tbuckley/cabot-search huggingface dataset:
Abstract 16377: Cardiovascular Computed Tomography Can Predict Branch Pulmonary Artery Stenosis in Neonates With Ductal Dependent Pulmonary Blood Flow
Authors: Kirsten K Graff, Shahryar M Chowdhury, Nicholas Aizcorbe, Scott M Bradley, Anthony Hlavacek
Journal: Circulation (2020)

Background: A subpopulation of neonates with ductal dependent pulmonary blood flow (PBF) are at risk for branch pulmonary artery (PA) stenosis in the PA that receives the patent ductus arteriosus (PDA). Identification of this population is important in planning initial and future interventions. The objective of this study was to identify novel cardiovascular computed tomography (CCT) measures in the preoperative period that are associated with the need for future branch PA surgical or catheter-based intervention. Methods: In this single center retrospective study, we identified neonates (&lt; 28 days) with ductal dependent PBF who underwent CCT prior to initial intervention from 11/2003-12/2019. A single reviewer made conventional and novel measurements of the branch PAs as well as PDA size and configuration. The primary outcome was reached if there was any initial or subsequent surgical or catheter-based intervention on the branch PA that received the PDA. Results: A total of 47 neonates (16 female, 31 male) were included. 30 (64%) reached the primary outcome. Upon multivariable regression analysis, PDA origin at the aortic isthmus [OR 7.13 (95% CI 1.01-50.4), p = 0.049] and distance to the largest diameter (DLD) (Figure 1) [OR 1.24 (95% CI 1.01-1.51), p = 0.040] were independently associated with the primary outcome. DLD is the distance of the largest diameter of the PA with the PDA from the bifurcation in confluent PAs or from the insertion of the PDA in discontinuous PAs. On receiver operating characteristic analysis, area under the curve for DLD = 0.75, p = 0.01. A DLD &gt; 6 mm displayed 82% sensitivity and 67% specificity in identifying patients who met the primary outcome. Conclusions: PDA origin at the aortic isthmus and DLD can risk stratify patients at high risk for requiring surgical or catheterization-based branch PA interventions. Further analysis is needed to determine if intervention strategies based on these measurements improve patient outcomes.
Kisspeptin receptor agonist has therapeutic potential for female reproductive disorders
Authors: Ali Abbara, Pei Chia Eng, Maria Phylactou, Sophie A. Clarke, Rachel Richardson, Charlene M. Sykes, Chayarndorn Phumsatitpong, Edouard Mills, Manish Modi, Chioma Izzi-Engbeaya, Debbie Papadopoulou, Kate Purugganan, Channa N. Jayasena, Lisa Webber, Rehan Salim, Bryn Owen, Paul Bech, Alexander N. Comninos, Craig A. McArdle, Margaritis Voliotis, Krasimira Tsaneva-Atanasova, Suzanne Moenter, Aylin Hanyaloglu, Waljit S. Dhillo
Journal: Journal of Clinical Investigation (2020)

