tbuckley/cabot-search huggingface dataset:
Adjunctive Treatments for Type 1 Diabetes
Authors: David M. Nathan
Journal: New England Journal of Medicine (2017)

The proliferation of new drug treatments for type 2 diabetes in the United States in the past 15 years, with more than 17 drugs approved in six new classes of antidiabetic drugs, has been promoted by several factors. First, the recognition of the importance of intensive glycemic control to reduce the risk of long-term complications has spurred development.1 Second, the epidemic of type 2 diabetes has created an enormous market with commensurate profits for the pharmaceutical industry. Finally, the relatively low bar set by the Food and Drug Administration (FDA) for the approval of new antidiabetic drugs — specifically, the . . .
Fluorocarbons Enhance Intracellular Delivery of Short STAT3-sensors and Enable Specific Imaging
Authors: Valeriy Metelev, Surong Zhang, Shaokuan Zheng, Anand T.N. Kumar, Alexei Bogdanov
Journal: Theranostics (2017)

Short oligonucleotide sequences are now being widely investigated for their potential therapeutic properties.The modification of oligonucleotide termini with short fluorinated residues is capable of drastically altering their behavior in complex in vitro and in vivo systems, and thus may serve to greatly enhance their therapeutic potential.The main goals of our work were to explore: 1) how modification of STAT3 transcription factor-binding oligodeoxynucleotide (ODN) duplexes (ODND) with one or two short fluorocarbon (FC)-based residues would change their properties in vitro and in vivo, and if so, how this would affect their intracellular uptake by cancer cells, and 2) the ability of such modified ODND to form non-covalent complexes with FC-modified carrier macromolecule.The latter has an inherent advantage of producing a 19 F-specific magnetic resonance (MR) imaging signature.Thus, we also tested the ability of such copolymers to generate 19 F-MR signals.Materials and Methods.Fluorinated nucleic acid residues were incorporated into ODN by using automated synthesis or via activated esters on ODN 5'-ends.To quantify ODND uptake by the cells and to track their stability, we covalently labeled ODN with fluorophores using internucleoside linker technology; the FC-modified carrier was synthesized by acylation of pegylated polylysine graft copolymer with perfluoroundecanoic acid (M5-gPLL-PFUDA).Results.ODN with a single FC group exhibited a tendency to form duplexes with higher melting points and with increased stability against degradation when compared to control non-modified ODNs.ODND carrying fluorinated residues showed complex formation with M5-gPLL-PFUDA as predicted by molecular dynamics simulations.Moreover, FC groups modulated the specificity of ODND binding to the STAT3 target.Finally, FC modification resulted in greater cell uptake (2 to 4 fold higher) when compared to the uptake of non-modified ODND as determined by quantitative confocal fluorescence imaging of A431 and INS-1 cells.Conclusion.ODND modification with FC residues enables fine-tuning of protein binding specificity to double-strand binding motifs and results in an increased internalization by A431 and INS-1 cells in culture.Our results show that modification of ODN termini with FC residues is both a feasible and powerful strategy for developing more efficient nucleic acid-based therapies with the added benefit of allowing for non-invasive MR imaging of ODND therapeutic targeting and response.
Validation of patient‐reported global severity of atopic dermatitis in adults
Authors: P. P. Vakharia, R. Chopra, R. Sacotte, N. Patel, S. Immaneni, T. White, R. Kantor, D. Y. Hsu, J. I. Silverberg
Journal: Allergy (2017)

Abstract Background Atopic dermatitis ( AD ) is associated with a heterogeneous presentation and clinical course. There is a lack of simple and validated severity assessments that are feasible for clinical practice and epidemiological research. Objectives We sought to validate patient‐reported global AD severity in adults. Methods We performed a prospective dermatology practice‐based study using questionnaires and evaluation by a dermatologist (n = 265). Results At baseline and follow‐up, patient‐reported global AD severity significantly correlated with oSCORAD (Spearman ρ = 0.56 and 0.49), SCORAD (0.64 and 0.56), EASI (0.56 and 0.50), BSA (0.52 and 0.45), NRS ‐itch (0.60 and 0.53), POEM (0.50 and 0.48), and DLQI (0.50 and 0.49) ( P &lt; .0001 for all). Patient‐reported moderate and severe AD vs mild AD were associated with significantly higher oSCORAD , SCORAD , EASI , BSA , NRS ‐itch, POEM , and DLQI ( P &lt; .0001 for all). There was moderate concordance between patient‐reported AD severity (mild, moderate, and severe) and previously developed severity strata for oSCORAD (κ = 0.39), SCORAD (κ = 0.47), EASI (κ = 0.37), NRS ‐itch (κ = 0.49), POEM (κ = 0.37), and DLQI (κ = 0.40). Among patients with severe disease at baseline, those who reported mild or moderate disease on follow‐up had significantly greater absolute reductions of oSCORAD (−23.4/−9.7/−1.8), SCORAD (−33.0/−13.2/−2.3), EASI (−17.1/−9.8/−3.2), BSA (−46%/−15%/−4%), NRS ‐itch (−5/−2/0), POEM (−5/−2/0), and DLQI (−8/−6/−1) than those who continued to report severe disease (Kruskal‐Wallis, P ≤ .0003 for all). Conclusions Patient‐reported AD severity appears to be sufficiently valid for assessing AD severity in the clinical and epidemiological setting.
