tbuckley/cabot-search huggingface dataset:
Topical Aminosalicylic Acid Improves Keratinocyte Differentiation in an Inducible Mouse Model of Harlequin Ichthyosis
Authors: Denny L. Cottle, Gloria M.A. Ursino, Lynelle K. Jones, Ming Shen Tham, Allara K. Zylberberg, Ian M. Smyth
Journal: Cell Reports Medicine (2020)

Mutations in the lipid transport protein ABCA12 cause the life-threatening skin condition harlequin ichthyosis (HI), which is characterized by the loss of skin barrier function, inflammation, and dehydration. Inflammatory responses in HI increase disease severity by impairing keratinocyte differentiation, suggesting amelioration of this phenotype as a possible therapy for the condition. Existing treatments for HI are based around the use of retinoids, but their value in treating patients during the neonatal period has been questioned relative to other improved management regimens, and their long-term use is associated with side effects. We have developed a conditional mouse model to demonstrate that topical application of the aminosalicylic acid derivatives 5ASA or 4ASA considerably improves HI keratinocyte differentiation without the undesirable side effects of the retinoid acitretin and salicylic acid (aspirin). Analysis of changes in gene expression shows that 4ASA in particular elicits compensatory upregulation of a large family of barrier function-related genes, many of which are associated with other ichthyoses, identifying this compound as a lead candidate for developing topical treatments for HI.
Gender performance and migration experience of Filipino transgender women entertainers in Japan
Authors: Tricia Okada
Journal: International Journal of Transgender Health (2020)

Background: Many unrepresented stories of Filipino transgender migrant workers in Japan are significant in Filipino trans women's struggle for visibility.Aim: This study aims to explore how migration and gender performance influence the gender affirmation of Filipino trans women or transpinay entertainers in Japan.Method: This study draws on a qualitative approach using grounded theory to collect data between 2012 and 2018 through participant observations and semi-structured interviews in Manila, Cebu, and Japan. Through snowball sampling and ties with the LGBTQ community, 14 participants shared their narratives that revolved around their background, gender identity, visa and job application process, entertainment work, and relationships before, during, and after migration.Results: The transpinays' migration experience is influential in their gender affirmation as in Japan and upon their return to the Philippines. The transpinay entertainers migrate to Japan is not solely for economic reasons; they also seek sexual emancipation. Before moving to Japan, they negotiate their gender identity to pass the auditions and apply for an entertainer visa. During their migration, doing and undoing gender is woven into their lives with their intersecting subordinate identities as a Filipino transgender woman and a migrant worker, resulting into an intersectional invisibility. Their entertainer profile as a Filipino transgender woman is an embodiment of gendered performances and ethnicity. Transpinay entertainers returned several times or chose to stay in Japan because they were marginalized in their home country.Conclusion: The transpinay entertainers provide a significant case for highlighting the temporal aspect of their gender performance and migration experience, in which their commitment toward entertainment work transforms over time. The migration experience in Japan indicates a positive outcome in their gender affirmation that does not necessarily lead to gender confirmation surgery.
Abstract 14084: Albuminuria and Prognosis Among Individuals With Atherosclerotic Cardiovascular Disease: The Atherosclerosis Risk in Communities (aric) Study
Authors: Yejin Mok, Shoshana Ballew, Richard Stacey, Joseph Rossi, Silvia Koton, Anna Kucharska-newton, Patricia Chang, Josef Coresh, Wayne D Rosamond, Kunihiro Matsushita
Journal: Circulation (2020)

