tbuckley/cabot-search huggingface dataset:
POS0112 CD8+ T-CELL INFILTRATION IS ASSOCIATED WITH LESIONAL GM-CSF OVEREXPRESSION IN GCA
Authors: W. F. Jiemy, R. Reitsema, A. Kwant, W. Abdulahad, A. Boots, P. Heeringa, E. Brouwer
Journal: Annals of the Rheumatic Diseases (2021)

Background: Giant cell arteritis (GCA) is a large-vessel vasculitis characterized by granulomatous T cell- and macrophage infiltration. Granulocyte-macrophage colony stimulating factor (GM-CSF) is present in GCA-affected vessels where it may be involved in skewing of tissue destructive macrophages (1). Furthermore, a recent phase 2 clinical trial demonstrated that GM-CSF receptor blockade was superior to placebo at 26 weeks in GCA. However, the cellular source of GM-CSF in GCA is still unclear. Objectives: As T cells have been identified as a major source of GM-CSF in other immune-mediated diseases such as multiple sclerosis, we investigated whether T cells are GM-CSF producers in GCA patients, both systemically and locally. Methods: GM-CSF production capacity by PMA-stimulated PBMCs from newly diagnosed, untreated GCA patients and HCs (N=10 each) was assessed using flow cytometry. Temporal artery biopsies (TABs, N=5) were immunohistochemically stained for CD3, CD8 and GM-CSF. Colocalization of these markers was assessed with immunofluorescence. Results: Proportions of CD4+ (median GCA=3.1%; HCs=2.76%) and CD8+ (median GCA=5.8%; HCs=5.8%) T cells produced GM-CSF after in vitro stimulation, but no significant differences were found between the groups. Immunofluorescence staining confirmed that CD3+ T cells (both CD8+ and CD8-) were positive for GM-CSF in TABs. Interestingly, GM-CSF positivity in TABs correlated strongly with the extent of CD8+ T-cell infiltration (r=0.74, p&lt;0.01), but not with CD3+ T-cell infiltration (r=0.38, p=0.16). Conclusion: Our data imply that T cells are an important source of GM-CSF in GCA lesions. The correlation of the extent of CD8+ T-cell infiltration with GM-CSF positivity suggests that CD8+ T cells are the major source of local GM-CSF overexpression in tissue. References: [1]W.F. Jiemy, Y. Sleen, K.S. Geest, H.A. Berge, W.H. Abdulahad, M. Sandovici, A.M. Boots, P. Heeringa, E. Brouwer, Distinct macrophage phenotypes skewed by local granulocyte macrophage colony stimulating factor (GM-CSF) and macrophage colony stimulating factor (M-CSF) are associated with tissue destruction and intimal hyperplasia in giant cell arteritis, Clin. Transl. Immunol. 9 (2020). Disclosure of Interests: William Febry Jiemy: None declared, Rosanne Reitsema: None declared, Ayla Kwant: None declared, Wayel Abdulahad: None declared, Annemieke Boots Consultant of: Grünenthal Gmbh until 2017, Peter Heeringa: None declared, Elisabeth Brouwer Speakers bureau: Roche, paid to the UMCG
Induction of apoptosis in renal cell carcinoma by combination of maitake mushroom extract (PDF) and vitamin C.
Authors: Brandon Louie, Paul Pyo, Karen Seiter, Hiroshi Tazaki, Muhammad Choudhury, Sensuke Konno
Journal: Cancer Research (2008)