Afatinib in patients with metastatic <i>HER2</i>-mutant lung cancers: An international multicenter study.
Authors: Wei-Chu Victoria Lai, Louisiane Lebas, Julie Milia, Tristan Alexandra Barnes, Oliver Gautschi, Solange Peters, Roberto Ferrara, Ai Ni, Joshua K. Sabari, Stephen John Clarke, Nick Pavlakis, Charles M. Rudin, Maria E. Arcila, Natasha B. Leighl, Frances A. Shepherd, Mark G. Kris, Julien Mazieres, Bob T. Li
Journal: Journal of Clinical Oncology (2017)

9071 Background: Human epidermal growth factor 2 ( HER2, ERBB2) mutations have been identified as oncogenic drivers in 3% of lung cancers. Afatinib is an irreversible tyrosine kinase inhibitor of HER1 (EGFR), HER2 and HER4 and has been described in case reports to have activity in HER2-mutant lung cancers. However, there is little data to inform the clinical use of afatinib. Methods: We reviewed patients with metastatic HER2-mutant lung cancers treated with afatinib among 7 institutions between 2009 and 2016. The primary endpoint was investigator assessed overall response rate using RECIST v1.1. Other data collected included types of HER2mutations, duration of afatinib treatment and overall survival. Results: We identified 27 patients with metastatic HER2-mutant lung cancers treated with afatinib. Median age at diagnosis was 63 (range 40 to 84); majority were men (n = 16; 59%) and never-smokers (n = 18; 67%). All tumors were adenocarcinomas, and the majority were Stage IV at initial diagnosis (n = 16; 59%). A 12-base pair (bp) in-frame insertion YVMA in exon 20 (p.A775_G776insYVMA) was present in 16 patients (59%). In addition, there were three 9-bp insertions, two 3-bp insertions and two single bp substitutions (L755F and D769H) in exon 20; two single bp substitutions (S310F) in exon 8; one exon 17 V659E mutation; and one single-nucleotide polymorphism (Ile655Val). Median duration on afatinib was 2 months (range 1 to 27); median line of prior treatment was 3 (range 1 to 6). Eight patients had previously received trastuzumab prior to afatinib and one concurrently with afatinib. Overall response rate was 15% (n = 4; 95% CI 4 to 34%); the four partial responses lasted 5, 5, 6 and 10 months. The 3 longest partial responders had a 12-bp insertion in exon 20 (YVMA); the remaining partial responder had a 9-bp insertion in exon 20. Median overall survival from diagnosis date of metastatic disease was 23 months (95% CI 18 to 62). Conclusions: Afatinib produced partial responses in 15% of patients with metastatic HER2-mutant lung cancers, including insertion YVMA. Our findings confirm the activity of afatinib and provide data supporting a framework for its use in the care of patients with HER2-mutant lung cancers.
