tbuckley/cabot-search huggingface dataset:
Genetics of Smoking and Risk of Atherosclerotic Cardiovascular Diseases
Authors: Michael G. Levin, Derek Klarin, Themistocles L. Assimes, Matthew S. Freiberg, Erik Ingelsson, Julie Lynch, Pradeep Natarajan, Christopher O’Donnell, Daniel J. Rader, Philip S. Tsao, Kyong-Mi Chang, Benjamin F. Voight, Scott M. Damrauer
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Smoking is associated with atherosclerotic cardiovascular disease, but the relative contribution to each subtype (coronary artery disease [CAD], peripheral artery disease [PAD], and large-artery stroke) remains less well understood. <h3>Objective</h3> To determine the association between genetic liability to smoking and risk of CAD, PAD, and large-artery stroke. <h3>Design, Setting, and Participants</h3> Mendelian randomization study using summary statistics from genome-wide associations of smoking (UK Biobank; up to 462 690 individuals), CAD (Coronary Artery Disease Genome Wide Replication and Meta-analysis plus the Coronary Artery Disease Genetics Consortium; up to 60 801 cases, 123 504 controls), PAD (VA Million Veteran Program; up to 24 009 cases, 150 983 controls), and large-artery stroke (MEGASTROKE; up to 4373 cases, 406 111 controls). This study was conducted using summary statistic data from large, previously described cohorts. Review of those publications does not reveal the total recruitment dates for those cohorts. Data analyses were conducted from August 2019 to June 2020. <h3>Exposures</h3> Genetic liability to smoking (as proxied by genetic variants associated with lifetime smoking index). <h3>Main Outcomes and Measures</h3> Risk (odds ratios [ORs]) of CAD, PAD, and large-artery stroke. <h3>Results</h3> Genetic liability to smoking was associated with increased risk of PAD (OR, 2.13; 95% CI, 1.78-2.56;<i>P</i> = 3.6 × 10<sup>−16</sup>), CAD (OR, 1.48; 95% CI, 1.25-1.75;<i>P</i> = 4.4 × 10<sup>−6</sup>), and stroke (OR, 1.40; 95% CI, 1.02-1.92;<i>P</i> = .04). Genetic liability to smoking was associated with greater risk of PAD than risk of large-artery stroke (ratio of ORs, 1.52; 95% CI, 1.05-2.19;<i>P</i> = .02) or CAD (ratio of ORs, 1.44; 95% CI, 1.12-1.84;<i>P</i> = .004). The association between genetic liability to smoking and atherosclerotic cardiovascular diseases remained independent from the effects of smoking on traditional cardiovascular risk factors. <h3>Conclusions and Relevance</h3> In this mendelian randomization analysis of data from large studies of atherosclerotic cardiovascular diseases, genetic liability to smoking was a strong risk factor for CAD, PAD, and stroke, although the estimated association was strongest between smoking and PAD. The association between smoking and atherosclerotic cardiovascular disease was independent of traditional cardiovascular risk factors.
Comorbidity screening in hidradenitis suppurativa: Evidence-based recommendations from the US and Canadian Hidradenitis Suppurativa Foundations
Authors: Amit Garg, Neeta Malviya, Andrew Strunk, Shari Wright, Afsaneh Alavi, Raed Alhusayen, Ali Alikhan, Steven D. Daveluy, Isabelle Delorme, Noah Goldfarb, Wayne Gulliver, Iltefat Hamzavi, Tarannum Jaleel, Alexa B. Kimball, Joslyn S. Kirby, Mark G. Kirchhof, Janice Lester, Hadar Lev-Tov, Michelle A. Lowes, Robert Micheletti, Lauren A. Orenstein, Vincent Piguet, Christopher Sayed, Jerry Tan, Haley B. Naik
Journal: Journal of the American Academy of Dermatology (2021)

Hidradenitis suppurativa (HS) is associated with comorbidities that contribute to poor health, impaired life quality, and mortality risk.To provide evidence-based screening recommendations for comorbidities linked to HS.Systematic reviews were performed to summarize evidence on the prevalence and incidence of 30 comorbidities in patients with HS relative to the general population. The screening recommendation for each comorbidity was informed by the consistency and quality of existing studies, disease prevalence, and magnitude of association, as well as benefits, harms, and feasibility of screening. The level of evidence and strength of corresponding screening recommendation were graded by using the Strength of Recommendation Taxonomy (SORT) criteria.Screening is recommended for the following comorbidities: acne, dissecting cellulitis of the scalp, pilonidal disease, pyoderma gangrenosum, depression, generalized anxiety disorder, suicide, smoking, substance use disorder, polycystic ovary syndrome, obesity, dyslipidemia, diabetes mellitus, metabolic syndrome, hypertension, cardiovascular disease, inflammatory bowel disease, spondyloarthritis, and sexual dysfunction. It is also recommended to screen patients with Down syndrome for HS. The decision to screen for specific comorbidities may vary with patient risk factors. The role of the dermatologist in screening varies according to comorbidity.Screening recommendations represent one component of a comprehensive care strategy.Dermatologists should support screening efforts to identify comorbid conditions in HS.
