tbuckley/cabot-search huggingface dataset:
The balance between the intronic miR-342 and its host gene Evl determines hematopoietic cell fate decision
Authors: Friederike Herbst, Tonio J. L. Lang, Elias S. P. Eckert, Peer Wünsche, Alexander A. Wurm, Tim Kindinger, Karin Laaber, Shayda Hemmati, Agnes Hotz-Wagenblatt, Oksana Zavidij, Anna Paruzynski, Junyan Lu, Christof von Kalle, Thorsten Zenz, Christoph Klein, Manfred Schmidt, Claudia R. Ball, Hanno Glimm
Journal: Leukemia (2021)

Abstract Protein-coding and non-coding genes like miRNAs tightly control hematopoietic differentiation programs. Although miRNAs are frequently located within introns of protein-coding genes, the molecular interplay between intronic miRNAs and their host genes is unclear. By genomic integration site mapping of gamma-retroviral vectors in genetically corrected peripheral blood from gene therapy patients, we identified the EVL/MIR342 gene locus as a hotspot for therapeutic vector insertions indicating its accessibility and expression in human hematopoietic stem and progenitor cells. We therefore asked if and how EVL and its intronic miRNA-342 regulate hematopoiesis. Here we demonstrate that overexpression (OE) of Evl in murine primary Lin − Sca1 + cKit + cells drives lymphopoiesis whereas miR-342 OE increases myeloid colony formation in vitro and in vivo, going along with a profound upregulation of canonical pathways essential for B-cell development or myelopoietic functions upon Evl or miR-342 OE, respectively. Strikingly, miR-342 counteracts its host gene by targeting lymphoid signaling pathways, resulting in reduced pre-B-cell output. Moreover, EVL overexpression is associated with lymphoid leukemia in patients. In summary, our data show that one common gene locus regulates distinct hematopoietic differentiation programs depending on the gene product expressed, and that the balance between both may determine hematopoietic cell fate decision.
Evaluation of Between-County Disparities in Premature Mortality Due to Stroke in the US
Authors: Suhang Song, Gaoting Ma, Michael G. Trisolini, Kenneth A. Labresh, Sidney C. Smith, Yinzi Jin, Zhi-Jie Zheng
Journal: JAMA Network Open (2021)

Identifying the factors associated with premature stroke mortality and measuring between-county disparities may provide insight into how to reduce variations and achieve more equitable health outcomes.To examine the between-county disparities in premature stroke mortality in the US, investigate county-level factors associated with mortality, and describe differences in mortality disparities by place of death and stroke subtype.This retrospective cross-sectional study linked the mortality and demographic data of US counties from the Centers for Disease Control and Prevention WONDER database to county-level characteristics from multiple databases. The outcome measure was county-level age-adjusted stroke mortality among adults aged 25 to 64 years in 2637 US counties from 1999 to 2018. This study was conducted from April 1, 2019, to October 31, 2020. Generalized linear Poisson regressions were fitted to investigate 4 sets of factors associated with county-level mortality: demographic composition, socioeconomic status, health care and environmental features, and population health. The Theil index score was calculated to assess the mortality disparities.Stroke mortality was measured as the number of deaths attributed to stroke in the data set. Out-of-stroke-unit death was defined as any death occurring in outpatient or emergency departments or at the pretransport location. Five stroke subtypes were included in the analysis.Although mortality did not change substantially from 1999 to 2018 (from 12.62 to 11.81 per 100 000 population), the proportion of deaths occurring out of the stroke unit increased from 23.56% (4328 of 18 369) to 34.57% (6978 of 20 188). A large percentage of stroke of an uncertain cause was reported, with most deaths (55.20%) occurring out of the stroke unit. In the county with the highest premature stroke mortality, the incidence was 20.78 times as high as that in the county with the lowest mortality (65.04 vs 3.13 deaths per 100 000 population). The highest between-county disparities were found for stroke of uncertain cause. For out-of-stroke-unit death, county-level mortality was largely associated with demographic composition (31.6%) and health care and environmental features (25.8%). For in-hospital death, 29.8% of county-level mortality was associated with population health and 28.7% was associated with demographic composition.These findings suggest that strategies addressing specific factors that underlie the mortality disparities among US counties, especially for out-of-stroke-unit death and stroke of uncertain cause, may be useful when tailored to the county-level context before implementing interventions for the neediest counties.
Abstract MP35: Association Of Orthostatic Blood Pressure Response With Incident Heart Failure: The Framingham Heart Study
Authors: Tara A Shrout, Vasan S Ramachandran, Vanessa Xanthakis
Journal: Circulation (2021)

