tbuckley/cabot-search huggingface dataset:
OP0002 IMMTOR NANOPARTICLES ENHANCE THE TOLEROGENIC ENVIRONMENT OF THE LIVER IN MICE
Authors: P. Ilyinskii, C. Roy, J. Leprevost, K. Kishimoto
Journal: Annals of the Rheumatic Diseases (2021)

Background: Tolerogenic ImmTOR biodegradable nanoparticles encapsulating rapamycin have been shown to mitigate the formation of anti-drug antibodies against pegadricase, a pegylated uricase enzyme, which enabled monthly dosing and sustained reduction of serum uric acid levels in a Phase 2 clinical trial of SEL-212, a combination of pegadricase + ImmTOR, in patients with symptomatic gout with hyperuricemia. Prior mechanism of action studies showed selective biodistribution of ImmTOR to the spleen and liver following intravenous (IV) administration in mice. In the spleen, ImmTOR has been demonstrated to induce tolerogenic dendritic cells and antigen-specific regulatory T cells and inhibit antigen-specific B cell activation. Splenectomized mice showed a partial but incomplete abrogation of the tolerogenic immune response mediated by ImmTOR. Objectives: Here we evaluated the ability of ImmTOR to enhance the tolerogenic environment in the liver. Results: All the major resident populations of liver cells, including liver sinusoidal endothelial cells (LSECs), Kupffer cells (KC), stellate cells (SC), and hepatocytes, actively took up fluorescent-labeled ImmTOR particles, which resulted in downregulation of MHC class II and co-stimulatory molecules and upregulation of the PD-L1 checkpoint molecule. The LSEC, known to play an important role in hepatic tolerance induction, emerged as a key target cell for ImmTOR. The tolerogenic environment led to a multi-pronged modulation of hepatic T cell populations, resulting in an increase in T cells with a regulatory phenotype, upregulation of PD-1 on CD4 + and CD8 + T cells, and the emergence of a large population of CD4 – CD8 – (double negative) T cell population. Modulation of T cell phenotype was seen to a lesser extent after administration by empty nanoparticles, but not free rapamycin. The upregulation of PD-1, but not the appearance of double negative T cells, was inhibited by antibodies against PD-L1 or CTLA-4. Conclusion: These results suggest that the liver may contribute to the tolerogenic properties of ImmTOR in mitigating anti-drug antibody responses to biologic therapies, such as pegadricase. Disclosure of Interests: Petr Ilyinskii Shareholder of: Selecta Biosciences, Employee of: Selecta Biosciences, Christopher Roy Shareholder of: Selecta Biosciences, Employee of: Selecta Biosciences, Julie LePrevost Shareholder of: Selecta Biosciences, Employee of: Selecta Biosciences, Kei Kishimoto Shareholder of: Selecta Biosciences, Employee of: Selecta Biosciences
AB0571 RELATIONSHIP BETWEEN SERUM CALPROTECTIN LEVEL AND PRESENCE OF SUBCLINICAL ATHEROSCLEROSIS AND ARTERIAL STIFFNESS IN PATIENT WITH PSORIATIC ARTHRITIS
Authors: I. T. Cheng, M. LI, E. K. LI, A. P. W. Lee, L. S. Tam
Journal: Annals of the Rheumatic Diseases (2021)

