tbuckley/cabot-search huggingface dataset:
Abstract P185: Adverse Cardiovascular Events In Patients With Psoriasis And Psoriatic Arthritis
Authors: Molly Ottensoser, Jeffrey Berger, Michael S Garshick
Journal: Circulation (2022)

Background: Patients with psoriasis who have severe enough disease to require biologic therapy have increased risk of cardiovascular (CV) disease and CV comorbidities. Complications of immune modulating therapy can include weight and lipid alterations, potentiation of heart failure, and athero or venoembolic events, which may also be race or gender dependent. Clinical trials of biologic therapy represent an opportunity to capture and study CV related events and important safety signals. The aim of this investigation was to evaluate the public reporting of CV related adverse events in the psoriatic patient population. Methods: The prevalence of reporting of demographics, and adverse CV related events was obtained from clinicaltrials.gov from registered clinical trials leading to FDA approval of biologic medications. Results: In total, 39 clinical trials of biologic therapy ranging from 2011 through 2020 were included encompassing 27,693 participants. Median age was 46 (IQR; 45 - 48) years and 68% (IQR; 48 - 69) male. Nineteen (49%) of the trials reported race, of which whites constituted 89% (range 67 - 98) of the enrolled population. Randomization of Blacks (median 2.3%, range 0 - 3.9) and Hispanics (median 10.3%, range 0.3 - 17) was low. Thirty-two of 39 (82%) of trials reported acute coronary syndrome as a serious adverse event. Other adverse cardiovascular endpoints were less frequently reported (Figure 1). Conclusion: There is significant underreporting of minority populations in clinical trials of biologics in patients with psoriasis. When reported, there is low representation of minority groups. Furthermore, adverse event reporting of CV disease is poor and inconsistent. These data represent a missed opportunity to study important safety signals in this high CV risk patient population across a diverse generalizable population.
Phase I Trial Combining Chemokine-Targeting with Loco-Regional Chemoimmunotherapy for Recurrent, Platinum-Sensitive Ovarian Cancer Shows Induction of CXCR3 Ligands and Markers of Type 1 Immunity
Authors: Brian Orr, Haider Mahdi, Yusi Fang, Mary Strange, Ibrahim Uygun, Mainpal Rana, Lixin Zhang, Adria Suarez Mora, Alexandra Pusateri, Esther Elishaev, Chaeryon Kang, George Tseng, William Gooding, Robert P. Edwards, Pawel Kalinski, Anda M. Vlad
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Increased prevalence of cytotoxic T lymphocytes (CTL) in the tumor microenvironment (TME) predicts positive outcomes in patients with epithelial ovarian cancer (EOC), whereas the regulatory T cells (Treg) predict poor outcomes. Guided by the synergistic activity of TLR3 ligands, IFNα, and COX-2 blockers in selectively enhancing CTL-attractants but suppressing Treg-attractants, we tested a novel intraperitoneal chemoimmunotherapy combination (CITC), to assess its tolerability and TME-modulatory impact in patients with recurrent EOC. Patients and Methods: Twelve patients were enrolled in phase I portion of the trial NCT02432378, and treated with intraperitoneal cisplatin, intraperitoneal rintatolimod (dsRNA, TLR3 ligand), and oral celecoxib (COX-2 blocker). Patients in cohorts 2, 3, and 4 also