tbuckley/cabot-search huggingface dataset:
Abstract 13846: Growth Differentiation Factor 15 and Risk of Clinical Bleeding Events in the Atherosclerosis in Communities (ARIC) Study
Authors: Lena Mathews, Ning Ding, Junichi Ishigami, Mahmoud Al Rifai, Ron C Hoogeveen, Josef Coresh, Ballantyne M Christie, Elizabeth Selvin, Kunihiro Matsushita
Journal: Circulation (2020)

Introduction: Growth differentiation factor 15 (GDF15), a cytokine growth factor, is a predictor of bleeding in people with cardiovascular disease (CVD). Potential mechanisms include direct inhibition of platelet activity or as a marker of tissue vulnerability. Hypothesis: We hypothesized that GDF15 will also be associated with bleeding in individuals without a history of CVD. Methods: We studied the association of GDF15 with clinical bleeding events among 9,850 ARIC participants without prior bleeding and CVD at baseline (mean age 60 years, 57% female, 21% black). Serum levels of GDF15 were measured in relative fluorescence units using DNA-based aptamer technology (SOMA scan assay). Bleeding events were ascertained using discharge codes. We examined incidence rates for bleeding using Poisson models, hazard ratios (HRs) of incident bleeding using Cox models, and the improvement in risk prediction of bleeding using the Harrell’s- c statistic with the addition of GDF15 to established predictors in a commonly used bleeding risk score. Results: There were 1,291 hospitalizations with bleeding during a median follow up of 22.1 years through 2018, with the majority (87.8%) being gastrointestinal bleeding. The incidence rate of bleeding per 1,000 person-years was 3.4 in the highest quartile of GDF15 and 1.8 in the lowest quartile. The highest quartile of GDF15 was associated with an adjusted HR of 1.52 (95% CI 1.27-1.81) for total bleeding and 1.55 (1.28-1.88) for gastrointestinal bleeding compared to the lowest quartile. The addition of GDF15 to a validated bleeding risk score improved the c- statistic by 0.030 (0.010-0.50) from 0.640 to 0.669. Conclusions: Higher levels of GDF15 were robustly associated with bleeding hospitalizations and improved risk prediction beyond conventional bleeding risk factors. Our results suggest the etiological contributions of GDF15 to bleeding and its potential usefulness for risk classification of bleeding in individuals without CVD.
Abstract 19981: Aortic Adventitial Fibroblast Sensitivity to Mitogen Activated Protein Kinase Inhibitors Depends on Substrate Stiffness
Authors: Rebecca A Scott, Prathamesh M Kharkar, Kristi L Kiick, Robert E Akins
Journal: Circulation (2016)

Introduction: Arterial stiffness changes due to pathogenic remodeling or vessel aging alter the mechanical environment of local adventitial cells; however, the effects of altered stiffness on adven...
Racial and Ethnic Disparities in Rates of Continuous Glucose Monitor Initiation and Continued Use in Children With Type 1 Diabetes
Authors: Charlene W. Lai, Terri H. Lipman, Steven M. Willi, Colin P. Hawkes
Journal: Diabetes Care (2020)

OBJECTIVE Racial/ethnic disparities in continuous glucose monitor (CGM) use exist among children with type 1 diabetes. It is not known whether differential rates of device initiation or sustained use are the cause of this disparity. Our objective was to compare CGM initiation rates and continued use among non-Hispanic White (NHW), non-Hispanic Black (NHB), and Hispanic children. RESEARCH DESIGN AND METHODS We conducted a retrospective review including children with type 1 diabetes attending the Children’s Hospital of Philadelphia between 1 January 2015 and 31 December 2018. RESULTS Of 1,509 eligible children, 726 (48%) started CGM during the study period. More NHW (54%) than NHB (31%) and Hispanic (33%) children started CGM (P &amp;lt; 0.001). One year after starting, fewer NHB (61%) than NHW (86%) and Hispanic (85%) children were using CGM (P &amp;lt; 0.001). CONCLUSIONS Lower CGM use in NHB children was due to lower rates of device initiation and higher rates of discontinuation. Interventions to address both of these barriers are needed to reduce disparities in CGM use.
The Fitz Patrick Lectures ON THE HISTORY OF MEDICINE: Delivered in the Royal College of Physicians
Authors: J. F. Payne
Journal: BMJ (1903)