Background: Calprotectin is a member of S100 leukocyte. Serum calprotectin is a sensitive biomarker of disease activity in patients with psoriatic arthritis (PsA). While various CV risk score only shown modest correlation with augmented CV risk in patient with PsA, whether calprotectin could play an addition role remains uncertain. Objectives: To elucidate the association between serum calprotectin and subclinical atherosclerosis and arterial stiffness in patient with PsA Methods: Seventy-eight PsA patient (age: 53±11 years, 47(54%) male) without CV event was recruited into this cross-sectional study. High resolution carotid ultrasound was performed to assess the presence of carotid plaque and intima-media thickness (IMT). Arterial stiffness was measured by branchial-ankle pulse wave velocity (PWV) and augmentation index (AIx). Serum calprotectin level was measured by QUANTA Lite Calprotectin Extended Range ELISA kit from (INOVA Diagnostics, San Diego, CA, USA). Results: 29/78 (38%) of patient had carotid plaque (CP+). Subject in CP+ group were of older age and higher inflammatory burden in terms of higher number of swollen joint and longer disease duration. The use of statins were also higher in CP+ group. Serum calprotectin level were significantly higher in CP+ group (639.2ng/ml ±378.2 in CP- group vs 911.8ng/ml ±429.4 in CP+ group, p =0.005) (Figure 1). Using multivariate logistic regression analysis, higher level of ln calprotectin were significantly associated with presence of carotid plaque (OR: 3.25, 95%CI: 1.22 to 8.69, p =0.019) after adjusting for baseline covariates. There was also significant correlation between calprotectin level and C-Reactive Protein (CRP) (r=0.237, p =0.037), mean IMT (r=0.301, p =0.021) and maximum IMT (r=0.265, p =0.043). However, no significant association were observed between calprotectin level and PWV or AIx. Figure 1. Conclusion: Increased calprotectin level were associated with presence of plaque and increased IMT. Serum calprotectin may be a novel biomarker for assessing CV risk in patient with PsA. Table 1. Multivariate analysis for factors associated with presence of carotid plaque. OR 95% CI p Disease duration (years) 1.10 1.02 to 1.19 0.018 Ln Calprotectin 3.25 1.22 to 8.69 0.019 *Factors included in the multivariate analysis: age, gender, disease duration, swollen joint count, hyperlipidemia, Framingham 10-year CVD risk &gt;10%, current use of statins, and calprotectin level Disclosure of Interests: Isaac T. Cheng: None declared., Martin Li: None declared., Edmund K. Li: None declared., Alex Pui Wai Lee: None declared., Lai-Shan Tam Grant/research support from: Grants from Norvatis, Pfizer.
Antibody responses after first and second Covid-19 vaccination in patients with chronic lymphocytic leukaemia
Authors: H. Parry, G. McIlroy, R. Bruton, M. Ali, C. Stephens, S. Damery, A. Otter, T. McSkeane, H. Rolfe, S. Faustini, N. Wall, P. Hillmen, G. Pratt, S. Paneesha, J. Zuo, A. Richter, P. Moss
Journal: Blood Cancer Journal (2021)

B-cell chronic lymphocytic leukaemia (CLL) is associated with immunosuppression and patients are at increased clinical risk following SARS-CoV-2 infection. Covid-19 vaccines offer the potential for protection against severe infection but relatively little is known regarding the profile of the antibody response following first or second vaccination. We studied spike-specific antibody responses following first and/or second Covid-19 vaccination in 299 patients with CLL compared with healthy donors. 286 patients underwent extended interval (10-12 week) vaccination. 154 patients received the BNT162b2 mRNA vaccine and 145 patients received ChAdOx1. Blood samples were taken either by venepuncture or as dried blood spots on filter paper. Spike-specific antibody responses were detectable in 34% of patients with CLL after one vaccine (n = 267) compared to 94% in healthy donors with antibody titres 104-fold lower in the patient group. Antibody responses increased to 75% after second vaccine (n = 55), compared to 100% in healthy donors, although titres remained lower. Multivariate analysis showed that current treatment with BTK inhibitors or IgA deficiency were independently associated with failure to generate an antibody response after the second vaccine. This work supports the need for optimisation of vaccination strategy in patients with CLL including the potential utility of booster vaccines.
CQC’s plans to rethink inspection ratings don’t go far enough, says BMA
Authors: Matthew Limb
Journal: BMJ (2021)

Doctors’ leaders have urged the Care Quality Commission (CQC) to rethink “crude” inspection ratings after it published a new strategy for regulating health and care in England.

The BMA said that the regulator’s plans were “moving in the right direction,” but it criticised “unfairly judgmental” inspections as a poor measure of quality and a drain on resources. It said that these inspections failed to acknowledge how workload pressures or staff shortages affect performance and could be “counterproductive.”

Chaand Nagpaul, BMA council chair, said, “Instead of instilling fear or blame in staff who are doing their best in a system under pressure, the CQC should identify specific areas of improvement and facilitate support for positive change, as occurs in regulatory approaches in many other countries.”