Background: The AHA/ACC 2018 Cholesterol Guideline categorizes ASCVD patients into very high-risk vs. high-risk to guide intensive therapy. This categorization is based on clinical conditions, including reduced kidney function, but does not take into account albuminuria, the other kidney measure often available in clinical practice. Methods: We studied 838 participants with major ASCVD (myocardial infarction, ischemic stroke, or symptomatic peripheral artery disease) from the ARIC study at baseline (1996 - 98). We compared urine albumin-to-creatinine ratio (ACR) and the eight high-risk conditions of age 65+, reduced kidney function, diabetes, etc. in the AHA/ACC Guideline regarding their associations with composite outcome of all-cause mortality, myocardial infarction, ischemic stroke, and heart failure. We also evaluated risk classification by adding ACR to the eight high-risk conditions. Results: During a median follow-up of 8 years, 724 (86%) participants developed a composite outcome. ACR ≥30 mg/g was associated with the composite outcome (adjusted hazard ratio [aHR] 1.45 [95% CI 1.20, 1.75]) beyond the eight high-risk conditions (aHR of these conditions ranged from 0.96 to 2.46). The addition of ACR improved the c-statistic by 0.011 (95% CI 0.003-0.019) from 0.661 to 0.672. ACR classified 4.6% of high-risk group to very high-risk and 11.2% of very high-risk group to extremely very high-risk with a reasonable calibration (Figure). Even ACR ≥10 mg/g showed a significant aHR of 1.38 (1.17, 1.63) and classified 13.4% of high-risk and 18.1% very high-risk to a higher risk category. Of our patients with ASCVD, 77% had diabetes, hypertension, or low kidney function, clinical conditions in which the ACR assessment is recommended. Conclusions: In ASCVD, albuminuria was a strong predictor of major adverse cardiovascular outcome and improved risk prediction. Clinicians should pay attention to albuminuria, in addition to eGFR, when managing ASCVD patients.
Combination of gemcitabine and anti-PD-1 antibody enhances the anticancer effect of M1 macrophages and the Th1 response in a murine model of pancreatic cancer liver metastasis
Authors: Tuyen Thuy Bich Ho, Alessandro Nasti, Akihiro Seki, Takuya Komura, Hiiro Inui, Takashi Kozaka, Yoji Kitamura, Kazuhiro Shiba, Taro Yamashita, Tatsuya Yamashita, Eishiro Mizukoshi, Kazunori Kawaguchi, Takashi Wada, Masao Honda, Shuichi Kaneko, Yoshio Sakai
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Pancreatic ductular adenocarcinoma (PDAC) is among the most dreadful of malignancies, in part due to the lack of efficacious chemotherapy. Immune checkpoint inhibitors, including anti-programmed cell death 1 (anti-PD-1) antibodies, are novel promising forms of systemic immunotherapy. In the current study, we assessed whether gemcitabine (GEM) combined with anti-PD-1 antibody treatment was efficacious as immunochemotherapy for advanced PDAC using a murine model of liver metastasis. Methods The murine model of PDAC liver metastasis was established by intrasplenically injecting the murine pancreatic cancer cell line PAN02 into immunocompetent C57BL/6J mice. The mice were treated with an anti-PD-1 antibody, GEM, or a combination of GEM plus anti-PD-1 antibody, and compared with no treatment (control); liver metastases, immune cell infiltration, gene expression, immune cell response phenotypes, and overall survival were investigated. Results In the metastatic tumor tissues of mice treated with GEM plus anti-PD-1 antibody, we observed the increased infiltration of Th1 lymphocytes and M1 macrophages. Gene expression profile analysis of peripheral blood cells obtained from mice treated with GEM plus anti-PD-1 antibody clearly highlighted T cell and innate immune signaling pathways. Survival of PDAC liver metastasis mice was significantly prolonged by the combination therapy (median survival, 66 days) when compared with that of GEM alone treatment (median survival, 56 days). Expanded lymphocytes, which were isolated from the splenocytes of PDAC liver metastasis mice treated with GEM plus anti-PD-1 antibody, had an increased number of M1 macrophages. Conclusion The combination of anti-PD-1 antibody immunotherapy with GEM was beneficial to treat a murine model of PDAC liver metastasis by enhancing the immune response mediated by Th1 lymphocytes and M1 macrophages and was associated with CD8+ T cells.
Abstract 15469: Malnutrition and Cognitive Dysfunction in the Elderly Patients With Acute Heart Failure
Authors: Michiaki NAGAI, Keigo Dote, Masaya Kato, Noboru Oda, Eiji Kunita, Eisuke Kagawa, AYA YAMANE, Hiroshi Kobatake, Osawa Ayano, Naoki Ishibashi, Kazuki Takahashi
Journal: Circulation (2020)

