tbuckley/cabot-search huggingface dataset:
Abstract MP060: Contributors to the Geographic Disparity in Stroke Incidence in the United States: Results From the Reasons for Geographic and Racial Disparities in Stroke Cohort
Authors: George Howard, Darwin R Labarthe, Virginia J Howard, Suzanne E Judd, Claudia S Moy, Brett M Kissela, Mary Cushman
Journal: Circulation (2017)

Introduction: Geographic disparities in US stroke risk have recently been confirmed by REGARDS, but contributors to this are unknown. Higher prevalence of risk factors (RF) and lower socioeconomic status (SES) may contribute to this geographic disparity. For a RF/SES to contribute to this disparity it must both : 1) have a large geographic difference in prevalence, and 2) be powerfully associated with stroke risk. Methods: The 1,623 counties of residence of 24,863 REGARDS participants were placed in quartiles of Vital Statistics stroke mortality. Logistic regression assessed the geographic difference in prevalence of each RF/SES by quartile of stroke mortality. Proportional hazards was used to calculate HR stroke for each RF/SES. Mediation analysis then estimated the proportion of increased stroke incidence in counties with high stroke mortality explained by each RF/SES. Results: Higher county-level stroke mortality was significantly associated with low neighborhood SES (nSES), and more weakly associated with low education and presence of RFs (left column of table). Over 8-years follow-up there were 1,194 stroke events. Hypertension, diabetes and heart disease were all more strongly associated with higher stroke risk (HR ≥1.59) than nSES (HR = 1.21) (center column of table). The large differences in nSES between regions overcame the somewhat weaker association of nSES with stroke risk, since nSES was the largest single contributor to the geographic disparity in stroke incidence, accounting for 20.5% of the disparity (95% CI: 7.1 - 34.0) (right column in table). In multivariable analysis nSES, hypertension and diabetes collectively mediated27% of the geographic disparity (95% CI: 20.0% - 34.0%), but the association with county-level mortality remained significant (p = 0.006). Conclusion: Lower nSES played the largest role in explaining the county-level geographic disparity in stroke incidence in REGARDS, however, 73% of the excess risk of stroke incidence was not explained by any studied factors.
Person-centred maternity care in low-income and middle-income countries: analysis of data from Kenya, Ghana, and India
Authors: Patience A Afulani, Beth Phillips, Raymond A Aborigo, Cheryl A Moyer
Journal: The Lancet Global Health (2018)

BackgroundSeveral qualitative studies have described disrespectful, abusive, and neglectful treatment of women during facility-based childbirth, but few studies document the extent of person-centred maternity care (PCMC)—ie, responsive and respectful maternity care—in low-income and middle-income countries. In this Article, we present descriptive statistics on PCMC in four settings across three low-income and middle-income countries, and we examine key factors associated with PCMC in each setting.MethodsWe examined data from four cross-sectional surveys with 3625 women aged 15–49 years who had recently given birth in Kenya, Ghana, and India (surveys were done from August, 2016, to October, 2017). The Kenya data were collected from a rural county (n=877) and from seven health facilities in two urban counties (n=530); the Ghana data were from five rural health facilities in the northern region (n=200); and the India data were from 40 health facilities in Uttar Pradesh (n=2018). The PCMC measure used was a previously validated scale with subscales for dignity and respect, communication and autonomy, and supportive care. We analysed the data using descriptive statistics and bivariate and multivariate regressions to examine predictors of PCMC.FindingsThe highest mean PCMC score was found in urban Kenya (60·2 [SD 12·3] out of 90), and the lowest in rural Ghana (46·5 [6·9]). Across sites, the lowest scores were in communication and autonomy (from 8·3 [3.3] out of 27 in Ghana to 15·1 [5·9] in urban Kenya). 3280 (90%) of the total 3625 women across all countries reported that providers never introduced themselves, and 2076 (57%) women (1475 [73%] of 1980 in India) reported providers never asked permission before performing medical procedures. 120 (60%) of 200 women in Ghana and 1393 (69%) of 1980 women in India reported that providers did not explain the purpose of examinations or procedures, and 116 (58%) women in Ghana and 1162 (58%) in India reported they did not receive explanations on medications they were given; additionally, 104 (52%) women in Ghana did not feel able to ask questions. Overall, 576 (16%) women across all countries reported verbal abuse, and 108 (3%) reported physical abuse. PCMC varied by socioeconomic status and type of facility in three settings (ie, rural and urban Kenya, and India).InterpretationRegardless of the setting, women are not getting adequate PCMC. Efforts are needed to improve the quality of facility-based maternity care.FundingBill & Melinda Gates Foundation, Marc and Lynne Benioff, and USAID Systems for Health.
Cryosurgery for the treatment of cutaneous sporotrichosis: experience with 199 cases
Authors: V. Fichman, A.C.F. Valle, D.F.S. Freitas, F.M.S. Sampaio, M.R. Lyra, P.M. Macedo, R. Almeida‐Paes, R.V.C. Oliveira, M.C. Gutierrez‐Galhardo
Journal: British Journal of Dermatology (2018)

