tbuckley/cabot-search huggingface dataset:
91O Pooled analysis of patient (pt)-reported outcomes (PROs) in the MONALEESA (ML)-2, -3, and -7 trials: Additional results and key subgroup findings
Authors: P.A. Fasching, A. Bardia, A. Nusch, G. Jerusalem, A. Chan, N.S. El Saghir, E. Alba Conejo, S-A. Im, W. Janni, D. Chandiwana, B.R. Lanoue, A. Thuerigen, E. Gu, N. Harbeck
Journal: Annals of Oncology (2021)
The role of allergen‐specific IgE, IgG and IgA in allergic disease
Authors: Mohamed H. Shamji, Rudolf Valenta, Theodore Jardetzky, Valerie Verhasselt, Stephen R. Durham, Peter A. Würtzen, R.J. Joost van Neerven
Journal: Allergy (2021)

Immunoglobulin E (IgE)-mediated allergy is the most common hypersensitivity disease affecting more than 30% of the population. Exposure to even minute quantities of allergens can lead to the production of IgE antibodies in atopic individuals. This is termed allergic sensitization, which occurs mainly in early childhood. Allergen-specific IgE then binds to the high (FcεRI) and low-affinity receptors (FcεRII, also called CD23) for IgE on effector cells and antigen-presenting cells. Subsequent and repeated allergen exposure increases allergen-specific IgE levels and, by receptor cross-linking, triggers immediate release of inflammatory mediators from mast cells and basophils whereas IgE-facilitated allergen presentation perpetuates T cell-mediated allergic inflammation. Due to engagement of receptors which are highly selective for IgE, even tiny amounts of allergens can induce massive inflammation. Naturally occurring allergen-specific IgG and IgA antibodies usually recognize different epitopes on allergens compared with IgE and do not efficiently interfere with allergen-induced inflammation. However, IgG and IgA antibodies to these important IgE epitopes can be induced by allergen-specific immunotherapy or by passive immunization. These will lead to competition with IgE for binding with the allergen and prevent allergic responses. Similarly, anti-IgE treatment does the same by preventing IgE from binding to its receptor on mast cells and basophils. Here, we review the complex interplay of allergen-specific IgE, IgG and IgA and the corresponding cell receptors in allergic diseases and its relevance for diagnosis, treatment and prevention of allergy.
Prognosis of French COVID-19 patients with chronic liver disease: A national retrospective cohort study for 2020
Authors: Vincent Mallet, Nathanael Beeker, Samir Bouam, Philippe Sogni, Stanislas Pol, Vincent Mallet, Nathanaël Beeker, Samir Bouam, Hélène Fontaine, Marion Corouge, Anaïs Vallet Pichard, Clémence Hollande, Loriane Lair Mehiri, Philippe Sogni, Stanislas Pol
Journal: Journal of Hepatology (2021)
Abstract 16115: The Society of Cardiovascular Angiography and Interventions Cardiogenic Shock Classification Predicts Mortality in Cardiac Arrest Patients Prior to Pci
Authors: Fernando Ortiz, George A Stouffer, Joseph Rossi, Jason N Katz
Journal: Circulation (2020)

Introduction: Acute coronary syndrome (ACS) complicated by cardiac arrest (CA) has a heterogeneous presentation, and risk can be challenging to stratify. This study aimed to apply the SCAI cardiogenic shock stages to patients with ACS complicated by CA at early pivotal time intervals when prompt interventions may have a greater impact. Methods: Patients undergoing PCI presenting with CA were stratified according to the SCAI shock classification, retrospectively, on arrival to the cardiac catheterization laboratory (CCL) and on arrival to the intensive care unit (ICU). The primary end-point was in-hospital mortality. Secondary end-points were mortality stratified by the use of mechanical circulatory support or the level of vasopressor support used. Results: Between 01/2014 -08/2018, seventy-nine patients presented with ACS complicated by a CA. The mean age was 70 (SD ± 12) years, and 19 (24%) were females. On arrival to the CCL 17 (22%) were stage A, 6 (8%) were stage B, 31 (40%) were stage C, 19 (24%) were stage D, and 6 (8%) were stage E. In general, there was a stepwise increase in mortality with increasing stage (A 35% vs. B 16% vs. C 48% vs. D 68% vs. E 83%; p=0.05). There was a similar trend when stratified on arrival to the ICU (Figure 1), although of marginal statistical significance (P = 0.07). Presentation with shock stage D or E to the CCL was predictive of mortality (OR 3.7 CI 1.3-10.5; p=0.01) on logistic regression models. The use of mechanical support was not associated with increased mortality. However, the use of an Impella in patients requiring high vasopressor support at arrival to the CCL was associated with a trend towards decreased mortality (25% vs. 61%, p=0.18). Conclusion: Increasing SCAI shock stages on arrival to the CCL and ICU is associated with increased in-hospital mortality among patients who presented after a CA and underwent PCI. The SCAI classification at defined time points has the potential to serve as an important research tool.
