tbuckley/cabot-search huggingface dataset:
Dolutegravir as First- or Second-Line Treatment for HIV-1 Infection in Children
Authors: Anna Turkova, Ellen White, Hilda A. Mujuru, Adeodata R. Kekitiinwa, Cissy M. Kityo, Avy Violari, Abbas Lugemwa, Tim R. Cressey, Philippa Musoke, Ebrahim Variava, Mark F. Cotton, Moherndran Archary, Thanyawee Puthanakit, Osee Behuhuma, Robin Kobbe, Steven B. Welch, Mutsa Bwakura-Dangarembizi, Pauline Amuge, Elizabeth Kaudha, Linda Barlow-Mosha, Shafic Makumbi, Nastassja Ramsagar, Chaiwat Ngampiyaskul, Godfrey Musoro, Lorna Atwine, Afaaf Liberty, Victor Musiime, Dickson Bbuye, Grace M. Ahimbisibwe, Suwalai Chalermpantmetagul, Shabinah Ali, Tatiana Sarfati, Ben Wynne, Clare Shakeshaft, Angela Colbers, Nigel Klein, Sarah Bernays, Yacine Saïdi, Alexandra Coelho, Tiziana Grossele, Alexandra Compagnucci, Carlo Giaquinto, Pablo Rojo, Deborah Ford, Diana M. Gibb
Journal: New England Journal of Medicine (2021)

Children with human immunodeficiency virus type 1 (HIV-1) infection have limited options for effective antiretroviral treatment (ART).We conducted an open-label, randomized, noninferiority trial comparing three-drug ART based on the HIV integrase inhibitor dolutegravir with standard care (non-dolutegravir-based ART) in children and adolescents starting first- or second-line ART. The primary end point was the proportion of participants with virologic or clinical treatment failure by 96 weeks, as estimated by the Kaplan-Meier method. Safety was assessed.From September 2016 through June 2018, a total of 707 children and adolescents who weighed at least 14 kg were randomly assigned to receive dolutegravir-based ART (350 participants) or standard care (357). The median age was 12.2 years (range, 2.9 to 18.0), the median weight was 30.7 kg (range, 14.0 to 85.0), and 49% of the participants were girls. By design, 311 participants (44%) started first-line ART (with 92% of those in the standard-care group receiving efavirenz-based ART), and 396 (56%) started second-line ART (with 98% of those in the standard-care group receiving boosted protease inhibitor-based ART). The median follow-up was 142 weeks. By 96 weeks, 47 participants in the dolutegravir group and 75 in the standard-care group had treatment failure (estimated probability, 0.14 vs. 0.22; difference, -0.08; 95% confidence interval, -0.14 to -0.03; P = 0.004). Treatment effects were similar with first- and second-line therapies (P = 0.16 for heterogeneity). A total of 35 participants in the dolutegravir group and 40 in the standard-care group had at least one serious adverse event (P = 0.53), and 73 and 86, respectively, had at least one adverse event of grade 3 or higher (P = 0.24). At least one ART-modifying adverse event occurred in 5 participants in the dolutegravir group and in 17 in the standard-care group (P = 0.01).In this trial involving children and adolescents with HIV-1 infection who were starting first- or second-line treatment, dolutegravir-based ART was superior to standard care. (Funded by ViiV Healthcare; ODYSSEY ClinicalTrials.gov number, NCT02259127; EUDRACT number, 2014-002632-14; and ISRCTN number, ISRCTN91737921.).
The effect of baseline cognition and delirium on long-term cognitive impairment and mortality: a prospective population-based study
Authors: Alex Tsui, Samuel D Searle, Helen Bowden, Katrin Hoffmann, Joanne Hornby, Arley Goslett, Maryse Weston-Clarke, Lee Hamill Howes, Rebecca Street, Rachel Perera, Kayvon Taee, Christoph Kustermann, Petronella Chitalu, Benjamin Razavi, Francesco Magni, Devajit Das, Sung Kim, Nish Chaturvedi, Elizabeth L Sampson, Kenneth Rockwood, Colm Cunningham, E Wesley Ely, Sarah J Richardson, Carol Brayne, Graciela Muniz Terrera, Zoë Tieges, Alasdair MacLullich, Daniel Davis
Journal: The Lancet Healthy Longevity (2022)

There is an unmet public health need to understand better the relationship between baseline cognitive function, the occurrence and severity of delirium, and subsequent cognitive decline. Our aim was to quantify the relationship between baseline cognition and delirium and follow-up cognitive impairment.
Abstract 11389: Prevalence and Trends of Ideal Cardiovascular Health in 18 Countries: A Pooled Analysis of 68 Nationally Representative Surveys
Authors: Alejandro Rana Custodio, Bin Zhou, Goodarz Danaei
Journal: Circulation (2021)