BACKGROUNDKisspeptin is a key regulator of hypothalamic gonadotropin-releasing hormone (GnRH) neurons and is essential for reproductive health. A specific kisspeptin receptor (KISS1R) agonist could significantly expand the potential clinical utility of therapeutics targeting the kisspeptin pathway. Herein, we investigate the effects of a KISS1R agonist, MVT-602, in healthy women and in women with reproductive disorders.METHODSWe conducted in vivo and in vitro studies to characterize the action of MVT-602 in comparison with native kisspeptin-54 (KP54). We determined the pharmacokinetic and pharmacodynamic properties of MVT-602 (doses 0.01 and 0.03 nmol/kg) versus KP54 (9.6 nmol/kg) in the follicular phase of healthy women (n = 9), and in women with polycystic ovary syndrome (PCOS; n = 6) or hypothalamic amenorrhea (HA; n = 6). Further, we investigated their effects on KISS1R-mediated inositol monophosphate (IP1) and Ca2+ signaling in cell lines and on action potential firing of GnRH neurons in brain slices.RESULTSIn healthy women, the amplitude of luteinizing hormone (LH) rise was similar to that after KP54, but peaked later (21.4 vs. 4.7 hours; P = 0.0002), with correspondingly increased AUC of LH exposure (169.0 vs. 38.5 IU∙h/L; P = 0.0058). LH increases following MVT-602 were similar in PCOS and healthy women, but advanced in HA (P = 0.004). In keeping with the clinical data, MVT-602 induced more potent signaling of KISS1R-mediated IP1 accumulation and a longer duration of GnRH neuron firing than KP54 (115 vs. 55 minutes; P = 0.0012).CONCLUSIONTaken together, these clinical and mechanistic data identify MVT-602 as having considerable therapeutic potential for the treatment of female reproductive disorders.TRIAL REGISTRATIONInternational Standard Randomised Controlled Trial Number (ISRCTN) Registry, ISRCTN21681316.FUNDINGNational Institute for Health Research and NIH.
Antibody response using six different serological assays in a completely PCR-tested community after a coronavirus disease 2019 outbreak—the CoNAN study
Authors: Sebastian Weis, André Scherag, Michael Baier, Michael Kiehntopf, Thomas Kamradt, Steffi Kolanos, Juliane Ankert, Stefan Glöckner, Oliwia Makarewicz, Stefan Hagel, Christina Bahrs, Aurelia Kimmig, Hans Proquitté, Joel Guerra, Dagmar Rimek, Bettina Löffler, Mathias W. Pletz, Thomas Hotz, None Local Cooperation Partners, Petra Enders, Renate Koch, Steffen Mai, Matthias Ullrich, Cora Richert, Cornelius Eibner, Bettina Meinung, Kay Stötzer, Julia Köhler, Hans Cipowicz, Christine Pinkwart, Michael Bauer, Petra Dickmann, Annika Licht, Juliane Scholz, Wibke Wetzker, Anita Hartung, Daniel Weiss, Lara Thieme, Gabi Hanf, Clara Schnizer, Jasmin Müller, Jennifer Kosenkow, Franziska Röstel, Nico Andreas, Raphaela Marquardt, Stefanie Deinhardt-Emmer, Sebastian Kuhn
Journal: Clinical Microbiology and Infection (2020)

ObjectivesDue to a substantial proportion of asymptomatic and mild courses, many severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections remain unreported. Therefore, assessment of seroprevalence may detect the real burden of disease. We aimed to determine and characterize the rate of SARS-CoV-2 infections and the resulting seroprevalence in a defined population. The primary objective of the study was to assess SARS-CoV-2 antibody seroprevalence using six different IgG-detecting immunoassays. Secondary objectives of the study were: (a) to determine potential risk factors for symptomatic versus asymptomatic coronavirus disease 2019 courses, and (b) to investigate the rate of virus RNA-persistence.MethodsCoNAN is a population-based cohort study performed in the community Neustadt am Rennsteig, Germany, which was quarantined from 22 March to 5 April after six SARS-CoV-2 cases were detected in the village's population. The SARS-CoV-2 outbreak comprised 51 cases and 3 deaths. The CoNAN study was performed from 13 May to 22 May 2020, 6 weeks after a SARS-CoV-2 outbreak.ResultsWe enrolled a total of 626 participants (71% of the community population) for PCR and antibody testing in the study. All actual SARS-CoV-2 PCR tests were negative. Fifty-two out of 620 (8.4%) participants had antibodies against SARS-CoV-2 in at least two different assays. There were 38 participants with previously PCR-confirmed SARS-CoV-2 infection. Of those, only 19 (50%) displayed anti-SARS-CoV-2 antibodies. We also show that antibody-positive participants with symptoms compatible with a respiratory tract infection had significantly higher antibody levels then asymptomatic participants (EU-assay: median 2.9 versus 7.2 IgG-index, p 0.002; DS-assay: median 45.2 versus 143 AU/mL, p 0.002). Persisting viral replication was not detected.ConclusionsOur data question the relevance and reliability of IgG antibody testing to detect past SARS-CoV-2 infections 6 weeks after an outbreak. We conclude that assessing immunity for SARS-CoV-2 infection should not rely on antibody tests alone.
Abstract 15885: Disagreement of the Current Diagnostic Criteria for Cardiac Sarcoidosis
Authors: Laura Ueberham, Cosima Jahnke, Ingo Paetsch, Kuehl Michael, Gerhard Hindricks, Borislav Dinov
Journal: Circulation (2020)

