tbuckley/cabot-search huggingface dataset:
Chronic airflow obstruction and ambient particulate air pollution
Authors: Andre F S Amaral, Peter G J Burney, Jaymini Patel, Cosetta Minelli, Filip Mejza, David M Mannino, Terence A R Seemungal, Padukudru Anand Mahesh, Li Cher Lo, Christer Janson, Sanjay Juvekar, Meriam Denguezli, Imed Harrabi, Emiel F M Wouters, Hamid Cherkaski, Kevin Mortimer, Rain Jogi, Eric D Bateman, Elaine Fuertes, Mohammed Al Ghobain, Wan Tan, Daniel O Obaseki, Asma El Sony, Michael Studnicka, Althea Aquart-Stewart, Parvaiz Koul, Herve Lawin, Asaad Ahmed Nafees, Olayemi Awopeju, Gregory E Erhabor, Thorarinn Gislason, Tobias Welte, Amund Gulsvik, Rune Nielsen, Louisa Gnatiuc, Ali Kocabas, Guy B Marks, Talant Sooronbaev, Bertrand Hugo Mbatchou Ngahane, Cristina Barbara, A Sonia Buist
Journal: Thorax (2021)

Smoking is the most well-established cause of chronic airflow obstruction (CAO) but particulate air pollution and poverty have also been implicated. We regressed sex-specific prevalence of CAO from 41 Burden of Obstructive Lung Disease study sites against smoking prevalence from the same study, the gross national income per capita and the local annual mean level of ambient particulate matter (PM 2.5 ) using negative binomial regression. The prevalence of CAO was not independently associated with PM 2.5 but was strongly associated with smoking and was also associated with poverty. Strengthening tobacco control and improved understanding of the link between CAO and poverty should be prioritised.
Effectiveness of England’s initial vaccine roll out
Authors: Andreas Martin Lisewski
Journal: BMJ (2021)

Effectiveness of England's initial vaccine roll outBoth vaccine candidates offer protection to older adults Andreas Martin LisewskiIn its human host, the spread of SARS-CoV-2 has followed unusually volatile and seemingly unpredictable patterns that are often driven by statistical extremes, such as superspreading events. 1 These drivers of infection range from household, through local, to community events and beyond, 2 in which multiple chains of infection coalesce into the regional and highly volatile epidemic waves that characterise this pandemic.
NKTR-255, a novel polymer-conjugated rhIL-15 with potent antitumor efficacy
Authors: Takahiro Miyazaki, Mekhala Maiti, Marlene Hennessy, Thomas Chang, Peiwen Kuo, Murali Addepalli, Palakshi Obalapur, Sara Sheibani, Joanna Wilczek, Rhoneil Pena, Phi Quach, Janet Cetz, Andrew Moffett, Yinyan Tang, Peter Kirk, Jicai Huang, Dawei Sheng, Ping Zhang, Werner Rubas, Loui Madakamutil, Saul Kivimäe, Jonathan Zalevsky
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background NKTR-255 is a novel polyethylene glycol-conjugate of recombinant human interleukin-15 (rhIL-15), which was designed to retain all known receptor binding interactions of the IL-15 molecule. We explored the biologic and pharmacologic differences between endogenous IL-15 receptor α (IL-15Rα)-dependent (NKTR-255 and rhIL-15) and IL-15Rα-independent (precomplexed rhIL-15/IL-15Rα) cytokines. Methods In vitro pharmacological properties of rhIL-15, NKTR-255 and precomplex cytokines (rhIL-15/IL-15Rα and rhIL-15 N72D/IL-15Rα Fc) were investigated in receptor binding, signaling and cell function. In vivo pharmacokinetic (PK) and pharmacodynamic profile of the cytokines were evaluated in normal mice. Finally, immunomodulatory effect and antitumor activity were assessed in a Daudi lymphoma model. Results NKTR-255 and rhIL-15 exhibited similar in vitro properties in receptor affinity, signaling and leukocyte degranulation, which collectively differed from precomplexed cytokines. Notably, NKTR-255 and rhIL-15 stimulated greater granzyme B secretion in human peripheral blood mononuclear cells versus precomplexed cytokines. In vivo, NKTR-255 exhibited a PK profile with reduced clearance and a longer half-life relative to rhIL-15 and demonstrated prolonged IL-15R engagement in lymphocytes compared with only transient engagement observed for rhIL-15 and precomplexed rhIL-15 N72D/IL-15Rα Fc. As a consequent, NKTR-255 provided a durable and sustained proliferation and activation of natural killer (NK) and CD8 + T cells. Importantly, NKTR-255 is more effective than the precomplexed cytokine at inducing functionally competent, cytotoxic NK cells in the tumor microenvironment and the properties of NKTR-255 translated into superior antitumor activity in a B-cell lymphoma model versus the precomplexed cytokine. Conclusions Our results show that the novel immunotherapeutic, NKTR-255, retains the full spectrum of IL-15 biology, but with improved PK properties, over rhIL-15. These findings support the ongoing phase 1 first-in-human trial ( NCT04136756 ) of NKTR-255 in participants with relapsed or refractory hematologic malignancies, potentially advancing rhIL-15-based immunotherapies for the treatment of cancer.