Effects of Education and Income on Treatment and Outcome in Patients With Acute Myeloid Leukemia in a Tax-Supported Health Care System: A National Population-Based Cohort Study
Authors: Lene Sofie Granfeldt Østgård, Mette Nørgaard, Bruno C. Medeiros, Lone Smidstrup Friis, Claudia Schoellkopf, Marianne Tang Severinsen, Claus Werenberg Marcher, Jan Maxwell Nørgaard
Journal: Journal of Clinical Oncology (2017)

Purpose Previous US studies have shown that socioeconomic status (SES) affects survival in acute myeloid leukemia (AML). However, no large study has investigated the association between education or income and clinical characteristics, treatment, and outcome in AML. Methods To investigate the effects of education and income in a tax-supported health care system, we conducted a population-based study using individual-level SES and clinical data on all Danish patients with AML (2000 to 2014). We compared treatment intensity, allogeneic transplantation, and response rates by education and income level using logistic regression (odds ratios). We used Cox regression (hazard ratios [HRs]) to compare survival, adjusting for age, sex, SES, and clinical prognostic markers. Results Of 2,992 patients, 1,588 (53.1%) received intensive chemotherapy. Compared with low-education patients, highly educated patients more often received allogeneic transplantation (16.3% v 8.7%). In intensively treated patients younger than 60 years of age, increased mortality was observed in those with lower and medium education (1-year survival, 66.7%; adjusted HR, 1.47; 95% CI, 1.11 to 1.93; and 1-year survival, 67.6%; adjusted HR, 1.55; CI, 1.21 to 1.98, respectively) compared with higher education (1-year survival, 76.9%). Over the study period, 5-year survival improvements were limited to high-education patients (from 39% to 58%), increasing the survival gap between groups. In older patients, low-education patients received less intensive therapy (30% v 48%; adjusted odds ratio, 0.65; CI, 0.44 to 0.98) compared with high-education patients; however, remission rates and survival were not affected in those intensively treated. Income was not associated with therapy intensity, likelihood of complete remission, or survival (high income: adjusted HR, 1.0; medium income: adjusted HR, 0.96; 95% CI, 0.82 to 1.12; low income: adjusted HR, 1.06; CI, .88 to 1.27). Conclusion In a universal health care system, education level, but not income, affects transplantation rates and survival in younger patients with AML. Importantly, recent survival improvement has exclusively benefitted highly educated patients.
AB1073 D-dimer as an early marker in patients with lupus mesenteric vasculitis
Authors: X Ma, X Feng, H Wang, B Hua, L Sun
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Gastrointestinal manifestations are common in systemic lupus erythematosus (SLE) patients. Lupus mesenteric vasculitis (LMV) is a major cause of acute abdominal pain in SLE patients. No early serum marker contributes to the diagnosis of lupus mesenteric vasculitis. <h3>Objectives</h3> The aim of this study was to investigate clinical significance of serum D-dimer level as an early diagnosis marker of LMV patients. <h3>Methods</h3> The 57 systemic lupus erythematosus patients were retrospectively analyzed and classified into LMV group (n=19) and Non-LMV group (n=38) between May 2010 and January 2016. The serum D-dimer level was measured on the first day after SLE patients presented acute abdomen as well as imaging, other laboratory-testing parameters, and SLEDAI during the same period. The maximum and mean D-dimer values were analyzed and compared with other potential markers for diagnosis of LMV. The correlation of D-dimer level with other potential severity markers and inflammation parameters were also studied. <h3>Results</h3> Both maximum and mean D-dimer level on the first day of presentation of acute abdomen were significantly higher in LMV patients. The D-dimer level was correlated well with L-lactate and SLEDAI. In addition, D-dimer level was detected poor correlation with white blood cell count and C-reactive protein level. <h3>Conclusions</h3> D-dimer level could be an effective and early serum diagnosis marker of LMV. <h3>Disclosure of Interest</h3> None declared
THU0739-HPR The phenomenon of alexithymia in systemic lupus erythematosus patients
Authors: M Ramkhelawon, RA Grekhoff, G Suleymanova
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Alexithymia as a radical in the structure of premorbid personality is attracting the attention of researchers as one of the possible psychological risk factors in the development of psychosomatic disorders in rheumatic diseases. Clinical experience supports the evidence of the relevance of alexithymia conception in relation to the many somatic patients, who show a limited ability to describe and differentiate emotion and create fantasies, and hence indicate the role of alexithymia phenomenon in the pathogenesis of psychosomatic disorders in SLE. <h3>Objectives</h3> To study the relationship of the levels of alexithymia with other clinico-psychological characteristics. <h3>Methods</h3> 87 patients with systemic lupus erythematosus (SLE) was surveyed with the Toronto Alexithymia Scale (TAS). <h3>Results</h3> According to the results obtained, SLE patients demonstrated a high level of alexithymia (73,86±2,6 points). The results of the research showed that the level of alexithymia, on one hand, does not depend upon gender, age, character and activity of the pathological process (p&gt;0.05). On the other hand, there was a significant inverse correlation between alexithymia and the level of the patient9s education (r = -0,42 p=0.031). Moreover, internality in interpersonal interaction (r = -0,44 p=0.028), and significant direct correlation with indicators such as, the disease duration (r = -0, 46 at p=0.01), the intensity of neurotic disorders (asthenia (r = -0,42 p=0.033), depression (r = -0,52 p=0.006), anxiety (r =0.43 p=0.028), hypochondriasis (r = -0,48 p=0.01), as well as psychological defense mechanism "Regression" (r =0,42 p=0,022). <h3>Conclusions</h3> Therefore, between the development of alexithymia in SLE patients and certain clinico-psychological characteristics, a particular association exists which provides a definite step for psychotherapeutic interventions aimed at correcting alexithymia personality traits of SLE patients. <h3>Disclosure of Interest</h3> None declared
Prediction of therapy failure after VEGF-based first-line treatment of kidney cancer patients by DNA hypermethylation biomarkers.