Reports of Forgone Medical Care Among US Adults During the Initial Phase of the COVID-19 Pandemic
Authors: Kelly E. Anderson, Emma E. McGinty, Rachel Presskreischer, Colleen L. Barry
Journal: JAMA Network Open (2021)

<h3>Importance</h3> The coronavirus disease 2019 (COVID-19) pandemic has caused major disruptions in the US health care system. <h3>Objective</h3> To estimate frequency of and reasons for reported forgone medical care from March to mid-July 2020 and examine characteristics of US adults who reported forgoing care. <h3>Design, Setting, and Participants</h3> This survey study used data from the second wave of the Johns Hopkins COVID-19 Civic Life and Public Health Survey, fielded from July 7 to July 22, 2020. Respondents included a national sample of 1337 individuals aged 18 years or older in the US who were part of National Opinion Research Center's AmeriSpeak Panel. <h3>Exposures</h3> The initial period of the COVID-19 pandemic in the US, defined as from March to mid-July 2020. <h3>Main Outcomes and Measures</h3> The primary outcomes were missed doses of prescription medications; forgone preventive and other general medical care, mental health care, and elective surgeries; forgone care for new severe health issues; and reasons for forgoing care. <h3>Results</h3> Of 1468 individuals who completed wave 1 of the Johns Hopkins COVID-19 Civic Life and Public Health Survey (70.4% completion rate), 1337 completed wave 2 (91.1% completion rate). The sample of respondents included 691 (52%) women, 840 non-Hispanic White individuals (63%), 160 non-Hispanic Black individuals (12%), and 223 Hispanic individuals (17%). The mean (SE) age of respondents was 48 (0.78) years. A total of 544 respondents (41%) forwent medical care from March through mid-July 2020. Among 1055 individuals (79%) who reported needing care, 544 (52%) reported forgoing care for any reason, 307 (29%) forwent care owing to fear of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, and 75 (7%) forwent care owing to financial concerns associated with the COVID-19 pandemic. Respondents who were unemployed, compared with those who were employed, forwent care more often (121 of 186 respondents [65%] vs 251 of 503 respondents [50%];<i>P</i> = .01) and were more likely to attribute forgone care to fear of SARS-CoV-2 transmission (78 of 186 respondents [42%] vs 120 of 503 respondents [24%];<i>P</i> = .002) and financial concerns (36 of 186 respondents [20%] vs 28 of 503 respondents [6%];<i>P</i> = .001). Respondents lacking health insurance were more likely to attribute forgone care to financial concerns than respondents with Medicare or commercial coverage (19 of 88 respondents [22%] vs 32 of 768 respondents [4%];<i>P</i> &lt; .001). Frequency of and reasons for forgone care differed in some instances by race/ethnicity, socioeconomic status, age, and health status. <h3>Conclusions and Relevance</h3> This survey study found a high frequency of forgone care among US adults from March to mid-July 2020. Policies to improve health care affordability and to reassure individuals that they can safely seek care may be necessary with surging COVID-19 case rates.