Introduction: Malnutrition, cognitive decline and heart failure (HF) frequently coexist in the elderly. A recent systematic review revealed that malnutrition was a possible contributing factor of cognitive impairment. Although several studies reported the association of malnutrition with poor HF prognosis, the underlying pathophysiology has been unclear. Hypothesis: We assessed the hypothesis that malnutritional status might be associated with cognitive dysfunction in the elderly with HF. In addition, we investigated whether left ventricular ejection fraction (LVEF) moderates that relationship or not. Methods: Nutritional status and cognitive function were evaluated using the geriatric nutritional risk index (GNRI), controlling nutritional status (CONUT) score and mini-mental state examination (MMSE) in 245 elderly inpatients in stable phase of HF (82.9±6.0 years old, male 49.4%). Echocardiography was performed at admission. HF with preserved EF (HFpEF) was defined according to LVEF more than 50% (n=129). Results: According to the quartile of MMSE score (&lt; 19, ≥19 to 27≤, &gt;27), significant associations of MMSE score were observed with GNRI (89.1 vs 95.4 vs 95.5, p=0.004) and CONUT score (3.50 vs 2.71 vs 2.61, p=0.039) among three groups. In the logistic regression analysis adjusted for the confounders including age, gender, LVEF, brain natriuretic peptide level, systolic blood pressure at admission, diuretics and antihypertensive medication use, GNRI (β=0.96, 95%CI:0.93 to 0.99, p=0.008) and CONUT score (β=1.18, 95%CI:1.01 to 1.37, p=0.03) each was significantly associated with cognitive dysfunction (defined as MMSE score &lt;19). According to the HF phenotype, GNRI (β=0.93, 95%CI:0.88 to 0.98, p=0.01) and CONUT (β=1.55, 95%CI:1.19 to 2.02, p=0.001) each had a significant relationship with cognitive dysfunction only in the group without HFpEF. Conclusions: In conclusion , lower GNRI and higher CONUT score were shown to be significant indicators of cognitive dysfunction in the elderly HF patients. These results highlight the importance of stratifying by nutritional status for a clinical intervention of cognitive dysfunction in the elderly patients without HFpEF.
Abstract 13772: Sepsis Induced Cardiomyopathy Confers Higher Mortality in Patients With Septic Shock
Authors: Balaram Krishna J Hanumanthu, Isaac Laniado, Obiageli Offor Lynda, Ankit Kushwaha, Anika Sasidharan Nair, Ankita Krishnan, Carla Rosenzvit, Adam Gershon, Jin Ei Chan, Simon Mendez-Bustamante, Perminder Gulani
Journal: Circulation (2019)

Introduction: Sepsis induced cardiomyopathy (SIC) is defined as reversible dysfunction of the left and/or right ventricle and is poorly characterized in literature. Hypothesis: This study was desig...
Abstract 118: Multicentric, Randomized Controlled Phase III Study of Centhaquine (Lyfaquin®) as an Effective First-in-class Resuscitative Agent in Hypovolemic Shock Patients
Authors: Anil Gulati, Rajat Choudhuri, Ajay Gupta, Saurabh Singh, S. K. Noushad Ali, Gursaran Kaur Sidhu, Parvez David Haque, Prashant Rahate, Aditya R. Bothra, G.P. Singh, Sanjeev Maheshwari, Deepak Jeswani, Sameer Haveri, Apurva Agarwal, Nilesh Radheshyam Agrawal
Journal: Circulation (2020)

