tbuckley/cabot-search huggingface dataset:
Abstract 17108: Natural History of Cardiomyopathy and Cardiac Stress Response in Young Dogs With Golden Retriever Muscular Dystrophy
Authors: Lee-Jae Guo, Amanda K Bettis, Peter P Nghiem, Jonathan H Soslow, Christopher F SPURNEY, Joe N Kornegay
Journal: Circulation (2020)

Introduction: Duchenne muscular dystrophy (DMD) and the genetically homologous model, golden retriever muscular dystrophy (GRMD), are x-linked conditions that cause progressive muscle wasting and cardiomyopathy. We previously defined a late onset DMD-like dilated cardiomyopathy in adult GRMD dogs and aimed to extend that work to young dogs used for preclinical studies. The goal of this study was to characterize the early natural history and cardiac stress response of GRMD cardiomyopathy. Methods: A prospective imaging study was completed in 10 GRMD dogs and 8 age-matched normal littermates at 3, 6, and 12 months of age. Electrocardiography (ECG), echocardiography with speckle tracking, and cardiac magnetic resonance (CMR) with late gadolinium enhancement (LGE) and myocardial T1 mapping were assessed. In an effort to identify early subclinical evidence of cardiomyopathy, we conducted a dobutamine stress test in an additional subset of dogs (17 GRMD vs. 6 normal). Fractional shortening (FS) was assessed using echocardiography during dobutamine infusion (5-25 μg/kg/min) at 2 months of age, with follow up studies (4 GRMD vs. 6 normal) at 4.5 and 6 months. Results: Heart rate and ECG Q/R ratios (lead II, III, and aVF) were greater in GRMD dogs at 12 months (p&lt;0.04 for all), and PR interval was shortened at 6 months (p=0.02). No systolic functional differences were seen between GRMD and normal dogs using echocardiography. No differences in circumferential strain were seen. CMR left ventricular end-diastolic volume, end-systolic volume, and myocardial mass were smaller in GRMD dogs from 6 months onward (p=0.014, 0.008, and 0.0013). LGE and extracellular volume calculated from T1 mapping did not differ on CMR. A diminished inotropic response, shown by a lower increase of FS (ΔFS), was seen in GRMD dogs during the dobutamine stress test (beginning at a dose of 5 μg/kg/min, 13.9±4.8% vs. 21.8±3.0%, p=0.003) at 2 months of age but not at 4.5 and 6 months. Conclusions: We demonstrated ECG changes and heart size differences in GRMD dogs as early as 6-12 months of age. While cardiac function was preserved, the inotropic response to dobutamine stress was blunted in 2-month-old GRMD dogs, potentially providing an early subclinical marker for DMD therapeutic research.
Author Correction: A regulatory T cell Notch4–GDF15 axis licenses tissue inflammation in asthma
Authors: Hani Harb, Emmanuel Stephen-Victor, Elena Crestani, Mehdi Benamar, Amir Massoud, Ye Cui, Louis-Marie Charbonnier, Sena Arbag, Safa Baris, Amparito Cunnigham, Juan Manuel Leyva-Castillo, Raif S. Geha, Amirhosein J. Mousavi, Boris Guennewig, Klaus Schmitz-Abe, Constantinos Sioutas, Wanda Phipatanakul, Talal A. Chatila
Journal: Nature Immunology (2020)
NO-008. ERIBULIN INDUCED NEUROPATHY IN A PATIENT WITH PREVIOUSLY UNDIAGNOSED CHARCOT-MARIE-TOOTH (CMT) DISEASE
Authors: Isabel Arrillaga-Romany, Kathryn Ruddy, Steven Greenberg, Lakshmi Nayak
Journal: Neuro-Oncology (2013)

BACKGROUND: Neuropathy can be a dose-limiting toxicity with numerous chemotherapeutics, and may be particularly disabling in the setting of pre-existing inherited neuropathic disorders. Deleterious effects on inherited neuropathies have been well-documented with vincristine, platinum drugs and taxan
Two-Year Results of the Phase 3 Randomized Controlled Study of Abicipar in Neovascular Age-Related Macular Degeneration
Authors: Rahul N. Khurana, Derek Kunimoto, Young Hee Yoon, Charles C. Wykoff, Andrew Chang, Raj K. Maturi, Hansjürgen Agostini, Eric Souied, David R. Chow, Andrew J. Lotery, Masahito Ohji, Francesco Bandello, Rubens Belfort, Xiao-Yan Li, Jenny Jiao, Grace Le, Kimmie Kim, Werner Schmidt, Yehia Hashad
Journal: Ophthalmology (2020)