Sporotrichosis is a worldwide distributed subcutaneous mycosis caused by the dimorphic fungi belonging to the genus Sporothrix.1 Since 1998, Rio de Janeiro (RJ), Brazil, became a hyperendemic region for cat-transmitted zoonotic sporotrichosis associated with the most virulent species, S. brasiliensis.1,2 Itraconazole is the first choice of treatment for cutaneous sporotrichosis, terbinafine and potassium iodide are alternative options. The median time until the cure is around 12 weeks, but it can be longer for some patients and adverse effects may lead to discontinuation of treatment.2-5 Cryosurgery is an effective method largely used in dermatology. This article is protected by copyright. All rights reserved.
Enhancing NY-ESO-1 antigen expression in lung cancer cells through gene hypomethylation using 5-Aza-2′-deoxycytidine
Authors: S. Dermime, V. Inchakalody, V. Nair, A. El-Ashi, S. Taleb, Q. Fernandes, L. Al-Zaidan, A. Iskandarani, S. Sivaraman, F. Sahir, R. Krishnankutty, L. Therachiyil, M. Merhi, A. Raza, S. Uddin, E. Elkord, A. Knuth
Journal: Annals of Oncology (2018)

Background: NY-ESO-1 is a highly immunogenic cancer-testis antigens and it is a potential candidate for immunotherapy. Cellular expression of NY-ESO-1 gene is heterogeneous depending on the demethylation status of its promoter. Exposure to 5-aza-2'-deoxycytidine (5-aza-CdR) has been reported to enhance NY-ESO-1 protein expression. Our aim is to study the effect of 5-aza-CdR on NY-ESO-1 expression in lung cancer cell lines. Methods: Three human lung cancer cell lines were treated with 5µM of 5-aza-CdR. NY-ESO-1 protein expression was analyzed using cellular ELISA. NCI-H1975 and NCI-H522 were tested for their dose response to increasing doses of 5-aza-CdR (2.5 to 10μM). Expression of NY-ESO-1 mRNA was assessed using qRT-PCR. Cellular ELISA, western blot (WB) and flow cytometry (FACS) techniques were used to assess NY-ESO-1 protein expression. Epigenetic modifications of CpG islands in NY-ESO-1 gene were analyzed using bisulfate sequencing. The proteomic profiling of the cells was carried out using label-free mass spectrometry analysis. Results: NCI-H1975 and NCI-H522 cells had significantly enhanced expression (11 and 1.6 folds) of NY-ESO-1 protein after exposure to 5µM of 5-aza-CdR. Cellular ELISA showed a dose-dependent increase of NY-ESO-1 protein in both cell lines with the highest expression for NCI-H1975 (16 folds vs. control). qRT-PCR data showed a dose-dependent increase in NY-ESO-1 mRNA expression in both cells, with peak expression in NCI-H1975 cells (128 folds) at 10μM of 5-aza-CdR. FACS and WB analysis revealed increased protein expression with increasing concentration of 5-aza-CdR. Moreover, the CpG islands in the NY-ESO-1 gene were significantly hypomethylated in treated cells especially at 5μM. Proteomic profiling resulted in identification of various proteins with differential expression and functions. Conclusions: We have shown that treatment with 5-aza-CdR enhances the expression of epigenetically silenced NY-ESO-1 antigen in lung cancer cells and this should trigger T cells immune responses against the NY-ESO-1 antigen resulting in tumor suppression. Further in vivo studies are required to apply such treatment to be as an innovative immunotherapeutic approach to treat lung cancer patients. Legal entity responsible for the study: Medical Research Center, Hamad Medical Corporation, Doha, Qatar. Funding: Medical Research Center, Hamad Medical Corporation, Doha, Qatar. Disclosure: All authors have declared no conflicts of interest.