received intraperitoneal IFNα at 2, 6, and 18 million units (MU), respectively. Primary objectives were to evaluate safety, identify phase 2 recommended dose (P2RD), and characterize changes in the immune TME. Peritoneal resident cells and intraperitoneal wash fluid were profiled via NanoString and Meso Scale Discovery (MSD) multiplex assay, respectively. Results: The P2RD of IFNα was 6 MU. Median progression-free survival and overall survival were 8.4 and 30 months, respectively. Longitudinal sampling of the peritoneal cavity via intraperitoneal washes demonstrated local upregulation of IFN-stimulated genes (ISG), including CTL-attracting chemokines (CXCL-9, -10, -11), MHC I/II, perforin, and granzymes. These changes were present 2 days after chemokine modulation and subsided within 1 week. Conclusions: The chemokine-modulating intraperitoneal-CITC is safe, tolerable, and associated with ISG changes that favor CTL chemoattraction and function. This combination (plus DC vaccine) will be tested in a phase II trial. See related commentary by Aranda et al., p. 1993
Abstract P104: High Lead Levels Associated With Elevated Blood Pressure In Haiti: A Warning Sign
Authors: Lily D Yan, Vanessa Rouzier, Jean Lookens Pierre, Myung Hee Lee, Paul Muntner, Patrick J Parsons, Alexandra Apollon, Rodolphe Malebranche, Gerard D Pierre, Evens Emmanuel, Denis Nash, Justin Kingery, Kathleen F Walsh, Caleigh Smith, Miranda Metz, Olga Tymejczyk, Marie Deschamps, Jean William Pape, Daniel FITZGERALD, Margaret Mcnairy
Journal: Circulation (2022)

Introduction: Cardiovascular disease is the leading cause of death in Haiti and many low-middle income countries. Environmental lead exposure is associated with higher blood pressure (BP) and cardiovascular disease mortality in high income countries but has not been systematically evaluated in lower income countries where 6.5 billion people reside. Hypothesis: We hypothesized higher lead levels would be associated with higher BP in Haiti. Methods: Blood lead levels (BLLs) were measured among 2,257 participants ≥18 years enrolled in a population-based longitudinal cohort study in Port-au-Prince (Haiti Cardiovascular Disease Cohort Study). BLL screening was conducted using LeadCare II (detection limit ≥3.3 μg/dL). BLLs below detection were imputed. Associations between BLLs (quartiles) and systolic BP (SBP) and diastolic BP (DBP) were assessed, adjusting for age, sex, obesity, smoking, physical activity, and income. BLLs were also categorized as ≥5 versus &lt;5 μg/dL. Results: The median age was 40 years; 62.6% were female. The geometric mean BLL was 4.60 μg/dL, 67.3% had detectable BLLs &gt;3.3 μg/dL, and 40.9% had elevated BLLs ≥5 μg/dL. BLLs in quartile four (≥6.5 μg/dL) in both unadjusted and adjusted analyses were associated with higher SBP (adjusted 3.02 mmHg; 95%CI 0.80, 5.25) and DBP (adjusted 2.19 mmHg; 95%CI 0.70, 3.67). BLL ≥5 μg/dL were associated with a higher SBP (2.21 mmHg; 95%CI 0.15, 4.26) and DBP (1.50 mmHg; 95%CI 0.20, 2.81) in unadjusted analysis. After adjustment there was no difference in SBP (1.41; 95%CI -0.25, 3.09) and 1.15 mmHg (95%CI 0.01, 2.30) higher DBP. Conclusions: Widespread environmental lead exposure is evident in urban Haiti, with higher BLLs associated with higher SBP and DBP. Lead is a modifiable pollutant in low-income countries that warrants urgent public health remediation.