To report the 2-year efficacy and safety of abicipar every 8 weeks and quarterly (after initial doses) compared with monthly ranibizumab in patients with treatment-naïve neovascular age-related macular degeneration (nAMD).Two multicenter, randomized, phase 3 clinical trials with identical protocols (CEDAR and SEQUOIA). Analyses used pooled trial data.The trials enrolled 1888 patients (1 eye/patient) with active choroidal neovascularization secondary to age-related macular degeneration and best-corrected visual acuity (BCVA) of 24 to 73 Early Treatment Diabetic Retinopathy Study letters.At enrollment, patients were assigned to study eye treatment with abicipar 2 mg every 8 weeks after initial doses at baseline and weeks 4 and 8 (abicipar Q8, n = 630), abicipar 2 mg every 12 weeks after initial doses at baseline and weeks 4 and 12 (abicipar Q12, n = 628), or ranibizumab 0.5 mg every 4 weeks (ranibizumab Q4, n = 630).Efficacy measures included stable vision (<15-letter loss in BCVA from baseline) and change from baseline in BCVA and central retinal thickness (CRT). Safety measures included adverse events (AEs).For patients who completed the study, efficacy of abicipar after initial doses was maintained through week 104. At week 104, the proportion of patients with stable vision was 93.0% (396/426), 89.8% (379/422), and 94.4% (470/498); mean change in BCVA from baseline was +7.8 letters, +6.1 letters, and +8.5 letters, and mean change in CRT from baseline was -147 μm, -146 μm, and -142 μm in the abicipar Q8 (14 injections), abicipar Q12 (10 injections), and ranibizumab Q4 (25 injections) groups, respectively. The overall incidence of intraocular inflammation (IOI) AEs was 15.4%, 15.3%, and 0.3% from baseline through week 52 and 16.2%, 17.6%, and 1.3% from baseline through week 104 in the abicipar Q8, abicipar Q12, and ranibizumab Q4 groups, respectively.Two-year results show efficacy of abicipar Q8 and Q12 in nAMD. First onset of IOI events with abicipar was much reduced in the second year and comparable with ranibizumab (0.8% and 2.3% vs. 1.0%). The extended duration of effect of abicipar allows for quarterly dosing and reduced treatment burden.
Abstract 155: Identification of Decreased Plasma Lysophosphatidylcholine Using Phospholipidomics in Cardiac Arrest: A Novel Therapeutic Application
Authors: Mitsuaki Nishikimi, Tsukasa Yagi, Ryosuke Takegawa, Shoaib Muhammad, Kei Hayashida, Tai Yin, Lance B Becker, Junhwan Kim
Journal: Circulation (2020)

Introduction: Cardiac arrest (CA) is a significant public health burden with few effective therapies available. Plasma phospholipids are important for proper organ function. We hypothesized that alterations in plasma phospholipids may play an important role in the pathophysiology of CA and normalizing these alterations may be a novel therapeutic application for the treatment of CA. Objective: The aim of this study was to test the phospholipid therapy as a novel therapeutic approach in CA. Methods and Results: We performed phospholipidomics on plasma samples from CA patients and controls from North Shore University Hospital to identify plasma phospholipids that correlate with injury severity. We then confirmed the finding using our rat model of 10 and 14 min of asphyxia-induced CA. Finally, we tested the effect of administering LPC using the same model. From the phospholipids analyzed, lysophosphatidylcholine (LPC) levels were found to be the most significantly decreased in CA patients, which was also associated with survival of patients. The same trend was observed in the rat model where rats after 14 min CA had significantly lower plasma LPC levels than rats after 10 min CA. We also found that LPC levels began to decrease continuously following resuscitation, but not during the ischemic phase of CA. Finally, we found that LPC administration substantially increased rat survival compared to the control group. Rats who survived in the LPC-treated group displayed significantly improved brain function and the neuroprotective effect of LPC is supported by improved brain histology. We also found LPC treatment increased plasma IL-10 levels and decreased IL-6 levels post-CA. Conclusion: Plasma LPC levels inversely correlated with survival and LPC treatment significantly improved brain function and rat survival. This data indicates that the decrease of plasma LPC is a major mechanism responsible for brain damage demonstrating the potential of LPC as a novel therapeutic in CA.
Sustained milk consumption after 2 years post–milk epicutaneous immunotherapy for eosinophilic esophagitis
Authors: Jonathan M. Spergel, Amanda B. Muir, Chris A. Liacouras, Deirdre Burke, Megan O. Lewis, Terri Brown‐Whitehorn, Antonella Cianferoni
Journal: Allergy (2020)

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Every hospital should have a specialist diabetes inpatient team, says review
Authors: Gareth Iacobucci
Journal: BMJ (2020)

All hospitals in England should have a specialist team dedicated to caring for inpatients with diabetes, a national clinically led review1 has advised.

