tbuckley/cabot-search huggingface dataset:
Abstract 14004: Long Term Outcomes of Ambulatory Outpatient Management of Acute Decompensated Heart Failure in a Heart Failure Specialist Nurse Delivered Consultant Led Unit versus Inpatient Management
Authors: Thomas Salmon, Hani essa, sophia brousas, Isobel Whybrow-huppatz, ashwin balu, carolyn jackson, Siji Nyjo, annmarie kelly, emeka oguguo, homeyra douglas, rajiv sankaranarayanan
Journal: Circulation (2021)

Introduction: Acutely decompensated heart failure (ADHF) usually results in hospitalisation for intravenous diuretics. The safety and efficacy of ambulatory or outpatient management of ADHF by heart failure specialist nurses has not been described before. Methods: This retrospective analysis compared 2 cohorts of consecutive ADHF patients - hospitalised in-patients (IP) versus outpatients (OP) who were treated with bolus intravenous diuretics in a specialist heart failure nurse delivered consultant led OP HF unit (Ambulatory HF Unit -AHFU) with input from various specialties (renal, diabetes, elderly care, chest, pharmacy, palliative, ascitic, pleural teams) from 2016 to 2020. Mean follow-up duration was similar for both groups (IP=46±8.1 months; OP=45.5± 7 months, p=0.1). We compared clinical risk scores using the Get With the Guidelines (GWTG) score, comorbidities using the Charlson Comorbidity Index (CCI) and frailty using the Rockwood Clinical Frailty Index (CFI). Results were expressed as mean±SD, analysed using the Student’s T test and Chi-squared test. Results: 1012 patients were treated in our specialist outpatient AHFU and 1889 patients were hospitalised. Mean number of visits per ambulatory spell was 5.1±-2.2 days and the median dose of furosemide was 220 mg (range 80-480). Average hospital stay for IP was 12.1±5 days. CCI (IP=6.5±2; OP=6.4±1.9; p=0.19) and mean GWTG scores were similar (IP=40.4±7.9; OP=39.9±7.1; p=0.09) between the 2 groups but mean Frailty Index was higher amongst the IP group (IP 5.1±1.2; OP 4.9±1; p=0&lt;0.001). 30 day hospitalisation and mortality (30 day,1 year and overall mortality) were lower in the OP cohorts. Conclusions: Ambulatory management of ADHF using bolus IV diuretics in a heart failure specialist nurse delivered consultant led multidisciplinary unit offers an effective alternative to hospitalisation and also leads to improved outcomes. Frailty Index can help assess suitability for outpatient management of ADHF.
Abstract 11991: Effects of Clozapine at Different Doses on Blood Pressure and Renal Sodium Transporters in Mice
Authors: Zhiyun Ren, Weiwan Wang, Chenyang Zhang, Min Ye, Xiaoyan Wang
Journal: Circulation (2021)