MIEDICAL JOURNAiL [UY 4~3 related I lhave lost but 3 from the operation, and these were all amongst my earlier operationis.This gives a mortality of just over 9 per cent.I feel sure that, witlh growing experi- ence, we sliall be able to reduce that mortality still further.if so, there is 11o reason wlhat tlhat condition known as catheter life slhould niot in the main disappear.To some, it is true, it proves a matter of but sliglit inconivenienice, but there are few wlio would n-ot gladly resume their more youtlhful lhabits of micturitioni, eveni at the risk of an operation, if they realized to the full the dangers tlley are incurring from sepsis, quite apart fromii tlle weakness and lack of energy which is brouglht on by frequently rising at niight to empty their bladders.If the best results are to be obtained, the operation must be performiied before the bladder becomes septic.
Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly
Authors: Guoliang Chai, Alice Webb, Chen Li, Danny Antaki, Sangmoon Lee, Martin W. Breuss, Nhi Lang, Valentina Stanley, Paula Anzenberg, Xiaoxu Yang, Trevor Marshall, Patrick Gaffney, Klaas J. Wierenga, Brian Hon-Yin Chung, Mandy Ho-Yin Tsang, Lynn S. Pais, Alysia Kern Lovgren, Grace E. VanNoy, Heidi L. Rehm, Ghayda Mirzaa, Eyby Leon, Jullianne Diaz, Alexander Neumann, Arnout P. Kalverda, Iain W. Manfield, David A. Parry, Clare V. Logan, Colin A. Johnson, David T. Bonthron, Elizabeth M.A. Valleley, Mahmoud Y. Issa, Sherif F. Abdel-Ghafar, Mohamed S. Abdel-Hamid, Patricia Jennings, Maha S. Zaki, Eamonn Sheridan, Joseph G. Gleeson
Journal: Neuron (2020)
Abstract 14213: Different Prognostic Value of Proteinuria According to the Severity of Heart Failure in Patients With Heart Failure With Preserved Ejection Fraction
Authors: Bolrathanak Oeun, Shungo Hikoso, Daisaku Nakatani, Hiroya Mizuno, Tetsuhisa Kitamura, Katsuki Okada, Tomoharu Dohi, Yohei Sotomi, Hirota Kida, Akihiro Sunaga, Taiki Sato, Takahisa Yamada, Yasumura Yoshio, Akito Nakagawa, Yusuke Nakagawa, Shunsuke Tamaki, Hayashi Takaharu, Masamichi Yano, Yasushi Sakata
Journal: Circulation (2020)

Introduction: Proteinuria reflects systemic inflammation and endothelial dysfunction, and is a prognosticator in heart failure with preserved ejection fraction (HFpEF). However, it remains elusive whether the prognostic impact of proteinuria is different according to the severity of HFpEF. Recently, we and other groups reported that echocardiographic diastolic dysfunction (DD) is a worse prognostic factor in HFpEF. Objectives: We aimed to clarify the prognostic value of proteinuria in HFpEF according to the severity of HFpEF. We used the evidence of DD as criteria of the severity of HFpEF. Methods: We assessed 575 discharged-alive patients (pts) in the PURSUIT-HFpEF registry. Pts were divided into 2 groups according to the absence (DD-) or presence of DD (DD+). DD was defined using the 2016 ASE recommendations. Each group was further classified into 2 subgroups according to the absence or presence of dipstick proteinuria (proteinuria trace or more). The study endpoint was a composite of all-cause mortality and HF hospitalization. Results: Median age 83 years and 58% female. The number of pts with DD-: 336 pts (221 pts: proteinuria-[G1], 115 pts: proteinuria+[G2]); and DD+: 239 pts (125 pts: proteinuria-[G3], 114 pts: proteinuria+[G4]). G4 had higher NT-proBNP level than G3, but not observed between G1 and G2. Proteinuria+ were more hypertensive, diabetic with worse renal function than proteinuria- in both DD-/DD+. The composite endpoint occurred more often in G4 than G3 (HR: 1.75, 95%CI: 1.18-2.62, log-rank P=0.005), but was similar between G1 and G2 (HR: 1.21, 95%CI: 0.76-1.92, log-rank P=0.431). Multivariable Cox regression adjusting for NT-proBNP, eGFR and other major confounding factors revealed that proteinuria was associated with the composite endpoint in DD+ (HR:1.85, 95% CI:1.16-2.93, P=0.009), but not in DD- (HR:0.96, 95% CI:0.55-1.69, P=0.900). Conclusions: Proteinuria may be an additive risk factor in pts with DD but not in those without DD in HFpEF.
Abstract 16661: Fluid Challenge During Right Heart Catheterization for Evaluation of Pulmonary Hypertension Identifies Patients With Decreased Right Ventricular Function
Authors: Vineet A Agrawal, Amelia Muhs, Tufik Assad, Ivan M Robbins, John Newman, Meredith E Pugh, Ryan J Tedford, Anna R Hemnes, Evan Brittain, Vineet Agrawal
Journal: Circulation (2020)