For some patients, uncoordinated inpatient diabetes care and a lack of specialist staff can cause complications that lead to longer hospital stays and a higher risk of mortality, says the latest report from the national Getting It Right First Time programme, which aims to share examples of good practice to reduce unwarranted variations in clinical care.

The report is based on visits to 108 NHS trusts, during which inpatient care, type 1 diabetes care, and diabetic foot care were identified as …
Helen Salisbury: Managing vaccine expectations
Authors: Helen Salisbury
Journal: BMJ (2020)

A drug company’s press release about the success of its covid-19 vaccine has led to a welcome feeling of optimism, as we face the grim statistics of rising cases in the UK and the highest death toll in Europe.12 The news was followed swiftly by a new part of the GP contract, which practices would have to sign up to before offering the vaccine to patients. We’re meant to be ready by December, although most of us doubt that the vaccine will be in our hands so soon.

Many GPs feel sidelined in the pandemic response, believing that work we should have coordinated in primary care was instead outsourced to multinational contractors who did a poor …
Abstract 14308: Integrative Epigenomic Analysis Identifies Enhancer Modifying Variants Linked to Cardiomyopathy Genes
Authors: Anthony M Gacita, Dominic Fullenkamp, Joyce C Ohiri, Tess Pottinger, Megan Puckelwartz, Marcello A Nobrega, Elizabeth M McNally
Journal: Circulation (2020)

Introduction: Inherited cardiomyopathy is caused by mutations in more than 100 genes. A well-recognized clinical feature of genetic cardiomyopathy is varying phenotypic expression. Even with identical primary mutations, there is a range of clinical outcomes. Genetic variants in protein coding regions have been shown to alter the phenotypic expression of primary cardiomyopathy-causing mutations. However, the contribution of noncoding variation has been less well studied. Methods and Results: We used an integrative analysis of &gt;20 publicly-available heart enhancer function and enhancer target datasets to identify genomic regions predicted to regulate the cardiomyopathy genes, MYH7 and LMNA . We identified two candidate enhancer clusters around the MYH7 gene and three clusters around the LMNA gene. We tested enhancers in these clusters using reporter assays and CRISPr-mediated deletion in human cardiomyocytes derived from induced pluripotent stem cells (iCMs). We identified a super enhancer upstream of MYH7 that is necessary for high MYH7 expression in iCMs. These regulatory regions contained sequence variants within transcription factor binding sites that altered enhancer function. We created an informatic pipeline that extended this strategy genomewide to identify an additional enhancer modifying variant upstream of MYH7 . This variant disrupts a transcription factor binding site upstream of MYH7 and limits MYH7 upregulation. We extended these analyses by examining clinical correlates, finding that this variant correlated with a more dilated left ventricle over time in patients with cardiomyopathy. Conclusions: We identified two enhancer regions important for MYH7 expression in iCMs. These enhancer regions may be utilized to induce MYH7 during human development and heart failure. MYH7 changes in heart failure have been linked to cardiomyopathy phenotypes. The variant upstream of MYH7 likely alters these changes and results in a more severe phenotype. These findings demonstrate that noncoding variants have clinical utility and targeted assessment of noncoding modifiers may become integrated into clinical care.
Somatic Epigenetic Silencing of <i>RIPK3</i> Inactivates Necroptosis and Contributes to Chemoresistance in Malignant Mesothelioma
Authors: Yinfei Tan, Eleonora Sementino, Mitchell Cheung, Suraj Peri, Craig W. Menges, Anna-Mariya Kukuyan, Ting Zhang, Vladimir Khazak, Lauren A. Fox, Eric A. Ross, Suresh Ramanathan, Suresh C. Jhanwar, Raja M. Flores, Siddharth Balachandran, Joseph R. Testa
Journal: Clinical Cancer Research (2020)