Introduction: Orthostatic hypotension (OH) and hypertension (OHT) are associated with cardiovascular disease and mortality. The relation of OH and OHT with heart failure (HF) in the community is not well explored, particularly among the elderly and those with hypertension. Moreover, there remains a paucity of longitudinal data on the development of HF subtypes (HF with reduced ejection fraction [HFrEF] and HF with preserved ejection fraction [HFpEF]) in those with OH and OHT. Hypothesis: We hypothesized that OH and OHT are associated with a higher risk of HF. Methods: We evaluated 1914 Framingham Heart Study participants (mean age 72 years, 1159 women [61%]), with available orthostatic blood pressure (BP) measurements. OH was defined as a decrease and OHT as an increase of 20/10 mmHg in systolic/diastolic BP from supine to standing position, respectively. We used a categorical variable (OH, OHT, absence of OH and OHT [referent]). Using Cox proportional hazards regression, we related OH and OHT to risk of HF and its subtypes (HFrEF, HFpEF), compared to the referent group, adjusting for age, sex, body mass index, systolic BP, diastolic BP, hypertension treatment, smoking, and diabetes. Results: There were 275 participants with OH (181 women, 66%) and 411 with OHT (236 women, 57%). On median follow-up of 13 years, 492 developed HF (292 women, 59%). In multivariable-adjusted analyses, OH was associated with higher risk of HF (Hazards Ratio [HR] 1.47; 95% CI, 1.13-1.92; Figure ) compared to referent. Further, OH was associated with higher risk of HFrEF (HR 2.56; 95% CI, 1.46-4.48), but not HFpEF. OHT was not associated with incident HF. Conclusions: Assessment of orthostatic BP response in the elderly may identify future HF risk. Further studies are warranted to investigate mechanisms underlying the observed associations.
Abstract 16657: Guideline Recommended Statin Therapy and Sex Based Cardiovascular Disease Outcomes: Data From a Multi-site Healthcare Network Primary Prevention Cohort
Authors: Anum Saeed, Jianhui Zhu, Floyd W Thoma, Oscar C MARROQUIN, Malamo E Countouris, Aryan Aiyer, Martha Gulati, Kathryn Berlacher, Erin D Michos, Khurram Nasir, Suresh R Mulukutla
Journal: Circulation (2020)