Background: Centhaquine (CQ) is a novel, first-in-class resuscitative agent for the treatment of hypovolemic shock. Methods: Efficacy of CQ for the treatment of hypovolemic shock as an adjuvant to standard of care (SOC) was evaluated in a prospective, multi-center, randomized, double-blind, placebo-controlled Phase 3 study. Key inclusion criteria were; systolic blood pressure of &lt;90 mm Hg, blood lactate levels of &gt; 2 mmol/L and patients receiving SOC in a hospital or ICU setting. Patients were randomized in a 2:1 ratio either to the CQ group receiving CQ dose of 0.01 mg/kg by IV infusion along with SOC or to the control group receiving SOC plus saline. Primary endpoints of the study were change in systolic blood pressure (SBP) and diastolic blood pressure (DBP), change in blood lactate levels and change in base deficit. Mortality through day 28 was the key secondary endpoint. Results: A total of 197 patients were screened, of which 105 patients met the eligibility criteria and were included in the study. Out of 105 patients, 71 patients were randomized to CQ group and 34 patients to control group. Demographics and baseline characteristics of patients in both groups was comparable. Hemoglobin level was 9.38 ± 0.71 g/dL and 8.73 ± 0.55 g/dL in control and CQ groups, respectively at the time of inclusion in the study. At 24 hours of resuscitation, SBP of more than 110 mmHg was in 59.38% patients of control and 81.82% patients of CQ group (P=0.00842). Similarly, at 24 hours of resuscitation, DBP of more than 70 mmHg was in 50.00% patients in control group and 78.46% patients in CQ group (P=0.002175). The number of patients with blood lactate levels of 1.5 mmol/L or less were 46.88% in the group with standard treatment compared to 69.35% in CQ group (P=0.0168). The number of patients with base-deficit of less than minus 2 were 46.88% in standard treatment group compared to 68.25% in those receiving CQ (P=0.0217). CQ treatment significantly reduced the mortality rate. In the control group, the mortality rate was 11.76% compared to 2.94% in the CQ group (odds ratio: 4.4; 95% CI 0.9651 to 23.74 and P=0.037). No drug related adverse event was reported. Conclusion: Centhaquine (Lyfaquin®) is a highly efficacious resuscitative agent for the treatment of hypovolemic shock as an adjuvant to SOC.
A distinct CD38+CD45RA+ population of CD4+, CD8+, and double-negative T cells is controlled by FAS
Authors: Maria Elena Maccari, Sebastian Fuchs, Patrick Kury, Geoffroy Andrieux, Simon Völkl, Bertram Bengsch, Myriam Ricarda Lorenz, Maximilian Heeg, Jan Rohr, Sabine Jägle, Carla N. Castro, Miriam Groß, Ursula Warthorst, Christoph König, Ilka Fuchs, Carsten Speckmann, Julian Thalhammer, Friedrich G. Kapp, Markus G. Seidel, Gregor Dückers, Stefan Schönberger, Catharina Schütz, Marita Führer, Robin Kobbe, Dirk Holzinger, Christian Klemann, Petr Smisek, Stephen Owens, Gerd Horneff, Reinhard Kolb, Nora Naumann-Bartsch, Maurizio Miano, Julian Staniek, Marta Rizzi, Tomas Kalina, Pascal Schneider, Anika Erxleben, Rolf Backofen, Arif Ekici, Charlotte M. Niemeyer, Klaus Warnatz, Bodo Grimbacher, Hermann Eibel, Andreas Mackensen, Andreas Philipp Frei, Klaus Schwarz, Melanie Boerries, Stephan Ehl, Anne Rensing-Ehl
Journal: The Journal of Experimental Medicine (2020)

The identification and characterization of rare immune cell populations in humans can be facilitated by their growth advantage in the context of specific genetic diseases. Here, we use autoimmune lymphoproliferative syndrome to identify a population of FAS-controlled TCRαβ+ T cells. They include CD4+, CD8+, and double-negative T cells and can be defined by a CD38+CD45RA+T-BET− expression pattern. These unconventional T cells are present in healthy individuals, are generated before birth, are enriched in lymphoid tissue, and do not expand during acute viral infection. They are characterized by a unique molecular signature that is unambiguously different from other known T cell differentiation subsets and independent of CD4 or CD8 expression. Functionally, FAS-controlled T cells represent highly proliferative, noncytotoxic T cells with an IL-10 cytokine bias. Mechanistically, regulation of this physiological population is mediated by FAS and CTLA4 signaling, and its survival is enhanced by mTOR and STAT3 signals. Genetic alterations in these pathways result in expansion of FAS-controlled T cells, which can cause significant lymphoproliferative disease.
Abstract 14842: Brain Fibroblast Growth Factor Receptor 4 Stimulation is Involved in High Phosphate Diet-Induced Skeletal Muscle Reflex Overactivation in Rats
Authors: Han-kyul Kim, Masaki Mizuno, Gary A Iwamoto, Rie Ishizawa, Jere H Mitchell, Johanne V Pastor, Orson W Moe, Scott A Smith, Wanpen Vongpatanasin
Journal: Circulation (2020)