Target-based anticancer indole derivatives and insight into structure‒activity relationship: A mechanistic review update (2018–2021)
Authors: Ashima Dhiman, Rupam Sharma, Rajesh K. Singh
Journal: Acta Pharmaceutica Sinica B (2022)

Cancer, which is the uncontrolled growth of cells, is the second leading cause of death after heart disease. Targeting drugs, especially to specific genes and proteins involved in growth and survival of cancer cells, is the prime need of research world-wide. Indole moiety, which is a combination of aromatic-heterocyclic compounds, is a constructive scaffold for the development of novel leads. Owing to its bioavailability, high unique chemical properties and significant pharmacological behaviours, indole is considered as the most inquisitive scaffold for anticancer drug research. This is illustrated by the fact that the U.S. Food and Drug Administration (FDA) has recently approved several indole-based anticancer agents such as panobinostat, alectinib, sunitinib, osimertinib, anlotinib and nintedanib for clinical use. Furthermore, hundreds of studies on the synthesis and activity of the indole ring have been published in the last three years. Taking into account the facts stated above, we have presented the most recent advances in medicinal chemistry of indole derivatives, encompassing hot articles published between 2018 and 2021 in anticancer drug research. The recent advances made towards the synthesis of promising indole-based anticancer compounds that may act via various targets such as topoisomerase, tubulin, apoptosis, aromatase, kinases, etc., have been discussed. This review also summarizes some of the recent efficient green chemical synthesis for indole rings using various catalysts for the period during 2018–2021. The review also covers the synthesis, structure‒activity relationship, and mechanism by which these leads have demonstrated improved and promising anticancer activity. Indole molecules under clinical and preclinical stages are classified into groups based on their cancer targets and presented in tabular form, along with their mechanism of action. The goal of this review article is to point the way for medicinal chemists to design and develop effective indole-based anticancer agents.
The economic and public health impact of intellectual property licensing of medicines for low-income and middle-income countries: a modelling study
Authors: Sébastien Morin, Hannah Barron Moak, Oliver Bubb-Humfryes, Christian von Drehle, Jeffrey V Lazarus, Esteban Burrone
Journal: The Lancet Public Health (2021)

Non-exclusive voluntary licensing that is access-oriented has been suggested as an option to increase access to medicines to address the COVID-19 pandemic. To date, there has been little research on the effect of licensing, mainly focused on economic and supply chain considerations, and not on the benefits in terms of health outcomes. We aimed to study the economic and health effect of voluntary licensing for medicines for HIV and hepatitis C virus (HCV) in low-income and middle-income countries (LMICs).
Abstract 036: Influence Of Physical Activity Measurement On The Association Between Life’S Simple 7 And Cardiovascular Disease In Older Women
Authors: Eric T Hyde, Steve Nguyen, Michael J Lamonte, Lesley Tinker, Andrea Z Lacroix, John Bellettiere
Journal: Circulation (2022)

Introduction: The AHA’s Life’s Simple 7 (LS7) includes physical activity (PA) as one of the metrics for assessing cardiovascular health. Using self-reported PA can misclassify those who meet the PA component of the LS7. Using accelerometer-measured PA may improve the utility of the LS7. Our study compares associations of LS7 and incident cardiovascular disease (CVD) associations using both self-reported and accelerometer-measured PA. Methods: Women’s Health Initiative (WHI) participants in the Objective Physical Activity and Cardiovascular Health Study (n=4075; mean±SD age = 79±7) with no history of CVD completed the WHI PA questionnaire (PAQ) and the Community Healthy Activities Model Program for Seniors (CHAMPS) PAQ prior to wearing a hip-worn accelerometer for up to 7 consecutive days. LS7 components (PA, diet, body mass index, smoking, blood pressure, fasting serum total cholesterol and glucose) were scored on a scale of 0-2 using AHA guidelines, resulting in an LS7 summary score ranging from 0-14 with higher scores reflecting more favorable status. Four LS7 summary scores were created using different PA measures: the WHI PAQ, the CHAMPS PAQ, and two accelerometer measures (MVPA min/week and mean steps/day). LS7 scores were analyzed using quartiles (LS7 scores 1-7, 8, 9, 10-14) and hazard ratios (HR) for incident physician-adjudicated CVD were estimated. Results: There were 500 incident CVD events (see Table) over an average 6 years of follow-up. Multivariable HRs (95% CI) comparing women with high (10-14) vs. low (1-7) LS7 scores were: WHI PAQ= 0.81 (0.60-1.09), CHAMPS PAQ= 0.80 (0.61-1.05), accelerometer (MVPA)= 0.61 (0.47-0.79), accelerometer (steps)= 0.65 (0.45-0.94; see Table). Conclusions: PA is just one component of the LS7, yet the LS7-incident CVD associations vary considerably by PA measurement. Accelerometer-measured PA, such as daily steps, improves the accuracy of the LS7 PA component used to classify cardiovascular health and may be feasible for practitioners to implement.