Introduction: Statin therapy has been shown to reduce ASCVD morbidity and mortality. Evidence on statin utilization per the ACC/AHA cholesterol guidelines and outcomes are limited in primary prevention cohorts of women. We investigated statin use outcomes per 10-year ASCVD risk in a large healthcare system stratified by sex. Methods: Statin prescription in patients without CAD (MI or revascularization) or ischemic stroke were evaluated (2013-2019). Risk categories per the ASCVD risk were defined as: Borderline (5%-7.4%), Intermediate (7.5%-19.9%) or High (≥20%). Guideline-directed statin intensity (GDSI), at time of first event, was defined as: “at least moderate” for Intermediate and high -risk groups. Cox regression hazard ratios (HR) [95% CI] were calculated for statin use and outcomes (MI, stroke and composite ASCVD events) stratified by gender. Interaction terms (age ≥75y and sex) were applied. Results: Among 159,100 women (out of 282,298 patients; mean age ~51y), 15,153 (9.5%), 26,697 (16.8%) and 10,583 (6.7%) were categorized as borderline, intermediate and high risk, respectively. Only 9,277 (35%) intermediate and 4,893 (46%) of high-risk women received any intensity of statin. High risk women (vs men) on GDSI, had lower association with CAD events (HR 0.8 [0.7-0.9]) and increased stroke risk (HR 1.2 [1.1-1.4]) ( Table). Intermediate and high-risk women (on &lt;GD statin or no statin) had higher stroke risk than those on GD statin (p for interaction &lt;0.001 ). Older women (≥75y) on “no statin” (vs GD statin) had independently increased risk of CAD (HR 1.30[1.1-1.6]) (p interaction &lt;0.001) . Conclusions: In a real-world primary prevention cohort, women on statin therapy had significantly improved ASCVD outcomes and lower mortality. However, approximately one-fourth of statin-eligible women were not prescribed any statin therapy. Further research can develop healthcare system strategies to optimize under-treatment of women for ASCVD prevention.
Prenatal Ambient Ultrafine Particle Exposure and Childhood Asthma in the Northeastern United States
Authors: Rosalind J. Wright, Hsiao-Hsien Leon Hsu, Yueh-Hsiu Mathilda Chiu, Brent A. Coull, Matthew C. Simon, Neelakshi Hudda, Joel Schwartz, Itai Kloog, John L. Durant
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Ambient ultrafine particles (UFPs; with an aerodynamic diameter < 0.1 μm) may exert greater toxicity than other pollution components because of their enhanced oxidative capacity and ability to translocate systemically. Studies examining associations between prenatal UFP exposure and childhood asthma remain sparse.
Abstract 11800: Impaired Left Ventricular Strain Despite Preserved Ejection Fraction and Risk of Incident Heart Failure With Ejection Fraction Above or Below 50% in Older Adults: The Community-Based Atherosclerosis Risk in Communities (ARIC) Study
Authors: Anne Marie Reimer Jensen, Hicham Skali, Kunihiro Matsushita, Tor Biering-Sørensen, Suma Konety, Kenneth Butler, Dalane W Kitzman, Scott D Solomon, Brian Clagget, Amil M Shah
Journal: Circulation (2018)

Introduction: Heart failure (HF) prevalence increases with age, and left ventricular ejection fraction (LVEF) is preserved in the majority of HF in the elderly. Left ventricular (LV) strain detects...
P150 Hospital Re-admissions With Exacerbation Of Obstructive Pulmonary Disease In Illicit Drug Smokers
Authors: R. Yadavilli, R. Huang, A. Collins, W. Y. Ding, N. Garner, J. Williams, H. Burhan
Journal: Thorax (2014)