Prevalence of aminoglycoside-induced hearing loss in drug-resistant tuberculosis patients: A systematic review
Authors: Lauren K. Dillard, Ricardo X. Martinez, Lucero Lopez Perez, Amanda M. Fullerton, Shelly Chadha, Catherine M. McMahon
Journal: Journal of Infection (2021)

Objectives estimate the prevalence of ototoxic hearing loss in drug-resistant tuberculosis (DR-TB) patients treated with aminoglycoside antibiotics via a systematic review and meta-analysis. Estimate the annual preventable cases of hearing loss in DR-TB patients and leverage findings to discuss primary, secondary and tertiary prevention. Methods studies published between 2005 and 2018 that reported prevalence of post-treatment hearing loss in DR-TB patients were included. We performed a random effects meta-analysis to determine pooled prevalence of ototoxic hearing loss overall and by medication type. Preventable hearing loss cases were estimated using World Health Organization (WHO) data on DR-TB treatment and prevalence determined by the meta-analysis. Results eighteen studies from 10 countries were included. Pooled prevalence of ototoxic hearing loss and the corresponding 95% confidence interval (CI) was 40.62% CI [32.77- 66.61%] for all drugs (kanamycin: 49.65% CI [32.77- 66.61%], amikacin: 38.93% CI [26.44-53.07%], capreomycin: 10.21% CI [4.33-22.21%]). Non-use of aminoglycosides may result in prevention of approximately 50,000 hearing loss cases annually. Conclusions aminoglycoside use results in high prevalence of ototoxic hearing loss. Widespread prevention of hearing loss can be achieved by following updated WHO guidelines for DR-TB treatment. When hearing loss cannot be avoided, secondary and tertiary prevention should be prioritized.
Hypoxia‐Inducible Factor 1 Alpha–Mediated RelB/APOBEC3B Down‐regulation Allows Hepatitis B Virus Persistence
Authors: Tobias Riedl, Suzanne Faure‐Dupuy, Maude Rolland, Svenja Schuehle, Zohier Hizir, Silvia Calderazzo, Xiaodong Zhuang, Jochen Wettengel, Martin Alexander Lopez, Romain Barnault, Valbona Mirakaj, Sandra Prokosch, Danijela Heide, Corinna Leuchtenberger, Martin Schneider, Bernd Heßling, Benjamin Stottmeier, Isabel M. Wessbecher, Peter Schirmacher, Jane A McKeating, Ulrike Protzer, David Durantel, Julie Lucifora, Emmanuel Dejardin, Mathias Heikenwalder
Journal: Hepatology (2021)

Background and Aims Therapeutic strategies against HBV focus, among others, on the activation of the immune system to enable the infected host to eliminate HBV. Hypoxia‐inducible factor 1 alpha (HIF1α) stabilization has been associated with impaired immune responses. HBV pathogenesis triggers chronic hepatitis‐related scaring, leading inter alia to modulation of liver oxygenation and transient immune activation, both factors playing a role in HIF1α stabilization. Approach and Results We addressed whether HIF1α interferes with immune‐mediated induction of the cytidine deaminase, apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B; A3B), and subsequent covalently closed circular DNA (cccDNA) decay. Liver biopsies of chronic HBV (CHB) patients were analyzed by immunohistochemistry and in situ hybridization. The effect of HIF1α induction/stabilization on differentiated HepaRG or mice ± HBV ± LTβR‐agonist (BS1) was assessed in vitro and in vivo . Induction of A3B and subsequent effects were analyzed by RT‐qPCR, immunoblotting, chromatin immunoprecipitation, immunocytochemistry, and mass spectrometry. Analyzing CHB highlighted that areas with high HIF1α levels and low A3B expression correlated with high HBcAg, potentially representing a reservoir for HBV survival in immune‐active patients. In vitro , HIF1α stabilization strongly impaired A3B expression and anti‐HBV effect. Interestingly, HIF1α knockdown was sufficient to rescue the inhibition of A3B up‐regulation and ‐mediated antiviral effects, whereas HIF2α knockdown had no effect. HIF1α stabilization decreased the level of v‐rel reticuloendotheliosis viral oncogene homolog B protein, but not its mRNA, which was confirmed in vivo . Noteworthy, this function of HIF1α was independent of its partner, aryl hydrocarbon receptor nuclear translocator. Conclusions In conclusion, inhibiting HIF1α expression or stabilization represents an anti‐HBV strategy in the context of immune‐mediated A3B induction. High HIF1α, mediated by hypoxia or inflammation, offers a reservoir for HBV survival in vivo and should be considered as a restricting factor in the development of immune therapies.