Introduction: Increasing the prevalence of the ideal cardiovascular health (CVH) phenotype over the coming decades would likely result in dramatic improvements in healthy longevity and reductions in healthcare costs. Therefore, it is of paramount importance to understand the global prevalence and trends of the ideal CVH behaviors and factors for monitoring progress and providing evidence to support policy efforts. Hypothesis: We aim to describe the prevalence of CVH for the AHA defined metrics of tobacco use, body mass index, total cholesterol, blood pressure and glucose levels, and estimate its trends worldwide. Methods: We used data from people aged &gt; 20 years who participated in 68 national health examination surveys from 1983 to 2017 in 18 countries: Australia, Czech Republic, Denmark, Germany, Greece, Ireland, Italy, Malaysia, Mexico, Poland, Seychelles, Slovakia, South Korea, Spain, Sweden, Turkey, the UK, and the USA. We calculated age-standardized prevalence of ideal CVH (no current smoking, BMI &lt; 25 kg/m2, untreated TC &lt; 200 mg/dL, untreated BP &lt; 120 / &lt; 80 mmHg, and absence of diabetes mellitus). Additionally, we examined the trends of the ideal CVH for countries that had at least two individual-level national surveys in two different decades (2000-2009 vs 2010-2019). Results: With the exception of Australia and South Korea, age-standardized prevalence of idea CVH was lower than 10% in women and lower than 5% in men across all countries. Older individuals had a lower prevalence of Ideal CVH than younger ones. Those over 65 years of age had a prevalence almost equal to zero. In ages 35-64 years, ideal CVH prevalence ranged from 3.6% to 25.4% among women, and from 0.6% to 7.1% among men. For the 10 countries where trends were estimated by age-sex groups, ideal CVH prevalence did not change or declined in the selected middle-income countries and increased in the selected high-income countries except for South Korea, where it plateaued for men and declined for women. Conclusions: Prevalence of ideal CVH worldwide is low and is declining for adults in middle-income countries in recent decades.
Clinical Trials Assessing Hypomethylating Agents Combined with Other Therapies: Causes for Failure and Potential Solutions
Authors: Phaedon D. Zavras, Aditi Shastri, Mendel Goldfinger, Amit K. Verma, Yogen Saunthararajah
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Azacitidine and decitabine are hypomethylating agents (HMA), that is, both inhibit and deplete DNA methyltransferase 1 (DNMT1). HMAs are standard single-agent therapies for myelodysplastic syndromes and acute myelogenous leukemias. Several attempts to improve outcomes by combining HMAs with investigational agents, excepting with the BCL2-inhibitor venetoclax, have failed in randomized clinical trial (RCT) evaluations. We extract lessons from decades of clinical trials to thereby inform future work. Experimental Design: Serial single-agent clinical trials were analyzed for mechanism and pathway properties of HMAs underpinning their success, and for rules for dose and schedule selection. RCTs were studied for principles, dos and don'ts for productive combination therapy. Results: Single-agent HMA trial results encourage dose and schedule selection to increase S-phase–dependent DNMT1 targeting, and discourage doses that cause indiscriminate antimetabolite effects/cytotoxicity, because these attrit myelopoiesis reserves needed for clinical response. Treatment-related myelosuppression should prompt dose/frequency reductions of less active investigational agents rather than more active HMA. Administering cytostatic agents concurrently with HMA can antagonize S-phase–dependent DNMT1 targeting. Supportive care that enables on-time administration of S-phase (exposure-time)–dependent HMA could be useful. Agents that manipulate pyrimidine metabolism to increase HMA pro-drug processing into DNMT1-depleting nucleotide, and/or inhibit other epigenetic enzymes implicated in oncogenic silencing of lineage differentiation, could be productive, but doses and schedules should adhere to therapeutic index/molecular–targeted principles already learned. Conclusions: More than 40 years of clinical trial history indicates mechanism, pathway, and therapeutic index properties of HMAs that underpin their almost exclusive success and teaches lessons for selection and design of combinations aiming to build on this treatment foundation.
In COVID-19, escalated- vs. prophylactic-dose anticoagulation does not reduce mortality and increases major bleeding
Authors: Dipayan Chaudhuri, Bram Rochwerg
Journal: Annals of Internal Medicine (2022)