FRI0225 Glucocorticosteroid and cytotoxic therapy
Authors: VI Vasiliev, MV Simonova, TN Safonova, NS Shornikova
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To assess the effect of long-term glucocorticosteroid (GCS) low doses and cytostatics taking on clinical-laboratory SS manifestations. <h3>Methods</h3> 500 SS pts divided into 4 groups were included into the study. 1st group – 200 of SS pts had 5 mg of Prednisolone daily, 1.8 for a year, 0.9–1.8 for subsequent years and chlorobutin – 2 mg daily for a year, 360–720 mg for the next 5–15 years. 2nd group – 100 SS pts had Prednisolone according the same scheme and cyclophosphane 200 mg twice a month, 4.8 mg for a year, 2.4–4.8 g for the next 5–15 years. 3d group – 100 SS pts had Prednisolone according the same scheme for 5–15 years. 4th group – 100 SS pts had only substitution therapy. Reliable improvement of stomatological (decrease of salivary glands, disappearing or decrease of frequency of parotitis, increase of salivation), ophthalmologic (residing of cornea dystrophy) and some systemic manifestations disappearing of artralgia, regional lymphadenopathy, decrease of morning stiffness) were noticed only in the fist three groups of pts and in the 1st and 2nd groups it was more pronounced (&lt;0.001). Only in the 1st and 2nd groups disappearing of purpura relapse in the third of pts. ESR, fibrinogens levels, general protein, G-globulins, 3 classes of immunoglobulins, CIC and RF titers decrease in 5 years was found only in the 1st and 2nd groups of pts (p &lt; 0.001). Substantial improvement (1st, 2nd groups – 30%, 3d – 10%) and moderate improvement (1st, 2nd groups – 25%, 3d – 20%) was found only in pts with cytostatics and GCS therapy. 30% (1st and 2nd groups) and 40% (3d group) pts needed more potent therapy, whereas 60% (4th) of pts had therapy due to development of different stage of severity of systemic manifestations. <h3>Results</h3> <h3>Conclusion</h3> Obtained data demonstrate the necessity of low doses of GCS and chlorobutin/cyclophosphane in early terms of SS with glandular manifestations. In some cases such therapy is effective during systemic manifestations of the disease which is not dangerous for the life of patient.
Short-Term Exposure to Ambient Air Pollution and Mortality From Myocardial Infarction
Authors: Yuewei Liu, Jingju Pan, Chuangang Fan, Ruijun Xu, Yaqi Wang, Chang Xu, Shuguang Xie, Hai Zhang, Xiuqing Cui, Zhe Peng, Chunxiang Shi, Yunquan Zhang, Hong Sun, Yun Zhou, Lan Zhang
Journal: Journal of the American College of Cardiology (2021)
Photocrosslinked, Tunable Protein Vesicles for Drug Delivery Applications
Authors: Yirui Li, Julie A. Champion
Journal: Advanced Healthcare Materials (2021)

Abstract Recombinant proteins have emerged as promising building blocks for vesicle self‐assembly because of their versatility through genetic manipulation and biocompatibility. Vesicles composed of thermally responsive elastin‐like polypeptide (ELP) fusion proteins encapsulate cargo during assembly. However, vesicle stability in physiological environments remains a significant challenge for biofunctional applications. Here, incorporation of an unnatural amino acid, para‐azido phenylalanine, into the ELP domain is reported to enable photocrosslinking of protein vesicles and tuning of vesicle size and swelling. The size of the vesicles can be tuned by changing ELP hydrophobicity and ionic strength. Protein vesicles are assessed for their ability to encapsulate doxorubicin and dually deliver doxorubicin and fluorescent protein in vitro as a proof of concept. The resulting photocrosslinkable vesicles made from full‐sized, functional proteins show high potential in drug delivery applications, especially for small molecule/protein combination therapies or targeted therapies.