The CQC’s new strategy was published on …
POS1448 EVIDENCE BASED PRACTICE: WHAT IS THE EVIDENCE THAT BRITISH SOCIETY FOR RHEUMATOLOGY GUIDELINES ARE EVIDENCE BASED?
Authors: M. Lee, G. Reynolds, M. Yates, J. Galloway
Journal: Annals of the Rheumatic Diseases (2021)

Background: Clinical practice guidelines are designed to ensure that patients are treated according to best evidence, with the goal of optimizing clinical outcomes and reducing unwarranted variation in care. They compile, rate and translate the data available into recommendations that form the basis of evidence-based practice for most clinicians. Despite their importance, the evidence base informing different guidelines varies in quality. A recent study of American College of Rheumatology (ACR) Practice Guidelines demonstrated only 17 of 35 class I (strong benefit to harm ratio) recommendations were supported by level A evidence (high quality randomized controlled trails or meta-analyses) 1 . Objectives: To review the evidence supporting the British Society for Rheumatology (BSR) guidelines. Methods: Thirteen sets of guidelines that were available on the BSR website as of October 16 th 2019 were reviewed ( https://www.rheumatology.org.uk/practice-quality/guidelines ). A range of methodologies (including Grading of Recommendations Assessment, Development and Evaluation (GRADE), Scottish Intercollegiate Guidelines Network (SIGN), EULAR and Royal College of Physicians (RCP) recommendations) were used to assess the quality of evidence and strength of recommendation. For comparability between guidelines the level of evidence was converted to a score between I (highest quality) and IV (lowest quality) and the strength of recommendation was converted to a rating between A and D. The polymyalgia rheumatica guideline was not assessed due to unclear methodology and lack of level of evidence for all recommendations. Results: Of the 12 BSR guidelines assessed, there were 554 recommendations in total. The number of recommendations per guideline ranged between 13 and 80. Across all assessed guidelines, 94 recommendations (17.0%) were classified as level I, 161 (29.1%) as level 2 and 299 (54.0%) as level 3 or 4. These figures are similar to those reported in the ACR guidelines (23%, 19% and 58% respectively) 1 . The proportion of level I evidence varied from 46.2% (Axial Spondyloarthropathy guideline) to 0% (Hot Swollen Joint guideline). Conclusion: Over half of all BSR guideline recommendations have level of supporting evidence of III/IV. A wide range of methodologies are used to generate BSR guidelines (GRADE, SIGN, RCP / EULAR). This makes it challenging for readers unfamiliar with these approaches to interpret evidence and hinders comparisons between guidelines. A standardized methodology for future guideline development would overcome these barriers. References: [1]Duarte-Garcia A, Zamore R &amp; Wong JB. The Evidence Basis for the American College of Rheumatology Practice Guidelines. JAMA Intern Med, 2018 Jan 1;178(1):146-148. Disclosure of Interests: None declared
In Situ Synthesized Selenium Nanoparticles‐Decorated Bacterial Cellulose/Gelatin Hydrogel with Enhanced Antibacterial, Antioxidant, and Anti‐Inflammatory Capabilities for Facilitating Skin Wound Healing
Authors: Lin Mao, Li Wang, Mingyue Zhang, Muhammad Wajid Ullah, Li Liu, Weiwei Zhao, Ying Li, Abeer Ahmed Qaed Ahmed, Haoyan Cheng, Zhijun Shi, Guang Yang
Journal: Advanced Healthcare Materials (2021)

Bacterial-associated wound infection and antibiotic resistance have posed a major burden on patients and health care systems. Thus, developing a novel multifunctional antibiotic-free wound dressing that cannot only effectively prevent wound infection, but also facilitate wound healing is urgently desired. Herein, a series of multifunctional nanocomposite hydrogels with remarkable antibacterial, antioxidant, and anti-inflammatory capabilities, based on bacterial cellulose (BC), gelatin (Gel), and selenium nanoparticles (SeNPs), are constructed for wound healing application. The BC/Gel/SeNPs nanocomposite hydrogels exhibit excellent mechanical properties, good swelling ability, flexibility and biodegradability, and favorable biocompatibility, as well as slow and sustainable release profiles of SeNPs. The decoration of SeNPs endows the hydrogels with superior antioxidant and anti-inflammatory capability, and outstanding antibacterial activity against both common bacteria (E. coli and S. aureus) and their multidrug-resistant counterparts. Furthermore, the BC/Gel/SeNPs hydrogels show an excellent skin wound healing performance in a rat full-thickness defect model, as evidenced by the significantly reduced inflammation, and the notably enhanced wound closure, granulation tissue formation, collagen deposition, angiogenesis, and fibroblast activation and differentiation. This study suggests that the developed multifunctional BC/Gel/SeNPs nanocomposite hydrogel holds a great promise as a wound dressing for preventing wound infection and accelerating skin regeneration in clinic.
Risk of prostate cancer in relatives of prostate cancer patients in Sweden: A nationwide cohort study
Authors: Xing Xu, Elham Kharazmi, Yu Tian, Trasias Mukama, Kristina Sundquist, Jan Sundquist, Hermann Brenner, Mahdi Fallah
Journal: PLoS Medicine (2021)

