tbuckley/cabot-search huggingface dataset:
Abstract EP38: Women With Type 2 Diabetes Are 1.5 Times More Likely To Have Alzheimer’s Disease Than Men
Authors: Chunmiao Zhou, Dongshan Zhu
Journal: Circulation (2022)

Introduction: Mounting evidence has suggested that diabetes mellitus (DM) is a risk factor for the development of dementia. However, whether the association of DM with dementia differs by sex remains unclear. Hypothesis: Almost two-thirds of Alzheimer's patients are women. We hypothesized that there might be a sex difference in the association between DM and dementia, and the effect of DM on the risk of dementia might be greater in women than in men. Methods: We used cohort data from UK Biobank, a large population-based prospective cohort study that recruited 502 649 individuals ages 40-69, between 2006 and 2010. Type 1 diabetes (T1DM), type 2 diabetes (T2DM) and all-cause dementia (including Alzheimer's disease (AD) and vascular dementia (VD)) were ascertained from hospital medical records. Cox proportional hazards models were used to estimate the sex-specific hazard ratios (HRs) and 95% confidence intervals (CI), and women-to-men ratio of HRs (RHR) for the association between DM and incident dementia. Results: A total of 502 422 people (54.4% women) with no prevalent dementia at baseline were included. After 11 years (median) follow-up, 5652 participants (46.6% women) developed dementia. The crude incidence rates of all-cause dementia were 8.53 for women and 11.97 for men, per 10,000 person-years. Both T1DM and T2DM were associated with higher risk of all-cause dementia, AD and VD. After the analyses were stratified by sex, compared to people without DM, the HRs (95%CI) between T2DM and AD in women (HR: 3.06, 95% CI 2.48-3.79) were higher than the estimates in men (1.94, 1.62-2.33), with an RHR (95%CI) of 1.56 (1.20, 2.02) (Table 1). No sex difference was observed in association between T2DM and VD, or T1DM and dementia. Conclusions: There is a sex difference in the association between T2DM and dementia. Women with type 2 diabetes are 1.5 times more likely to experience AD than men.
Why don’t children and young people engage with diabetes services?
Authors: Helen Saul, Deniz Gursul, Samantha Cassidy, Darren Sharpe
Journal: BMJ (2022)

The studySharpe D, Rajabi M, Harden A, et al. Supporting disengaged children and young people living with diabetes to self-care: a qualitative study in a socially disadvantaged and ethnically diverse urban area. BMJ Open 2021;11:e046989.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/why-dont-young-people-engage-with-diabetes-services/.
Maintenance with Hypomethylating Agents after Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome: A Systematic Meta-Analysis
Authors: Smith Kungwankiattichai, BEN Ponvilawan, Claudie Roy, Pattaraporn Tunsing, Florian Kuchenbauer, Weerapat Owattanapanich
Journal: Blood (2021)
Replicative history marks transcriptional and functional disparity in the CD8+ T cell memory pool
Authors: Kaspar Bresser, Lianne Kok, Arpit C. Swain, Lisa A. King, Laura Jacobs, Tom S. Weber, Leïla Perié, Ken R. Duffy, Rob J. de Boer, Ferenc A. Scheeren, Ton N. Schumacher
Journal: Nature Immunology (2022)
Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer
Authors: Javier Cortés, Sung-Bae Kim, Wei-Pang Chung, Seock-Ah Im, Yeon Hee Park, Roberto Hegg, Min Hwan Kim, Ling-Ming Tseng, Vanessa Petry, Chi-Feng Chung, Hiroji Iwata, Erika Hamilton, Giuseppe Curigliano, Binghe Xu, Chiun-Sheng Huang, Jee Hyun Kim, Joanne W Y Chiu, Jose Luiz Pedrini, Caleb Lee, Yali Liu, Jillian Cathcart, Emarjola Bako, Sunil Verma, Sara A Hurvitz
Journal: New England Journal of Medicine (2022)