AB0530 CHARACTERISTICS AND MEDIUM-TERM OUTCOMES OF TAKAYASU ARTERITIS–RELATED RENAL ARTERY STENOSIS: ANALYSIS OF A LARGE CHINESE COHORT
Authors: Y. Sun, X. Dai, P. LV, Z. Dong, J. Lin, L. Jiang
Journal: Annals of the Rheumatic Diseases (2020)

Background: The incidence of renal artery stenosis in Takayasu arteritis (TA) was 20%–60% according to previous reports. The specific characteristics of patients with TA-related renal artery stenosis and the effect of revascularization procedures on prognosis have not been fully investigated. Objectives: To investigate the characteristics of patients with TA-related renal artery stenosis and identify the predictors of medium-term adverse outcomes. Methods: Data for 567 patients registered in a large prospective observational cohort-the East China Takayasu arteritis cohort-up to April 30, 2019, were retrospectively analyzed. Results: Renal artery stenosis was confirmed in 172/567 (30.34%) patients, with left renal artery involvement seen in 73/172 (42.44%) patients. Renal insufficiency at presentation (HR = 2.37, 95% CI: 1.76-15.83, p = 0.03), bilateral renal artery involvement (HR = 6.95, 95% CI: 1.18-21.55, p = 0.01), and severe (&gt;75%) stenosis (HR = 4.75, 95% CI 1.08-11.33, p = 0.05) were predictors of adverse outcomes. Revascularization was performed for 46/172 (26.74%) patients. Patients without preoperative treatment had higher rate of restenosis (44.44% vs. 15.79%, p &lt; 0.01) and hypertension deterioration (25.93% vs. 10.53%, p &lt; 0.01) after the procedure. Non-receipt of preoperative treatment (HR = 6.5, 95% CI: 1.77-32.98, p = 0.04) and active disease at revascularization (HR = 4.21, 95% CI 2.01-21.44, p = 0.04) were independent predictors of adverse outcomes after revascularization. Conclusion: Patients with uncontrolled or worsening hypertension or/and renal function may benefit from revascularization. Those who have received preoperative treatment may have more favorable revascularization outcomes. Prognosis appears to be poorer for patients with renal insufficiency at presentation, bilateral artery involvement, and severe stenosis. References: [1]Watanabe Y, Miyata T, Tanemoto K. Current clinical features of new patients with Takayasu arteritis observed from a cross-country research in Japan: age and sex specificity. Circulation 2015; 132: 1701-9. [2]Peng M, Jiang XJ, Dong H, et al. Etiology of renal artery stenosis in 2047 patients: a single-center retrospective analysis during a 15-year period in China. J Hum Hypertens 2016; 30: 124-8 Disclosure of Interests: None declared
Blocking TIM-3 in Treatment-refractory Advanced Solid Tumors: A Phase Ia/b Study of LY3321367 with or without an Anti-PD-L1 Antibody
Authors: James J. Harding, Victor Moreno, Yung-Jue Bang, Min Hee Hong, Amita Patnaik, José Trigo, Anna M. Szpurka, Noboru Yamamoto, Toshihiko Doi, Siqing Fu, Boris Calderon, Nieves Velez de Mendizabal, Emiliano Calvo, Danni Yu, Leena Gandhi, Zhuqing Tina Liu, Violeta Regnier Galvao, Ching Ching Leow, Maria J. de Miguel
Journal: Clinical Cancer Research (2021)

Abstract Purpose: T-cell immunoglobulin and mucin-domain–containing molecule-3 (TIM-3) blunts anticancer immunity and mediates resistance to programmed death 1 (PD-1) and PD ligand 1 (PD-L1) inhibitors. We assessed a novel, first-in-class, TIM-3 mAb, LY3321367, alone or in combination with the anti-PD-L1 antibody, LY300054 in patients with advanced solid tumor. Patients and Methods: This open-label, multicenter, phase Ia/b study aimed to define the safety/tolerability and recommended phase II dose (RP2D) of LY3321367 with or without LY300054. Secondary objectives included pharmacokinetics/pharmacodynamics, immunogenicity, and efficacy. Biomarkers were assessed in exploratory analysis. Results: No dose-limiting toxicities were observed in the monotherapy (N = 30) or combination (N = 28) dose escalation. LY3321367 treatment-related adverse events (≥2 patients) included pruritus, rash, fatigue, anorexia, and infusion-related reactions. Dose-proportional increase in LY3321367 concentrations was not affected by either LY300054 or antidrug antibodies (observed in 50%–70% of patients). Pharmacokinetic/pharmacodynamic modeling indicated 100% target engagement at doses ≥600 mg. LY3321367 RP2D was 1,200 mg biweekly for four doses followed by 600 mg every 2 weeks thereafter. In the non–small cell lung cancer monotherapy expansion cohort, outcomes varied by prior anti-PD-1 therapy response status: anti-PD-1/L1 refractory patients [N = 23, objective response rate (ORR) 0%, disease control rate (DCR) 35%, progression-free survival (PFS) 1.9 months] versus anti-PD-1/L1 responders (N = 14, ORR 7%, DCR 50%, PFS 7.3 months). In combination expansion cohorts (N = 91), ORR and DCR were 4% and 42%; CD8 infiltration in paired biopsies increased in approximately half these patients. Conclusions: LY3321367 exhibited acceptable safety profile with favorable pharmacokinetics/pharmacodynamics but only modest antitumor activity. The therapeutic relevance of TIM-3 blockade requires further investigation.