2680  Introduction and Objective: A bioactive extract (PDF) obtained from maitake mushroom (Grifola frondosa) has been demonstrated to have anticancer and immunostimulatory activity. Such bioactivity has also been shown to be synergistically activated by vitamin C (V.C). Although several conventional therapeutic options for renal cell carcinoma (RCC) are currently available, the unsatisfactory outcomes compellingly require for establishing a more effective treatment modality. Accordingly, we examined the combined effects of PDF and V.C on the growth of RCC in vitro as a possible complementary and alternative approach.  Methods: The standardized form of mushroom extract, PDF, was obtained commercially. Human RCC, ACHN cell line, was employed and exposed to various concentrations of PDF or in combination with V.C, and cell viability/growth was assessed at specified times. To explore the growth inhibitory mechanism, cell cycle analysis and Western blot analysis on several apoptotic parameters were performed.  Results: A dose-dependent study showed that PDF was capable of inducing a ~45% and ~70% growth reduction at 700 and 1000 μg/ml, respectively. When the lower, ineffective concentrations of PDF were combined with V.C (200 μM), ~90% cell death was attained with the combination of 300 µg/ml PDF and V.C. Yet, a given concentration (200 µM) of V.C itself had no effects. Cell cycle analysis revealed that compared to controls, there was an 88% decrease in the S phase cell population with a concomitant 80% increase in the G1 cells following PDF/V.C treatment. Western blots further revealed that PDF/V.C-induced cell death was associated with a down-regulation of anti-apoptotic bcl-2, an up-regulation of pro-apoptotic Bax, and degradation of poly-(ADP-ribose)-polymerase (PARP).  Conclusions:  The present study demonstrates that PDF has antiproliferative and cytotoxic effects on renal carcinoma ACHN cells in vitro. Although the higher concentrations (>1000 µg/ml) of PDF alone are required to be significantly effective, the lower concentration (300 μg/ml) of PDF can be synergistically potentiated with V.C (200 μM), becoming extremely cytotoxic to these cancer cells (~90% cell death). Such a cytotoxic mechanism is associated with a G1 cell cycle arrest (blocking the G1-S phase transition) and the modulation of critical apoptotic regulators (bcl-2, Bax, and PARP), leading ultimately to apoptosis. Thus, PDF is a potential apoptosis-inducing agent that may have implications in a safer, more effective alternative therapeutic modality for RCC.
POS1016 ANKYLOSING SPONDYLITIS IN WEST AFRICAN PATIENTS: A SERIES OF 37 CASES REPORTED IN TOGO
Authors: P. Houzou, V. E. S. Koffi-Tessio, S. Oniankitan, K. Kakpovi, E. Fianyo, K. Tagbor, O. Oniankitan, M. Mijiyaw
Journal: Annals of the Rheumatic Diseases (2021)

Background: Spondyloarthritis (SpA) is generally uncommon in sub-Saharan Africa, in part because of the rarity of HLA-B27 in this region. Objectives: The aim of our study was to determine the epidemiological, semiological, paraclinical and therapeutic aspects of ankylosing spondylitis in rheumatology in Togo. Methods: This was a retrospective multicenter descriptive study on the files of patients suffering from ankylosing spondylitis seen in an outpatient setting or hospitalized in one of the four Rheumatology departments of Togo in the period from January 1, 2000 to December 31, 2019. The diagnosis was essentially radio-clinical based on the modified New York criteria. Results: In 20 years, and out of a population of 35,304 rheumatic patients, we have collected 37 cases of ankylosing spondylitis, meaning a hospital frequency of 0.10% and an annual frequency of 1.85 cases. There was clearly a male predominance with an M / F ratio of 4.28. The onset of the disease was on average of 29.62 ± 10.27 years and the diagnosis delay on average of 9.45 ± 9.20 years. The clinic was dominated by spinal pain in the form of chronic inflammatory cervical-dorsal-lumbar pain (41.2%) or lumbar pain (29.4%). Common joint injuries were those of the knees (57.69%), ankles (26.9%) and shoulders (23.1%). The most frequent extra-articular manifestations were ocular with conjunctivitis (62.5%) and uveitis (37.5%). Due to the delayed diagnosis, significant spinal deformities including hypercyphosis, straightness and ankylosis were found; the radiography of the spine objectified syndesmophytes (50.0%) with ankyloses and the bamboo column (23.5%) and that of the pelvis objectified sacroiliitis at stage 3 (54.6%) and at stage 4 (27.3%). The HLA B27 antigen was positive in 10.8% of cases. NSAIDs and sulfasalazine were the most commonly used drugs in management, respectively in 94.3% of symptomatic treatment and 92.6% of background therapy. Conclusion: Ankylosing spondylitis is relatively rare in Togo, affecting more men and young adults. There are no clinical or paraclinical particularity. The delay in diagnosis reflects the importance of the radiological signs. Treatment is mainly done by NSAIDs and DMRADs in particular sulfasalazine, due to their accessibility. References: [1]Dean LE, Jones GT, MacDonald AG, Downham C, Sturrock RD, Macfarlane GJ. Global Prevalence of Ankylosing Spondylitis. Rheumatology (Oxford). 2014;53:650-7. [2]Zabsonre TWJ, Sawadogo SA, Kabore F, Ilboudo A, Sougue C, Zongo E, et al. Ankylosing Spondylitis in Sub-Saharan Africa: A Series of 48 Cases Reported in Burkina Faso (West Africa). Open J Rheumatol Autoimmune Dis. 2018;8:87-92. [3]Mijiyawa M. Ankylosing Spondylitis in Togolese Patients. Med Trop. 1993;53:185-9. Disclosure of Interests: None declared.
POS1082 CATASTROPHIZING IN PATIENTS WITH PSORIATIC ARTHRITIS
Authors: C. Gaujoux-Viala, B. Coste, C. Traverson, E. Filhol, S. Laurent-Chabalier, J. Morel, B. Combe, C. Daien, C. Lukas, C. Hua
Journal: Annals of the Rheumatic Diseases (2021)