Trastuzumab emtansine is the current standard treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer whose disease progresses after treatment with a combination of anti-HER2 antibodies and a taxane.We conducted a phase 3, multicenter, open-label, randomized trial to compare the efficacy and safety of trastuzumab deruxtecan (a HER2 antibody-drug conjugate) with those of trastuzumab emtansine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. The primary end point was progression-free survival (as determined by blinded independent central review); secondary end points included overall survival, objective response, and safety.Among 524 randomly assigned patients, the percentage of those who were alive without disease progression at 12 months was 75.8% (95% confidence interval [CI], 69.8 to 80.7) with trastuzumab deruxtecan and 34.1% (95% CI, 27.7 to 40.5) with trastuzumab emtansine (hazard ratio for progression or death from any cause, 0.28; 95% CI, 0.22 to 0.37; P<0.001). The percentage of patients who were alive at 12 months was 94.1% (95% CI, 90.3 to 96.4) with trastuzumab deruxtecan and 85.9% (95% CI, 80.9 to 89.7) with trastuzumab emtansine (hazard ratio for death, 0.55; 95% CI, 0.36 to 0.86; prespecified significance boundary not reached). An overall response (a complete or partial response) occurred in 79.7% (95% CI, 74.3 to 84.4) of the patients who received trastuzumab deruxtecan and in 34.2% (95% CI, 28.5 to 40.3) of those who received trastuzumab emtansine. The incidence of drug-related adverse events of any grade was 98.1% with trastuzumab deruxtecan and 86.6% with trastuzumab emtansine, and the incidence of drug-related adverse events of grade 3 or 4 was 45.1% and 39.8%, respectively. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 10.5% of the patients in the trastuzumab deruxtecan group and in 1.9% of those in the trastuzumab emtansine group; none of these events were of grade 4 or 5.Among patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane, the risk of disease progression or death was lower among those who received trastuzumab deruxtecan than among those who received trastuzumab emtansine. Treatment with trastuzumab deruxtecan was associated with interstitial lung disease and pneumonitis. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast03 ClinicalTrials.gov number, NCT03529110.).
Abstract EP05: Plasma Water T <sub>2</sub> Is A Global Marker Of Cardiometabolic Health: The Premier Study
Authors: Diana F Sandoval, Erin B Campbell, Rinkal Patel, Vipulkumar Patel, Alok Dwivedi, David P Cistola
Journal: Circulation (2022)

Introduction: Plasma water T 2 detects the multi-component pathophysiology of metabolic syndrome: insulin resistance, dyslipidemia and a pro-inflammatory, pro-coagulation state. In this study, we aimed to determine factors associated with plasma water T 2 to determine if it could serve as a marker of cardiometabolic health. To do so, we analyzed bio-banked samples from the PREMIER study. Hypothesis: Plasma water T 2 is associated with multiple measures of cardiometabolic health among PREMIER participants at baseline. Materials and Methods: This is an auxiliary study of PREMIER with an observational, cross-sectional design. The parent study recruited 810 subjects: 63% female, 35% black, 65% non-black. The exclusion criteria were diabetes, heart failure, prior CV event, cancer, or psychiatric hospitalization within 2 years. In the present study, we analyzed a subset of participants (n=455), based on the availability of bio-banked samples that had been frozen only once. Transverse relaxation time (T 2 ) decay curves were recorded at 37°C for unmodified human plasma using a CPMG pulse sequence and a Bruker mq20 benchtop nuclear magnetic resonance relaxometer. Water T 2 was resolved from non-water components using a discrete inverse Laplace transform. Total plasma protein and albumin were determined, as well as a panel of acute phase proteins, apolipoproteins and metabolic markers. Proteomic analysis was performed using Luminex xMAP technology with Milliplex plates. Statistical analyses were conducted using JMP Pro v16.1.0 (SAS, Inc.). The association of plasma water T 2 (outcome variable) with predictors of cardiometabolic health was analyzed in four stages: (1) screening of predictors using a bootstrap forest machine learning algorithm, (2) clustering of predictors using principal component analysis, (3) associations of predictors with T 2 using multiple linear regression, and (4) validation of regression models using bootstrap forest. Effect size was quantified as standardized beta coefficients, with standard errors and p-values. Results: The final regression model includes the following predictors for plasma water T 2 : albumin, globulins, LDL-cholesterol, C-reactive protein, hepatocyte growth factor, serum retinol, race, post-treadmill heart rate, household income and fasting C-peptide. This model had an adjusted R 2 of 0.57; all terms were significant. Thus, plasma water T 2 was independently associated with markers of dyslipidemia, inflammation, hyperinsulinemia, physical fitness, nutrition (vegetable intake), race and household income. Conclusion: The association of plasma water T 2 with multiple predictors of cardiometabolic health in PREMIER validates T 2 as a global biomarker of cardiometabolic health in individuals without diabetes. This measurement is practical for the point-of-care and shows promise for cardiometabolic health screening and monitoring.
The Futility of Futility Analyses in Adjuvant Trials in Hormone Receptor–Positive Breast Cancer
Authors: Ana Elisa Lohmann, Marguerite Ennis, Wendy R Parulekar, Bingshu E Chen, George Tomlinson, Pamela J Goodwin
Journal: JNCI Journal of the National Cancer Institute (2022)