A novel premature termination mutation in <i> <scp>FDPS</scp> </i> in a Chinese family with disseminated superficial actinic porokeratosis
Authors: P.‐Q. Zhu, H.‐M. Yan, H.‐J. Zhao, D.‐Y. Guo, W. Jiang
Journal: British Journal of Dermatology (2018)
DNA Analysis of Mutations in the Kinase Domain of BCR-ABL1 By Allele-Specific Digital PCR Is Highly Sensitive and Refines Prediction of Kinetics of Resistant CML Clones
Authors: Vaclava Polivkova, Nikola Curik, Hana Zizkova, Adela Benesova, Pavel Burda, Pavla Pecherkova, Eliska Motlova, Jana Brezinova, Sarka Ransdorfova, Hana Klamova, Lenka Hovorkova, Jan Zuna, Thomas Ernst, Simona Soverini, Katerina Machova
Journal: Blood (2018)
PD-L1 blockade during ex vivo expansion of virus-specific T cells for the treatment of infections after allogeneic hematopoietic stem cell transplantation modulates the phenotype and functional activity of T cells
Authors: M. Merhi, M. Jalis, S. Sivaraman, V. Inchakalody, A. Raza, M. Bakr, G. Pittari, S. Uddin, A. Knuth, S. Dermime
Journal: Annals of Oncology (2018)

Background: Viral infection is a major cause of disease and mortality after allogeneic hematopoietic stem cell transplantation (AHSCT) in hematologic malignancies. It has been shown that adoptive transfer of expanded virus-specific T cells (VSTs) was capable of treating infections that are resistant to conventional therapies. Recently, it has been shown that PD-L1 expression by activated T cells plays a major role on their survival and activity. Here, we investigated PD-L1 expression during VSTs expansion and the effect of PD-L1 blockade on the phenotype and functional activity of these VSTs. Methods: VSTs were generated from healthy donors PBMCs with or without the addition of PD-L1 antibody after stimulation in G-Rex-10 flasks with a pool of 11 overlapping peptides libraries spanning the 5 most immunodominant viral antigens. All VSTs were collected at day 14. We used ELISpot assay to measure IFN-γ production by VSTs and flow cytometry analysis for phenotyping. Results: Blockade of PD-L1 has induced 1.8 folds higher proliferation rate and 2 folds increase in IFN-γ production against the viral antigens. After 6 days of expansion, 78% of CD4+ and 60% of CD8+ VST subsets expressed the PD-L1 molecule. At the end of expansion, CD4+ PD-L1+ VSTs were reduced to 6.8% whereas the CD8+ PD-L1+ VSTs were increased to 87.6%. Interestingly, PD-L1 blockade resulted in a further reduction in the CD4+ PD-L1+ population (2.2%), without affecting the CD8+ PD-L1+ VSTs (89.5%). After PD-L1 treatment, the cytotoxicity marker CD107 was slightly increased (1.2 folds) in the CD4+ cells but decreased by 2 folds in the CD8+ VSTs and CD4+ CD45RO+ memory T cells were decreased from 46.1% to 33%. Conclusions: We have standardized an ex vivo protocol for rapid expansion of VSTs against major viruses causing infection after AHSCT. These VSTs were shown to highly express PD-L1. Blocking of PD-L1 improved the expansion, the anti-viral specificity and the cytotoxicity of these VSTs. This should promote a long-lasting antiviral activity of VSTs in patients undergoing AHSCT. Further investigations are being carried out to confirm these results. Legal entity responsible for the study: Medical Research Center, Hamad Medical Corporation, Doha, Qatar. Funding: Medical Research Center, Hamad Medical Corporation, Doha, Qatar. Disclosure: All authors have declared no conflicts of interest.
Quantifying Importance of Major Risk Factors for Coronary Heart Disease
Authors: Michael J. Pencina, Ann Marie Navar, Daniel Wojdyla, Robert J. Sanchez, Irfan Khan, Joseph Elassal, Ralph B. D’Agostino, Eric D. Peterson, Allan D. Sniderman
Journal: Circulation (2019)