Background: Catastrophizing is a negative cognitivo-affective response to an anxiety-provoking stimulus, especially anticipated or actual pain. It can be quickly assessed using a validated questionnaire: the Pain Catastrophizing Scale (PCS) 1 . Catastrophizing plays a role in maintaining chronic pain and is associated with several pain-related outcomes in osteoarthritis and low back pain. To our knowledge, there are no data on catastrophizing in patients with psoriatic arthritis (PsA). Objectives: To assess the prevalence of catastrophizing and associated factors in PsA. Methods: We performed a bi-centric observational, prospective study. All patients aged 18 or over with PsA fulfilling the 2006 CASPAR criteria were consecutively included. Sociodemographic data, information on the disease and its treatments were collected as well as questionnaires for disease activity (BASDAI), function (HAQ, BASFI), quality of life (SF12, EQ5D), anxiety and depression (HADS, GAD7), fibromyalgia (FiRST), insomnia (ISI) and catastrophizing scores (PCS). Statistical analysis included samples T-test, one-way variance analysis, Spearman’s correlation coefficient, Chi 2 test, Fisher’s exact test, Wilcoxon test, multivariate linear regression (considering catastrophizing as a continuous variable) and multivariate logistics regression (considering catastrophizing as a categorical variable: PCS ≥ 20 = high level catastrophizing). Results: From September 2019 to March 2020, 85 PsA patients were included: 54.1% were women, the median age was 54.0 years and 33 patients (39.8%) were professionally active. The majority of patients (88.2%) had a disease lasting for more than 2 years. Axial involvement was found for 39 patients (45.9%), almost all patients (98.8%) had peripheral involvement, 32 patients (37.7%) had enthesitic involvement and 14 patients (16.7%) had erosions. Median DAS28 CRP was 3.12 [2.13-4.46] and the median BASDAI score was 5.50 [4.30-6.70]. The prevalence of a PCS score ≥20 was 45.9% [35.3;56.5]. The median PCS score was 16 [6-29]. In multivariate logistics regression, high-level catastrophizing was significantly associated with the HADS anxiety score (OR=1.35 [1.15-1.61]) and pain VAS (OR=1.04 [1.02-1.06]). In multivariate linear regression, catastrophizing was significantly associated with the HADS anxiety score (p= 0.004), pain VAS (p=0.001), HADS depression score (p=0.018) and insomnia score (p=0.034). Conclusion: Almost half the patients with PsA were high catastrophizers. Catastrophizing is related to anxiety, pain, depression and insomnia. It may be interesting to detect catastrophizing in order to improve the care of our patients. References: [1]Sullivan MJL. et al. Psychological Assessment. 1995;7(4):524–32 Disclosure of Interests: None declared.
Abstract 16130: Race-Ethnicity Modulates Atrial Fibrillation Symptom Burden and Quality of Life
Authors: Mary Carolina Rodriguez Ziccardi, Maha Ahmed, Yining Chen, Vivek Mehta, Zain Alzahrani, Faisal Darbar, Aylin Ornelas-Loredo, Aamir Twing, Ahmad Musa, Baha’a Al-Azzam, Sreenivas Konda, Dawood Darbar
Journal: Circulation (2019)