Background Evidence-based guidance for starting ages of screening for first-degree relatives (FDRs) of patients with prostate cancer (PCa) to prevent stage III/IV or fatal PCa is lacking in current PCa screening guidelines. We aimed to provide evidence for risk-adapted starting age of screening for relatives of patients with PCa. Methods and findings In this register-based nationwide cohort study, all men (aged 0 to 96 years at baseline) residing in Sweden who were born after 1931 along with their fathers were included. During the follow-up (1958 to 2015) of 6,343,727 men, 88,999 were diagnosed with stage III/IV PCa or died of PCa. The outcomes were defined as the diagnosis of stage III/IV PCa or death due to PCa, stratified by age at diagnosis. Using 10-year cumulative risk curves, we calculated risk-adapted starting ages of screening for men with different constellations of family history of PCa. The 10-year cumulative risk of stage III/IV or fatal PCa in men at age 50 in the general population (a common recommended starting age of screening) was 0.2%. Men with ≥ 2 FDRs diagnosed with PCa reached this screening level at age 41 (95% confidence interval (CI): 39 to 44), i.e., 9 years earlier, when the youngest one was diagnosed before age 60; at age 43 (41 to 47), i.e., 7 years earlier, when ≥ 2 FDRs were diagnosed after age 59, which was similar to that of men with 1 FDR diagnosed before age 60 (41 to 45); and at age 45 (44 to 46), when 1 FDR was diagnosed at age 60 to 69 and 47 (46 to 47), when 1 FDR was diagnosed after age 69. We also calculated risk-adapted starting ages for other benchmark screening ages, such as 45, 55, and 60 years, and compared our findings with those in the guidelines. Study limitations include the lack of genetic data, information on lifestyle, and external validation. Conclusions Our study provides practical information for risk-tailored starting ages of PCa screening based on nationwide cancer data with valid genealogical information. Our clinically relevant findings could be used for evidence-based personalized PCa screening guidance and supplement current PCa screening guidelines for relatives of patients with PCa.
Assessing the Association of Targeted Therapy and Intracranial Metastatic Disease
Authors: Anders W. Erickson, Steven Habbous, Frances Wright, Aisha K. Lofters, Katarzyna J. Jerzak, Sunit Das
Journal: JAMA Oncology (2021)

Targeted therapies have been hypothesized to prolong survival in the treatment of patients with intracranial metastatic disease (IMD) but, paradoxically, increase IMD incidence by improving systemic disease control and prolonging survival from the primary tumor. The real-world benefits of targeted therapy in treating patients with IMD are unclear, as clinical trials have excluded patients with IMD and lacked end points that report intracranial outcomes.To assess the association of targeted therapy and IMD with patient survival.This retrospective cohort study included all patients in Ontario, Canada, who received a diagnosis of IMD from April 2005 to January 2018 with primary diagnoses of breast cancer, lung or bronchus cancer, or melanoma and control patients who were matched by primary disease without IMD. The data were analyzed between March and October 2020.EGFR-, ERBB2 (HER2-), or BRAF-targeted therapy or IMD status.Kaplan-Meier and multivariable Cox regression analyses were performed to compare overall survival (OS) between patient subcohorts divided by primary disease and stratified by targeted therapy receipt or IMD status.In this cohort of 26 676 patients with IMD and breast cancer, lung and bronchus cancer, or melanoma, 57% of patients were women, and the median age at IMD diagnosis was 64 years (interquartile range, 56-72 years). Post-IMD targeted therapy was associated with prolonged OS in patients with ERBB2-positive breast cancer (hazard ratio [HR], 0.41; 95% CI, 0.33-0.50), EGFR-positive lung cancer (HR, 0.28; 95% CI, 0.23-0.34), and BRAF-positive melanoma (HR, 0.20; 95% CI, 0.14-0.29) compared with those who did not receive post-IMD targeted therapy. The presence of IMD was associated with shorter OS in patients with metastatic ERBB2-positive breast cancer (HR, 1.80; 95% CI, 1.56-2.08) and metastatic EGFR-positive lung cancer (HR, 1.22; 95% CI, 1.08-1.39) but not metastatic BRAF-positive melanoma (HR, 1.11; 95% CI, 0.77-1.61) compared with those without IMD.The findings of this cohort study suggest an association between real-world use of targeted therapies and prolonged OS in patients with IMD in the setting of ERBB2-positive breast cancer, EGFR-positive lung cancer, and BRAF-positive melanoma. Including patients with IMD in clinical trials and using end points that interrogate IMD will be critical to determine the role of targeted therapies in treating patients with IMD.
Dielectric Elastomer Actuators, Neuromuscular Interfaces, and Foreign Body Response in Artificial Neuromuscular Prostheses: A Review of the Literature for an In Vivo Application
Authors: Alessandro Bruschi, Davide Maria Donati, Peter Choong, Enrico Lucarelli, Gordon Wallace
Journal: Advanced Healthcare Materials (2021)