To optimize preventive strategies for coronary heart disease (CHD), it is essential to understand and appropriately quantify the contribution of its key risk factors. Our objective was to compare the associations of key modifiable CHD risk factors-specifically lipids, systolic blood pressure (SBP), diabetes mellitus, and smoking-with incident CHD events based on their prognostic performance, attributable risk fractions, and treatment benefits, overall and by age.Pooled participant-level data from 4 observational cohort studies sponsored by the National Heart, Lung, and Blood Institute were used to create a cohort of 22 626 individuals aged 45 to 84 years who were initially free of cardiovascular disease. Individuals were followed for 10 years from baseline evaluation for incident CHD. Proportional hazards regression was used to estimate metrics of prognostic model performance (likelihood ratio, C index, net reclassification, discrimination slope), hazard ratios, and population attributable fractions for SBP, non-high-density lipoprotein cholesterol (non-HDL-C), diabetes mellitus, and smoking. Expected absolute risk reductions for antihypertensive and lipid-lowering treatment were assessed.Age, sex, and race capture 63% to 80% of the prognostic performance of cardiovascular risk models. In contrast, adding either SBP, non-HDL-C, diabetes mellitus, or smoking to a model with other risk factors increases the C index by only 0.004 to 0.013. However, primordial prevention could have a substantial effect as demonstrated by population attributable fractions of 28% for SBP≥130 mm Hg and 17% for non-HDL-C≥130 mg/dL. Similarly, lowering the SBP of all individuals to <130 mm Hg or lowering low-density lipoprotein cholesterol by 30% would be expected to lower a baseline 10-year CHD risk of 10.7% to 7.0 and 8.0, respectively (absolute risk reductions: 3.7% and 2.7%, respectively). Prognostic performance decreases with age (C indices for age groups 45-54, 55-64, 65-74, 75-84 are 0.75, 0.72, 0.66, and 0.62, respectively), whereas absolute risk reductions increase (SBP: 1.1%, 2.3%, 5.4%, 10.3%, respectively; non-HDL-C: 1.1%, 2.0%, 3.7%, 5.9%, respectively).Although individual modifiable CHD risk factors contribute only modestly to prognostic performance, our models indicate that eliminating or controlling these individual factors would lead to substantial reductions in total population CHD events. Metrics used to judge importance of risk factors should be tailored to the research objectives.
OA03 Afatinib Followed by Osimertinib in Real-World Patients with EGFR Mutation-Positive Advanced NSCLC: The Giotag Study
Authors: M.J. Hochmair, A. Morabito, D. Hao, C. Yang, R. Soo, J.C. Yang, R. Gucalp, B. Halmos, A. Golembesky, A. Märten, T. Cufer
Journal: Journal of Thoracic Oncology (2018)
Abstract 11105: Cardiovascular Safety of the SGLT2 Inhibitor Dapagliflozin: Meta-Analysis With >6000 Patient-Years Exposure
Authors: Anna Maria Langkilde, Peter Johansson, Agata Ptasynska, Eva Johnsson
Journal: Circulation (2013)