Introduction: Atrial fibrillation (AF) guidelines rely on the severity of symptoms experienced by patients to select a rate or rhythm control treatment strategy. While the severity of symptoms is v...
Comparison of Duration of Response vs Conventional Response Rates and Progression-Free Survival as Efficacy End Points in Simulated Immuno-oncology Clinical Trials
Authors: Chen Hu, Meihua Wang, Cai Wu, Heng Zhou, Cong Chen, Scott Diede
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Phase 2 trials and early efficacy end points play a crucial role in informing decisions about whether to continue to phase 3 trials. Conventional end points, such as objective response rate (ORR) and progression-free survival (PFS), have demonstrated inconsistent associations with overall survival (OS) benefits in immune checkpoint inhibitor (ICI) trials. Restricted mean duration of response (DOR) is a rigorous metric that combines both response status and duration information. However, its utility in clinical development has not been comprehensively explored. <h3>Objective</h3> To determine whether using restricted mean DOR in phase 2 trials can advance promising regimens to phase 3 trials sooner and eliminate unfavorable regimens earlier and with a higher degree of confidence compared with PFS and ORR. <h3>Design, Setting, and Participants</h3> This simulated modeling study randomized phase 2 screening trials by resampling 1376 patients from 2 completed randomized phase 3 trials of ICIs. Data were analyzed from August 2019 to July 2020. <h3>Exposures</h3> Use of ICIs. <h3>Main Outcomes and Measures</h3> Restricted mean DOR, PFS, ORR, and OS were estimated and compared between groups. Three scenarios were considered: (1) significant differences in OS, PFS, and ORR; (2) significant differences in OS and noticeable differences in ORR but not PFS; and (3) no differences in OS, PFS, or ORR. For each setting, 5000 randomized phase 2 trials with different sample sizes were simulated, with additional censoring applied to mimic staggered accruals and ensure fair comparisons between different analysis methods. Probabilities of concluding positive phase 2 trials using PFS, ORR, and DOR were summarized and compared. <h3>Results</h3> The restricted mean DOR difference correctly estimated a positive OS benefit more frequently than did the ORR or PFS tests, across different sample sizes, significance levels, and censoring levels evaluated. When both OS and PFS differed, the ranges of true-positive or power rates were 79.2% to 98.7% for DOR, 56.3% to 93.2% for PFS, and 67.0% to 96.0% for ORR. When OS differed but PFS did not, the ranges of power rates were 24.0% to 76.0% for DOR, 3.0% to 19.0% for PFS, and 10.5% to 38.0% for ORR. When OS was similar, the false-positive rate of restricted mean DOR test was close to the chosen significance level. <h3>Conclusions and Relevance</h3> These findings suggest that restricted mean DOR in randomized phase 2 trials is potentially more sensitive and useful than PFS and ORR in estimating the subsequent phase 3 conclusions and, thus, may be considered to complementarily facilitate decision-making in future clinical development.
Protecting Olympic Participants from Covid-19 — The Urgent Need for a Risk-Management Approach
Authors: Annie K Sparrow, Lisa M Brosseau, Robert J Harrison, Michael T Osterholm
Journal: New England Journal of Medicine (2021)

Protecting Olympic Participants from Covid-19 Plans to protect participants and the public from Covid-19 during the Olympics aren’t built on rigorous risk assessment. They fail to consider the ways...
OP0240 EPIDEMIOLOGY, PREDICTORS OF MORTALITY AND ROLE OF PROPHYLAXIS FOR PNEUMOCYSTITIS JIROVECI PNEUMONIA AMONG RHEUMATIC PATIENTS: A TERRITORY-WIDE STUDY
Authors: C. W. S. Chan, H. Y. Chung, W. Y. Yeung, C. S. Lau, P. H. LI
Journal: Annals of the Rheumatic Diseases (2021)