Introduction: one of major side effects of clozapine (common antipsychotic drug) is hypertension. Kidney regulates blood pressure by initiating and responding to renin-angiotensin-aldosterone system (RAAS) physiologically and pathophysiologically;the pathogenesis of hypertension is linked to, generally, the increases in the protein expressions and functions of renal sodium transport proteins along the nephron with or without RAAS activation. Methods: we examined the blood pressures (BP) and protein expressions of major sodium transport proteins profiled along the renal tubules in the C57Bl6/J male mice (9 weeks old, n=4-5/group) treated with clozapine at three doses of 5,10 and 20 mg/ kg for 1 week via intraperitoneal injection. Result: blood pressures (tail-cuff, BP98A, softron, Japan) were higher in clozapine at 20mg/kg/day than vehicle (SBP: 130±1.64 vs 109±1.39, DBP: 87 ±4.12 vs 69±2.10 mmHg, n=5/group) and not altered at 5 &amp; 10 mg/kg/day. BW was similar between groups. There were no differences in serum/urine creatinine and electrolytes except for a slight increase in serum sodium at dose of 20 mg/kg (152.8±0.71 vs 150.6±0.40, mmol/L).The renal protein expressions of NaPi2 (western blotting, 199±26 , % of vehicle), NKCC2(184±20), NCC(213±14), and ENaC-α(217±47)were higher at 20 mg/kg than vehicle. No increases were found in protein expressions of NHE3, αNKA, ENaC-β and ENaC-γ. The expressions of renin, AT1R and ACE at 20mg/kg were similar between groups while ACE2 was decreased (42±10). Renal protein expression of NKCC2 was increased in 5mg/kg (360±80, % of vehicle) and 10mg/kg (247±50) groups; NCC was increased at 5 mg/kg (175±9); α NKA was increased in 5mg/kg (216±5) and 10mg/kg (163±2) groups. Additional mice were treated with clozapine at 20mg/kg/day via osmotic mini-pump for 1 week (mini-pump) or administrated by intraperitoneal injection for 2 weeks (2wks). Increases of renal NKCC2 (mini-pump:180±21, 2wks:153±18) and NCC (mini-pump:171±22, 2 wks:160±23) were also found in those models. Conclusions: increases of renal sodium transport proteins, mainly NCC and NKCC2, contribute to the dose-related increase of BP in mice treated with clozapine and may play an important role in the pathogenesis of theclozapine-induced hypertension.
Abstract 12910: Impact of Perioperative Management of Cardiogenic Shock Using Percutaneous Ventricular Assist Device for Cardiovascular Surgery
Authors: Keitaro Domae, Koichi Toda, Masatoshi Hata, Keiwa Kin, Noriko Kodani, fumio yamana, Daisuke Yoshioka, Takuji Kawamura, Takafumi Masai, Shigeru Miyagawa, Yoshiki Sawa
Journal: Circulation (2021)

Introduction: Cardiogenic shock (CS) is still most challenging clinical conditions in cardiovascular medicine. Recently, hemodynamic support using percutaneous ventricular assist device (pVAD) demonstrated feasible and safe for CS, however the use of p-LVAD in the perioperative management presenting refractory CS eligible for cardiovascular surgery (CVS) is still unclear. Hypothesis: We hypothesize that the perioperative use of pLVAD was safe and effective and allow LV unload that can be associated with the good cardiac recovery. Methods: This was a retrospective study including 17 patients admitted at our centers who presented CS and with indication to CSV (average STS score 32.4%), in which p-LVAD was used as a bridge for hemodynamic stabilization. The primary endpoint was the clinical and hemodynamic stabilization before CVS, and the secondary endpoint was cardiac recovery and 30-day mortality. Results: The significant increasing of cardiac power output (0.41 to 0.82 W, p&lt;0.05) with titration the dose of inotropes (inotrope score 10.4 to 6.2, p&lt;0.05) was observed. Serum lactate level was also decreased (5.8 to 1.6, p&lt;0.01), which is indicator of tissue perfusion. The perioperative stabilization allowed the 15 patients (88.2 %) to be eligible for scheduled CVS after a median time of 2.0 days under pLVAD. Postoperatively, all patients could wean off p-PVAD with improvement of LVEF (38.6 to 47.4%, p&lt;0.05). 30-day mortality was 17.6 % which was superior to STS score. Conclusions: The use of the pLVAD is safe and feasible in patients eligible for CVS presenting refractory CS. It is also effective for clinical and hemodynamic stabilization preoperatively and postoperative cardiac recovery and improvement of clinical outcomes.
Subscribe to thrive: paid subscriptions to online medical education materials should be included with tuition fees
Authors: Katharine Lynch-Kelly
Journal: BMJ (2021)

Medical students across the UK subscribe to "paid for" online content in addition to spending significant amounts of (often loaned) money on tuition fees.I am one of them.You might be asking yourself why.I've thought about this too.Why is a student already paying £9250 a year in tuition fees adding further to their expenditure?Then I think about how I have an exam in a week, confirm the last four digits of my card number, and succumb to the inevitable.The products offered to students are hugely diverse in content, quality, and price, 1 ranging from question banks, online "textbooks," videos summarising conditions, and live lectures on "high yield" topics hosted by junior doctors.Many of these materials are so ingrained in medical school culture that they've become part of students' vernacular, with their names used as verbs synonymous with "to study.
EXTH-16. LP-184, A NOVEL ALKYLATING AGENT, IS EFFECTIVE IN GLIOBLASTOMA
Authors: Bachchu Lal, Aditya Kulkarni, Joseph McDermott, Umesh Kathad, Kishor Bhatia, Panna Sharma, John Laterra
Journal: Neuro-Oncology (2021)