Introduction: Diagnosis of cardiac sarcoidosis (CS) poses a clinical challenge. Different diagnostic recommendations are proposed from JSNC, WASOG, and HRS expert consensus statement. Hypothesis: Current CS scoring systems classify patients inconsistent. The aim of this study was to compare the later with imaging-based cardiac magnetic resonance imaging (CMR) and 18F-fluorodeoxyglucose (FDG)- positron emission tomography (PET) criteria for diagnosis of CS. Methods: Between January 2016 and April 2020 patients with suspected cardiac sarcoidosis were systematically evaluated by history, ECG, lab values, echocardiogram, cardiac biopsy and both CMR and PET. Current scoring systems and criteria for diagnosis of CS were applied and compared to proposed imaging classifications. Results: Out of 45 patients (mean age 53 ± 9 years, 66.7% males), 40.0% were diagnosed with CS according to the JSNC guidelines. Applying the WASOG criteria, CS was "at least probable" in 91%, whereas the HRS guidelines classified 24.4% as CS patients. Using CMR imaging criteria 13.3%, 48.9% and 11.1% were categorized as possible, probable or highly probable for CS, and based on FDG-PETs 15.6%, 11.1% and 31.1%, respectively. There were only 9 patients (20.0%) that were classified as CS in all 4 scoring systems, and 4 patients (8.9%) that did not fulfil criteria for CS in any of the scoring systems. Conclusions: Current scoring systems for cardiac sarcoidosis showed significant disagreement and led to an inconclusive classification of CS likelihood. A refinement of the diagnostic tools for cardiac sarcoidosis is necessary.
Abstract 13289: Incidence of Heart Failure Hospital Admissions Among Type 2 Diabetes Mellitus Patients and the Potential Impact of SGLT2 Inhibitors in Japan: A Population-based Study From the Shizuoka Kokuho Database
Authors: Shiori Nishimura, Hiraku Kumamaru, Shun Kohsaka, Satoshi Shoji, Eiji Nakatani, Hiroyuki Yamamoto, Nao Ichihara, Yoshiki Miyachi, Hiroaki Miyata
Journal: Circulation (2020)

Introduction: Recent large-scale clinical trials have shown that the use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduces the risk of cardiovascular (CV) events, particularly heart failure (HF) hospitalizations, in type 2 diabetes mellitus (T2DM) patients with established CV disease. We aimed to assess (1) the incidence of HF admissions, and (2) the potential reduction in HF admissions with the further introduction of SGLT2i, in a contemporary large administrative claims database in Japan. Methods: We selected patients aged ≥40 years, without previous HF diagnosis, who newly initiated oral antidiabetics in Shizuoka Kokuho Database between 2013 and 2018. We estimated the 5-year cumulative incidence of hospitalization for HF, myocardial infarction (MI), and stroke, treating death as a competing risk. Among the subgroup of patients with laboratory data, we identified patients meeting the inclusion criteria for EMPA-REG OUTCOME (EMPA-REG) or DECLARE-TIMI 58 (DECLARE) regarding HbA1c, eGFR, and CV disease. We estimated the number of events that can be reduced if they benefited the same risk reduction from the trials. Results: Among 23,340 oral antidiabetic drug initiators (46.0% women, 21.9% ≥75 years old) included, 2.6% were initiated on SGLT2i. The 5-year cumulative incidences of hospitalization for HF, MI, and stroke were 5.4% (95% confidence interval: 4.9-5.9%), 1.9% (1.7-2.2%), and 6.1% (5.7-6.6%), respectively. Among 6192 patients with laboratory data, 651 (10.5%) and 2680 (43.3%) patients met the EMPA-REG-like and DECLARE-like criteria, respectively (Figure). The 5-year cumulative incidence among the 2849 patients meeting either of the criteria was estimated to decrease from 97.1 to 75.2 events via 75% adoption of SGLT2i. Conclusion: The burden of HF among Japanese T2DM patients was high, almost equivalent to stroke. Increased use of SGLT2i among patients with high CV risk may significantly reduce its disease burden.
Hidradenitis suppurativa odour and drainage scale: a novel method for evaluating odour and drainage in patients with hidradenitis suppurativa
Authors: M.O. Machado, J.D. Lu, R. Brar, J.S. Kirby, A. Garg, M.L. Lowes, V. Piguet, A. Alavi
Journal: British Journal of Dermatology (2020)
Integrated immunological analysis of a successful conversion of locally advanced hepatocellular carcinoma to resectability with neoadjuvant therapy
Authors: Won Jin Ho, Gaurav Sharma, Qingfeng Zhu, Genevieve Stein-O'Brien, Jennifer Durham, Robert Anders, Aleksandra Popovic, Guanglan Mo, Ihab Kamel, Matthew Weiss, Elizabeth Jaffee, Elana J Fertig, Mark Yarchoan
Journal: Journal for ImmunoTherapy of Cancer (2020)