Authors: Inga Peters, Natalia Dubrowskaja, Mahmoud Abbas, Christoph Seidel, Michael Kogosov, Ralph Scherer, Kai Gebauer, Axel S. Merseburger, Markus A. Kuczyk, Viktor Grünwald, Juergen Serth
Journal: Journal of Clinical Oncology (2013)

e22076 Background: Kidney Cancer (RCC) is one of the top ten causes of cancer dependent death. Anti-VEGF targeted therapy has demonstrated increased progression-free (PFS) and overall survival in RCC patients, though the clinical outcome is still poor overall. Stratification of patient treatment currently depends on different clinical scoring systems such as the Memorial Sloan Kettering Cancer Center score. However, identification of molecular phenotypes of RCC patients could improve stratification of targeted therapies and prediction of clinical course. We investigated whether DNA hypermethylation-based markers can predict the PFS following first-line therapy. Methods: We examined primary tumor tissues obtained from 18 patients receiving anti-VEGF targeted therapy. Quantitative methylation-specific PCRs were carried out for CpG island (CGI) methylation analysis of 5 candidate genes CST6, GATA5, LAD1, hsa-miR124-3 and hsa-miR9.1 identified in advance as potential prognosticators for RCC. For Kaplan Meier survival analysis relative methylation values were uniformly dichotomized and logrank statistics calculated. The analyses of sensitivity and specificity were carried out using a cutoff of 6 months for PFS to categorize for therapy failure and response. Results: Hypermethylation of CST6 and LAD1 shows a highly significant association with a shortened PFS following first-line therapy (p=0.009, p=0.004, logrank test). The median survival observed for the high and low methylation group was 2.0 and 11.4 months for CST6 and LAD1. Moreover, LAD1 methylation showed a specificity of 1.0 (0.65-1.0, 95%CI) and a sensitivity of 0.73 (0.43-0.90, 95%CI) for detection of therapy failure. For CST6a specificity of 0.86 (0.49-0.97, 95%CI) and a sensitivity of 0.82 (0.52-0.95, 95%CI) was detected. Conclusions: The analysis of our discovery cohort revealed that CGI methylation of CST6 and LAD1 predicts a shortened PFS of patients after anti-VEGF therapy. Provided, these results can be confirmed in an independent larger evaluation cohort, detection of hypermethylated loci in primary RCC would allow, to our knowledge for the first time, a molecular-based clinical management of patients.
Personality Change in the Preclinical Phase of Alzheimer Disease
Authors: Antonio Terracciano, Yang An, Angelina R. Sutin, Madhav Thambisetty, Susan M. Resnick
Journal: JAMA Psychiatry (2017)

Changes in behavior and personality are 1 criterion for the diagnosis of dementia. It is unclear, however, whether such changes begin before the clinical onset of the disease.To determine whether increases in neuroticism, declines in conscientiousness, and changes in other personality traits occur before the onset of mild cognitive impairment or dementia.A cohort of 2046 community-dwelling older adults who volunteered to participate in the Baltimore Longitudinal Study of Aging were included. The study examined personality and clinical assessments obtained between 1980 and July 13, 2016, from participants with no cognitive impairment at first assessment who were followed up for as long as 36 years (mean [SD], 12.05 [9.54] years). The self-report personality scales were not considered during consensus diagnostic conferences.Change in self-rated personality traits assessed in the preclinical phase of Alzheimer disease and other dementias with the Revised NEO Personality Inventory, a 240-item questionnaire that assesses 30 facets, 6 for each of the 5 major dimensions: neuroticism, extraversion, openness, agreeableness, and conscientiousness.Of the 2046 participants, 931 [45.5%] were women; mean (SD) age at first assessment was 62.56 (14.63) years. During 24 569 person-years, mild cognitive impairment was diagnosed in 104 (5.1%) individuals, and all-cause dementia was diagnosed in 255 (12.5%) participants, including 194 (9.5%) with Alzheimer disease. Multilevel modeling that accounted for age, sex, race, and educational level found significant differences on the intercept of several traits: individuals who developed dementia scored higher on neuroticism (β = 2.83; 95% CI, 1.44 to 4.22; P < .001) and lower on conscientiousness (β = -3.34; 95% CI, -4.93 to -1.75; P < .001) and extraversion (β = -1.74; 95% CI, -3.23 to -0.25; P = .02). Change in personality (ie, slope), however, was not significantly different between the nonimpaired and the Alzheimer disease groups (eg, neuroticism: β = 0.00; 95% CI, -0.08 to 0.08; P = .91; conscientiousness: β = -0.06; 95% CI, -0.16 to 0.04; P = .24). Slopes for individuals who developed mild cognitive impairment (eg, neuroticism: β = 0.00; 95% CI, -0.12 to 0.12; P = .98; conscientiousness: β = -0.09; 95% CI, -0.23 to 0.05; P = .18) and all-cause dementia (eg, neuroticism: β = 0.02; 95% CI, -0.06 to 0.10; P = .49; conscientiousness: β = -0.08; 95% CI, -0.16 to 0.00; P = .07) were also similar to those for nonimpaired participants.No evidence for preclinical change in personality before the onset of mild cognitive impairment or dementia was identified. These findings provide evidence against the reverse causality hypothesis and strengthen evidence for personality traits as a risk factor for dementia.