Introduction: Fluid challenge during right heart catheterization (RHC) identifies occult left heart diastolic dysfunction (Occ-DD) in 10-20% of patients initially diagnosed with pre-capillary pulmonary hypertension (PH). The prognostic implications of the response to fluid challenge are not known. Abnormal right ventricular (RV) function is a poor prognostic indicator in all forms of PH. Hypothesis: We hypothesized that fluid challenge during RHC identifies patients with worse RV function and survival. Methods: Consecutive patients referred for RHC with fluid challenge from 2009-2016 were studied. Occ-DD was defined by a resting pulmonary arterial wedge pressure (PAWP) &lt; 15 mmHg, and a PAWP &gt; 18 mmHg after 500cc fluid challenge. Resting DD was defined by resting PAWP &gt; 15 mmHg. RV function was assessed by pulmonary artery pulsatility index (PAPi) or RV stroke work index (RVSWI). Statistical analysis was conducted using Kruskal Wallis test. Survival analysis was conducted by log rank test. Results: Of the 310 patients identified, 83% were female with a mean age of 54 + 14 years. The cohort consisted of 204 (66%) patients without DD, 30 (10%) with Occ-DD, and 76 (24%) with resting DD. Patients with Occ-DD were older (59 + 12 vs 51 + 14, p &lt; 0.0001) with greater BMI (31 + 6 vs 28 + 7, p &lt; 0.0001), but had similar prevalence of obesity, hypertension, diabetes mellitus, and coronary disease to all groups. Patients with Occ-DD had lower PAPi (7.8 + 0.4 vs 8.5 + 0.4, p &lt; 0.0001), lower RVSWI (9.9 + 0.8 vs 17.8 + 0.7 mmHg*ml/m2, p &lt; 0.0001) (Figure), and decreased survival (3.7 + 3.5 vs 4.9 + 3.5 years, p &lt; 0.0001) compared to those without DD. After adjustment for RV function, survival was no longer different between groups. Conclusions: Patients with Occ-DD after fluid challenge during RHC have decreased survival due to worse RV function compared to patients without DD. These findings suggest important prognostic implications for fluid challenge in the evaluation of patients with PH.
Idiopathic Retroperitoneal Fibrosis With Intense Uptake of 68Ga-Fibroblast Activation Protein Inhibitor and 18F-FDG
Authors: Qingqing Pan, Yaping Luo, Wen Zhang
Journal: Clinical Nuclear Medicine (2020)

Abstract A 26-year-old man presented with a retroperitoneal mass with left urinary tract obstruction and hydronephrosis recently. 18 F-FDG PET/CT showed the retroperitoneal mass had intense and homogeneous FDG avidity. In 68 Ga-FAPI PET/CT, the retroperitoneal mass showed intense radioactivity without other organ involvements. The patient was finally diagnosed with idiopathic retroperitoneal fibrosis. After treatment, the follow-up CT showed significant decrease in size of the retroperitoneal mass. The current case indicated that idiopathic retroperitoneal fibrosis had active uptake of 68 Ga-FAPI.
Abstract 15808: Relationship Between Myocardial Injury, Wall Motion Abnormalities and Mortality in Patients With Covid-19: The Circ-19 Registry
Authors: Anton Camaj, Gennaro Giustino, Michael Miller, Annapoorna Kini, Giulio Stefanini, Solomon Bienstock, Renato Bragato, Jeffrey Silbiger, Marco Vicenzi, Tatyana Danilov, Nina Kukar, Nada Shaban, Connor Oates, Samin K Sharma, Stamatios Lerakis, Lori B Croft, Martin E Goldman
Journal: Circulation (2020)