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer death worldwide with a minority of patients being diagnosed early enough for curative-intent interventions. We report the first use of preoperative cabozantinib plus nivolumab to successfully downstage what presented as unresectable HCC as part of an ongoing phase 1b study. Preoperative treatment with cabozantinib and nivolumab led to &gt;99% reduction in alpha-fetoprotein, −37.3% radiographic reduction by RECIST 1.1 and a near complete pathologic response (80% to 100% necrosis). An integrated immunological analysis was performed on the post-treatment surgical tumor sample and matched pre-treatment and post-treatment peripheral blood samples with high-dimensional imaging and cytometry techniques. Bayesian non-negative matrix factorization (CoGAPS, Coordinated Gene Activity in Pattern Sets) and self-organizing map (FlowSOM) algorithms were used to distinguish changes in functional markers across cellular neighborhoods in the single cell data sets. Brisk immunological infiltration into the tumor microenvironment was observed in non-random, organized cellular neighborhoods. Systemically, combination therapy led to marked promotion of effector cytotoxic T cells and effector memory helper T cells. Natural killer cells also increased with therapy. The patient remains without disease recurrence and with a normal alpha-fetoprotein approximately 2 years from presentation. Our study provides proof-of-concept that borderline resectable or locally advanced HCC warrants consideration of downstaging with effective neoadjuvant systemic therapy for subsequent curative resection.
Efficacy of Intensive Acupuncture Versus Sham Acupuncture in Knee Osteoarthritis: A Randomized Controlled Trial
Authors: Jian‐Feng Tu, Jing‐Wen Yang, Guang‐Xia Shi, Zhang‐Sheng Yu, Jin‐Ling Li, Lu‐Lu Lin, Yu‐Zheng Du, Xiao‐Gang Yu, Hui Hu, Zhi‐Shun Liu, Chun‐Sheng Jia, Li‐Qiong Wang, Jing‐Jie Zhao, Jun Wang, Tong Wang, Yang Wang, Tian‐Qi Wang, Na Zhang, Xuan Zou, Yu Wang, Jia‐Kai Shao, Cun‐Zhi Liu
Journal: Arthritis & Rheumatology (2020)

To assess the efficacy of intensive acupuncture (3 times weekly for 8 weeks) versus sham acupuncture for knee osteoarthritis (OA).In this multicenter, randomized, sham-controlled trial, patients with knee OA were randomly assigned to receive electroacupuncture (EA), manual acupuncture (MA), or sham acupuncture (SA) 3 times weekly for 8 weeks. Participants, outcome assessors, and statisticians were blinded with regard to treatment group assignment. The primary outcome measure was response rate, which is the proportion of participants who simultaneously achieved minimal clinically important improvement in pain and function by week 8. The primary analysis was conducted using a Z test for proportions in the modified intent-to-treat population, which included all randomized participants who had ≥1 post-baseline measurement.Of the 480 participants recruited in the trial, 442 were evaluated for efficacy. The response rates at week 8 were 60.3% (91 of 151), 58.6% (85 of 145), and 47.3% (69 of 146) in the EA, MA, and SA groups, respectively. The between-group differences were 13.0% (97.5% confidence interval [97.5% CI] 0.2%, 25.9%; P = 0.0234) for EA versus SA and 11.3% (97.5% CI -1.6%, 24.4%; P = 0.0507) for MA versus SA. The response rates in the EA and MA groups were both significantly higher than those in the SA group at weeks 16 and 26.Among patients with knee OA, intensive EA resulted in less pain and better function at week 8, compared with SA, and these effects persisted though week 26. Intensive MA had no benefit for knee OA at week 8, although it showed benefits during follow-up.
Abstract 13722: There Will be Blood: A Cautionary Tale of Triple Therapy
Authors: Negeen Shahandeh, Eric H Yang, Rushi Parikh
Journal: Circulation (2020)