Sex Differences in Risk of Severe Adverse Events in Patients Receiving Immunotherapy, Targeted Therapy, or Chemotherapy in Cancer Clinical Trials
Authors: Joseph M. Unger, Riha Vaidya, Kathy S. Albain, Michael LeBlanc, Lori M. Minasian, Carolyn C. Gotay, N. Lynn Henry, Michael J. Fisch, Shing M. Lee, Charles D. Blanke, Dawn L. Hershman
Journal: Journal of Clinical Oncology (2022)

PURPOSE Women have more adverse events (AEs) from chemotherapy than men, but few studies have investigated sex differences in immune or targeted therapies. We examined AEs by sex across different treatment domains. METHODS We analyzed treatment-related AEs by sex in SWOG phase II and III clinical trials conducted between 1980 and 2019, excluding sex-specific cancers. AE codes and grade were categorized using the Common Terminology Criteria for Adverse Events. Symptomatic AEs were defined as those aligned with the National Cancer Institute's Patient-Reported Outcome–Common Terminology Criteria for Adverse Events; laboratory-based or observable/measurable AEs were designated as objective (hematologic v nonhematologic). Multivariable logistic regression was used, adjusting for age, race, and disease prognosis. Thirteen symptomatic and 14 objective AE categories were examined. RESULTS In total, N = 23,296 patients (women, 8,838 [37.9%]; men, 14,458 [62.1%]) from 202 trials experiencing 274,688 AEs were analyzed; 17,417 received chemotherapy, 2,319 received immunotherapy, and 3,560 received targeted therapy. Overall, 64.6% (n = 15,051) experienced one or more severe (grade ≥ 3) AEs. Women had a 34% increased risk of severe AEs compared with men (odds ratio [OR] = 1.34; 95% CI, 1.27 to 1.42; P &lt; .001), including a 49% increased risk among those receiving immunotherapy (OR = 1.49; 95% CI, 1.24 to 1.78; P &lt; .001). Women experienced an increased risk of severe symptomatic AEs among all treatments, especially immunotherapy (OR = 1.66; 95% CI, 1.37 to 2.01; P &lt; .001). Women receiving chemotherapy or immunotherapy experienced increased severe hematologic AE. No statistically significant sex differences in risk of nonhematologic AEs were found. CONCLUSION The greater severity of both symptomatic AEs and hematologic AEs in women across multiple treatment modalities indicates that broad-based sex differences exist. This could be due to differences in AE reported, pharmacogenomics of drug metabolism/disposition, total dose received, and/or adherence to therapy. Particularly large sex differences were observed for patients receiving immunotherapy, suggesting that studying AEs from these agents is a priority.