Introduction: Myocardial injury is commonly observed in patients (pts) with Coronarvirus disease 2019 (Covid-19) but its anatomical correlate has not been elucidated. We evaluated the association between presence of transthoracic echocardiographic (TTE) left ventricular (LV) regional wall motion abnormalities (RWMA), myocardial injury and outcomes in Covid-19 pts. Methods: We conducted a cohort study including 7 hospitals in New York City (US) and Milan (Italy) of hospitalized pts with confirmed Covid-19 who had a TTE during their index hospitalization. Myocardial injury was defined as any elevation in cardiac troponin (cTn) during the hospitalization. Using multivariable logistic regression, we analyzed the association between RWMA, myocardial injury and in-hospital death. Results: Among 305 total pts included in the study, 49 (16%) had RWMA and 44 (14%) had global LV systolic dysfunction. Among those with RWMA, 31/49 (63%) had LV ejection fraction &lt;50%. Compared to pts without RWMA, pts with RWMA more commonly had chest pain at time of presentation (36% vs. 14%; p=0.001), ST segment changes on ECG (33% vs. 6%; p&lt;0.0001) and myocardial injury (90% vs. 57%; p&lt;0.001). After multivariable analysis, RWMA remained associated with myocardial injury (adjOR: 5.92; 95% CI: 2.17-16.17), but not death. Left heart catheterization (LHC) was performed in 9 of the 49 (18%) pts with RWMA, 8 of which had confirmed ACS and 7 underwent PCI. Myocardial injury was associated with higher risk of death regardless of the presence or absence of RWMA ( Figure 1 ). Conclusion: In Covid-19 pts, RWMA are associated with typical ACS presentation: chest pain, ST changes and cTn elevations. Accordingly, a large proportion of pts with RWMA who underwent LHC had confirmed ACS warranting PCI. Though myocardial injury was associated with increased risk of in-hospital death regardless of the presence of RWMA, LHC should be considered for pts with RWMA and myocardial injury to rule-out obstructive disease.
Clinicogenomic Analysis of <i>FGFR2</i>-Rearranged Cholangiocarcinoma Identifies Correlates of Response and Mechanisms of Resistance to Pemigatinib
Authors: Ian M. Silverman, Antoine Hollebecque, Luc Friboulet, Sherry Owens, Robert C. Newton, Huiling Zhen, Luis Féliz, Camilla Zecchetto, Davide Melisi, Timothy C. Burn
Journal: Cancer Discovery (2020)

Abstract Pemigatinib, a selective FGFR1–3 inhibitor, has demonstrated antitumor activity in FIGHT-202, a phase II study in patients with cholangiocarcinoma harboring FGFR2 fusions/rearrangements, and has gained regulatory approval in the United States. Eligibility for FIGHT-202 was assessed using genomic profiling; here, these data were utilized to characterize the genomic landscape of cholangiocarcinoma and to uncover unique molecular features of patients harboring FGFR2 rearrangements. The results highlight the high percentage of patients with cholangiocarcinoma harboring potentially actionable genomic alterations and the diversity in gene partners that rearrange with FGFR2. Clinicogenomic analysis of pemigatinib-treated patients identified mechanisms of primary and acquired resistance. Genomic subsets of patients with other potentially actionable FGF/FGFR alterations were also identified. Our study provides a framework for molecularly guided clinical trials and underscores the importance of genomic profiling to enable a deeper understanding of the molecular basis for response and nonresponse to targeted therapy. Significance: We utilized genomic profiling data from FIGHT-202 to gain insights into the genomic landscape of cholangiocarcinoma, to understand the molecular diversity of patients with FGFR2 fusions or rearrangements, and to interrogate the clinicogenomics of patients treated with pemigatinib. Our study highlights the utility of genomic profiling in clinical trials. This article is highlighted in the In This Issue feature, p. 211
Surface decoration of development-inspired synthetic N-cadherin motif via Ac-BP promotes osseointegration of metal implants
Authors: Meiling Zhu, Kunyu Zhang, Lu Feng, Sien Lin, Qi Pan, Liming Bian, Gang Li
Journal: Bioactive Materials (2020)

Research works on the synergistic effect of surface modified bioactive molecules and bone metal implants have been highlighted. N-cadherin is regarded as a key factor in directing cell–cell interactions during the mesenchymal condensation preceding the osteogenesis in the musculoskeletal system. In this study, the N-cadherin mimetic peptide (Cad) was biofunctionalized on the titanium metal surface via the acryloyl bisphosphonate (Ac-BP). To learn the synergistic effect of N-cadherin mimetic peptide, when tethered with titanium substrates, on promoting osteogenic differentiation of the seeded human mesenchymal stem cells (hMSCs) and the osseointegration at the bone-implant interfaces. Results show that the conjugation of N-cadherin mimetic peptide with Ac-BP promoted the osteogenic gene markers expression in the hMSCs. The biofunctionalized biomaterial surfaces promote the expression of the Wnt/β-catenin downstream axis in the attached hMSCs, and then enhance the in-situ bone formation and osseointegration at the bone-implant interfaces. We conclude that this N-cadherin mimetic peptide tethered on Ti surface promote osteogenic differentiation of hMSCs and osseointegration of biomaterial implants in vitro and in vivo. These findings demonstrate the importance of the development-inspired surface bioactivation of metal implants and shed light on the possible cellular mechanisms of the enhanced osseointegration.
Abstract 305: Contemporary Analysis of Percutaneous Intraaortic Balloon Pump Therapy as a Bridge to Orthotopic Heart Transplant
Authors: Nadia H Bakir, Michael J Finnan, Joel D Schilling, Gregory A Ewald, Justin M Vader, Kunal D Kotkar, Akinobu Itoh, Marc R Moon, Muhammad F Masood
Journal: Circulation (2020)