Abstract Temozolomide (TMZ) is currently the most effective standard-of-care chemotherapy based on its ability to prolong survival of patients with newly diagnosed MGMT-methylated GBM. Blood-brain barrier permeable agents effective against TMZ-resistant GBMs (i.e. recurrent GBM, MGMT unmethylated GBM) are desperately needed. Lantern Pharma is currently developing LP-184, a hydroxyurea methyl acylfulvene derivative of irofulven guided by its AI platform RADRⓇ analysis showing that tumor cell sensitivity to LP-184 correlates positively with genes commonly upregulated in GBM and either associated with TMZ resistance (e.g. MGMT, UGDH) or tumor promotion (e.g. EGFR, ANXA2). In an in vitro 3D model that mimics the human BBB, the apparent permeability for LP-184 was 1.53E-04 cm/s at 30 minutes, comparable to 1.72E-04 cm/s for TMZ under identical conditions. LP-184 predominantly alkylates DNA at 3’-adenine predicting insensitivity to MGMT expression. In vitro cell toxicity assays in a panel of GBM cell lines and neurospheres reveal an IC50 range of 30 - 400 nM with the MGMT unmethylated cell line LN-18 being among the most sensitive. A single cycle of LP-184 (4 mg/kg, i.v, every other day X 4 doses) induced rapid and near complete regression of subcutaneous U87 xenografts pre-established in immune-deficient mice and statistically significantly prolonged survival of mice bearing pre-established orthotopic U87 xenografts (p &amp;lt; 0.0001). LP-184-induced DNA damage is associated with synthetic lethality in tumor cell lines with decreased expression of Nucleotide Excision Repair (NER) genes. Furthermore, interrogation of clinical databases for expression of 112 NER genes revealed that 25 - 37% of clinical GBM clusters in a low NER expression subgroup, predicting high sensitivity of low NER GBM subsets to LP-184. These findings identify LP-184 as a promising new alkylating agent and support its further development for GBM therapy.
Abstract 9746: Rig-1 Agonists Regulate Cardiac Reprogramming via Yy1
Authors: Syeda Baksh, Jiabiao Hu, Richard E Pratt, Victor J Dzau, Conrad Hodgkinson
Journal: Circulation (2021)

We have discovered that innate immunity plays an important role in the reprogramming of fibroblasts into cardiomyocytes. Previously, we have focused on the role of the TLR3-NFkB pathway. We have now found evidence for an alternative Rig-1:YY1 pathway. Specific Rig-1 agonists such as 3p-hpRNA were found to enhance the efficacy of cardiac reprogramming with cardiomyocyte-specific gene expression increasing by 10 to 20 fold (Actn2, Myh6, Tnni3; N=6; P&lt;0.01). Similarly, formation of new cardiomyocytes was increased 5 fold (N=3, P&lt;0.01). To determine the mechanism of action, MNase-seq was performed. MNase-seq indicated that Rig-1 activation induced transcription factor binding to genomic regions immediately downstream of the transcription start site of cardiomyocyte-specific genes (N=3, P&lt;0.01). Further analysis of the binding regions revealed an overabundance of YY1 binding sequences (N=3, P&lt;0.001). To understand the role of YY1, knockdown experiments were performed. YY1 knockdown completely ablated the effects of Rig-1 agonists on cardiac reprogramming (N=5, P&lt;0.01). To understand how YY1 was activating cardiomyocyte-specific genes, ChIP-seq and ChIP-qPCR was carried out. ChIP-seq and ChIP-qPCR indicated that following Rig-1 activation, YY1 associated with Kdm6 and P300. Kdm6 and P300 were found to work in concert; activating cardiomyocyte-specific gene expression via the removal of the inhibitory epigenetic mark tri-methylated lysine-27 of Histone-H3 and deposition of the stimulatory epigenetic mark acetylated lysine-4 of Histone-H3 (N=3, P&lt;0.01). To conclude, the Rig-1:YY1 pathway plays a critical role in cardiac reprogramming. Manipulation of the Rig-1:YY1 pathway may enhance the effectiveness of cardiac reprogramming in vivo.
Index60 Identifies Individuals at Appreciable Risk for Stage 3 Among an Autoantibody-Positive Population With Normal 2-Hour Glucose Levels: Implications for Current Staging Criteria of Type 1 Diabetes
Authors: Brandon M. Nathan, Maria J. Redondo, Heba Ismail, Laura Jacobsen, Emily K. Sims, Jerry Palmer, Jay Skyler, Laura Bocchino, Susan Geyer, Jay M. Sosenko
Journal: Diabetes Care (2021)