Association of Socioeconomic Status With Dementia Diagnosis Among Older Adults in Denmark
Authors: Jindong Ding Petersen, Sonja Wehberg, Aake Packness, Nanna Herning Svensson, Nana Hyldig, Søren Raunsgaard, Merethe Kirstine Andersen, Jesper Ryg, Stewart W. Mercer, Jens Søndergaard, Frans Boch Waldorff
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Low socioeconomic status (SES) has been identified as a risk factor for the development of dementia. However, few studies have focused on the association between SES and dementia diagnostic evaluation on a population level. <h3>Objective</h3> To investigate whether household income (HHI) is associated with dementia diagnosis and cognitive severity at the time of diagnosis. <h3>Design, Setting, and Participants</h3> This population- and register-based cross-sectional study analyzed health, social, and economic data obtained from various Danish national registers. The study population comprised individuals who received a first-time referral for a diagnostic evaluation for dementia to the secondary health care sector of Denmark between January 1, 2017, and December 17, 2018. Dementia-related health data were retrieved from the Danish Quality Database for Dementia. Data analysis was conducted from October 2019 to December 2020. <h3>Exposures</h3> Annual HHI (used as a proxy for SES) for 2015 and 2016 was obtained from Statistics Denmark and categorized into upper, middle, and lower tertiles within 5-year interval age groups. <h3>Main Outcomes and Measures</h3> Dementia diagnoses (Alzheimer disease, vascular dementia, mixed dementia, dementia with Lewy bodies, Parkinson disease dementia, or other) and cognitive stages at diagnosis (cognitively intact; mild cognitive impairment but not dementia; or mild, moderate, or severe dementia) were retrieved from the database. Univariable and multivariable logistic and linear regressions adjusted for age group, sex, region of residence, household type, period (2017 and 2018), medication type, and medical conditions were analyzed for a possible association between HHI and receipt of dementia diagnosis. <h3>Results</h3> Among the 10 191 individuals (mean [SD] age, 75 [10] years; 5476 women [53.7%]) included in the study, 8844 (86.8%) were diagnosed with dementia. Individuals with HHI in the upper tertile compared with those with lower-tertile HHI were less likely to receive a dementia diagnosis after referral (odds ratio, 0.65; 95% CI, 0.55-0.78) and, if diagnosed with dementia, had less severe cognitive stage (β, −0.16; 95% CI, −0.21 to −0.10). Individuals with middle-tertile HHI did not significantly differ from those with lower-tertile HHI in terms of dementia diagnosis (odds ratio, 0.92; 95% CI, 0.77-1.09) and cognitive stage at diagnosis (β, 0.01; 95% CI, −0.04 to 0.06). <h3>Conclusions and Relevance</h3> The results of this study revealed a social inequality in dementia diagnostic evaluation: in Denmark, people with higher income seem to receive an earlier diagnosis. Public health strategies should target people with lower SES for earlier dementia detection and intervention.