Receptor-interacting protein kinase 3 (RIPK3) phosphorylates effector molecule MLKL to trigger necroptosis. Although RIPK3 loss is seen in several human cancers, its role in malignant mesothelioma is unknown. This study aimed to determine whether RIPK3 functions as a potential tumor suppressor to limit development of malignant mesothelioma.RIPK3 expression was examined in 66 malignant mesothelioma tumors and cell lines. Promoter methylation and DNMT1 siRNA studies were performed to assess the mode of RIPK3 silencing in RIPK3-deficient malignant mesothelioma cells. Restoration of RIPK3 expression in RIPK3-negative malignant mesothelioma cells, either by treatment with 5-aza-2'-deoxycytidine or lentiviral expression of cDNA, was performed to assess effects on cell viability, necrosis, and chemosensitization.Loss of RIPK3 expression was observed in 42/66 (63%) primary malignant mesotheliomas and malignant mesothelioma cell lines, and RT-PCR analysis demonstrated that downregulation occurs at the transcriptional level, consistent with epigenetic silencing. RIPK3-negative malignant mesothelioma cells treated with 5-aza-2'-deoxycytidine resulted in reexpression of RIPK3 and chemosensitization. Ectopic expression of RIPK3 also resulted in chemosensitization and led to necroptosis, the latter demonstrated by phosphorylation of downstream target MLKL and confirmed by rescue experiments. Mining of RIPK3 expression and survival outcomes among patients with malignant mesothelioma available from The Cancer Genome Atlas repository revealed that promoter methylation of RIPK3 is associated with reduced RIPK3 expression and poor prognosis.These data suggest that RIPK3 acts as a tumor suppressor in malignant mesothelioma by triggering necroptosis and that epigenetic silencing of RIPK3 by DNA methylation impairs necroptosis and contributes to chemoresistance and poor survival in this incurable disease.
Abstract 14616: Tailored Low Voltage Zones Ablation Using Contact Force Sensing Technology in Patients With Persistent Atrial Fibrillation (TWEET-AF): A Pilot Study
Authors: Gabriele DAmbrosio, Santi Raffa, Silvio Romano, Markus Frommhold, Obaida Alothman, Georgi Borisov, Karam Issa, Maria Penco, Christoph Geller
Journal: Circulation (2020)

Introduction: Although pulmonary vein (PV) isolation (PVI) is very effective in paroxysmal atrial fibrillation (AF), in patients (pts) with persistent AF, PVI often is not sufficient. Many studies suggested that low voltage zones (LVZs) outside of the PV might be involved in the complex mechanisms perpetuating AF. However ablation strategies involving substrate modification (SM) did not show additional benefits in persistent AF pts. Those studies were performed before the introduction of contact force technology, and the most likely explanation for these results could be the inability to achieve effective transmural lesions and continuous linear ablation. Hypothesis: We hypothesized that the use of contact force technology would improve ablation efficacy. Therefore, we analyzed the long-term outcome after two different ablation strategies in pts with persistent AF depending on whether there was evidence of LVZs in the left atrium or not. Methods: The presence of LVZs were defined as sites of &gt;3 adjacent low-voltage points &lt;0.5 mV during electrophysiology study. Depending on the location of the LVZ, linear ablation was performed. Catheter ablation was performed using TactiCath™ or SmartTouch™ ablation catheters aiming at contact values ≥10g &lt;20g and FTI &gt;400g/s. Ablation was performed in a temperature-controlled fashion with energy of 30W except at the posterior wall (20-25W). Results: 121 consecutive pts with persistent AF (46 female, median age 66 [59-72] years, mean duration of AF 16 [7-73] months, CT derived LA volume index 66 [56-75]ml/m2) were included: pts without LVZs underwent PVI alone (n = 74), in pts with LVZs, PVI + SM (n = 47) was performed (mitral Isthmus line in 2, supero-septal line in 39, and roof line in 47; bidirectional block was achieved in 100%, 97%, and 100%, respectively). After a median follow-up of 13 [6-21] months, 86% of pts without and 78% with substrate were in sinus rhythm, mainly without antiarrhythmic drugs (89% PVI only, 84% PVI + SM). Conclusions: In patients with persistent AF without LVZs, PVI alone leads to excellent 2-year freedom from AF. In pts with LVZs, additional substrate modification with CF sensing technology is associated with improved success rates compared to previous studies.
Abstract 16977: Coronary Chronic Total Occlusions: Insights on Upstream Management
Authors: Stanley Swat, Annika Hebbe, Stephen Waldo, Javier A Valle
Journal: Circulation (2020)

