tbuckley/cabot-search huggingface dataset:
Abstract 9803: Most SCN5A Missense Loss-of-Function Variants Also Have a Dominant Negative Effect
Authors: Matthew J Oneill, Ayesha Muhammad, Lynn Hall, Joseph F Solus, Laura Short, Dan M Roden, Andrew Glazer
Journal: Circulation (2021)

Introduction: Up to 30% of patients with Brugada Syndrome (BrS) carry loss of function (LoF) variants in the cardiac sodium channel gene SCN5A . Recent studies have suggested that the protein product Na V 1.5 can form dimers, suggesting the possibility that LoF variants may have dominant negative effects. Methods: We identified 36 SCN5A missense variants previously found to have peak current &lt;10% compared to wild-type (WT). HEK293T cells were engineered to stably express one or two copies of SCN5A using AttB-AttP landing pad and Sleeping Beauty transposon systems. Cell lines were created expressing the missense LoF SCN5A variants alone or in heterozygous co-expression with WT SCN5A . Channel expression was validated by flow cytometry and peak sodium currents were measured using automated patch clamp (&gt;20 replicate cells/variant). To assess clinical risk, we compared case versus control ratios among different variant mechanisms using a published BrS case consortium and the gnomAD population database. Results: 32/36 LoF variants studied alone had peak current &lt;10% as expected. In heterozygous experiments, WT alone was normalized to 100% and WT+WT showed ~200% peak current. In heterozygous expression with WT, 29/32 LoF variants showed a reduction to less than 75% normalized peak current, demonstrating a dominant negative effect. We next tested the hypothesis that dominant negative variants carry a higher disease risk than other variant classes. We observed a 5.0-fold enrichment for BrS cases among carriers of dominant negative missense variants compared to putative haploinsufficient variants (frameshift/splice site) (p=0.003). Conclusions: Most SCN5A missense LoF variants also have a dominant negative effect. Case-control comparisons reveal that this variant class carries an outsized BrS risk compared to other classes of pathogenic variants. Figure . A) SCN5A homozygous expression. B) SCN5A heterozygous expression. C) Case-control analysis.
Role of Inflammation on the Control of the Arterial Hypertension among Patients with Metabolic Syndrome.
Authors: Ylber Jani, Atila Rexhepi, Bekim Pocesta, Ahmet Kamberi, Fatmir Ferati, Sotiraq Xhunga, Artur Serani, Dali Lala, Agim Zeqiri, Arben Mirto, Lutfi Zylbeari
Journal: Clinical Cardiology and Cardiovascular Interventions (2021)

BACKGROUND: It is widely accepted that hypertension is a pro-inflammatory disease and that the immune system plays a vital role in mediating hypertensive outcomes, end organ damages . and modulation of hypertensive pathology [2]. Patient with MetS usually present increased levels of C-reaktive protein (CRP) wich is a prototypic marker of inflammation [5], however the data of the influence of incresed levels of CRP on the control of the aterial hypertension in patients with MetS, are scarce. OBJECTIVE: We sought to determine the incresed CRP levels influence on the control of the aterial hypertension in patients with MetS. METHODS: We conducted a multicenter observational cross-sectional study. The study population recruited from a coule of outpatient clinic between june 2018 and june 2019. The population study consisted of 420 patients with MetS aged ≥ 18 years, divided in two groups:211 with level of CRP&gt;3mg/l , and 209 participans with CRP level &lt;3mg/l. RESULTS: Among those with CRP level &gt; 3mg/l(N=211) controlled BP according to evidence and current guidelines, was achieved in 23.6% of participans, whereas among those with CRP level &lt;3mg/l(N=209) controlled BP was achived in 48.3%; p=0.000). There was independent association of CRP levels &gt;3mg/l with uncontrolled BP (OR=3.1, 95%CI 2.06 - 4.75). There were signifiacant association of uncontrolled BP with: uncontrolled glycemia (OR =1.4,95%CI 0.97-1.84); increased BMI (OR=4.4; 95%CI 3.02-4.05) and five risk factors for MetS.(OR=2.3, 95%CI 1.93-2.81). CONCLUSIONS: We think,we brought some good evidence,in our present study ,that patients with MetS and higher CRP level have a higher prevalence of unconrolled BP.
Abstract 11197: Nano-Triciribine Reduces SARS-CoV-2 Infection by Sequestering ACE2 and the Novel Host Factor LDLR
Authors: Jose Manuel Condor Capcha, Camila Iansen Irion, Guerline Lambert, AHMED CHAHDI, Peter Buchwald, Derek Dykxhoorn, Hamidreza Farzaneh, Sapna deo, Sylvia Daunert, Karen C Young, Lina A Shehadeh
Journal: Circulation (2021)