Association of Prenatal, Early Postnatal, or Current Exposure to Secondhand Smoke With Attention-Deficit/Hyperactivity Disorder Symptoms in Children
Authors: Li-Zi Lin, Shu-Li Xu, Qi-Zhen Wu, Yang Zhou, Hui-Min Ma, Duo-Hong Chen, Gong-Bo Chen, Hong-Yao Yu, Bo-Yi Yang, Xiao-Wen Zeng, Li-Wen Hu, Guang-Hui Dong
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Few studies have investigated the association between the exposure window (prenatal, early postnatal, and current period) of secondhand smoke (SHS) and attention-deficit/hyperactivity disorder (ADHD) symptoms and subtypes in children. <h3>Objective</h3> To evaluate the associations of prenatal, early postnatal, or current SHS exposure with ADHD symptoms and subtypes among school-aged children. <h3>Design, Setting, and Participants</h3> In this cross-sectional study, 48 612 children aged 6 to 18 years from elementary and middle schools in Liaoning province, China, between April 2012 and January 2013 were eligible for participation. Data on SHS exposure and ADHD symptoms and subtypes for each child were collected via questionnaires administered to parents or guardians by school teachers. Data were analyzed from September 14 to December 2, 2020. <h3>Main Outcomes and Measures</h3> The ADHD symptoms and subtypes (inattention, hyperactivity-impulsivity, and combined) were measured based on a validated tool developed from the<i>Diagnostic and Statistical Manual of Mental Disorders</i>(Fourth Edition). Generalized linear mixed models were evaluated to estimate the association of SHS exposure with ADHD symptoms and subtypes. <h3>Results</h3> A total of 45 562 participants completed the questionnaires and were included in this study (22 905 girls [50.3%]; mean [SD] age, 11.0 [2.6] years; 2170 [4.8%] with ADHD symptoms). Compared with their unexposed counterparts, children who were ever exposed (odds ratio [OR], 1.50; 95% CI, 1.36-1.66) or always exposed to SHS (OR, 2.88; 95% CI, 2.55-3.25) from pregnancy to childhood had higher odds of having ADHD symptoms and subtypes (ORs ranged from 1.46 [95% CI, 1.31-1.62] to 2.94 [95% CI, 2.09-4.13]). Compared with their unexposed counterparts, children with SHS exposure had higher odds of having ADHD symptoms when exposed in the prenatal period (OR, 2.28; 95% CI, 2.07-2.51), early postnatal period (OR, 1.47; 95% CI, 1.29-1.68), or current period (OR, 1.20; 95% CI, 1.09-1.31). Compared with their unexposed counterparts, children whose fathers smoked 10 or more cigarettes/d on both weekdays and weekends had higher odds of having ADHD symptoms and subtypes (ORs ranged from 1.48 [95% CI, 1.28-1.70] to 2.25 [95% CI, 1.29-3.93]). <h3>Conclusions and Relevance</h3> Being exposed to SHS from pregnancy to childhood was associated with higher odds of having ADHD symptoms and subtypes among school-aged children, and the associations were somewhat stronger for SHS exposure during prenatal and early postnatal periods. Our findings highlight the important public health implications of reducing SHS exposure, which may decrease the health and economic burdens of individuals with ADHD.
Did Everolimus Break the Rules?
Authors: Shumei Kato, Ezra E.W. Cohen
Journal: Clinical Cancer Research (2021)

Abstract A phase II study with everolimus (mTORC1 inhibitor) among advanced solid tumors patients with TSC1/TSC2 or MTOR alterations was recently published. Although efficacy was limited, the study provided the future groundwork to advance the targeted therapy approach. See related article by Adib et al., p. 3845
Autoimmune Cytopenias (AIC) Following Allogeneic Haematopoietic Stem Cell Transplant for Acquired Aplastic Anaemia: A Joint Study of the Autoimmune Diseases and Severe Aplastic Anaemia Working Parties (ADWP/SAAWP) of the European Society for Blood and Marrow Transplantation (EBMT)
Authors: Paul D E Miller, John A Snowden, J. Alejandro Madrigal, Simona Iacobelli, Diderik-Jan Eikema, Cora Knol, Judith Marsh, Carmel Rice, Mickey Koh, Franca Fagioli, Sridhar Chaganti, Jürgen Finke, Rafael F Duarte, Peter Bader, Jakob R. Passweg, Regis Peffault De Latour, Carlo Dufour
Journal: Blood (2017)
Risks of recurrent stroke and all serious vascular events after spontaneous intracerebral haemorrhage: pooled analyses of two population-based studies
Authors: Linxin Li, Michael T C Poon, Neshika E Samarasekera, Luke A Perry, Tom J Moullaali, Mark A Rodrigues, James J M Loan, Jacqueline Stephen, Christine Lerpiniere, Maria A Tuna, Sergei A Gutnikov, Wilhelm Kuker, Louise E Silver, Rustam Al-Shahi Salman, Peter M Rothwell
Journal: The Lancet Neurology (2021)

Patients with stroke due to spontaneous (non-traumatic) intracerebral haemorrhage (ICH) are at risk of recurrent ICH, ischaemic stroke, and other serious vascular events. We aimed to analyse these risks in population-based studies and compare them with the risks in RESTART, which assessed antiplatelet therapy after ICH.