Ortega-Paz L, Galli M, Capodanno D, et al. Safety and efficacy of different prophylactic anticoagulation dosing regimens in critically and non-critically ill patients with COVID-19: a systematic review and meta-analysis of randomized controlled trials. Eur Heart J Cardiovasc Pharmacother. 2021. [Epub ahead of print.] 34519777.
Single-cell RNA sequencing reveals induction of distinct trained-immunity programs in human monocytes
Authors: Bowen Zhang, Simone J.C.F.M Moorlag, Jorge Dominguez-Andres, Özlem Bulut, Gizem Kilic, Zhaoli Liu, Reinout van Crevel, Cheng-Jian Xu, Leo A.B. Joosten, Mihai G. Netea, Yang Li
Journal: Journal of Clinical Investigation (2022)

Trained immunity refers to the long-lasting memory traits of innate immunity. Recent studies have shown that trained immunity is orchestrated by sustained changes in epigenetic marks and metabolic pathways, leading to an altered transcriptional response to a second challenge. However, the potential heterogeneity of trained-immunity induction in innate immune cells has not been explored. In this study, we demonstrate cellular transcriptional programs in response to 4 different inducers of trained immunity in monocyte populations at single-cell resolution. Specifically, we identified 3 monocyte subpopulations upon the induction of trained immunity, and replicated these findings in an in vivo study. In addition, we found gene signatures consistent with these functional programs in patients with ulcerative colitis, sepsis, and COVID-19, suggesting the impact of trained-immunity programs in immune-mediated diseases.
A phase 1, first-in-human (FIH) study of adenovirally transduced autologous macrophages engineered to contain an anti-HER2 chimeric antigen receptor (CAR) in subjects with HER2 overexpressing solid tumors.
Authors: Kim Anna Reiss, Yuan Yuan, Debora Barton, Daniel Cushing, Amy Ronczka, Michael Klichinsky, Elizabeth Claire Dees
Journal: Journal of Clinical Oncology (2022)

TPS668 Background: Adoptive T cell therapies have led to remarkable advances among patients with hematologic malignancies, but not in those with solid tumors. Macrophages are actively recruited into, and are abundantly present in the solid tumor microenvironment (sTME). Tumor- associated macrophages typically display immunosuppressive behavior, but when engineered to be proinflammatory, may be an ideal vector to administer adoptive cellular therapy in solid tumors. Furthermore, insertion of a CAR on the macrophages allow them to selectively recognize and phagocytose antigen overexpressing cancer cells. CAR macrophages reprogram the sTME and present neoantigens to T cells, leading to epitope spreading and immune memory. Human Epidermal Growth Factor Receptor 2 (HER2) overexpression promotes tumorigenesis in many cancers (Table). CT-0508 is a cell product comprised of autologous monocyte-derived pro-inflammatory macrophages expressing an anti-HER2 CAR. Pre-clinical studies have shown that CT-0508 induced targeted cancer cell phagocytosis while sparing normal cells, decreased tumor burden and prolonged survival in relevant models. CT-0508 cells were safe and effective in a semi-immunocompetent mouse model of human HER2 overexpressing ovarian cancer. Methods: This is a FIH Phase 1 study to evaluate safety, tolerability, cell manufacturing feasibility, trafficking and preliminary evidence of efficacy of investigational product CT-0508 in 18 subjects with locally advanced (unresectable) or metastatic solid tumors overexpressing HER2, who have failed available therapies, including anti-HER2 therapies when indicated. Filgrastim is being used to mobilize autologous hematopoietic progenitor cells for monocyte collection by apheresis. The CT-0508 CAR macrophage product is manufactured, prepared and cryopreserved from mobilized peripheral blood monocytes. Group 1 subjects receive CT-0508 infusion split over D1, 3 and 5. Dose limiting toxicities will be observed and addressed by a Safety Review Committee. Group 2 subjects will receive the full CT-0508 infusion on D1. Pre and post treatment biopsies and blood samples will be collected to investigate correlates of safety (immunogenicity), trafficking (PCR, RNA scope), CT-0508 persistence in blood and in the tumor, target antigen engagement, TME modulation (single cell RNA sequencing), immune response (TCR sequencing) and others. Clinical trial information: NCT04660929. [Table: see text]
8MO The efficacy and safety of TQ-B3101 monotherapy in the first-line treatment in patients with ROS1-positive non-small cell lung cancer
Authors: S. Lu, H. Pan, L. Wu, Y. Yao, J. He, Y. Wang, X. Wang, X. Wang, X. Cai, Y. Yu, Z. Ma, X. Min, Z. Yang, L. Cao, H. Yang, Y. Shu, W. Zhuang, S. Cang, J. Fang, K. Li
Journal: Annals of Oncology (2022)
Trends and Demographic Disparities in Diabetes Hospital Admissions: Analyses of Serial Cross-Sectional National and State Data, 2008–2017
Authors: Sara D. Turbow, Tegveer S. Uppal, J. Sonya Haw, Puneet Chehal, Gail Fernandes, Megha Shah, Swapnil Rajpathak, Mohammed K. Ali, K.M. Venkat Narayan
Journal: Diabetes Care (2022)