<h3>Introduction</h3> Patients with obstructive pulmonary disease (asthma or chronic obstructive pulmonary disease – COPD) who smoke illicit drugs are at an increased risk of hospital admissions. We compared hospital re-admission rates due to exacerbations of obstructive pulmonary disease amongst current/ex-illicit drug smokers versus current/ex-tobacco smokers. Hypothesis ’Are those who smoke illicit drugs admitted to hospital with a clinical diagnosis of exacerbation of COPD more likely to be re-admitted with a further exacerbation than current/ex-tobacco smokers?’ <h3>Methods</h3> Re-admission was defined as any admission, after the first, with an exacerbation of obstructive pulmonary disease during the study period. All admissions with a presumptive diagnosis of ‘exacerbation of COPD’ between January 2009 and September 2011 were reviewed. This was performed retrospectively using our COPD admission database. <h3>Results</h3> There were 950 sequential hospital admissions in 709 patients over a 33 month period. We found 250 ex-tobacco smokers, 370 current tobacco smokers and 89 current or ex-illicit drug smokers. Re-admission rates with exacerbation of obstructive pulmonary disease were higher in illicit drug smokers compared to current/ex-tobacco smokers (1.00 v. 0.22/0.26, p &lt; 0.001). Illicit drug smokers were younger (50 v. 72.9/69.9 [mean 71.2] years, p &lt; 0.001) and had shorter length of hospital stay (7.44 v. 9.28/10.69 [mean 9.87] days, p = 0.038). Illicit drug smokers with FEV<sub>1</sub> &lt; 1 litre (L) had higher readmissions (2.56) than ex/current tobacco smokers (0.6) with FEV<sub>1</sub> &lt; 1L (p &lt; 0.001) [Table 1]. Illicit drug smokers with FEV<sub>1</sub> &gt; 1L did not show this trend (p = 0.236). Tobacco pack years were higher in tobacco smokers (40.22) compared to illicit drug smokers (22.47), p. Admissions requiring non-invasive ventilation (NIV) for type 2 respiratory failure were more common in illicit drug smokers (8.4 v. 3%, p &lt; 0.002). <h3>Conclusion</h3> We have shown that readmission rates in illicit drug smokers are higher than in tobacco smokers. These patients tend to be younger, have a male predominance, have shorter length of hospital stay and are more likely to require NIV; readmissions were more predominant in illicit drug smokers with an FEV<sub>1</sub>1.
Mobile Health: making the leap to research and clinics
Authors: Joy P. Ku, Ida Sim
Journal: npj Digital Medicine (2021)

Health applications for mobile and wearable devices continue to experience tremendous growth both in the commercial and research sectors, but their impact on healthcare has yet to be fully realized. This commentary introduces three articles in a special issue that provides guidance on how to successfully address translational barriers to bringing mobile health technologies into clinical research and care. We also discuss how the cross-organizational sharing of data, software, and other digital resources can lower such barriers and accelerate progress across mobile health.
Doxycycline Significantly Enhances Induction of Induced Pluripotent Stem Cells to Endoderm by Enhancing Survival Through Protein Kinase B Phosphorylation
Authors: Caitlin Peaslee, Cristina Esteva‐Font, Tao Su, Antonio Munoz‐Howell, Caroline C. Duwaerts, Zhe Liu, Sneha Rao, Ke Liu, Marisa Medina, Julie B. Sneddon, Jacquelyn J. Maher, Aras N. Mattis
Journal: Hepatology (2021)

Background and Aims Induced pluripotent stem cells (iPSCs) provide an important tool for the generation of patient‐derived cells, including hepatocyte‐like cells, by developmental cues through an endoderm intermediate. However, most iPSC lines fail to differentiate into endoderm, with induction resulting in apoptosis. Approach and Results To address this issue, we built upon published methods to develop an improved protocol. We discovered that doxycycline dramatically enhances the efficiency of iPSCs to endoderm differentiation by inhibiting apoptosis and promoting proliferation through the protein kinase B pathway. We tested this protocol in &gt;70 iPSC lines, 90% of which consistently formed complete sheets of endoderm. Endoderm generated by our method achieves similar transcriptomic profiles, expression of endoderm protein markers, and the ability to be further differentiated to downstream lineages. Conclusions Furthermore, this method achieves a 4‐fold increase in endoderm cell number and will accelerate studies of human diseases in vitro and facilitate the expansion of iPSC‐derived cells for transplantation studies.
Cellular senescence inhibits renal regeneration after injury in mice, with senolytic treatment promoting repair
Authors: Katie J. Mylonas, Eoin D. O’Sullivan, Duncan Humphries, David P. Baird, Marie-Helena Docherty, Sarah A. Neely, Paul J. Krimpenfort, Anette Melk, Roland Schmitt, Sofia Ferreira-Gonzalez, Stuart J. Forbes, Jeremy Hughes, David A. Ferenbach
Journal: Science Translational Medicine (2021)