Introduction: People with previous CVD hospitalized for COVID-19 have elevated death rate. We reported that patients with diabetes and HF higher protein levels of the low density lipoprotein receptor (LDLR). We hypothesized that LDLR is a novel host factor for the SARS-CoV-2-Spike (S2S) protein that may be regulated by the Akt inhibitor Triciribine (TCN), a drug being tested in Phase III studies for breast cancer. We also hypothesized that nano-formulation of Triciribine (NanoTriciribine; NTCN) would enhance its efficacy and allow for intranasal delivery. Methods: Interactions between the recombinant proteins Spike-RBD (receptor binding domain), ACE2, LDLR and its ectodomains (EGFA-EFFB, C2-C5 and C2) were analyzed by binding assays and co-IP in HepG2, HK2, and 293T cells. Viral entry assays were performed with 2 S2S pseudoviruses using 293T cells + hACE2 and TMPRSS2 or Furin protease. The effect of NTCN or the LXR agonist GW-3965 on viral uptake (pseudotyped VSVΔG-GFP*S2S or chimera VSV-S2S-eGFP virus) was assessed. Akt, pAkt, ACE2, and LDLR levels were determined in 293T+hACE2 by flow cytometry. Assays were done in triplicates and 1-way-ANOVA with Tukey’s correction was used for statistics. Results: RBD protein binds modestly to the human LDLR (EC 50 :10μM) and its C2-C5 ectodomain (EC 50 :13.8μM). Co-IP revealed a novel and strong LDLR-ACE2 interaction in several human cell lines. LDLR overexpression in human cells increased the uptake of VSVΔG-GFP*S2S (FC=2.32;p&lt;0.001) and chimera virus (FC=.33; p&lt;.0001). NTCN and TCN each reduced pAkt/Akt ratio. 1μM TCN or NTCN reduced LDLR (7.2%;p&lt;.01 &amp; 15.6%;p&lt;0.0001) and ACE2 (32%;p&lt;0.05 &amp; 44.7%;p&lt;.01) cell surface expression, respectively. 1μM NTCN or GW-3965 reduced S2S viral entry by 64.2% (p&lt;.0001) and 40.7% (p&lt;.01), respectively, confirming a role for LDLR in S2S infection. In hACE2tg mice, chimera VSV-S2S caused significant lung infection as measured by qPCR, GFP expression in proximal and distal lung airway epithelial cells, and electron microscopy. Intranasal delivery of NTCN was well tolerated. Conclusions: LDLR enhanced S2S viral entry supporting the elevated COVID-19 susceptibility seen in patients with heart disease. NTCN is a promising candidate for prophylactic treatment against COVID-19.
Identification of Previously Unrecognized Multiple Myeloma Risk Subgroups with a Novel Biological Disease Stratifier
Authors: Afsaneh M. Shariatpanahi, Sarah Grasedieck, Matthew C. Jarvis, Faezeh Borzooee, Reuben S. Harris, Mani Larijani, Kevin Song, Arefeh Rouhi, Florian Kuchenbauer
Journal: Blood (2021)
Abstract 14356: Trends of Acute Myocardial Infarction Mortality Rates in the United States From 1999-2019: A Retrospective Study
Authors: Nithin R Venepally, Thao Dang, Pradyumna Agasthi, Juan Sierra, Carlos Matute, Banveet K Khetarpal, Bibek Bakhati, Mungara Sai, Govind Jha, Reza Arsanjani
Journal: Circulation (2021)