Background: Pneumocystis jiroveci pneumonia (PJP) is an opportunistic infection affecting immunocompromised individuals. Due to its high mortality, PJP prophylaxis is commonly recommended for many immunocompromising conditions. However, evidence regarding the burden and role of prophylaxis in PJP among rheumatic patients remains limited. There is lack of consensus for when and for whom to initiate prophylaxis. Delineating the epidemiology, predictors of mortality and efficacy of prophylaxis in PJP among rheumatic patients is urgently needed. Objectives: To delineate the epidemiology of PJP, identify predictors of mortality and evaluate the usefulness of prophylaxis in rheumatology patients. Methods: We performed a big-data cohort study based on the territory-wide healthcare database of the Hong Kong Hospital Authority. All patients with a diagnosis of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), immune-mediated myositis (IMM), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), or spondyloarthritis (SpA) between 2015-2019 were included. PJP were identified based on physician diagnosis and/or positive microbiological results from deep respiratory tract specimens. Prophylaxis was defined as prescription of a prophylactic dose of co-trimoxazole for at least 2 weeks and/or inhaled pentamidine. Prevalence of PJP, prophylaxis and mortality among rheumatic patients were calculated. Demographics, blood parameters and immunosuppressants use was also collected for multivariate analysis. Number needed to treat (NNT) analysis was performed based on absolute risk reduction of PJP in patients with and without prior PJP prophylaxis. Results: A total of 21,587 unique rheumatic patients were analysed (54% RA, 25% SLE, 13% SpA, 5% IMM, 2% AAV and 1% SSc). Between 2015-2019, 1141 (5.3%) patients were prescribed PJP prophylaxis and 48 (0.2%) developed PJP. None of those patients who developed PJP had received prophylaxis prior to infection. The risk of PJP was highest among SSc (1.8%), AAV (1.4%) and IMM (0.7%) patients, with NNT of SSc 36, AAV 48 and IMM 114. Within these disease entities, the majority of PJP occurred at prednisolone dose of 15mg/day (P15) or above (100% in SSc and IIM, 66.7% in AAV). Overall, PJP was associated with a mortality-rate of 39.6%. Glucocorticoid dose (daily prednisolone dose equivalent 29.1±23.5mg vs 11.4±7.2mg, P&lt;0.01) and lymphopenia (0.44x10 9 /L vs 0.90x10 9 /L, P= 0.04) at PJP diagnosis were associated with PJP mortality in rheumatic patients. Conclusion: PJP is an uncommon but important infection in rheumatic patients associated with significant mortality. PJP prophylaxis is effective and should be considered in patients with SSc, AAV and IMM, especially in those receiving a steroid dose above P15. Disclosure of Interests: None declared
Using Readmission Rates as a Quality Indicator in Sepsis—Addressing the Problem or Adding to It?
Authors: Mitchell M. Levy
Journal: JAMA Network Open (2021)