Comprehensive analysis of ADA2 genetic variants and estimation of carrier frequency driven by a function-based approach
Authors: Hyuk Jee, Zhengping Huang, Samantha Baxter, Yuelong Huang, Maria L. Taylor, Lauren A. Henderson, Sofia Rosenzweig, Aman Sharma, Eugene P. Chambers, Michael S. Hershfield, Qing Zhou, Fatma Dedeoglu, Ivona Aksentijevich, Peter A. Nigrovic, Anne O’Donnell-Luria, Pui Y. Lee
Journal: Journal of Allergy and Clinical Immunology (2021)
Five-Year Extension Results of the Phase 1 START Trial of Onasemnogene Abeparvovec in Spinal Muscular Atrophy
Authors: Jerry R. Mendell, Samiah A. Al-Zaidy, Kelly J. Lehman, Markus McColly, Linda P. Lowes, Lindsay N. Alfano, Natalie F. Reash, Megan A. Iammarino, Kathleen R. Church, Aaron Kleyn, Matthew N. Meriggioli, Richard Shell
Journal: JAMA Neurology (2021)

This ongoing study assesses long-term safety and durability of response in infants with spinal muscular atrophy (SMA) type 1 after dosing with onasemnogene abeparvovec gene replacement therapy.The primary objective of this ongoing study is to assess safety. The secondary objective is to determine whether developmental milestones achieved in the START phase 1 clinical trial were maintained and new milestones gained.This study is an ongoing, observational, follow-up study for continuous safety monitoring for 15 years in patients from the START phase I study (conducted May 5, 2014, through December 15, 2017) at Nationwide Children's Hospital in Columbus, Ohio. Participants were symptomatic infants with SMA type 1 and 2 copies of SMN2 previously treated with an intravenous dose of onasemnogene abeparvovec (low dose, 6.7 × 1013 vg/kg; or therapeutic dose, 1.1 × 1014 vg/kg) in START. Thirteen of 15 original START patients are included in this analysis; 2 patients' families declined follow-up participation. Data were analyzed from September 21, 2017, to June 11, 2020.Median time since dosing of 5.2 (range, 4.6-6.2) years; 5.9 (range, 5.8-6.2) years in the low-dose cohort and 4.8 (range, 4.6-5.6) years in the therapeutic-dose cohort.The primary outcome measure was the incidence of serious adverse events (SAEs).At data cutoff on June 11, 2020, 13 patients treated in START were enrolled in this study (median age, 38.9 [range, 25.4-48.0] months; 7 females; low-dose cohort, n = 3; and therapeutic-dose cohort, n = 10). Serious adverse events occurred in 8 patients (62%), none of which resulted in study discontinuation or death. The most frequently reported SAEs were acute respiratory failure (n = 4 [31%]), pneumonia (n = 4 [31%]), dehydration (n = 3 [23%]), respiratory distress (n = 2 [15%]), and bronchiolitis (n = 2 [15%]). All 10 patients in the therapeutic-dose cohort remained alive and without the need for permanent ventilation. Prior to baseline, 4 patients (40%) in the therapeutic-dose cohort required noninvasive ventilatory support, and 6 patients (60%) did not require regular ventilatory support, which did not change in long-term follow-up. All 10 patients treated with the therapeutic dose maintained previously acquired motor milestones. Two patients attained the new milestone of "standing with assistance" without the use of nusinersen.The findings of this ongoing clinical follow-up of patients with SMA type 1 treated with onasemnogene abeparvovec supports the long-term favorable safety profile up to 6 years of age and provides evidence for sustained clinical durability of the therapeutic dose.ClinicalTrials.gov Identifier: NCT03421977.