Introduction: In the current study, we examined the temporal trends in mortality across gender, race, and 10-year age groups over last two-decades. Methods: We conducted a retrospective population-based study using Centers for Disease Control and Prevention database. Subjects with underlying cause of death from AMI were identified using validated ICD10 codes. Age adjusted mortality rates were calculated for gender and race whereas crude rates were calculated for 10-year age group. Using Poisson regression, we estimated the rate ratio between race/ethnicity pairs adjusting for age and sex in order to analyze temporal trend. Results: We identified 2,709,173 subjects with reported underlying cause of death as AMI between January-2000 to December-2019 of which 54.7% were males (n=1,483,163). The age adjusted mortality rate per 100,000 was higher in males compared to females (52.4% vs 30.7%, OR: 1.66 [1.45-1.89]). Among ethnicities African American (AA) population had the highest age adjusted mortality rate per 100,000 [Table 1]. As expected, age group &gt;85 years had the highest mortality rate per 100,000 constituting 30% of total deaths (78% of total deaths were noted in &gt;65yr age group). AMI age adjusted mortality rates/100,000 showed significant decline across gender and race with highest decline in female population (66.5% decline). Highest percentage decline in mortality was noted in AA female population (68.2%) whereas in males it was the white population (62%). In females, highest percentage decline in mortality was noted in 75-84 age-group (70%) while it was &gt;85 age-group (67%) in males. Conclusion: Over last two decades there has been a significant decline in AMI mortality rates across gender and race. AA continue to have higher age adjusted mortality rate among both male and female population (38% and 22% respectively). Further studies are needed to identify and provide targeted prevention and intervention strategies in high-risk populations.
Abstract 10749: A Prospective Study of Health-Related Quality of Life Outcomes in Thoracic Aortopathy Patients
Authors: Wynne Zheng, Samantha Xu, Natalie M Szpakowski, Barbara Bittel, Susan Ospina, Vidyasagar Kalahasti, Eric E ROSELLI, Lars G Svensson, Scott Frank, Milind Y Desai
Journal: Circulation (2021)

Introduction: Health-related quality of life (QOL) outcomes in thoracic aortopathy (TA) patients who have not yet met the surgical threshold, but need significant lifestyle/weightlifting restrictions, are not well understood. We prospectively studied a newly developed QOL instrument to examine the associations between patient characteristics and self-reported QOL scores in TAA patients not anticipated to undergo aortic intervention for at least 6 months. Methods: All 128 adult TA patients (57±10 years, mean thoracic aortic diameter = 4.4±0.3cm, 77% male) were recruited prospectively as a single center and completed a baseline QOL instrument. The 70-item QOL instrument was adapted from validated QOL questionnaires. All patients signed informed consent. Results: Mean QOL scores for the eight scales of the instrument (range, 0 to 5, with 5 reflecting best function/QOL) were self-reported and as follows: physical function (4.2±0.8), depression (3.9±0.8), anxiety (3.8±0.9), post-traumatic stress disorder (PTSD) (4.1±0.9), social function (4.4±0.6), spiritual acceptance of diagnosis (3.6±0.7), self-efficacy (4.2±0.7), and resilience (4.1±0.6). Higher physical function score was associated with higher emotional (β=0.67, p&lt;0.001) and social function (β=0.52, p&lt;0.001) scores. Higher physical function (β=0.535), less depression (β=0.47), less anxiety (β=0.45), less PTSD (β =0.43), and higher social function (β=0.281) scores were all significant predictors of higher perceived overall health (all p&lt;0.001). The degree of TA dilatations had no significant association with lower social function (β=-0.89, p=0.65), lower self-efficacy (β=-2.73, p=0.21), or lower resilience. Conclusion: In TA patients not requiring aortic surgery, higher physical, emotional, and social function scores were significantly associated with self-perceived overall health. However, the actual size had no significant association with these metrics. Further research is needed to elucidate trends of patient-reported QOL and their correlation to clinical/imaging changes.
Methotrexate(MTX) Induced Leukoencephalopathy(LE) and Relation of Vitamin B12, Folate and / or Homocysteine Levels with MTX Toxicity: A Prospective Study
Authors: Akshay Lahoti, Prabodha k Das, Sonali Mohapatra, Suprava Naik, Ashutosh Panigrahi, Biswajit Bhuyan
Journal: Blood (2021)
Serum metabolite profiling yields insights into health promoting effect of A. muciniphila in human volunteers with a metabolic syndrome
Authors: Clara Depommier, Amandine Everard, Céline Druart, Dominique Maiter, Jean-Paul Thissen, Audrey Loumaye, Michel P. Hermans, Nathalie M. Delzenne, Willem M. de Vos, Patrice D. Cani
Journal: Gut Microbes (2021)