Protection against the Omicron Variant from Previous SARS-CoV-2 Infection
Authors: Heba N Altarawneh, Hiam Chemaitelly, Mohammad R Hasan, Houssein H Ayoub, Suelen Qassim, Sawsan AlMukdad, Peter Coyle, Hadi M Yassine, Hebah A Al-Khatib, Fatiha M Benslimane, Zaina Al-Kanaani, Einas Al-Kuwari, Andrew Jeremijenko, Anvar H Kaleeckal, Ali N Latif, Riyazuddin M Shaik, Hanan F Abdul-Rahim, Gheyath K Nasrallah, Mohamed G Al-Kuwari, Adeel A Butt, Hamad E Al-Romaihi, Mohamed H Al-Thani, Abdullatif Al-Khal, Roberto Bertollini, Patrick Tang, Laith J Abu-Raddad
Journal: New England Journal of Medicine (2022)

InfectionTo the Editor: Natural infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) elicits strong protection against reinfection with the B.1.1.7 (alpha), 1,2 B.1.351(beta), 1 and B.1.617.2 (delta) 3 variants.However, the B.1.1.529(omicron) variant harbors multiple mutations that can mediate immune evasion.We estimated the effectiveness of previous infection in preventing symptomatic new cases caused by omicron and other SARS-CoV-2 variants in Qatar.In this study, we extracted data regarding coronavirus disease 2019 (Covid-19) laboratory testing, vaccination, clinical infection data, and related demographic details from the national SARS-CoV-2 databases, which include all results of polymerase-chain-reaction (PCR) testing, vaccinations, and hospitalizations and deaths for Covid-19 in Qatar since the start of the pandemic.The effectiveness of previous SARS-CoV-2 infection in preventing reinfection was defined as the proportional reduction in susceptibility to infection among persons who had recovered from infection as compared with those who had not been infected. 4Previous SARS-CoV-2 infection was defined as a positive result on PCR assay at least 90 days before a new positive PCR finding. 4We used a test-negative, case-control study design to assess the effectiveness of previ-Downloaded from nejm.org
Public availability of HIV-1 drug resistance sequence and treatment data: a systematic review
Authors: Soo-Yon Rhee, Seble G Kassaye, Michael R Jordan, Vinie Kouamou, David Katzenstein, Robert W Shafer
Journal: The Lancet Microbe (2022)

HIV-1 pol sequences from antiretroviral therapy (ART)-naive and ART-experienced people living with HIV-1 are fundamental to understanding the genetic correlates and epidemiology of HIV-1 drug resistance (HIVDR). To assess the public availability of HIV-1 pol sequences and ART histories of the individuals from whom sequenced viruses were obtained, we performed a systematic review of PubMed and GenBank for HIVDR studies published between 2010 and 2019 that reported HIV-1 pol sequences. 934 studies met inclusion criteria, including 461 studies of ART-naive adults, 407 of ART-experienced adults, and 66 of ART-naive and ART-experienced children. Sequences were available for 317 (68·8%) studies of ART-naive individuals, 190 (46·7%) of ART-experienced individuals, and 45 (68·2%) of children. Among ART-experienced individuals, sequences plus linked ART histories were available for 82 (20·1%) studies. Sequences were available for 21 (29·2%) of 72 clinical trials. Among journals publishing more than ten studies, the proportion with available sequences ranged from 8·3% to 86·9%. Strengthened implementation of data sharing policies is required to increase the number of studies with available HIVDR data to support the enterprise of global ART in the face of emerging HIVDR.
Pimavanserin for negative symptoms of schizophrenia: results from the ADVANCE phase 2 randomised, placebo-controlled trial in North America and Europe
Authors: Dragana Bugarski-Kirola, Celso Arango, Maurizio Fava, Henry Nasrallah, I-Yuan Liu, Brandon Abbs, Srdjan Stankovic
Journal: The Lancet Psychiatry (2021)
The clinical implication of hepatic venous territory mapping in living donor liver transplantation using right liver graft
Authors: Young Ju Oh, Jinsoo Rhu, Kyeong Deok Kim, Jaehun Yang, Ji Eun Kwon, Eun Sung Jeong, Gyu-Seong Choi, Jong Man Kim, Woo Kyoung Jeong, Jae-Won Joh
Journal: International Journal of Surgery (2022)
Abstract P096: Developing A Lifestyle-Based Cardiovascular Health Tool For Teens
Authors: Elizabeth Zeichner, Kolbi Bradley, Sierra Patterson, Holly C Gooding
Journal: Circulation (2022)