Cardiovascular disease (CVD) risk is increased in patients with type 2 diabetes mellitus (T2DM). Dapagliflozin (DAPA), a selective SGLT2 inhibitor, is approved treatment for T2DM in several countri...
Metastatic Bulk Independently Predicts Outcomes for EGFR Precision Targeting in Colorectal Cancer
Authors: Jeremy D. Kratz, Nataliya V. Uboha, Sam J. Lubner, Daniel L. Mulkerin, Linda Clipson, Yanyao Yi, Menggang Yu, Kristina A. Matkowskyj, Noelle K. LoConte, Dustin A. Deming
Journal: Journal of the National Comprehensive Cancer Network (2018)

Background: Molecular profiles guide the clinical management of metastatic colorectal cancer (mCRC), particularly related to the use of anti–epidermal growth factor receptor (EGFR) antibodies. Tumor sidedness has also been implicated in resistance to these therapies, but has largely been studied in the first-line setting. We examined the role of tumor sidedness and disease bulk in predicting clinical outcomes to anti-EGFR therapy in the treatment-refractory setting. Methods: We identified a retrospective cohort of 62 patients with KRAS wild-type mCRC who received anti-EGFR therapy in the late-line setting. Response was assessed per RECIST 1.1, with bulky disease defined as any single lesion >35 mm in longest cross-sectional diameter or nodal short axis. Primary sidedness was defined in relation to the splenic flexure. Results: Patients with right-sided primary tumors at time of late-line EGFR therapy presented with increased tumor bulk and worsened overall survival (OS) relative to left-sided primary tumors. Tumor bulk, defined as either a categorical or continuous variable, predicted worsened progression-free survival (PFS) and OS, which persisted when controlling for differences in the primary tumor location. Within the right-sided cohort, no objective responses were observed for bulky disease or during treatment with anti-EGFR monotherapy. The nonbulky cohort experienced clinical benefit with anti-EGFR monotherapy, showing similar PFS and an improved response rate compared with sequential chemotherapy. Conclusions: In an effort to expand understanding of the role of primary sidedness in clinical response to anti-EGFR therapy, we identified sidedness and tumor bulk as potential predictive biomarkers of clinical response in late-line mCRC. Future prospective studies of EGFR targeting should consider tumor bulk in addition to molecular profiling in the identification of populations most likely to achieve meaningful clinical benefit.
Enhancers in the Peril lincRNA locus regulate distant but not local genes
Authors: Abigail F. Groff, A. Rasim Barutcu, Jordan P. Lewandowski, John L. Rinn
Journal: Genome biology (2018)

Recently, it has become clear that some promoters function as long-range regulators of gene expression. However, direct and quantitative assessment of enhancer activity at long intergenic noncoding RNA (lincRNA) or mRNA gene bodies has not been performed. To unbiasedly assess the enhancer capacity across lincRNA and mRNA loci, we performed a massively parallel reporter assay (MPRA) on six lincRNA loci and their closest protein-coding neighbors.For both gene classes, we find significantly more MPRA activity in promoter regions than in gene bodies. However, three lincRNA loci, Lincp21, LincEnc1, and Peril, and one mRNA locus, Morc2a, display significant enhancer activity within their gene bodies. We hypothesize that such peaks may mark long-range enhancers, and test this in vivo using RNA sequencing from a knockout mouse model and high-throughput chromosome conformation capture (Hi-C). We find that ablation of a high-activity MPRA peak in the Peril gene body leads to consistent dysregulation of Mccc1 and Exosc9 in the neighboring topologically associated domain (TAD). This occurs irrespective of Peril lincRNA expression, demonstrating this regulation is DNA-dependent. Hi-C confirms long-range contacts with the neighboring TAD, and these interactions are altered upon Peril knockout. Surprisingly, we do not observe consistent regulation of genes within the local TAD. Together, these data suggest a long-range enhancer-like function for the Peril gene body.A multi-faceted approach combining high-throughput enhancer discovery with genetic models can connect enhancers to their gene targets and provides evidence of inter-TAD gene regulation.
Quantitative Label‐Free Imaging of 3D Vascular Networks Self‐Assembled in Synthetic Hydrogels
Authors: Gaurav Kaushik, Daniel A. Gil, Elizabeth Torr, Elizabeth S. Berge, Cheryl Soref, Peyton Uhl, Gianluca Fontana, Jessica Antosiewicz‐Bourget, Collin Edington, Michael P. Schwartz, Linda G. Griffith, James A. Thomson, Melissa C. Skala, William T. Daly, William L. Murphy
Journal: Advanced Healthcare Materials (2018)