Reduction of A. muciniphila relative abundance in the gut microbiota is a widely accepted signature associated with obesity-related metabolic disorders. Using untargeted metabolomics profiling of fasting plasma, our study aimed at identifying metabolic signatures associated with beneficial properties of alive and pasteurized A. muciniphila when administrated to a cohort of insulin-resistant individuals with metabolic syndrome. Our data highlighted either shared or specific alterations in the metabolome according to the form of A. muciniphila administered with respect to a control group. Common responses encompassed modulation of amino acid metabolism, characterized by reduced levels of arginine and alanine, alongside several intermediates of tyrosine, phenylalanine, tryptophan, and glutathione metabolism. The global increase in levels of acylcarnitines together with specific modulation of acetoacetate also suggested induction of ketogenesis through enhanced β-oxidation. Moreover, our data pinpointed some metabolites of interest considering their emergence as substantial compounds pertaining to health and diseases in the more recent literature.
QOLP-08. THE LANDSCAPE OF EPILEPSY ASSOCIATED WITH DIFFUSELY INFILTRATIVE GLIOMAS
Authors: Michael Drumm, Jessica Templer, Omar Bushara, Dusten Unruh, Jordain Walshon, Rodrigo Javier, Kathleen McCortney, Kirsten Burdett, Jonathan Kurz, Geoff Swanson, Craig Horbinski
Journal: Neuro-Oncology (2021)

Abstract Seizures are among the most prevalent co-morbidities associated with glioma, and pose a serious threat to patients. Our prior work showed that IDH mutation (IDHmut) was associated with much greater seizure frequency at the time of initial glioma diagnosis. However, less is known about the variables that contribute to seizure risk throughout the course of disease. We therefore collected data from 247 patients with grade 2–4 glioma, and determined seizure risk using Kaplan-Meier survival probabilities and multivariable cox regression analyses. Median follow-up of IDH wildtype (IDHwt) and IDHmut glioma patients was 15 months and 36 months, respectively. Incidence of pre-operative seizures for IDHwt and IDHmut patients was 75/168 (45%) and 60/79 (76%), and incidence of post-operative seizures was 70/168 (42%) and 43/79 (54%), respectively. Patients who had a pre-operative seizure had a shorter time to their first post-operative seizure than patients who never had a pre-operative seizure in both IDHwt (P&amp;lt; 0.0001) and IDHmut (P= 0.039) cohorts. Among IDHmut glioma patients, those with subtotal resections developed post-operative seizures faster (median time to first seizure= 9.9 months) than those with gross-total resections (median not reached) (P= 0.0005), but a similar pattern was not observed in IDHwt glioma patients (P= 0.20). Those with IDHmut astrocytomas more quickly developed post-operative seizures (median= 11.1 months), compared to those with IDHwt astrocytomas (24.9 months) or IDHmut oligodendrogliomas (median not reached) (P= 0.033). Tumor progression closely followed post-operative seizures in patients with IDHwt gliomas when either their first post-operative seizure occurred longer than 6 months following resection, or when their post-operative seizures worsened in quality. These data suggest the best predictors of post-operative seizures are as follows: the presence of pre-operative seizures; extent of surgical resection; IDHmut status. These data will help clinicians better manage glioma patients by identifying those at greatest risk of seizures.
Abstract 12955: Clonal Hematopoiesis of Indeterminate Potential: A Novel Risk Factor for Atrial Fibrillation in the UK Biobank Cohort
Authors: Seyedmohammad Saadatagah, Benjamin Satterfield, Ozan Dikilitas, Iftikhar J Kullo
Journal: Circulation (2021)

Introduction: The prevalence of atrial fibrillation (AF) increases with age and inflammation plays a key pathophysiologic role. Somatic mosaicism increases with age and promotes inflammation. Therefore, we investigated whether Clonal Hematopoiesis of Indeterminate Potential (CHIP) is a risk factor for incident AF. Methods: We assessed exome sequence (ES) data from 200,628 participants in the UK biobank. Using the Genome Analysis Toolkit pipeline, we ascertained a predefined list of CHIP mutations in DNMT3A , TET2 , and ASXL1 . CHIP was defined as variant allele frequency (VAF) &gt;10% and those with VAF &lt;2% served as controls. AF was ascertained based on self-report and ICD codes. Lone AF was defined as AF in the absence of heart failure, mitral stenosis, mitral valve repair/valvotomy/replacement, and congenital heart disease. Those with AF prior to or at the time of enrollment were excluded from analyses to ascertain incident events. Cox proportional hazard models adjusted for age, sex, self-reported race/ethnicity, diabetes, hypertension, smoking, and obesity were used to identify associations between CHIP and incident AF. Results: Of 200,628 participants, 3885 (1.9%) had CHIP. The number of participants with mutations in DNMT3A , TET2 , and ASXL1 was 2512, 1065, and 439, respectively. During a median follow-up of 9 years, 4,676 incident AF and 3,584 incident lone AF occurred. CHIP was an independent risk factor for developing incident AF and also for developing lone AF. CHIP in TET2 and ASXL1 but not DNMT3A was associated with AF ( Table 1 ). Conclusions: The presence of CHIP involving TET2 and ASXL1 is associated with an increased risk of incident AF including the subset with lone AF. Our findings reveal somatic mosaicism in blood cells to be a novel risk factor for AF.
Abstract 13785: Profile and Characteristics of Peripheral T Cell Receptor Repertoires in Patients With Rheumatic Heart Disease Through High-Throughput Sequencing
Authors: Lu Zhang, kuan zeng, Minnan Gao, Jianfen Li, Huiqi Jiang, Congyong Liu, Yanqi Yang
Journal: Circulation (2021)