A 54-year-old man with coronary artery disease, chronic kidney disease, atrial flutter, and chronic right internal carotid artery (ICA) occlusion was transferred to our institution for management of cardiogenic shock following an anterior ST-elevation myocardial infarction status post percutaneous coronary intervention of the left main coronary artery (LMCA). He was placed on short-term triple antithrombotic therapy. On the day before discharge, he acutely developed left sided neurological deficits and hypotension. Exam was concerning for a right hemispheric stroke. Labs revealed a creatinine of 2.8 mg/dL, INR of 3.7, and a hemoglobin of 6.6 g/dL (previously 10 g/dL). Prior to sending the patient for brain imaging, we performed a bedside echocardiogram to further evaluate his hypotension. This revealed a large pericardial effusion with tamponade physiology. We suspected hemorrhagic cardiac tamponade secondary to triple antithrombotic therapy. His hypotension initially responded to intravenous fluids and packed red blood cells, resulting in an improved neurologic exam and supporting our hypothesis that his deficits represented right cerebral hemispheric hypoperfusion in the setting of a known right ICA occlusion and tamponade. Pericardiocentesis was initially deferred, as the risk of bleeding appeared prohibitive without reversal of apixaban and his coagulopathy, and these measures would subject the patient to a significant risk of thrombosis (e.g. LMCA stent thrombosis). Unfortunately, the patient developed progressive shock. After careful informed consent, we proceeded with high-risk pericardiocentesis involving pre-procedural reversal of apixaban with andexanet alfa and successful evacuation of 300 ml of hemorrhagic fluid. The pericardial pressure improved from 24 mmHg to 4 mmHg with complete resolution of the patient’s shock and neurological deficits. Our case demonstrates the risks associated with triple antithrombotic therapy as well as the nuanced clinical decision-making and risk-benefit assessment required when considering the use of anticoagulant reversal agents to prevent bleeding complications in the context of recent ischemic events and the need for urgent invasive procedures.
Targeting Germline- and Tumor-Associated Nucleotide Excision Repair Defects in Cancer
Authors: Sabine Topka, Zoe Steinsnyder, Vignesh Ravichandran, Kaitlyn Tkachuk, Yelena Kemel, Chaitanya Bandlamudi, Mogens Winkel Madsen, Helena Furberg, Ouathek Ouerfelli, Charles M. Rudin, Gopa Iyer, Steven M. Lipkin, Semanti Mukherjee, David B. Solit, Michael F. Berger, Dean F. Bajorin, Jonathan E. Rosenberg, Barry S. Taylor, Elisa de Stanchina, Joseph Vijai, Kenneth Offit
Journal: Clinical Cancer Research (2020)