Maternal Early‐Pregnancy Glucose Concentrations and Liver Fat Among School‐Age Children
Authors: Madelon L. Geurtsen, Rama J. Wahab, Janine F. Felix, Romy Gaillard, Vincent W.V. Jaddoe
Journal: Hepatology (2021)

Background and Aims Gestational diabetes seems to be associated with offspring NAFLD. We hypothesized that maternal glucose concentrations across the full range may have persistent effects on offspring liver fat accumulation. Approach and Results In a multiethnic, population‐based, prospective cohort study among 2,168 women and their offspring, maternal early‐pregnancy glucose concentrations were measured at a median of 13.1 weeks’ gestation (95% CI, 9.6‐17.2). Liver fat fraction was measured at 10 years by MRI. NAFLD was defined as liver fat fraction ≥5.0%. We performed analyses among all mothers with different ethnic backgrounds and those of European ancestry only. The multiethnic group had a median maternal early‐pregnancy glucose concentration of 4.3 mmol/L (interquartile range, 3.9‐4.9) and a 2.8% (n = 60) prevalence of NAFLD. The models adjusted for child age and sex only showed that in the multiethnic group, higher maternal early‐pregnancy glucose concentrations were associated with higher liver fat accumulation and higher odds of NAFLD, but these associations attenuated into nonsignificance after adjustment for potential confounders. Among mothers of European ancestry only, maternal early‐pregnancy glucose concentrations were associated with increased odds of NAFLD (OR, 1.95; 95% CI, 1.32; 2.88, after adjustment for confounders) per 1‐mmol/L increase in maternal early‐pregnancy glucose concentration. These associations were not explained by maternal prepregnancy and childhood body mass index, visceral fat, and metabolic markers. Conclusions In this study, maternal early‐pregnancy glucose concentrations were only among mothers of European ancestry associated with offspring NAFLD. The associations of higher maternal early‐pregnancy glucose concentrations with offspring NAFLD may differ between ethnic groups.
Single Center Experience in Vascular and Endovascular Surgery during the COVID-19 Pandemic: Walking on the Icy Road
Authors: Görkem Yiğit
Journal: Clinical Cardiology and Cardiovascular Interventions (2021)

Background: Along with other areas of specialization, the cardiovascular surgery clinic is a department that has a significant contribution to the COVID-19 pandemic process with both the management of vascular emergencies and the rapid and effective use of interventional methods. This study aims to present endovascular and open vascular surgical procedures performed in single center between March 2020 and December 2020 during the ongoing pandemic. Materials and methods: A total of 230 patients underwent open surgery 60 patients and endovascular / interventional treatment 170 patients by the Cardiovascular Surgery clinic were included in the study. It was aimed to determine the procedural details of the patients, follow-up results, complications and mortality rates. The compatibility of the variables to normal distribution was examined using visual and analytical methods. The Shapiro-Wilk test was used to check the normal distribution of continuous variables. Results: In the open vascular surgery group, the mean age was 51.4±23.2 years (range 12–90 years). Sixteen (26.7%) patients were female and 44 (73.3%) male. The median follow-up from the time of the open vascular procedure was 4.3±1.2 months. There were ten (16.7%) minor complications. There were five deaths after procedures. In the endovascular / interventional group, the mean age was 58.5±18.6 years (range 18–94 years). Ninety one (53.5%) patients were female and 79 (46.5%) male. The median follow-up from the time of the drug-eluting balloon angioplasty and pharmacomechanical thrombectomy patients were 4.0±1.1 months. There were thirty four (20%) minor complications and two deaths after procedures. Conclusion: Our experience and successful results shows how surgical and interventional procedures participated in the care of hospitalized COVID-19 patients during the height of the coronavirus pandemic.