We assessed whether Index60, a composite measure of fasting C-peptide, 60-min C-peptide, and 60-min glucose, could improve the metabolic staging of type 1 diabetes for progression to clinical disease (stage 3) among autoantibody-positive (Ab+) individuals with normal 2-h glucose values (<140 mg/dL).We analyzed 3,058 Type 1 Diabetes TrialNet Pathway to Prevention participants with 2-h glucose <140 mg/dL and Index60 <1.00 values from baseline oral glucose tolerance tests. Characteristics associated with type 1 diabetes (younger age, greater Ab+, higher HLA DR3-DQ2/DR4-DQ8 prevalence, and lower C-peptide) were compared among four mutually exclusive groups: top 2-h glucose quartile only (HI-2HGLU), top Index60 quartile only (HI-IND60), both top quartiles (HI-BOTH), and neither top quartile (LO-BOTH). Additionally, within the 2-h glucose distribution of <140 mg/dL and separately within the Index60 <1.00 distribution, comparisons were made between those above or below the medians.HI-IND60 and HI-BOTH were younger, with greater frequency of more than two Ab+, and lower C-peptide levels, than either HI-2HGLU or LO-BOTH (all P < 0.001). The cumulative incidence for stage 3 was greater for HI-IND60 and HI-BOTH than for either HI-2HGLU or LO-BOTH (all P < 0.001). Those with Index60 values above the median were younger and had higher frequency of two or more Ab+ (P < 0.001) and DR3-DQ2/DR4-DQ8 prevalence (P < 0.001) and lower area under the curve (AUC) C-peptide levels (P < 0.001) than those below. Those above the 2-h glucose median had higher AUC C-peptide levels (P < 0.001), but otherwise did not differ from those below.Index60 identifies individuals with characteristics of type 1 diabetes at appreciable risk for progression who would otherwise be missed by 2-h glucose staging criteria.
Abstract 11193: Incremental Diabetogenic Effect of Statin According to Its Intensity in Acute Myocardial Infarction Patients Following Successful Percutaneous Coronary Intervention
Authors: Jah Choi, Jieun Lee, Byoung Geol Choi, Soohyung Park, Kyuho Lee, Seungmin Back, Dong Kang, Woohyeun KIM, Seung-young Roh, Jin Na, Cheol Ung Choi, Eung Ju Kim, Chang Gyu Park, Hong-Seog Seo, Myung Ho Jeong, Seung Woon Rha
Journal: Circulation (2021)