OBJECTIVE To analyze national and state-specific trends in diabetes-related hospital admissions and determine whether disparities in rates of admission exist between demographic groups and geographically dispersed states. RESEARCH DESIGN AND METHODS We conducted serial cross-sectional analyses of the National Inpatient Sample (2008, 2011, 2014, and 2016) and State Inpatient Databases for Arizona, Florida, Kentucky, Iowa, Maryland, Nebraska, New Jersey, New York, North Carolina, Utah, and Vermont for 2008, 2011, 2014, and 2016/2017 among adult patients with type 1 and type 2 diabetes–related ICD codes (ICD-9 [250.XX] or ICD-10 [E10.XXX, E11.XXX, and E13.XXX]. We measured hospitalization rates for people with diabetes (all-cause hospitalizations) and for admissions with a primary diagnosis of diabetes or diabetes-related complications (diabetes-specific hospitalizations) per 10,000 people per year. RESULTS Nationally, all-cause and diabetes-specific hospitalizations declined by 3.1% (95% CI −5.5, −0.7) and 19.1% (95% CI −21.6, −16.6), respectively, over 2008 to 2016. The analysis of individual states showed that diabetes-specific admissions in individuals ≥65 years old declined during this time (16.3–48.8% decrease) but increased among patients 18–29 years old (10.5–81.5% increase) and that rural diabetes-specific admissions decreased in just over half of the included states (15.2–69.2% decrease). There were no differences in changes in admission rates among different racial/ethnic groups. CONCLUSIONS Overall, rates of diabetes-related hospitalizations decreased over 2008 to 2016/2017, but there were large state-level differences across subgroups of patients. The rise in diabetes hospitalizations among young adults is a cause for concern. These state- and subpopulation-level differences highlight the need for state-level policies and interventions to address disparities in diabetes health care use.
Experiences of staff providing specialist palliative care during COVID-19: a multiple qualitative case study
Authors: Andy Bradshaw, Lesley Dunleavy, Ian Garner, Nancy Preston, Sabrina Bajwah, Rachel Cripps, Lorna K Fraser, Matthew Maddocks, Mevhibe Hocaoglu, Fliss EM Murtagh, Adejoke O Oluyase, Katherine E Sleeman, Irene J Higginson, Catherine Walshe
Journal: Journal of the Royal Society of Medicine (2022)

Summary Objective To explore the experiences of, and impact on, staff working in palliative care during the COVID-19 pandemic. Design Qualitative multiple case study using semi-structured interviews between November 2020 and April 2021 as part of the CovPall study. Data were analysed using thematic framework analysis. Setting Organisations providing specialist palliative services in any setting. Participants Staff working in specialist palliative care, purposefully sampled by the criteria of role, care setting and COVID-19 experience. Main outcome measures Experiences of working in palliative care during the COVID-19 pandemic. Results Five cases and 24 participants were recruited (n = 12 nurses, 4 clinical managers, 4 doctors, 2 senior managers, 1 healthcare assistant, 1 allied healthcare professional). Central themes demonstrate how infection control constraints prohibited and diluted participants’ ability to provide care that reflected their core values, resulting in experiences of moral distress. Despite organisational, team and individual support strategies, continually managing these constraints led to a ‘crescendo effect’ in which the impacts of moral distress accumulated over time, sometimes leading to burnout. Solidarity with colleagues and making a valued contribution provided ‘moral comfort’ for some. Conclusions This study provides a unique insight into why and how healthcare staff have experienced moral distress during the pandemic, and how organisations have responded. Despite their experience of dealing with death and dying, the mental health and well-being of palliative care staff was affected by the pandemic. Organisational, structural and policy changes are urgently required to mitigate and manage these impacts.
Abstract 060: Association Of Antecedent Statin Use With Outcomes Of People With Covid-19 Admitted At Northwestern Medicine Health System
Authors: Adovich Rivera, Omar Al-Heeti, Lucia Petito, Janna L Williams, Matthew J Feinstein, Babafemi Taiwo, Chad Achenbach
Journal: Circulation (2022)

