from plants and fungi prolong lifespan and prevent age‐related diseases in model organisms. These plant and fungal compounds modulate the same cellular and physiological pathways as CR, including those involving insulin and insulin‐like growth factor‐1, mammalian target of rapamycin, and sirtuins. Modulation of these aging‐related pathways results in the activation of various cellular processes such as autophagy, DNA repair, and neutralization of reactive oxygen species. Together, these cellular processes are believed to delay aging and prevent chronic diseases by improving bodily functions and stress resistance. We review here the mechanisms of action of plant and fungal molecules possessing antiaging properties and discuss the possibilities and challenges associated with the development of antiaging compounds isolated from natural products.
FRI0425 Association between tissue oxygen delivery and digital ulcers in systemic sclerosis
Authors: A. Sari, Y.Z. Sener, M. Oksul, B. Armagan, A. Erden, L. Kilic, A. Akdogan
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Digital ulcers (DUs) are common manifestations of vascular disease in systemic sclerosis (Ssc) patients. <h3>Objectives</h3> To investigate the association between the amount of oxygen delivered to periferal tissues and the development of DUs in SSc patients. <h3>Methods</h3> One hundred and eleven SSc patients (103 female) were recruited consecutively to the study. Thirty age and sex matched controls were also enrolled. Transthoracic echocardiography (TTE) was performed for each patient to estimate cardiac output (CO). Arterial oxygen saturation (SaO2) with pulse oximeter in room temperature and serum haemoglobin concentration (Hb) were measured at the time of TTE. The amount of oxygen delivered to tissues (D02) in 1 min was estimated using the equation D02=CO*(SaO2*1.39*Hb) and adjusted for body weight. Demographic, clinical and laboratory data were retrieved from hospital records. DUs were described as ulcerations on the skin distal to proksimal interphalangeal joints (PIF) of the digits. Patients were divided into 2 groups according to presence of DUs wıthin 1 year of study enrollment (Group1=with DU, Group2=without DU). Chi-square and Mann-Whitney U tests were used for comparing categorical and continuous variables between the groups, respectively. <h3>Results</h3> Mean age was 52.6 (11.8) years in SSc patients and 51.3 (13.0) in controls. Median disease duration was 138.0 (1.8–415.2) months. Diffuse disease was present in 30.6% of patients. There were no differences in terms of Hb level, left ventricular ejection fraction (LVEF) and calculated D02 between SSc patients and controls. Mean CO was higher in healthy controls (6.1 vs. 5.1, p=0.004). İnterestingly, mean S02 measurements was lower in control group (96.8 vs. 98.0, p=0.005). Comparison of demographics, disease characteristics, tissue oxygen delivery and relevant variables were summarised in table 1. When patients with active DUs were compared with patients without active DUs; no difference was found in Hb,S02, CO and D02 between groups. <h3>Conclusions</h3> Although the haemoglobin concentration was higher in the non ulcer group, there was no difference in the amount of delivered oxygen between patients with and without DUs. These findings imply that vasculopathy and/or peripheral artery disease plays a major role in the development of ulcers. <h3>Disclosure of Interest</h3> None declared
OP0098 Clinical picture and spectrum of conditions associated with nlrp12 gene mutations
Authors: M. Kostik, E. Suspitsin, A. Levina, M. Guseva, M. Dubko, L. Snegireva, T. Likhacheva, A. Kazantseva, M. Makhova, A. Sokolenko, E. Imyanitov, V. Chasnyk
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> NLRP12-related autoinflammatory disease (NLRP12-AID) is an exceptionally rare autosomal-dominant disorder caused by germ-line mutations in NLRP12 gene. Very few patients with NLRP12-AD have been identified worldwide, therefore there is a scarcity of data on phenotypic presentation of this syndrome. <h3>Objectives</h3> Here we provide evidence that NLRP12-AID may have clinical manifestations characteristic for primary immune deficiencies (PID). <h3>Methods</h3> 246 children with periodic fever (PF) of unknown origin were subjects to the next generation sequencing (NGS) analysis; 213 of these patients had signs of primary immunodeficiency (PID) manifested by recurrent infections, while 33 kids had isolated PF. The NGS panel was composed of 302 genes implicated in PID and/or AID. <h3>Results</h3> NLRP12 variants were detected in 20 cases (see the table 1). Median age of first AID-related fever episode was 12 months, ranging from 2 months to 13 years. Increased association with immune-mediated diseases (n=15, 75%) was observed. Nine patients demonstrated increased susceptibility to infection and two children suffered from Crohn's disease. Administration of short courses of NSAID or corticosteroids resulted in resolution of the disease flare. In one severe case canakinumab (anti-interleukine-1β antibody) was successfully used. <h3>Conclusions</h3> Significant number of patients with genetically assigned diagnosis of NLPR12-AID have clinical features which close resemble PID. This phenotypic overlap may result in underdiagnosis of NLPR12-AID among patients with PID. <h3>Acknowledgements</h3> This work has been supported by Russian Foundation for Basic Research (grant number RFBR 16–04–00 159a). <h3>Disclosure of Interest</h3> None declared
Simultaneous co-delivery of neuroprotective drugs from multi-loaded PLGA microspheres for the treatment of glaucoma
Authors: A. Arranz-Romera, B.M. Davis, I. Bravo-Osuna, S. Esteban-Pérez, I.T. Molina-Martínez, E. Shamsher, N. Ravindran, L. Guo, M.F. Cordeiro, R. Herrero-Vanrell
Journal: Journal of Controlled Release (2019)