Abstract 16683: Profiling Cardiac Inflammation and Molecular Changes During the Transition of Hypertrophic to Dilated Cardiomyopathy
Authors: Fnu MOHAMMED ARIF, Sakthivel sadayappan, Phillip Owens, Richard BECKER
Journal: Circulation (2020)

Introduction: Hypertrophic cardiomyopathy (HCM) is a disease caused primarily by sarcomere gene mutations [like myosin-binding protein C3 ( MYBPC3 )], with several distinct phenotypes. Tissue-level inflammation has been reported in human HCM, tissue-specific neutrophil subsets, and their dysregulation cause inflammatory myopathies, and neutrophil extracellular traps (NETs) are associated with cardiac fibrosis in aged rodents. However, the mechanism(s) responsible for the broad phenotypic variability and changes observed over time transitioning from HCM to dilated cardiomyopathy (DCM) has not yet been elucidated. Objective: To determine the cardiac inflammatory signature of HCM and transition from HCM to DCM and its relationship to fibrosis and ventricular remodeling in an established MYBPC3 ( cMyBP-C t/t ) mouse model. Method and Results: Mixed-gender cMyBP-C +/+ (WT) and mutant mice ( cMyBP-C t/t ) underwent echocardiography and were euthanized at one, two and three months of age (n=8) and blood and hearts were harvested. Echocardiography and histopathology examination confirmed significant heart dysfunction and tissue remodeling in cMyBP-C t/t mice showing cardiac hypertrophy at one month of age (Left ventricular (LV) posterior wall systole 1.20 ±0.39 vs 1.51±0.49 and LV posterior wall diastole 0.96 ±0.22 vs 1.38 ±0.36 mm; * p&lt;0.05 ), and DCM phenotype (LV internal diameter systole 2.40 ±0.41 vs 3.67 ±0.25 and LV internal diameter diastole 3.44 ±0.29 vs 4.30 ±0.39 mm; * p&lt;0.05 ) along with myofibrillar loss and increased cardiac fibrosis at three months. Interestingly, LV dysfunction and hypertrophy resulted in a time-dependent increase in the activation of coagulation, as measured by plasma microvesicle tissue factor activity, thrombin antithrombin, and D-dimer. In silico analysis of RNA-Seq data from 3-months old cMyBP-C t/t mice heart revealed key genes and pathways associated with HCM, DCM, tissue remodeling, renin-angiotensin-aldosterone signaling, fibrosis, apoptosis, NETosis, and inflammation. Conclusions: The transition from HCM to a DCM phenotype involves proinflammatory and profibrotic signaling. Therapies directed at tissue-specific inflammation and NETs may be a novel and impactful strategy for HCM.