Nucleotide excision repair (NER) gene alterations constitute potential cancer therapeutic targets. We explored the prevalence of NER gene alterations across cancers and putative therapeutic strategies targeting these vulnerabilities.We interrogated our institutional dataset with mutational data from more than 40,000 patients with cancer to assess the frequency of putative deleterious alterations in four key NER genes. Gene-edited isogenic pairs of wild-type and mutant ERCC2 or ERCC3 cell lines were created and used to assess response to several candidate drugs.We found that putative damaging germline and somatic alterations in NER genes were present with frequencies up to 10% across multiple cancer types. Both in vitro and in vivo studies showed significantly enhanced sensitivity to the sesquiterpene irofulven in cells harboring specific clinically observed heterozygous mutations in ERCC2 or ERCC3. Sensitivity of NER mutants to irofulven was greater than to a current standard-of-care agent, cisplatin. Hypomorphic ERCC2/3-mutant cells had impaired ability to repair irofulven-induced DNA damage. Transcriptomic profiling of tumor tissues suggested codependencies between DNA repair pathways, indicating a potential benefit of combination therapies, which were confirmed by in vitro studies.These findings provide novel insights into a synthetic lethal relationship between clinically observed NER gene deficiencies and sensitivity to irofulven and its potential synergistic combination with other drugs.See related commentary by Jiang and Greenberg, p. 1833.
Autologous CD4 T Lymphocytes Modified with a Tat-Dependent, Virus-Specific Endoribonuclease Gene in HIV-Infected Individuals
Authors: Jeffrey M. Jacobson, Julie K. Jadlowsky, Simon F. Lacey, Joseph A. Fraietta, Gabriela Plesa, Hideto Chono, Dong H. Lee, Irina Kulikovskaya, Chelsie Bartoszek, Fang Chen, Lifeng Tian, Alexander Dimitri, Bruce L. Levine, Elizabeth A. Veloso, Wei-Ting Hwang, Carl H. June
Journal: Molecular Therapy (2020)

MazF is an Escherichia coli-derived endoribonuclease that selectively cleaves ACA sequences of mRNA prevalent in HIV. We administered a single infusion of autologous CD4 T lymphocytes modified to express a Tat-dependent MazF transgene to 10 HIV-infected individuals (six remaining on antiretroviral therapy [ART]; four undergoing treatment interruption post-infusion) in order to provide a population of HIV-resistant immune cells. In participants who remained on ART, increases in CD4 and CD8 T cell counts of ~200 cells/mm
Abstract 195: Associations of Cardiovascular Health During Late Adolescence and Young Adulthood With Incident Premature Cardiovascular Events and Mortality: The Coronary Risk Development in Young Adults Study (CARDIA)
Authors: Amanda M Perak, Hongyan Ning, Sadiya S Khan, Joshua D Bundy, Norrina B Allen, Cora E Lewis, David R Jacobs, Linda VAN HORN, Donald M Lloyd-jones
Journal: Circulation (2020)

Introduction: Mid-life cardiovascular health (CVH) is strongly associated with risks of later-life CVD and mortality across race and sex groups. Adolescent and young-adult CVH are associated with risk of subclinical CVD, but data are lacking regarding CVD events or mortality. Hypotheses: (1) CVH in late adolescence/young adulthood (18-30y) is associated with risks of premature CVD and mortality; (2) Event rates are uniformly low across sociodemographic subgroups with high baseline CVH. Methods: CVH (defined by AHA’s 7 metrics) was measured at baseline and total CVH scores were categorized as high (12-14 pts), moderate (8-11) or low (0-7). CVD events and cause-specific mortality were adjudicated over 32y of follow-up. We estimated adjusted associations of baseline CVH with outcomes using Cox models and calculated population attributable fractions (PAFs; adjusted for competing risk of death as applicable) and event rates by CVH category. Results: See Table . Among 4836 participants, mean age was 24.9y (SD 3.6), 44.1% were aged 18-24y, 54.8% were female, and 50.5% were black. Baseline CVH was high in 28.8%, moderate in 65.0%, and low in 6.3%. In total, 306 CVD events and 431 deaths occurred. CVH was significantly associated with all outcomes, with similar patterns by age, sex, and race. PAFs for moderate/low (vs high) CVH ranged from 0.42 (all-cause mortality) to 0.63 (CVD) to 0.81 (CVD mortality) overall; PAFs were not significantly different across sociodemographic subgroups. Among individuals with high CVH, event rates were low across all sociodemographic subgroups (e.g., CVD rates/1000 person-yrs: age 18-24y 0.64, 25-30y 0.65, women 0.36, men 1.04, black 0.90, white 0.50). Conclusions: High CVH at age 18-30y was associated with low rates of premature CVD and mortality. Preservation of high CVH to at least age 18y may reduce CVD and mortality burdens and disparities, and adolescent/young-adult CVH may be a valid intermediate outcome for early-life determinants of risk.