Background: Several observational studies have found that antecedent statin use (i.e., use prior to getting admitted) was associated with lower mortality risk in hospitalized COVID-19 patients, but this is not a consistent finding. Differences maybe due to covariate imbalance, model misspecification, or selection bias. Objective: Estimate the association of antecedent statin use with adverse outcomes (in-hospital death, intubation, ICU admission) in patients admitted for COVID-19 in an academic health system in Chicago. Methods: We analyzed electronic health records from an academic health system in Chicago (Mar ‘20-Mar ‘21) comparing rates of adverse events (composite and per outcome) between antecedent users and non-users. Eligible individuals were ≥40 years old in Illinois, admitted for ≥24 hours, and tested positive for COVID-19 in the 30 days before to 7 days after admission. Antecedent use is defined as existence of statins prescription ≥30 days before admission. We used augmented inverse probability weighting (AIPW) with targeted maximum likelihood estimation to improve covariate balance and estimate the risk difference. Compared to standard methods, this approach allowed use of machine learning models and is doubly robust to misspecification. Results: Of 6267 admitted, 1337 (20%) were antecedent users. Users tend to be older, male, White, smoke, and have a comorbidity. Unadjusted analysis showed significantly higher rates of negative outcomes in non-users except in-hospital death. Analysis using AIPW improved covariate balance and showed that users had significantly lower rates of the composite outcome (RD: -3.9%, 95%CI: -6.0, -1.9) and ICU admissions (RD: -4.0, 95%CI: -7.0, -1.0). No differences in intubation and mortality rates were detected. Conclusion: Antecedent statin use is associated with lower risk of ICU admissions but not with intubation or in-hospital mortality. We were not able to confirm the mortality benefit detected by prior studies nor any differences in rates of intubations.
18F-SynVesT-1 PET in Focal Cortical Dysplasia Type II With Thickening Cortex
Authors: Yongxiang Tang, Jie Yu, Ming Zhou, Chen Chen, Shuo Hu
Journal: Clinical Nuclear Medicine (2022)

Abstract A case of 2-year-old girl with intractable seizures underwent 18 F-FDG PET and MRI for seizure focus localization. MRI demonstrated cortical thickening and blurring of the gray-white matter interface in the right postcentral gyrus with focal hypometabolism in 18 F-FDG PET. The patient subsequently was enrolled in clinical trial of 18 F-SynVesT-1 PET study in epilepsy; a more restricted area of reduced 18 F-SynVesT-1 uptake was noted in the thickened postcentral gyrus. The surgical limits of resection were defined based on ictal semiology, electroencephalography, and imagings. The patient is seizure-free after epilepsy surgery, with histopathology of focal cortical dysplasia type IIb.
Abstract 10147: Temporal Change and Its Determinants of Psychological Symptoms During Hospitalization in Patients with Heart Failure
Authors: Yasuhiro Hamatani, Moritake Iguchi, Masaharu Akao
Journal: Circulation (2021)

Introduction: Patients with heart failure (HF) could suffer from psychological symptoms such as anxiety and depression. However, these symptoms are rarely evaluated in hospitalized patients with HF, and may be underrecognized in daily practice. Methods: We prospectively evaluated consecutive hospitalized patients with HF at our institution between October 2019 and January 2021 using Hospital Anxiety and Depression Scale (HADS) on admission and at discharge. The HADS consists of 7 questions each for anxiety (HADS-A) and depression (HADS-D), both of which are graded by 0-3. Total scores were categorized as follows; 0-7 indicating no symptoms, 8-10 indicating mild, and 11-21 indicating significant anxiety or depression. Worsening symptoms during hospitalization was defined as that category of HADS at discharge was poorer than that on admission. Results: Of 224 (mean age: 77.5±12.4 years, median N-terminal pro B-type natriuretic peptide: 4527 pg/mL and mean left ventricular ejection fraction: 44%), 35 (16%) and 62 (28%) had significant symptoms of anxiety and depression, respectively. During hospitalization, HADS-A significantly decreased, whereas HADS-D did not improve ( Figure ). Worsening anxiety and depression during hospitalization occurred in 19 (10%) and 40 (21%), respectively. In multivariable logistic regression analysis, advanced age (odds ratio [OR]: 1.41, 95% confidence interval [CI]: 1.02-1.94; P=0.02), higher natriuretic peptide level (OR: 1.89, 95% CI: 1.23-2.90; P&lt;0.01) and acute on chronic HF (OR: 3.70, 95% CI: 1.25-11.00; P=0.01) were associated with worsening anxiety, and longer hospitalization length (OR: 2.17, 95% CI: 1.08-4.35; P=0.03) was associated with worsening depression. Conclusions: Anxiety and depression were common and depression persisted during hospitalization for HF. We found several risk factors for worsening these symptoms, providing the optimal candidate for psychological care in hospitalized patients with HF.