Suppression of local type I interferon by gut microbiota–derived butyrate impairs antitumor effects of ionizing radiation
Authors: Kaiting Yang, Yuzhu Hou, Yuan Zhang, Hua Liang, Anukriti Sharma, Wenxin Zheng, Liangliang Wang, Rolando Torres, Ken Tatebe, Steven J. Chmura, Sean P. Pitroda, Jack A. Gilbert, Yang-Xin Fu, Ralph R. Weichselbaum
Journal: The Journal of Experimental Medicine (2021)

The antitumor effects of ionizing radiation (IR) are mediated in part through activation of innate and adaptive immunity. Here we report that gut microbiota influences tumor control following IR. Vancomycin decreased the abundance of butyrate-producing gut bacteria and enhanced antitumor responses to IR. Oral administration of Lachnospiraceae, a family of vancomycin-sensitive bacteria, was associated with increased systemic and intratumoral butyric acid levels and impaired the efficacy of IR in germ-free (GF) mice. Local butyrate inhibited STING-activated type I IFN expression in dendritic cells (DCs) through blockade of TBK1 and IRF3 phosphorylation, which abrogated IR-induced tumor-specific cytotoxic T cell immune responses without directly protecting tumor cells from radiation. Our findings demonstrate that the selective targeting of butyrate-producing microbiota may provide a novel therapeutic option to enhance tumor radiation sensitivity.
Initial experience of TAS-102 chemotherapy in Australian patients with chemorefractory metastatic colorectal cancer.
Authors: Azim Jalali, Hui-Li Wong, Rachel Wong, Margaret Lee, Lucy Gately, Matthew Loft, Jeremy David Shapiro, Suzanne Kosmider, Jeanne Tie, Sumitra Ananda, Justin Yeung, Ross Jennens, Belinda Lee, Joseph James McKendrick, Lionel Lim, Muhammad Adnan Khattak, Peter Gibbs
Journal: Journal of Clinical Oncology (2021)

71 Background: For patients with refractory metastatic colorectal cancer (mCRC) treatment with Trifluridine/Tipiracil, also known as TAS-102, improves overall survival. In Australia, TAS-102 was initially made available locally through patients self-funding, later via an industry sponsored Medicine Access Program (MAP) and then via the Pharmaceutical Benefits Scheme (PBS). This study aims to investigate the efficacy and safety of TAS-102 in real world Australian population. Methods: A retrospective analysis of prospectively collected data from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry was undertaken. The characteristics and outcomes of patients receiving TAS-102 were assessed and compared to all TRACC patients and those enrolled in the registration study (RECOURSE). Results: Across 13 sites, 107 patients were treated with TAS-102 (non-PBS n = 27, PBS n = 80), The median number of patients per site was 7 (range: 1-17). The median age was 60 years (range: 31-83), compared to 67 for all TRACC patients and 63 for RECOURSE. Comparing registry TAS-102 and RECOURSE patients, 75% vs 100% were ECOG performance status 0-1, 74% vs 79% had initiated treatment more than 18 months from diagnosis of metastatic disease and 39% vs 49% were RAS wild type. Median time on treatment was 10.4 weeks (range: 1.7-32). Median clinician assessed progression-free survival was 3.3 compared to RECIST defined PFS of 2 months in RECOURSE study, while median overall survival was the same at 7.1 months. Two patients (2.3%) had febrile neutropenia and there were no treatment-related deaths in the real-world series, where TAS102 dose at treatment initiation was at clinician discretion. In the RECOURSE study there was a 4% febrile neutropenia rate and one treatment-related death. Conclusions: TRACC registry patients treated with TAS102 were younger than both TRACC patients overall and those from the RECOURSE trial. Less strict application of RECIST criteria and less frequent imaging may have contributed to an apparently longer PFS. However overall survival outcomes achieved with TAS102 in real world patients were comparable to findings from this pivotal trial with an acceptable rate of major adverse events.