The inability to replace human muscle in surgical practice is a significant challenge. An artificial muscle controlled by the nervous system is considered a potential solution for this. Here, this is defined as a neuromuscular prosthesis. Muscle loss and dysfunction related to musculoskeletal oncological impairments, neuromuscular diseases, trauma or spinal cord injuries can be treated through artificial muscle implantation. At present, the use of dielectric elastomer actuators working as capacitors appears a promising option. Acrylic or silicone elastomers with carbon nanotubes functioning as the electrode achieve mechanical performances similar to human muscle in vitro. However, mechanical, electrical, and biological issues have prevented clinical application to date. Here materials and mechatronic solutions are presented which can tackle current clinical problems associated with implanting an artificial muscle controlled by the nervous system. Progress depends on the improvement of the actuation properties of the elastomer, seamless or wireless integration between the nervous system and the artificial muscle, and on reducing the foreign body response. It is believed that by combining the mechanical, electrical, and biological solutions proposed here, an artificial neuromuscular prosthesis may be a reality in surgical practice in the near future.
Equity and the JAMA Network
Authors: Phil B. Fontanarosa, Annette Flanagin, John Z. Ayanian, Robert O. Bonow, Neil M. Bressler, Dimitri Christakis, Mary L. Disis, S. Andrew Josephson, Melina R. Kibbe, Dost Öngür, Jay F. Piccirillo, Rita F. Redberg, Frederick P. Rivara, Kanade Shinkai, Clyde W. Yancy
Journal: JAMA Surgery (2021)

The key objective of JAMA is "To promote the science and art of medicine and the betterment of the public health"; similar objectives and mission statements are supported by all 12 JAMA Network Journals.Together this family of journals is committed to publishing the best research, reviews, and opinion articles to advance medical science, promote public health, and improve patient care.The ultimate goal is to promulgate truth in science and medicine.On February 23, 2021, a podcast titled "Structural Racism for Doctors-What Is It?" was posted by the JAMA Network and on the following day, a tweet was posted to promote the podcast.Assertions in both that disavowed the presence of structural racism in medicine and among physicians were wrong, misguided, and uninformed.An extensive evidence base strongly supports the presence of structural racism in medicine and its adverse influence on health. 1 The process for reviewing and publishing the podcast and tweet was also flawed.On March 4, 2021, Howard Bauchner, MD, editor in chief of JAMA and the 12 JAMA Network Journals, took responsibility and issued an apology for the podcast and tweet.This editorial team also expresses a profound apology for the misinformation in the podcast and tweet and recognizes the hurt, anger, and outrage that resulted.These events and developments make it clear that JAMA and the JAMA Network Journals can and must do better and advance toward inclusion and antiracism in all journalrelated activities.Even though these journals have made progress, additional commitment and work are needed to build on and intensify these efforts to achieve meaningful, sustainable change.For instance, previous efforts include the more than 650 research, review, and opinion articles on race, racism, and racial and ethnic disparities and inequities that have been published in JAMA and the JAMA Network Journals since 2015, 1 including editorials in JAMA on topics such as race and medical research, 2 race and poverty and medicine, 3 enhancing diversity in medical schools, 4 and equity related to COVID-19 vaccines. 5n addition, within the past year, JAMA Network Open and JAMA Health Forum issued calls for manuscripts on prevention and effects of systemic racism in health 6,7 ; JAMA Psychiatry initiated an editorial fellowship prioritized to early-career academic psychiatrists from underrepresented backgrounds; and JAMA Surgery issued a "Call to Action" to all surgery journal editors for diversity in the editorial and peer review process.