Clinical Implications of Poststent Optical Coherence Tomographic Findings
Authors: Byung Gyu Kim, Mateusz Kachel, Jung-Sun Kim, Giulio Guagliumi, Choongki Kim, In-Soo Kim, Yong-Joon Lee, Oh-Hyun Lee, Young Sup Byun, Byung Ok Kim, Krzysztof Milewski, Seung-Jun Lee, Sung-Jin Hong, Chul-Min Ahn, Dong-Ho Shin, Byeong-Keuk Kim, Young-Guk Ko, Donghoon Choi, Yangsoo Jang
Journal: JACC. Cardiovascular imaging (2021)
Abstract 14787: Loss of Wnt7a is Associated With Reduced Vegf-a/vegfr2 Mediated Endothelial Tip Cell Formation and Angiogenesis in Pulmonary Arterial Hypertension
Authors: Ananya Chakraborty, Abinaya Nathan, Mark Orcholski, Stuti Agarwal, Elya Shamskou, Joyce Yu, Alden Mallory, Jose Acosta, Roberto Gunzman, Ke Yuan, Vanesa Rojas, Joseph T Crossno, Lai-Ming Yung, Paul B Yu, Thomas Spencer, Robert A Winn, Vinicio A De Jesus Perez
Journal: Circulation (2020)

Rationale: Pulmonary arterial hypertension (PAH) is characterized by loss of microvessels. The Wnt pathways control pulmonary angiogenesis but their role in PAH is incompletely understood. Objective: We hypothesized that Wnt activation in pulmonary microvascular endothelial cells (PMVECs) is required for pulmonary angiogenesis and its loss contributes to PAH. Methods: Lung tissue and PMVECs from healthy donors and PAH patients were screened for Wnt ligand production. Tip cell dynamics were analyzed using 3D spheroid assays and in vivo studies were carried out with tamoxifen-inducible Wnt knockout mice exposed to chronic hypoxia and Sugen-hypoxia (SuHx). Results: Healthy PMVECs demonstrated ~6-fold Wnt7a expression that was absent in PAH PMVECs and vascular lesions. Wnt7a expression correlated with formation of tip cells, an endothelial phenotype critical for angiogenesis. To analyze PMVEC tip cell formation, we developed a 3D PMVEC spheroid model combined with live imaging to monitor the behavior of healthy and PAH PMVECs in response to VEGF-A and Wnt7a. We found that PAH PMVECs demonstrated reduced tip cell formation as evidenced by reduced filopodia formation and random motility, which could be partially rescued by recombinant Wnt7a. The mechanism by which Wnt7a promotes VEGF signaling activity is dependent on its capacity to activate the small GTPase cdc42 and facilitate phosphorylation of the Y951 and Y1175 tyrosine residues in VEGFR2 following VEGF-A stimulation. While there was no phenotypic difference between wild type and mice with endothelial-specific Wnt7a knockout (Wnt7a EC/EC ) under chronic hypoxia and SuHx, we found that global Wnt7a +/- mice demonstrated higher pressures and vascular remodeling compared to wild type mice. Interestingly, we found that global Wnt7a knockout (Wnt7a KO/KO ) mice succumbed 10 days after tamoxifen injection demonstrating interstitial thickening associated with expansion of the pulmonary capillaries, an unexpected phenotype resembling alveolar capillary dysplasia. Conclusions: We have identified Wnt7a as a novel angiogenic factor that plays a pivotal role in pulmonary angiogenesis by promoting VEGF-A mediated tip cell formation. Targeting Wnt7a could promote recovery of small vessel loss in PAH.
Cell-Stage Dependent Outcomes of the NAMPT/SIRT2-Mediated Activation of LMO2 By Deacetylation in Normal Hematopoiesis and in T-ALL
Authors: Tatsuya Morishima, Christian Lindner, Benedikt Oswald, Marcus Hartmann, Masoud Nasri, Lothar Kanz, Patrick Müller, Karl Welte, Julia Skokowa
Journal: Blood (2017)
Five-year Clinical Outcome of Distal Protection Using PercuSurge in Patients with Acute Myocardial Infarction Who Underwent Emergent Percutaneous Coronary Intervention
Authors: Niwa Toru, Mukawa Hiroaki, Tsuboi Hideyuki, Morishima Itsurou, Uesugi Michitaka, Sasaki Hiromi, Morimoto Ryouta, Izumi Yusuke, Yamamoto Toshihiko, Ichihasi Kei, Kanzaki Yasunori, Nagai Hiroaki, Sone Takahito
Journal: Circulation (2010)