Objective: Intra-aortic balloon pump (IABP) support has been used as a bridge to transplant (BTT) therapy for acutely deteriorating patients awaiting orthotopic heart transplantation (OHT). Given recent changes to the heart allocation algorithm which have expanded IABP use for BTT, the evaluation of device strategy, complications, and near-term survival is warranted. Methods: Patients bridged with IABP who underwent OHT between October 2018 and January 2020 at our institution were retrospectively reviewed (n=21). Chart review was conducted to assess IABP insertion site, timing of support, device-related complications, removal strategy, and thirty-day post-transplant mortality. Results: Patients were bridged with femoral (n=6), axillary (n=9), or femoral with axillary conversion (n=6) approaches for IABP insertion. Common complications included pump malposition (n=5), hematuria (n=4), pump exchange (n=9), and insertion site bleeding (n=2). Median duration of IABP support was 12 [7, 18] days and median time to removal after OHT was 1 [1, 2] day. IABP removal occurred at the bedside with direct pressure application for all femoral pumps (n=6). Among axillary pumps (n=15), 11 were removed at the bedside with direct pressure, 3 were removed in the operating room, and 1 was removed in the catheterization lab with device closure. There was no thirty-day mortality following OHT. Conclusion: Following the changes to the heart allocation algorithm, IABP has become the most common method of temporary mechanical circulatory support for patients awaiting OHT at our center with excellent early survival and acceptable complication rates. In addition to allowing patients to ambulate while on IABP, we find that axillary insertion did not result in excess bleeding complications and that bedside removal with direct pressure was a safe method for postoperative decannulation.
Optimized Doxorubicin Chemotherapy for Diffuse Large B-cell Lymphoma Exploits Nanocarrier Delivery to Transferrin Receptors
Authors: Artavazd Arumov, Piumi Y. Liyanage, Asaad Trabolsi, Evan R. Roberts, Lingxiao Li, Braulio C.L.B. Ferreira, Zhen Gao, Yuguang Ban, Austin D. Newsam, Melissa W. Taggart, Francisco Vega, Daniel Bilbao, Roger M. Leblanc, Jonathan H. Schatz
Journal: Cancer Research (2021)

Abstract New treatments are needed to address persistent unmet clinical needs for diffuse large B-cell lymphoma (DLBCL). Overexpression of transferrin receptor 1 (TFR1) is common across cancer and permits cell-surface targeting of specific therapies in preclinical and clinical studies of various solid tumors. Here, we developed novel nanocarrier delivery of chemotherapy via TFR1-mediated endocytosis, assessing this target for the first time in DLBCL. Analysis of published datasets showed novel association of increased TFR1 expression with high-risk DLBCL cases. Carbon–nitride dots (CND) are emerging nanoparticles with excellent in vivo stability and distribution and are adaptable to covalent conjugation with multiple substrates. In vitro, linking doxorubicin (Dox) and transferrin (TF) to CND (CND–Dox–TF, CDT) was 10–100 times more potent than Dox against DLBCL cell lines. Gain- and loss-of-function studies and fluorescent confocal microscopy confirmed dependence of these effects on TFR1-mediated endocytosis. In contrast with previous therapeutics directly linking Dox and TF, cytotoxicity of CDT resulted from nuclear entry by Dox, promoting double-stranded DNA breaks and apoptosis. CDT proved safe to administer in vivo, and when incorporated into standard frontline chemoimmunotherapy in place of Dox, it improved overall survival by controlling patient-derived xenograft tumors with greatly reduced host toxicities. Nanocarrier-mediated Dox delivery to cell-surface TFR1, therefore, warrants optimization as a potential new therapeutic option in DLBCL. Significance: Targeted nanoparticle delivery of doxorubicin chemotherapy via the TRF1 receptor presents a new opportunity against high-risk DLBCL tumors using potency and precision.
Exome Sequencing as a Potential Diagnostic Adjunct in Sporadic Congenital Hydrocephalus
Authors: William Sullivan, Benjamin C. Reeves, Phan Q. Duy, Carol Nelson-Williams, Weilai Dong, Sheng Chih Jin, Kristopher T. Kahle
Journal: JAMA Pediatrics (2020)

This study evaluates whole-exome sequencing as a diagnostic tool in a cohort of neurosurgically treated congenital hydrocephalus probands.