Abstract An interim analysis is commonly used in phase III superiority trials to compare treatment arms, with the goal of terminating exposure of patients to ineffective or unsafe drugs or to identify highly effective therapies for earlier public disclosure. Traditionally, interim analyses have been designed to identify early evidence of extremely large benefit of the experimental approach, potentially leading to early dissemination of effective treatments. Increasingly, interim analysis has also involved analysis of futility, which may lead to early termination of a trial that will not yield additional useful information. This presents an important challenge in early stage hormone receptor–positive breast cancer, where recurrence often occurs late, with a steady annual event rate up to 20 years. Early analysis of events may miss late treatment effects that can be observed only with longer follow-up. We discuss approaches to futility analysis in adjuvant clinical trials in hormone receptor–positive breast cancer, the role of the Data Safety Monitoring Committee in such analyses, considerations of the potential harms vs benefits of treatment, and the risks of continuing vs early termination of a trial.
VE-Cadherin: A Critical Sticking Point for Lymphatic System Maintenance: Role of VE-Cadherin in Lymphatic Maintenance
Authors: Brandon J. Nakashima, Young-Kwon Hong
Journal: Circulation Research (2022)

E-cadherin (vascular endothelial cadherin) plays a multitude of roles in endothelial cells, including the vital function of cell-cell adhesion and interaction as well as transmembrane signal transduction.These adhesion molecules provide the foundational function of regulating vessel permeability.Vascular permeability is intimately linked with immune cell transportation, solute concentration gradient establishment, and fluid homeostasis.With booming interest in the role of lymphatic vessels in normal and pathological states, the importance of lymphatic endothelial cell (LEC) interaction in vessel development, maintenance, and function has come into focus.Recent ex vivo models of lymphatic vessel permeability have demonstrated a significant increase in permeability to both small and large solutes when vessels are exposed to functional VE-cadherin blockade. 1he mechanotransducive role of constitutively bound VE-cadherin to VEGFR (vascular endothelial growth factor receptor) 2 and VEGFR3 has been previously demonstrated in blood endothelial cells 2 and, more recently, in the formation and maintenance of lymphatic valves, 3 further bolstering the evidence of the critical role VEcadherin plays in the realm of lymphatics.
P2Y12 inhibitor monotherapy or dual antiplatelet therapy after coronary revascularisation: individual patient level meta-analysis of randomised controlled trials
Journal: BMJ (2022)

P2Y12 inhibitor monotherapy or dual antiplatelet therapy after coronary revascularisation: individual patient level meta-analysis of randomised controlled trialsThis research paper by Valgimigli and colleagues (BMJ 2021;373:n1332; doi:) used data from publications that have since been corrected.Haemoglobin values were not reported correctly in the GLASSY trial, so data on haemoglobin in table 1 and supplementary table E of the paper have been corrected.The PRECISE-DAPT score was not correctly reported in the GLASSY trial because the score was calculated using haemoglobin, so data on the PRECISE-DAPT score in table 1, figure 2, supplementary table E, and supplementary figures C, D, F, and G have been corrected.Four procedural variables were not correctly reported."Number of vessels treated at index PCI," "Number of lesions treated at index PCI," and "Bifurcation lesion treated with at least two stents" have been corrected in the GLASSY trial."Number of vessels treated at index PCI" has been corrected in the STOPDAPT-2 trial."Bifurcation lesion treated with at least two stents" and "TIMI pre-PCI 0-1" have been corrected in the TWILIGHT trial.Accordingly, data in supplementary tables F and G have been corrected.In addition, data on the "Complex PCI" subgroup have been corrected in figure 2 and supplementary figures C, D, F, and G.These corrections were necessary because the "Complex PCI" subgroup was defined based on procedural variables (see above).
Awake Extracorporeal Membrane Oxygenation for COVID-19-induced Acute Respiratory Distress Syndrome.
Authors: Sebastian Mang, Christian Reyher, Haitham Mutlak, Ruslan Natanov, Christopher Lotz, Daniel Gill-Schuster, Robert Bals, Guy Danziger, Patrick Meybohm, Alain Combes, Christian Kühn, Philipp M Lepper, Ralf M Muellenbach
Journal: American Journal of Respiratory and Critical Care Medicine (2022)
CXCR2 inhibition enables NASH-HCC immunotherapy
Authors: Jack Leslie, John B G Mackey, Thomas Jamieson, Erik Ramon-Gil, Thomas M Drake, Frédéric Fercoq, William Clark, Kathryn Gilroy, Ann Hedley, Colin Nixon, Saimir Luli, Maja Laszczewska, Roser Pinyol, Roger Esteban-Fabró, Catherine E Willoughby, Philipp K Haber, Carmen Andreu-Oller, Mohammad Rahbari, Chaofan Fan, Dominik Pfister, Shreya Raman, Niall Wilson, Miryam Müller, Amy Collins, Daniel Geh, Andrew Fuller, David McDonald, Gillian Hulme, Andrew Filby, Xabier Cortes-Lavaud, Noha-Ehssan Mohamed, Catriona A Ford, Ximena L Raffo Iraolagoitia, Amanda J McFarlane, Misti V McCain, Rachel A Ridgway, Edward W Roberts, Simon T Barry, Gerard J Graham, Mathias Heikenwälder, Helen L Reeves, Josep M Llovet, Leo M Carlin, Thomas G Bird, Owen J Sansom, Derek A Mann
Journal: Gut (2022)