Senescent renal epithelia promote fibrosis and functional loss after injury, whereas depletion improves regeneration in aged or irradiated kidneys.
CAPD患者の腹膜におけるAGE(マクロファージ受容体のためのリガンド)の免疫組織化学的検出
Authors: Nakamura S, Tobita K, Tachikawa T, Akamatsu S, Ohno Y, Kan A, Katsuragawa M, Yasumura K, Miyazaki S, Sakai S, Morita T, Hirashawa Y, Niwa T
Journal: Kidney International (2003)
Abstract P133: Added Sugar Intake Is Associated With Greater 2-hour Glucose And Lower Muscle Quality In Adults Free Of Diabetes: Coronary Artery Risk Development In Young Adults Study
Authors: So-Yun Yi, Lyn M Steffen, James G Terry, Daniel A Duprez, Brian Steffen, James M Shikany, Xia Zhou, Andrew O Odegaard, Cora E Lewis, John J Carr, David R Jacobs
Journal: Circulation (2021)

Background: - Excess added sugar (AS) intake was shown to promote insulin resistance in skeletal muscle in animal studies, while sugar sweetened beverage (SSB) intake was associated with insulin resistance and lipids in skeletal muscle in humans. However, SSBs account for only 40% of AS intake. US adults consume excessive AS from foods and beverages relative to the 2015-2020 Dietary Guidelines recommendation which limit AS intake to &lt;10% of energy intake per day. We evaluated the hypothesis that AS intake is adversely associated with glucose metabolism, insulin, and lean muscle attenuation (MA) in Black and white men and women aged 18-30 years at baseline (Y0). Methods: - After exclusions for diabetes defined as MD diagnosis, insulin or oral agent use, fasting glucose ≥126 mg/dL, or HbA1c ≥6.5%, outlying energy intake, and missing 2-hour glucose, 2,016 adults were included in the analyses. Dietary intake was assessed by Diet History at Y0, Y7 and Y20. At Y25 follow-up, participants free of diabetes underwent a fasting blood draw for glucose, insulin, and triglycerides, an oral glucose tolerance test for 2-hour post-challenge glucose, and an abdominal CT scan for lean MA (an indicator of muscle quality). AS intake was averaged across Y0, Y7, and Y20 and divided into tertiles. General linear regression models estimated the associations across tertiles of AS intake with 2-hour glucose, fasting glucose, insulin, and triglycerides, and lean MA adjusted for potential confounders. Results: - AS intake (Table) was positively associated with 2-hour glucose and fasting insulin and triglycerides (p trend =0.004, 0.04, and 0.01, respectively) and inversely associated with lean MA (p trend =0.02). AS intake was not associated with fasting glucose (p trend =0.57). Conclusions: - Among adults free of diabetes, greater long-term AS intake was associated with higher 2-hour glucose and fasting insulin and triglycerides, and lower muscle quality. Our findings are consistent with the US Dietary Guidelines for Americans recommendation to limit AS intake.
Abstract 12625: Promoting Health Equity in Female San Joaquin South Asian Population
Authors: Maha Siddiqui
Journal: Circulation (2020)