Introduction: Although statin therapy is strongly recommended in acute myocardial infarction (AMI) patients, there has been consistent concern regarding the development of new onset diabetes mellitus (NODM). Currently, there has been no data whether diabetogenic effect of statin is intensity dependent. In this study, we investigated the impact of different statin intensity on incidence of NODM up to 3 years. Methods: Among 13,104 AMI patients enrolled in the Korea AMI Registry (KAMIR) between November 2011 and May 2015, we enrolled the 5,906 patients without diabetes mellitus and successful percutaneous coronary intervention (PCI). There were 22.8% (1,349/5,906) of patients received high intensity stain and 76.0% (4,488/5,906) patients received moderate intensity, and only 1.2% (69/5,906) patients received low intensity statin. The incidence of NODM were investigated among three different intensity of statins up to 3 years. Results: At baseline, high intensity statin group showed higher baseline LDL cholesterol level, body mass index, and abdominal circumference compared to other groups. In Kaplan-Meier curve, the cumulative incidence of NODM was significantly higher in high intensity group than mild and moderate intensity group (7.8% vs. 1.5% vs. 5.9% respectively, Log rank p-value = 0.002, Figure 1A). The incremental diabetogenic tendency was observed in each individual statin in dose-dependant manner (Figure 1B). In Cox regression, the intensity of statin was statistically significant prognostic factor of NODM after adjusting age, and other metabolic variables, such as body mass index, abdominal circumstance, and level of serum triglyceride. Conclusions: Among the AMI patients underwent successful PCI, higher intensity statin was associated with higher incidence of NODM, showing the diabetogenic effect of statin intensity.
CTIM-01. PHASE II TRIAL OF PEMBROLIZUMAB AND LENVATINIB FOR LEPTOMENINGEAL METASTASES
Authors: Nancy Wang, Elizabeth Gerstner, Daniel Cahill, Kevin Oh, Jennifer Cahill, Priscilla Brastianos
Journal: Neuro-Oncology (2021)

Abstract Leptomeningeal metastasis (LMD) is a late complication of cancer with poor prognosis and median survival of approximately 4-6 weeks without treatment. Whole brain radiation remains the mainstay of treatment, however it can cause significant neurocognitive sequelae and has not been shown to prolong overall survival. Thus, new treatment strategies are urgently needed to improve outcomes in patients with LMD. Results from recent Phase 2 studies of immune checkpoint inhibitors in LMD shows promising improvement in overall survival. Combining anti-VEGF therapy and immunotherapy may control symptoms due to inflammation and tumor-induced irritation, minimize steroid use, and promote improved efficacy of immunotherapy through modulation of the tumor immune microenvironment. We designed a multi-institutional, single-arm Phase 2 study of pembrolizumab in combination with lenvatinib in patients with LMD from any solid tumor. The primary objective is to estimate the overall survival rate at 6 months (OS6). A Simon two-stage design with a total sample size of 19 evaluable patients will be used to compare a null hypothesis of OS6 of 25% against an alternative hypothesis of 55%. Secondary objectives include assessing safety of pembrolizumab and lenvatinib in this patient population, systemic response rate, intracranial/intraspinal response rate, and progression-free survival. We will also explore clinician-reported neurologic outcomes and patient-reported quality of life and symptom burden. Blood, cerebrospinal fluid, and tissue biomarkers will be analyzed to determine predictors of response. Patients must be on minimal doses of steroids prior to study enrollment and cannot have received prior immune checkpoint inhibitor or anti-VEGF therapy. Response to treatment will be determined using RANO-BM for intracranial disease and RECIST 1.1 for systemic disease. Study accrual is anticipated over 12-24 months with anticipated total study duration of 30 months.
NCMP-02. NEUROTOXICITY RELATED TO CAR T-CELL THERAPY IN PATIENTS WITH SECONDARY CENTRAL NERVOUS SYSTEM LYMPHOMA
Authors: Carlen Yuen, Sarah Wesley, Koen Van Besien, Jing-Mei Hsu, Ran Reshef, Fabio Iwamoto, Aya Haggiagi, Rajiv Magge
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Patients with secondary CNS lymphoma (SCNSL) were excluded from the pivotal trials that led to the approval of chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory (R/R) B-cell lymphomas due to concern for neurotoxicity (NT). Limited evidence exists for axicabtagene ciloleucel (axi-cel, Yescarta®) in SCNSL patients. METHODS In this retrospective study, 15 R/R lymphomas patients with SCNSL (14 DLBCL, 1 chronic lymphocytic leukemia) were treated with commercial axi-cel between March 2019 and April 2021 for systemic disease and assessed for NT using the Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) and CTCAE toxicity grading systems. RESULTS Seven of 15 patients (47%) developed NT, all of whom had cytokine release syndrome (CRS). Four (27%) developed severe NT (Grade III-IV). In the 8 patients (53%) with active SCNSL, 6 (75%) did not develop NT and 2 (25%) developed severe NT. In the 4 severe NT patients, all had multifocal CNS disease and 3/4 (75%) had leptomeningeal disease. Two thirds of patients previously treated with RT developed severe NT (1 whole brain RT, 1 skull base). The third patient had RT to the eye. Four of 8 (50%) patients with prior intrathecal chemotherapy developed severe NT. Five patients relapsed (3 in the CNS), none of whom had NT. At 11.7 month median follow-up, 8 patients remain alive, 5 are deceased (1 from NT, 3 from progression, 1 from infection), 2 lost to follow-up. The patient who died from NT had prior temporal arteritis. Three additional patients with autoimmune disease did not develop severe NT. CONCLUSION In this limited cohort, presence of SCNSL did not increase NT incidence compared to historical outcomes of CAR T-cell therapy patients without SCNSL. This cohort will be compared to CAR T-cell therapy patients without SCNSL. Prospective studies of CAR T-cell therapy in SCNSL patients will be informative.
Persistent symptoms following SARS-CoV-2 infection amongst children and young people: A meta-analysis of controlled and uncontrolled studies
Authors: S.A. Behnood, R. Shafran, S.D. Bennett, A.X.D. Zhang, L.L. O'Mahoney, T.J. Stephenson, S.N. Ladhani, B.L. De Stavola, R.M. Viner, O.V. Swann
Journal: Journal of Infection (2021)