Hepatocellular carcinoma (HCC) is increasingly associated with non-alcoholic steatohepatitis (NASH). HCC immunotherapy offers great promise; however, recent data suggests NASH-HCC may be less sensitive to conventional immune checkpoint inhibition (ICI). We hypothesised that targeting neutrophils using a CXCR2 small molecule inhibitor may sensitise NASH-HCC to ICI therapy. Neutrophil infiltration was characterised in human HCC and mouse models of HCC. Late-stage intervention with anti-PD1 and/or a CXCR2 inhibitor was performed in murine models of NASH-HCC. The tumour immune microenvironment was characterised by imaging mass cytometry, RNA-seq and flow cytometry. Neutrophils expressing CXCR2, a receptor crucial to neutrophil recruitment in acute-injury, are highly represented in human NASH-HCC. In models of NASH-HCC lacking response to ICI, the combination of a CXCR2 antagonist with anti-PD1 suppressed tumour burden and extended survival. Combination therapy increased intratumoural XCR1+ dendritic cell activation and CD8+ T cell numbers which are associated with anti-tumoural immunity, this was confirmed by loss of therapeutic effect on genetic impairment of myeloid cell recruitment, neutralisation of the XCR1-ligand XCL1 or depletion of CD8+ T cells. Therapeutic benefit was accompanied by an unexpected increase in tumour-associated neutrophils (TANs) which switched from a protumour to anti-tumour progenitor-like neutrophil phenotype. Reprogrammed TANs were found in direct contact with CD8+ T cells in clusters that were enriched for the cytotoxic anti-tumoural protease granzyme B. Neutrophil reprogramming was not observed in the circulation indicative of the combination therapy selectively influencing TANs. CXCR2-inhibition induces reprogramming of the tumour immune microenvironment that promotes ICI in NASH-HCC.
Abstract EP69: Age, Sex And Race Disparities In Hypertension Control: The Multi-Ethnic Study Of Atherosclerosis (MESA)
Authors: Siddharth Bhayani, Ramon Durazo-Arvizu, Kiang Liu, Martha L Daviglus, Erin Michos, Talar Markossian, Michael Rakotz, Greg Wozniak, Brent M Egan, Holly J Kramer
Journal: Circulation (2022)