Outcomes among newly diagnosed AL amyloidosis patients with a very high NT-proBNP: implications for trial design
Authors: I. Vaxman, S. K. Kumar, F. Buadi, M. Q. Lacy, D. Dingli, Y. Hwa, A. Fonder, M. Hobbs, S. Hayman, T. Kourelis, R. Warsame, E. Muchtar, N. Leung, P. Kapoor, M. Grogan, R. Go, Y. Lin, W. Gonsalves, M. Siddiqui, R. A. Kyle, S. V. Rajkumar, M. A. Gertz, A. Dispenzieri
Journal: Leukemia (2021)
Abstract 15520: Prognostic Value of Soluble ST2 Measurements for Morbidity and Mortality in Ambulatory Patients With HFpEF
Authors: Alexander O Gong, Nina Balac, Sagar V Patel, Jennifer Hwang, Jennifer M McLeod, Luanda P Grazette
Journal: Circulation (2020)

Background: Soluble ST2 (sST2) has emerged as a powerful prognostic marker in chronic systolic heart failure with reduced ejection fraction (HFrEF). Elevated levels of sST2 are associated with adverse cardiac remodeling and fibrosis. However, few studies have investigated the relative prognostic value of sST2 collected from ambulatory patients with chronic heart failure with preserved ejection fraction (HFpEF) for long term outcomes. Hypothesis: We sought to determine the prognostic utility of a baseline sST2 partition value in the ambulatory setting as it related to risk for heart failure hospitalization and all-cause mortality. Methods: Single-center, retrospective observational study of subjects presenting to an ambulatory heart failure (HF) clinic from July 2014 to December 2016. Baseline sST2 levels were available for 156 subjects with stage C heart failure.. For purposes of this analysis in HFpEF, we excluded patients with EF ≤ 40% resulting in a study cohort of 73 subjects. The mean follow-up was 3.09 years ± 1.46 years. Analysis was performed with IBM SPSS Statistics 26. Discrete variables were expressed as counts (percentage) and were compared using the Chi-squared test. Mean differences of continuous variables were expressed as a mean ± standard deviation and compared using the unpaired Student’s t- test. The log-rank test (Mantel-Cox) was used to compare survival times on Kaplan-Meier curves. Results: Patients who had baseline sST2 ≥ 35 ng/ml were at increased risk for heart failure hospitalization (p=0.189) and all-cause mortality (p=0.073) compared to patients who had sST2 &lt; 35 ng/ml. Patients with sST2 ≥ 35 ng/ml had a mean of 1.03 HF hospitalizations, 24.1% of this group had ≥ 2 HF hospitalizations and 17.2% all-cause mortality. Patients with sST2 &lt; 35 ng/ml had a mean of 0.57 HF hospitalizations, 14.0% had ≥ 2 HF hospitalizations and 4.55% all-cause mortality. Conclusion: Subjects with sST2 levels ≥ 35 ng/ml were at increased risk of recurrent hospitalization and all-cause mortality. The results of this study highlight the value of sST2 concentrations as a prognostic biomarker for identifying patients with HFpEF that are at increased risk for morbidity and mortality in the ambulatory setting.