Phase II study of pembrolizumab plus capecitabine and bevacizumab in microsatellite stable (MSS) metastatic colorectal cancer (mCRC): Interim analysis.
Authors: Andrea Grace Bocobo, Renee Wang, Spencer Behr, Julia C. Carnevale, Pelin Cinar, Eric Andrew Collisson, Lawrence Fong, Wesley Allen Kidder, Andrew H. Ko, Kanti Pallav Kolli, Megan Kennedy, Angela Laffan, Sheila Lindsay, Sneha Nalla, Gabriel Schwartz, Julia Whitman, Patricia Zendejas, Li Zhang, Katherine Van Loon, Chloe Evelyn Atreya
Journal: Journal of Clinical Oncology (2021)

77 Background: MSS mCRC rarely responds to pembrolizumab monotherapy, but capecitabine and bevacizumab may induce immune-stimulatory effects. This study evaluates the safety, tolerability and preliminary efficacy of pembrolizumab in combination with capecitabine and bevacizumab in MSS mCRC. We present results at the planned interim analysis. Methods: Design:single-arm, open-label, single-site phase 2 trial with a safety lead-in to confirm the recommended phase 2 dose (RP2D) for capecitabine and expansion cohorts. Per the Simon’s 2-stage design, ≤1 response in 29 patients (pts) requires trial suspension. Key eligibility criteria: MSS mCRC with stable disease (SD) or progressive disease (PD) on prior fluoropyrimidine-based therapy. Treatment: RP2D PO capecitabine on days 1-14 plus 200 mg IV pembrolizumab and 7.5 mg/kg IV bevacizumab on day 1 in 21-day cycles. Pts are followed for toxicity and radiographic response. Results: From 04/2018-09/2020, 29 pts were enrolled, of whom 15 (52%) were female; 21 (72%) white; and median age was 55 years (range 36-77 years). Prior therapies: 2 (7%) pts had SD and 27 (93%) pts had PD on fluoropyrimidine-containing regimens; 24 (83%) pts had prior exposure to bevacizumab. The RP2D for capecitabine was 1000 mg/m2 PO BID, with no dose limiting toxicities observed. Complete toxicity data are available for 25 off-treatment pts. The most common related adverse events (AEs) were palmar-plantar erythrodysesthesia (PPE) (64%) and fatigue (68%). Grade ≥3 related AEs occurred in 9 (36%) pts, including immune-related AEs of Grade 3 dyspnea, hypophosphatemia, and pancreatitis in 1 pt each. Treatment related AEs leading to dose interruptions, reductions, or delays occurred in 15 (60%) pts, most commonly PPE in 13 (52%) pts. No pt had a related AE leading to treatment discontinuation or death. Disposition: of 29 pts enrolled, 24 were removed for PD and 1 was removed for an unrelated AE. Best response by RECIST 1.1 in 23 evaluable pts: partial response (PR) in 2 (9%); SD in 14 (61%); PD in 7 (30%). Median time on treatment was 6 months (range 2-26 months). Conclusions: Combination of pembrolizumab with capecitabine and bevacizumab was found to be tolerable with an expected toxicity profile in MSS mCRC pts. With 2 responses, the study met interim analysis criteria to continue accrual. Tissue and blood-based immune correlatives are planned. Clinical trial information: NCT03396926.