THU0529 Methotrexate treatment response in non-systemic juvenile idiopathic arthritis
Authors: R Bakry, G Horneff
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Methotrexate is approved and recommend as first line disease modifying antirheumatic drug (DMARD) in polyarticular juvenile idiopathic arthritis (JIA). In can be used orally or via s.c. injection. <h3>Objectives</h3> S.c MTX is thought to be more efficious or act more rapidly than oral MTX. Thus we want to analyse the kinetic of response in JIA patients treated with oral versus s.c. MTX. <h3>Methods</h3> In the German BIKER registry a cohort of biologics naïve JIA patients starting treatment with MTX was built. The data bank was screened for patients treated with MTX orally vs. s.c for the first time. The JIA-ACR 90 and the JADAS10 definition of remission were used as outcome parameters. <h3>Results</h3> 410 JIA patients received treatment with oral MTX and 384 received s.c. MTX. RF negative polyarthritis was the most common JIA category (50%/51%) followed by by extended oligoarthritis (27%/26%), polyarticular psoriatic arthritis (18%/16%) and RF positive polyarthritis (5%/8%). Disease duration (2.3+/-3.0 vs 1.9+/-2.7 was statistically higher in the oral cohort (p=0.04) but age at onset and baseline were similar. The baseline disease activity was higher in the s.c. cohort (JADAS10 16.5+/-7.2 compared to 14.7+/-8.2; p&lt;0.001 and active joint count 9.0+/-10.1 vs. 7.4+/-7.7; p=0,011). The weekly MTX dosages were comparable with 13.6+/-5.4mg and 13.3+/-4.5 mg. Concomitant treatment with NSAIDS (95%/89%), oral steroids (24%/25%) or intraarticular steroids (6%/8%) were comparable. After 12 months of treatment, 150 (38.3%) reached a JIA ACR90 with oral MTX and 131 (35%) with s.c MTX while 86 (21. 8%) and 72 (19.5%) reached JADAS-remission (JADAS10≤1). By Kaplan-Meyer- analysis no difference in the early kinetic of response was found. Upon total observation for up to 7.5 years in the intention to treat population (patients discontinuing MTX due to inefficacy or intolerance or starting a biologic were calculated as non-responders) more patients in the oral cohort reached a JADAS-remission (162; 41%) than with s.c MTX (126; 34%) which was stastically borderline significant (p=0,05; odd9s ratio 1.2 [95CI 1.0–1.8]). <h3>Conclusions</h3> Data from the BIKER registry out of the clinical practice do show a high rate of JIA patients reaching a significant JIA-ACR response as well as JADAS-remission upon MTX as a sole DMARD. However, on the long term more patients with oral MTX reached JADAS remission. By Kaplan Meyer analyses we did not observe a superiority of s.c. MTX in the kinetic of response. The limitations of our analysis lie the character of a registry study, the lack of randomisation and study protocol leaving all decisions to start or to stop MTX by the responsible rheumatologist. Thus such data are preliminary and should be confirmed by randomized studies. <h3>Disclosure of Interest</h3> None declared
Microbes in Pool Filter Backwash as Evidence of the Need for Improved Swimmer Hygiene — Metro-Atlanta, Georgia, 2012
Authors: Christopher Hutcheson, Ryan Cira, Stanley L. Gaines, Kevin R. Jones, Walter Howard, David Hornsby, Maurice Redmond, R. Christopher Rustin, Michele C. Hlavsa, Jennifer L. Murphy, Jothikumar Narayanan, Candace D. Miller, Brittany Cantrell, Vincent R. Hill, Michael J. Beach
Journal: MMWR Morbidity and Mortality Weekly Report (2013)