Abstract 15386: Integrated Phosphoproteome and Transcriptome Analysis of Biased Agonists at CXCR3 Reveals Differential Cellular Outputs of Inflammation
Authors: Kevin Z Zheng, Dylan Eiger, Jeffrey S Smith, Anmol Warman, Chia-Feng Tsai, John M Jacobs, Tujin Shi, Sudarshan Rajagopal
Journal: Circulation (2020)

Background and Objective: G-protein-coupled receptors (GPCRs) are the most common cell surface receptor class and are known to influence nearly every biological process. GPCRs signal through downstream effectors such as G proteins and β-arrestins. Certain ligands drive activation of G protein over β-arrestin signaling, or vice versa - a phenomenon known as biased agonism. To investigate the mechanisms and implications of biased agonism, we studied CXCR3, a chemokine receptor expressed on T cells, which binds three biased endogenous ligands, CXCL9, CXCL10, and CXCL11. Importantly, CXCR3 has been implicated in atherosclerosis and other inflammatory diseases. Methods: To obtain a broad view of biased signaling at CXCR3, we performed global phosphoproteomic and transcriptomic analyses of CXCR3-transfected HEK 293 cells and activated human CD8+ T-cells, respectively, treated with CXCL9, CXCL10, and CXCL11. To assess the phosphoproteome, we utilized an antibody-free mass spectrometry approach with high-pressure, high-resolution separation and intelligent selection. RNA-seq was performed to assess transcriptomic changes in activated CD8+ T-cells. Results: Our analyses revealed 1532 phosphosites and 887 transcripts differentially regulated between treatment groups. Gene Set Enrichment Analysis (GSEA) of CXCL11-treated cells revealed enrichment of pro-inflammatory targets including the Myc and TNF-α pathways via NFKB not observed in CXCL10- or CXCL9-treated cells. GSEA of CXCL10- and CXCL11-treated cells also revealed enrichment of the IL6-JAK-STAT3 pathway, linked to chronic inflammatory conditions. Kinase-Substrate Enrichment Analysis (KSEA) revealed differential phosphorylation activity associated with multiple kinases including AURKB (CXCL9), ROCK1 (CXCL9, 10, 11), CDK9 (CXCL10), and ATM (CXCL10, 11) - all known to regulate pro-inflammatory targets. Several phosphoproteins were transcription factors, including p53, known to mediate IL-6 production and atherosclerosis pathogenesis. Conclusion: Together, our integrated analysis of phosproteomic and transcriptomic data reveal the extent of differential cellular outputs produced by biased agonists at CXCR3 in modulating targets implicated in inflammatory diseases.
147P When a single G-CSF administration is better than longer duration: Example in patients treated by eribulin
Authors: A. Schmitt, M. Reda, P. Macaire, H. Bellio, L. Uwer, S.M. Ilie, V. Lorgis, A. Hennequin, S. Ladoire, E. Rederstorff, P. Fumoleau, N. Isambert, N. Bonnin, B. You, G. Freyer, I. Desmoulins
Journal: Annals of Oncology (2021)
非転移性前立腺癌男性の身体機能およびクオリティ・オブ・ライフに対するアンドロゲン枯渇療法の効果
Authors: M H Alibhai Shabbir, Breunis Henriette, Timilshina Narhari, Johnston Calvin, Tomlinson George, Tannock Ian, Krahn Murray, E Fleshner Neil, Warde Padraig, Canning Sarah Duff, Klotz Lawrence, Naglie Gary
Journal: Journal of Clinical Oncology (2010)
Machine Learning for Predicting Rare Clinical Outcomes—Finding Needles in a Haystack
Authors: Fei Wang
Journal: JAMA Network Open (2021)

Jeph Herrin, PhD; Neena S. Abraham, MD; Xiaoxi Yao, PhD; Peter A. Noseworthy, MD; Jonathan Inselman, MS; Nilay D. Shah, PhD; Che Ngufor, PhD
Abstract 16182: Prognostic Value of Peak Oxygen Uptake Trajectories for Mortality Risk in Patients With Heart Failure
Authors: Emily Mansour, chao cao, Alyssa Purtiz, Qiaonan Zhong, Andrea Soares, Linda R Peterson, Susan B RACETTE
Journal: Circulation (2020)