Purpose: Previous studies have shown that young women have low awareness of heart disease, despite cardiovascular (CV) disease being the number one cause of death in women. While CV risk assessment tools exist for adults, there are no similar tools specifically for adolescents. This project focuses on developing a lifestyle-based CV health prediction tool and behavior intervention for young women. Methods: We report a qualitative case study of four hour-long semi-structured interviews with young women aged 13-21 years participating in a larger study to develop the new CV health tool. Patients were recruited from a primary care practice in Atlanta, GA. Participants completed the Healthy Heart Score survey, an existing web-based CV prediction tool developed for adults, while providing feedback on how to adapt the tool for young women. Topics included conditions to engage with the tool (e.g. at school or doctor’s office), app architecture (including layout, word choice, and use of visuals), and suggestions for improvement of the tool. We used qualitative coding and thematic analyses to synthesize data. Results: Prior to engaging with the Heart Healthy Score tool, participants initially demonstrated minimal knowledge of heart attacks/strokes (“I don’t know about preventing” [heart attacks and strokes]) and of their own risk (“I’ve never associated… young women with [heart disease]”). As participants used the tool, their knowledge of heart healthy choices and awareness of their own choices increased, cueing action (“I definitely need to get my health… together now before it’s too late”). Throughout the survey, teens had varied emotional reactions, from shame/embarrassment about health (“I… got upset because… I shouldn’t be eating this much”), to surprise/shock (“I thought I ate way more fruits and vegetables''), to enthusiasm to engage with app in the future (“I might like to use this tool because it’ll … help me [have] a better way of understanding … what to eat, what is healthy”). Participant recommendations to improve the tool for future use with teens focused on the importance of using examples and visual representations (“All the examples … really help me … figure out … how much I’m eating”, “I don’t really have a good idea of… what ounces really look like… a little visual would help [figure] that out”), and the importance of goal-setting and motivational language to incentivize teens to engage with the tool (“Instead of just telling you what you need to do to become better, they give you… an actual goal”). Conclusions: Through this case study, young women demonstrate a knowledge gap about heart disease risk and healthy choices. Adapting a CV health assessment tool for teens, with added examples, visuals, and motivational language, will allow teens to reflect on their own lifestyle choices, increase awareness of their risk for future heart disease, and ultimately serve as an impetus for behavior change.
Reprogramming dysfunctional CD8+ T cells to promote properties associated with natural HIV control
Authors: Federico Perdomo-Celis, Caroline Passaes, Valérie Monceaux, Stevenn Volant, Faroudy Boufassa, Pierre de Truchis, Morgane Marcou, Katia Bourdic, Laurence Weiss, Corinne Jung, Christine Bourgeois, Cécile Goujard, Laurence Meyer, Michaela Müller-Trutwin, Olivier Lambotte, Asier Sáez-Cirión
Journal: Journal of Clinical Investigation (2022)

Virus-specific CD8+ T cells play a central role in HIV-1 natural controllers to maintain suppressed viremia in the absence of antiretroviral therapy. These cells display a memory program that confers them stemness properties, high survival, polyfunctionality, proliferative capacity, metabolic plasticity, and antiviral potential. The development and maintenance of such qualities by memory CD8+ T cells appear crucial to achieving natural HIV-1 control. Here, we show that targeting the signaling pathways Wnt/transcription factor T cell factor 1 (Wnt/TCF-1) and mTORC through GSK3 inhibition to reprogram HIV-specific CD8+ T cells from noncontrollers promoted functional capacities associated with natural control of infection. Features of such reprogrammed cells included enrichment in TCF-1+ less-differentiated subsets, a superior response to antigen, enhanced survival, polyfunctionality, metabolic plasticity, less mTORC1 dependency, an improved response to γ-chain cytokines, and a stronger HIV-suppressive capacity. Thus, such CD8+ T cell reprogramming, combined with other available immunomodulators, might represent a promising strategy for adoptive cell therapy in the search for an HIV-1 cure.
95P Role of postoperative follow-up with 18F-FDG PET/CT in asymptomatic NSCLC patients: A retrospective single institution study
Authors: A. Kaumanns, D. König, A. Hojski, M. Cattaneo, A-F. Chirindel, M. Tamm, D. Lardinois, S.I. Rothschild
Journal: Annals of Oncology (2022)