Vascularization is an important strategy to overcome diffusion limits and enable the formation of complex, physiologically relevant engineered tissues and organoids. Self-assembly is a technique to generate in vitro vascular networks, but engineering the necessary network morphology and function remains challenging. Here, autofluorescence multiphoton microscopy (aMPM), a label-free imaging technique, is used to quantitatively evaluate in vitro vascular network morphology. Vascular networks are generated using human embryonic stem cell-derived endothelial cells and primary human pericytes encapsulated in synthetic poly(ethylene glycol)-based hydrogels. Two custom-built bioreactors are used to generate distinct fluid flow patterns during vascular network formation: recirculating flow or continuous flow. aMPM is used to image these 3D vascular networks without the need for fixation, labels, or dyes. Image processing and analysis algorithms are developed to extract quantitative morphological parameters from these label-free images. It is observed with aMPM that both bioreactors promote formation of vascular networks with lower network anisotropy compared to static conditions, and the continuous flow bioreactor induces more branch points compared to static conditions. Importantly, these results agree with trends observed with immunocytochemistry. These studies demonstrate that aMPM allows label-free monitoring of vascular network morphology to streamline optimization of growth conditions and provide quality control of engineered tissues.
The Biopolitics of Passing and the Possibility of Radically Inclusive Transgender Health Care
Authors: Patrick R. Grzanka, Elliott DeVore, Kirsten A. Gonzalez, Lex Pulice-Farrow, David Tierney
Journal: The American Journal of Bioethics (2018)

For them, the decision to have cosmetic surgery is described as a way to become ‘ordinary’, ‘normal’—‘just like everyone else’. Based on these stories, I concluded that it makes more sense to frame...
Many patients in England are waiting more than two weeks to see a GP, figures show
Authors: Jacqui Wise
Journal: BMJ (2018)

A fifth of patients waited more than two weeks for a general practice appointment in October, show new figures from NHS Digital.1 General practices in England had 27 million appointments in October, with almost five million of them taking place between 15 and 28 days from the booking date.

The figures show that 40.2% of appointments took place on the same day they were booked. A further 6.6% of patients were seen within one day and 20% between two and seven days after booking.

It is the first time that the NHS in England has collected and issued figures in this way and comes after a request from …
Cell Free Tumor DNA for DLBCL Genotyping in a Phase II Randomized Trial Comparing Standard RCHOP Versus Brcap As First Line Treatment in Patients with Poor IPI DLBCL
Authors: Nerea Martinez, Sonia González de Villambrosia, Ainara Pereña, Raul Tonda, Sergi Beltran, Marta Gut, Estrella Carrillo-Cruz, Carlos Grande, Alejandro Martín, Concepcion Nicolas, Jose Maria Roncero, Maria J. Rodriguez-Salazar, Jaime Perez De Oteyza, Eulogio Conde, Eva Gonzalez-Barca, Santiago Montes-Moreno
Journal: Blood (2018)
Abstract 18487: Characteristics and Outcomes of Patients With Severe Aortic Stenosis (Peak Gradients > 125 mm Hg)
Authors: Nishtha Sodhi, Kanhaiya Lal Poddar, Sachin Goel, Dhruv Modi, Navkaranbir Bajaj, Shiraz Rahim, E. Murat Tuzcu, Lars G Svensson, Brian P Griffin, Samir R Kapadia
Journal: Circulation (2013)

Background: Limited data exists about the unique echocardiographic characteristics of patients with very high gradient severe aortic stenosis (VHG-SAS). We sought to determine if there are differen...