Introduction: South Asians (SA) have a higher death rate than any other population for cardiovascular disease (CVD) and high blood pressure (HBP). 1 out of 4 women die of heart disease in America. San Joaquin (SJ) has a growing rate of SA immigrant women who may be at risk for CVD. Objectives: Trainees conducted hypertension and CVD screenings at SA religious organizations to reduce the risk of CVD and spread awareness about the factors that lead to CVD and its implications in the SA female population due to environmental racism in the most underserved county for healthcare, SJ. Methods: I trained low-income minority medically ambitious female high school students to conduct weekly blood pressure screenings and serve as a health technology coach by each student monitoring 1 female hypertensive patient of 24 hypertensive or at risk hypertensive and low-income female SJ residents and constantly stressed, and at risk for CVD. CVD screenings were conducted at all SJ gurdwaras and mosques to spread awareness about female heart health and track hypertension in the SA community. Findings: -74.2% of the San Joaquin South Asian female population (SJSAFP) are at risk for CVD-52.9% of the SJSAFP are Stage 1 hypertensive-60.9% of the SJSAFP are Stage 2 hypertensive-22.4% of the SJSAFP have normal blood pressure but consume red meat more than 4 times a month-16.3% of the SJSAFP female population of SJ are hypotensive Direct Outcomes of Events: -Development of self advocacy in the SJSAFP community and females became activists for their own heart health-SJ female high school students trained for community outreach events and determined to practice medicine in SJ to address female health disparities-Youth learned the value of empathy, multiculturalism, gender health equity and service to disadvantaged communities through the program and volunteering-Increased participation of youth and women, in an otherwise adult and male dominant environment (i.e. the mosques and gurdwaras)-Increased awareness on the determinants of CVD and hypertension in SJSAFP-Increased interaction between community members of different religions, creed and genders -Awareness and education among the SJSAFP community for better heart health-Improved patient provider trust
Deconstructing Inequities — Transparent Values in Measurement and Analytic Choices
Authors: Marjory L. Givens, Keith P. Gennuso, Elizabeth A. Pollock, Sheri L. Johnson
Journal: New England Journal of Medicine (2021)

Deconstructing Inequities An important step in addressing racism as a U.S. public health crisis is accurate measurement of progress necessary to hold ourselves collectively accountable. Public Heal...
Machine-learning model derived gene signature predictive of paclitaxel survival benefit in gastric cancer: results from the randomised phase III SAMIT trial
Authors: Raghav Sundar, Nesaretnam Barr Kumarakulasinghe, Yiong Huak Chan, Kazuhiro Yoshida, Takaki Yoshikawa, Yohei Miyagi, Yasushi Rino, Munetaka Masuda, Jia Guan, Junichi Sakamoto, Shiro Tanaka, Angie Lay-Keng Tan, Michal Marek Hoppe, Anand D. Jeyasekharan, Cedric Chuan Young Ng, Mark De Simone, Heike I. Grabsch, Jeeyun Lee, Takashi Oshima, Akira Tsuburaya, Patrick Tan
Journal: Gut (2021)

Objective To date, there are no predictive biomarkers to guide selection of patients with gastric cancer (GC) who benefit from paclitaxel. Stomach cancer Adjuvant Multi-Institutional group Trial (SAMIT) was a 2×2 factorial randomised phase III study in which patients with GC were randomised to Pac-S-1 (paclitaxel +S-1), Pac-UFT (paclitaxel +UFT), S-1 alone or UFT alone after curative surgery. Design The primary objective of this study was to identify a gene signature that predicts survival benefit from paclitaxel chemotherapy in GC patients. SAMIT GC samples were profiled using a customised 476 gene NanoString panel. A random forest machine-learning model was applied on the NanoString profiles to develop a gene signature. An independent cohort of metastatic patients with GC treated with paclitaxel and ramucirumab (Pac-Ram) served as an external validation cohort. Results From the SAMIT trial 499 samples were analysed in this study. From the Pac-S-1 training cohort, the random forest model generated a 19-gene signature assigning patients to two groups: Pac-Sensitive and Pac-Resistant. In the Pac-UFT validation cohort, Pac-Sensitive patients exhibited a significant improvement in disease free survival (DFS): 3-year DFS 66% vs 40% (HR 0.44, p=0.0029). There was no survival difference between Pac-Sensitive and Pac-Resistant in the UFT or S-1 alone arms, test of interaction p&lt;0.001. In the external Pac-Ram validation cohort, the signature predicted benefit for Pac-Sensitive (median PFS 147 days vs 112 days, HR 0.48, p=0.022). Conclusion Using machine-learning techniques on one of the largest GC trials (SAMIT), we identify a gene signature representing the first predictive biomarker for paclitaxel benefit. Trial registration number UMIN Clinical Trials Registry: C000000082 (SAMIT); ClinicalTrials.gov identifier, 02628951 (South Korean trial)