Introduction: Hypertension control is lower among women than men after age 65 years, but it is unknown whether age and sex disparities in hypertension control differ by race and ethnicity. We used data from the Multi-Ethnic Study of Atherosclerosis (MESA), to assess the association of age, sex, and race with hypertension control. Methods: At baseline, MESA enrolled 6814 adults aged 45 to 84 years without clinical CVD during years 2000-2002 followed by 5 follow-up exams. Due to loss of follow-up after exam 5, analysis was limited to participants with use of BP lowering medications at any of the first 5 MESA exams (n=2017). Hypertension control was defined as BP &lt; 140/90 mmHg based on average of second and third BP readings at each exam. Among 873 men and 1144 women with treated hypertension, mean baseline age was 64.1 (9.1 [SD]) years and race/ethnicity was non-Hispanic white in 34.1%, 10.1% Chinese, 35.1% Non-Hispanic Black and 20.7% Hispanic. Results: Figure 1 shows the fully adjusted proportion of participants with hypertension control at any of the first five MESA exams by age group, sex and by race and ethnicity. In all racial and ethnic groups, hypertension control declined with age among women and was lowest at age 75+ years. However, this decline in hypertension control with advancing age was most pronounced among Hispanic women, a group with the lowest adjusted proportion with hypertension control at age 75+ years (45.2%; 95% CI 35.3, 55.1). Hypertension control increased with advancing age among non-Hispanic Black men and stayed stable among Chinese men. Among white and Hispanic men, the adjusted proportion with hypertension control decreased from 81.1% (95% CI 76.7, 85.5) and 70.9% (95% CI 64.1, 77.8), respectively, at age 45-64 years, to 75.4% (95% CI 69.6, 81.3) and 61.5% (95% CI 55.3, 70,8), respectively, at age 75+ years. Conclusion: Age and sex differences in hypertension control are present in these four race and ethnic groups but declines in hypertension control with advancing age appear more prominent among Hispanic women.
ASpediaFI: Functional Interaction Analysis of Alternative Splicing Events
Authors: Kyubin Lee, Doyeong Yu, Daejin Hyung, Soo Young Cho, Charny Park
Journal: Genomics Proteomics & Bioinformatics (2022)

Alternative splicing (AS) regulates biological processes governing phenotypes and diseases. Differential AS (DAS) gene test methods have been developed to investigate important exonic expression from high-throughput datasets. However, the DAS events extracted using statistical tests are insufficient to delineate relevant biological processes. In this study, we developed a novel application, Alternative Splicing Encyclopedia: Functional Interaction (ASpediaFI), to systemically identify DAS events and co-regulated genes and pathways. ASpediaFI establishes a heterogeneous interaction network of genes and their feature nodes (i.e., AS events and pathways) connected by co-expression or pathway gene set knowledge. Next, ASpediaFI explores the interaction network using the random walk with restart algorithm and interrogates the proximity from a query gene set. Finally, ASpediaFI extracts significant AS events, genes, and pathways. To evaluate the performance of our method, we simulated RNA sequencing (RNA-seq) datasets to consider various conditions of sequencing depth and sample size. The performance was compared with that of other methods. Additionally, we analyzed three public datasets of cancer patients or cell lines to evaluate how well ASpediaFI detects biologically relevant candidates. ASpediaFI exhibits strong performance in both simulated and public datasets. Our integrative approach reveals that DAS events that recognize a global co-expression network and relevant pathways determine the functional importance of spliced genes in the subnetwork. ASpediaFI is publicly available at https://bioconductor.org/packages/ASpediaFI.
Rates of viral suppression in a cohort of people with stable HIV from two community models of ART delivery versus facility-based HIV care in Lusaka, Zambia: a cluster-randomised, non-inferiority trial nested in the HPTN 071 (PopART) trial
Authors: Mohammed Limbada, David Macleod, Vasty Situmbeko, Ellen Muhau, Osborn Shibwela, Bwalya Chiti, Sian Floyd, Albertus J Schaap, Richard Hayes, Sarah Fidler, Helen Ayles, Richard Hayes, Sarah Fidler, Nulda Beyers, Helen Ayles, Peter Bock, Wafaa El-Sadr, Myron Cohen, Virginia Bond, Susan Eshleman, Deborah Donnell, Sian Floyd, Graeme Hoddinott, Deborah Donnell, Dave Macleod, David Burns, Christopher Fraser, Lynda Emel, Heather Noble, Anne Cori, Niru Sista, Sam Griffith, Ayana Moore, Tanette Headen, Rhonda White, Eric Miller, James Hargreaves, Katharina Hauck, Ranjeeta Thomas, Mohammed Limbada, Justin Bwalya, Alwyn Mwinga, Michael Pickles, Kalpana Sabapathy, Albertus J Schaap, Mwelwa Phiri, Bwalya Chiti, Lawrence Mwenge, Rory Dunbar, Kwame Shanaube, Blia Yang, Musonda Simwinga, Peter C Smith, Nomtha Mandla, Nozizwe Makola, Anneen Van Deventer, Ephraim Sakala, Karen Jennings, Barry Kosloff, Sarah Kanema, Will Probert, Ramya Kumar, Andrew Silumesi, Tim Skalland, Krista Yuhas
Journal: The Lancet HIV (2021)