Michael S. Yoo, MD; Shiyun Zhu, MPH; Yun Lu, MD, MPH; John D. Greene, MA; Helen L. Hammer, MD; Colin T. Iberti, MD; Siamack Nemazie, MD; Martin P. Ananias, MD; Caitlin M. McCarthy, MD; Robert M. O’Malley, MD; Karlyn L. Young, MD; Karolin O. Reed, MD; Robert A. Martinez, MD; Kawai Cheung, MD; Vincent X. Liu, MD, MS
A Randomized Controlled Trial Comparing Two Different Schedules for Cisplatin Treatment in Patients with Locoregionally Advanced Nasopharyngeal Cancer
Authors: Wei-Xiong Xia, Xing Lv, Hu Liang, Guo-Ying Liu, Rui Sun, Qi Zeng, Si-Wei Li, Hao-Yuan Mo, Fei Han, Dong-Hua Luo, Qing Liu, Meng-Yun Shi, Yan-Fang Ye, Jing Yang, Liang-Ru Ke, Meng-Yun Qiang, Wen-Ze Qiu, Ya-Hui Yu, Kui-Yuan Liu, Xin-Jun Huang, Wang-Zhong Li, Shu-Hui Lv, Zhuo-Chen Cai, Jing-Jing Miao, Ling Guo, Ming-Yuan Chen, Ka-Jia Cao, Lin Wang, Chong Zhao, Pei-Yu Huang, Qiu-Yan Chen, Yi-Jun Hua, Lin-Quan Tang, Chao-Nan Qian, Hai-Qiang Mai, Xiang Guo, Yan-Qun Xiang
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Previous studies suggest that a cumulative cisplatin dose of 200 mg/m2 might be adequate in the intensity-modulated radiation therapy (IMRT) era for locoregionally advanced nasopharyngeal carcinoma (LANPC). However, two cycles of once-every-3-weeks cisplatin at 100 mg/m2 has never been prospectively compared with standard once-a-week cisplatin regimen. Patients and Methods: This trial was conducted at three hospitals from 2011 to 2016. Patients who met the eligibility criteria were recruited (ChiCTR-TRC-12001979) and randomly assigned (1:1) via a computer-generated sequence to receive once-every-3-weeks cisplatin at 100 mg/m2 for two cycles or once-a-week cisplatin at 40 mg/m2 for six cycles concurrently with IMRT. Primary endpoint was failure-free survival and between-group absolute difference of 10% as the noninferiority margin. Results: A total of 510 patients were enrolled. Median follow-up time was 58.3 months with 85.4% of 3-year failure-free survival in the once-every-3-weeks group and 85.6% in the once-a-week group. An absolute difference of −0.2% (95% confidence interval, −6.3 to 5.9; Pnoninferiority = 0.0016). Acute toxicities of grade 3 or higher occurred in 55.8% in the once-every-3-weeks group and 66.3% in the once-a-week group (P = 0.015). The most common acute toxicities were hematologic abnormalities, including leukopenia (16% vs. 27%; P = 0.0022) and thrombocytopenia (1% vs. 5%; P = 0.015). The late grade 3–4 auditory loss rate was significantly lower in the once-every-3-weeks group than the once-a-week group (6% vs. 13%; P = 0.0039). Conclusions: Once-every-3-weeks cisplatin as concurrent chemoradiotherapy is noninferior to once-a-week cisplatin in the treatment efficacy in the LANPC. Although both regimens are well tolerated, severe acute toxicities and late-onset auditory loss are higher in the once-a-week group.
Sixty seconds on . . . free parking
Authors: Abi Rimmer
Journal: BMJ (2021)

I’m sorry to be the bearer of bad news but the government has decided to withdraw its guidance on emergency parking passes for NHS staff, health and social care workers, and NHS volunteer responders in England.

These passes were made available through NHS trusts and allowed staff to park for free in local authority owned off-street car parks and on-street bays during …
Mimosine functionalized gold nanoparticles (Mimo-AuNPs) suppress β-amyloid aggregation and neuronal toxicity
Authors: Bibin G. Anand, Qi Wu, Govindarajan Karthivashan, Kiran P. Shejale, Sara Amidian, Holger Wille, Satyabrata Kar
Journal: Bioactive Materials (2021)

Evidence suggests that increased level/aggregation of beta-amyloid (Aβ) peptides initiate neurodegeneration and subsequent development of Alzheimer's disease (AD). At present, there is no effective treatment for AD. In this study, we reported the effects of gold nanoparticles surface-functionalized with a plant-based amino acid mimosine (Mimo-AuNPs), which is found to cross the blood-brain barrier, on the Aβ fibrillization process and toxicity. Thioflavin T kinetic assays, fluorescence imaging and electron microscopy data showed that Mimo-AuNPs were able to suppress the spontaneous and seed-induced Aβ1-42 aggregation. Spectroscopic studies, molecular docking and biochemical analyses further revealed that Mimo-AuNPs stabilize Aβ1-42 to remain in its monomeric state by interacting with the hydrophobic domain of Aβ1-42 (i.e., Lys16 to Ala21) there by preventing a conformational shift towards the β-sheet structure. Additionally, Mimo-AuNPs were found to trigger the disassembly of matured Aβ1-42 fibers and increased neuronal viability by reducing phosphorylation of tau protein and the production of oxyradicals. Collectively, these results reveal that the surface-functionalization of gold nanoparticles with mimosine can attenuate Aβ fibrillization and neuronal toxicity. Thus, we propose Mimo-AuNPs may be used as a potential treatment strategy towards AD-related pathologies.