Data on the long-term impact of SARS-CoV-2 infection in children and young people (CYP) are conflicting. We assessed evidence on long-term post-COVID symptoms in CYP examining prevalence, risk factors, type and duration.
Abstract P419: Revealing The Dynamics Of Vesicle Formation During Clathrin-mediated Endocytosis In Living Endothelial Cells
Authors: Tomasz Nawara, Tejeshwar Rao, Alexa Mattheyses
Journal: Circulation Research (2021)

Clathrin-mediated endocytosis (CME) is an essential cellular process for internalizing nutrients and therapeutics at endothelial cell barriers. Studying the formation of cargo containing endocytic vesicles in living cells is challenging due to the limited resolution of fluorescence microscopy and the highly dynamic nature of CME. Moreover, it is currently unknown how the physiological conditions present in vasculature affect CME in endothelial cells. To address this challenge we used a novel microscopy approach, Simultaneous Two-wavelength Axial Ratiometry (STAR), to image vesicle formation dynamics with nanometer axial resolution in living cells. High-throughput analysis revealed that 80% of de novo clathrin accumulations contributed to endocytosis while 20% remained flat, consistent in both human umbilical vein endothelial cells (HUVECs) and our test-bed model green monkey kidney fibroblast-like (Cos-7) cells. We next investigated the interplay between coat curvature and clathrin accumulation in vesicle initiation to identify the mechanism of vesicle formation. Our results support the flexible model of vesicle formation with curvature and clathrin accumulation initiating together at shorter-lived vesicles (&lt;20s) and through a flat-to-curved transition of clathrin lattices at longer-lived vesicles (&gt;20s). Finally, we addressed if physiological conditions present in vasculature alter the dynamics of vesicle formation. We show that increasing osmotic pressure decreased the total number of internalizations but had no impact on the number of flat clathrin accumulations or the mechanism of vesicle formation in Cos-7 cells. In future research, we will test the hypothesis that HUVECs have distinct mechanisms to retain vesicle formation under osmotic pressure or shear stress conditions similar to their native environment. Additionally targeted drug delivery to vascular endothelial cells, for example nanocarriers binding to flat lattices or CCVs leading to different therapeutic outcomes or bioavailability, can potentially be informed by identifying clathrin morphology and dynamics and the mechanisms of endocytosis using STAR microscopy.