Introduction: Valve damage in rheumatic heart disease (RHD) is caused by immune cross-reaction to A streptococci attacking heart valve tissue of the host in which T cell is thought to play a key role. However, the immunological mechanism of is still poorly understood. The aim of the present study is to assess T cell receptor (TCR) repertoires in patients with RHD in comparison with healthy individuals. Hypothesis: T cells play a key role in regulating cell mediated immune response associated with heart valve damage in RHD. Methods: In the study, 21 subjects were enrolled, including 11 patients with RHD matching the diagnostic criteria of 2020 ACC/AHA guideline who accepted valve surgery, and 10 healthy individuals. The patient group had an average age of 52.5 years and 36.4% male. The healthy group had an average age of 37.1 years and 50% male. The TCR repertoires in all subjects were assessed by using high-throughput sequencing. Bio-informatics analysis was performed. Results: The overall immune characteristics of the patients and healthy individuals are obviously different. The TCR repertoire in the patients with RHD presented a significantly lower diversity than that in the healthy (D50-p&lt;0.05) which implied that number of frequently expressed clonotypes were fewer in the patient group than that in the healthy group. The average fraction of the top 200 TCRs sequences was 20.95±8.89% in the patients which was significantly greater than that of 17.59±4.93% in healthy individuals (p&lt;0.05), suggesting the TCR distribution in the patient group was more concentrated than in the healthy group. Heterogeneity of TCR repertoire was more pronounced in the patient group comparing to those in the healthy group (p&lt;0.01). Both clonotype feature and TRBV-J combination feature of TCRs profile in the patient group demonstrated significant specificity for RHD(AUC&gt;0.84, p&lt; 0.05 and AUC&gt;0.93, p&lt; 0.05). Conclusions: TCR repertoires in patients with RHD is different from that in healthy individuals. The characteristics of TCR repertoires in patients with RHD indicated specific T cell response in the development of the disease,which provided clues to searching for biomarkers for early diagnosis of RHD and early blocking.
Abstract 12624: Optimal Patient Selection for Simultaneous Heart-Kidney Transplant: A Modified Cost-Effectiveness Analysis
Authors: Brian Wayda, Xingxing S Cheng, Jeremy D Goldhaber-Fiebert, Kiran K Khush
Journal: Circulation (2021)

Introduction: Increasing rates of simultaneous heart-kidney (SHK) transplant in the United States exacerbate the shortage of deceased donor kidneys (DDK) for kidney-only transplant (KT-only) candidates. Current allocation policy imposes no constraints on eligibility for SHK, and how best to do so remains unknown. Methods: We apply a decision analytic model to evaluate options for heart transplant (HT) candidates with comorbid kidney dysfunction, comparing 1) upfront SHK transplant (using a DDK) and 2) a “Safety Net” strategy, in which HT-only is performed first and DDK transplant is performed six months later if native kidneys do not recover. We measure “cost” in expected number of DDKs allocated to HT recipients, effectiveness in quality-adjusted life years (QALYs), and cost-effectiveness in terms of QALYs gained per kidney. We evaluate each outcome for patients of varying “reversibility”, defined as their probability of native kidney recovery after HT-only. We identify those for whom SHK (compared to Safety Net) is efficient from a societal standpoint, producing more QALYs per kidney than each additional kidney used for KT-only. Results: For a candidate with 50% reversibility, SHK (compared to Safety Net) produces 0.54 - 0.77 more QALYs (varying by age) at a cost of 0.58 more kidneys used. SHK is inefficient in this scenario, producing fewer QALYs per DDK (0.92 - 1.31) than an additional DDK allocated for KT-only (2.2 QALYs per kidney, derived from published estimates). SHK confers more benefit and is more cost-effective with decreasing age and reversibility, and is preferred to Safety Net for patients with reversibility under 24 - 38%. Conclusions: A Safety Net strategy produces greater societal benefit than SHK for HT candidates with concurrent kidney dysfunction, excepting only those with a low probability of native kidney recovery. This finding favors implementation of a Safety Net provision and should inform the use of objective criteria to limit SHK eligibility.