Introduction: Peak oxygen uptake (VO 2peak ), as determined by cardiopulmonary exercise testing (CPET), is informative of cardiovascular fitness and heart failure (HF) disease progression. Due to their clinical meaningfulness, many patients with HF undergo multiple CPETs throughout their lifetimes. However, a gap in knowledge exists regarding the prognostic value of longitudinal changes in VO 2peak for mortality risk. The aim of this study was to investigate whether VO 2peak trajectories are predictive of mortality among patients with HF. Methods: Patients with HF who completed two CPETs (separated by at least 3 months, mean = 25.3 months) at Washington University School of Medicine between May 1993 and February 2020 were included in the study. Vital statuses and mortality dates were collected from May 2019 to May 2020 via electronic health records and the Social Security Death Index. Kaplan-Meier and Cox proportional hazards regression analyses were used to evaluate associations between changes in VO 2peak and mortality. Results: The sample included 162 patients with a mean age of 48.5 years (SD 10.5) at baseline. VO 2peak averaged 18.1 (SD 4.9) ml·kg -1 ·min -1 in 121 men and 15.1 (SD 4.1) ml·kg -1 ·min -1 in 41 women. During a median follow-up of 11.8 years (range 1-23 years), 70 patients died. A significant negative association between VO 2peak and mortality was observed (hazard ratio [HR] = 0.92; 95% Confidence Interval [CI] = 0.87 to 0.98; P = 0.011). Patients whose VO 2peak increased from their baseline to second CPET had higher survival rates compared to patients whose VO 2peak decreased. Moreover, the annual rate of change in VO 2peak was associated with mortality rates. A 9% lower mortality rate was observed for each unit increase in VO 2peak change (i.e., 1 ml·kg -1 ·min -1 ) for the entire follow-up period (HR = 0.91; 95% CI = 0.85 to 0.97) and at 10-year follow-up (HR = 0.91; 95% CI = 0.85 to 0.98), while a 12% lower mortality rate was observed at 5-year follow-up (HR = 0.88, 95% CI = 0.78 to 1.00) relative to baseline CPETs. Conclusion: Increases in VO 2peak were associated with increased survival rate among patients with HF. These findings highlight the importance of promoting exercise and cardiac rehabilitation for patients with HF.
Abstract 14795: Oral Anticoagulation Associated With Lower Risk of Stroke in Patients With Post-operative Atrial Fibrillation
Authors: Xiaoxi Yao, Holly Van Houten, Konstantinos Siontis, Bernard J Gersh, Peter A Noseworthy
Journal: Circulation (2020)

Introduction: Recent studies showed post-operative atrial fibrillation (POAF) is associated with increased stroke risk - even approaching that of unprovoked AF. This raises the question of whether patients with POAF should receive anticoagulation. We aim to compare different anticoagulation strategies in patients with POAF after cardiac and non-cardiac surgeries. Methods: Using a large national administrative database (OptumLabs Data Warehouse), we identified 33,981 patients with POAF between 1/1/2013-9/30/2019. Patients were divided to four groups based on the initial treatment within 30 days of POAF: (1) no anticoagulation (N=28,807) (2) apixaban (N=2178) (3) rivaroxaban (N=1320) (4) warfarin (N=1676). Follow up started at the 30 th day after POAF to exclude patients who died shortly after surgery and minimize immortal time bias. The follow up continued until patients changed treatment strategies, insurance, or died. 1:1 propensity score matching was performed between each anticoagulant to no treatment to balance on 86 baseline characteristics. Results: The mean age was 71.1±11.2 yr; mean CHA 2 DS 2 -VASc was 4.1±1.8; 29.1% received cardiac surgeries; 15.2% received anticoagulation within 30 days of POAF. The event rate per 100 person years was 1.58 for stroke in no-anticoagulation group, and 1.29 for anticoagulation group; 2.86 for major bleeding in no-anticoagulation group and 4.50 for anticoagulation group. After matching, apixaban and rivaroxaban were associated with a lower risk of stroke, but a higher risk of major bleeding; warfarin was not associated with a lower risk of stroke, but a higher risk of major bleeding (Figure). The effect was consistent across subgroups, e.g., age and surgery type. Conclusions: In patients with POAF, the stroke rate was lower than what was typically observed in clinical AF. Treatment with apixaban and rivaroxaban immediately after POAF was associated with a reduced risk of stroke but an increased risk of major bleeding.