Introduction: Percutaneous coronary intervention (PCI) of coronary artery chronic total occlusions (CTO) has increased over time, despite representing higher procedural risk than traditional PCI. While guidelines for stable ischemic heart disease recommend antianginal therapy prior to attempted revascularization, the frequency with which this occurs for CTO PCI remain unknown. We propose to assess the frequency and variability in upstream use of antianginal therapy prior to CTO PCI attempt over time. Methods: This study identified all patients who underwent a CTO PCI attempt from January 2012 to September 2018 across the Veterans Affairs Healthcare System using the Veterans Affairs Clinical Assessment, Reporting and Tracking (CART) program. Patients were categorized by upstream management: (A) &lt;2 antianginal medications prescribed in year prior to CTO PCI, (B) ≥ 2 antianginals (C) Stress testing within 3 months of CTO PCI attempt and (D) ≥2 antianginals AND stress testing. Antianginal medications included beta blockers, nitrates, calcium channel blockers, and ranolazine. Multivariable logistic regression was used to estimate the propensity for receiving each category of treatment over time. Results: During the study period, 4250 patients underwent CTO PCI, with 1716 (40%) on ≥2 antianginal medications, 2534 (60%) on &lt;2 antianginals, 1023 (24%) with stress testing, and 338 (8%) on ≥2 antianginals with stress testing. Trends in upstream medical management of patients undergoing CTO PCI were unchanged over each fiscal year (Figure 1A) while odds of preprocedural stress testing decreased across fiscal years (Figure 1B). Conclusions: The majority of patients were on low intensity antianginal medical therapy prior to CTO PCI. Utilization of preprocedural stress testing decreased over time while patterns of upstream medical management remained constant, suggesting an opportunity to improve guideline compliance among patients undergoing attempted CTO PCI.
Abstract 15433: The Left Atrium and Pulmonary Vascular Disease in PVDOMICS Cohorts
Authors: Evelyn M Horn, Brett Larive, Erika Rosenzweig, Robert Frantz, Paul Hassoun, Anna R Hemnes, Franz Rischard, Emanuel Finet, Jane A Leopold
Journal: Circulation (2020)

Left atrial (LA) size and function is recognized as a cumulative index of pulmonary capillary wedge pressure (PCWP) and an index of left heart disease (LHD). While anticipated that LA features contribute to LHD-associated pulmonary hypertension (PH), we hypothesized that LA abnormalities (LAA) may exist in other WSPH groups. Therefore, we examined LA structure and function in the PVDOMICS cohorts. PVDOMICS enrolled 1097 total subjects with PH (mPA &gt; 25 mmHg) and at-risk disease comparators (mPA&lt;25 mmHg) for each of the WSPH groups. Patients with WSPH Groups 1, 3, 4, and 5 [non-Group 2] (n=618) were younger (56.2 ± 14.5 vs 60.1 ± 12.7 yrs, p&lt;.02) and had less hypertension (38.6% vs 51.5 %, p&lt;.02) than their non-Group 2 comparators (n=204). They also had less hypertension, diabetes, and a lower BMI than WSPH Group 2 (n=145), whereas WSPH Group 2 and its comparator Group 2 (n=130) were similar. LA area by echo was greater in WSPH Group 2 compared to non-Group 2 (22.8 ± 6.6 vs 16.9 ± 5.0 cm 2 , p&lt;.02), in the comparator Group 2 vs. non-Group 2 comparators (22.7 ± 7.9 vs 16.4 ± 4.7 cm 2 , p&lt;.02) but similar between WSPH group 2 and its comparator. MRI LA ejection fraction was lowest in Group 2 (33.2 ± 17.7%) and comparator Group 2 (38.9 ±16.7%, p=ns), significantly lower than WSPH non-Group 2 (45.9 ±14.7%, p&lt;.02) which was lower than comparator non-Group 2 (50.9 14.6%, p&lt;.02) which was lower than normal controls (n=96) (58.4 ±1.7%, p&lt;.02). At right heart catheterization, whereas mPA pressures were similar between WSPH non-Group 2 and Group 2, resting PCW (11.1± 5.3 vs 20.3 5.6 mm Hg, p&lt;0.02) was lower in WSPH non-Group 2 , PVR was higher (5.5[3.3, 8.7] vs. 3.7[7.2, 5.7] WU, p&lt;0.02), and cardiac output was higher (5.4 ± 1.9 vs. 4.9 ± 1.6 L/min, p&lt;0.02). Following a fluid challenge, PCW remained lower (14.9 ± 5.8 vs 20.7 ± 4.5 mm Hg, p&lt;0.02) and PVR higher (5.2[3.1, 7.8] vs. 3.2[2.3, 5.5] WU, p&lt;0.02). PCW and PVR at rest were lower in the comparator non-Group 2 vs WSPH non-Group 2 (8.9 ± 4.1 vs 11.1± 5.3 mm Hg, p&lt;.02) and 1.7[1.2, 2.3] vs 5.5[3.3, 8.7] WU, p&lt;.02. Thus, while LAA are most notable in WSPH and comparator Group 2’s, LAA differ between WSPH non-Group 2 and its non-Group 2 comparators. The role of LAA as predictors of PH outcomes remains to be determined.