An increasing number of studies have reported a deleterious role of inorganic phosphate (Pi) in promoting hypertension. Previously, we have shown high Pi diet-induced excessive pressor and sympathetic responses to muscle contraction in otherwise normal rats, which were primarily mediated by an overactive exercise pressor reflex (EPR), a reflex arising from contracting muscle. However, the mechanism underlying these abnormalities generated by excess Pi intake remains unclear. Dietary Pi is known to increase release of bone-derived fibroblast growth factor (FGF) 23 to regulate Pi homeostasis. Evidence suggests that FGF23 and FGF receptors (FGFRs) are also present in the central nervous system. The aim of this study was to determine the role of brain FGFRs in mediating augmented EPR activity induced by dietary Pi excess. Accordingly, we assessed cerebrospinal fluid FGF23 levels in Sprague-Dawley rats fed either a normal 0.6% Pi diet (NP) or a high 1.2% Pi diet (HP) for 12 weeks. To determine the role of central FGFRs in mediating the EPR, we measured mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) responses to hindlimb muscle contraction before and after intracerebroventricular (ICV) administration of either a selective FGFR4 inhibitor BLU9931 or a FGFR1/2/3 inhibitor AZD4547 in decerebrate NP and HP animals. Cerebrospinal fluid FGF23 levels were significantly higher in HP rats compared to NP rats (8.3±0.9 vs. 7.2±0.8 pM, P&lt;0.01). ICV BLU9931 injection markedly attenuated (all P&lt;0.01) the heightened MAP (Δ=41±14 vs. 20±14 mmHg) and RSNA (Δ=112±70 vs. 65±46 %) responses to EPR activation in HP animals, but did not significantly affect the responses in NP animals (ΔMAP=11±3 vs. 7±4 mmHg, ΔRSNA=21±17 vs. 15±5 %). MAP and RSNA responses to EPR stimulation were unchanged by ICV AZD4547 administration in NP or HP rats. In conclusion, our data demonstrate a novel action of central FGFR4 inhibition by reducing the high Pi diet-mediated skeletal muscle reflex overactivation. Importantly, the results implicate that activation of brain FGFR4 may lead to sympathetic dysregulation contributing to the abnormal hypertensive responsiveness after excess Pi consumption.
Abstract 15184: Association Between Positive End-Expiratory Pressure With Mortality and Mechanical Ventilation Duration in Patients With Left and Right Ventricular Dysfunction: Insights From the Medical Information Mart for Intensive Care (MIMIC-III) Database
Authors: Albert Y Lui, Leonid Garber, Christopher Cosgriff, Vincent J Major, Jordan Poles, Marie Charpignon, Leo A Celi, Sean Van Diepen, Nathaniel Smilowitz, Carlos L Alviar
Journal: Circulation (2019)

Background: The hemodynamic response to mechanical ventilation (MV) may be influenced by left ventricular (LV) and right ventricular (RV) function, but data are limited to small preclinical and cli...
Abstract 115: Extracorporeal Cardiopulmonary Resuscitation for Refractory Out of Hospital Cardiac Arrest (EROCA) - Results of a Randomized Feasibility Trial of Expedited Prehospital Transport
Authors: William J Meurer, Robert Domeier, Cindy H Hsu, Jennifer Fowler, Sage Whitmore, Benjamin Bassin, Kyle Gunnerson, Jonathan Haft, William Lynch, Brahmajee Nallamothu, Renee Havey, Kelley Kidwell, William Stacey, Robert Silbergleit, Robert Bartlett, Robert W Neumar
Journal: Circulation (2020)

Introduction: Extracorporeal cardiopulmonary resuscitation (ECPR) for out-of-hospital cardiac arrest (OHCA) is promising but is unproven, and outcomes are strongly dependent on time to initiation of therapy. Expedited transport may facilitate opportunities for ECPR in clinical practice and future trials. Hypotheses: We hypothesized that a real-time dispatch-based computer algorithm could select refractory OHCA patients who could be reliably transported to the emergency department (ED) within 30 min of the 911 call, and that Emergency Medicine physicians could initiate ECPR in eligible patients within 30 min of ED arrival. Methods: In a 2-tiered EMS system serving a US city of 100k in 29 square miles with an ECPR capable primary destination hospital, adults with refractory shockable or witnessed OHCA were randomized 4:1 to expedited transport (ET) or standard prehospital care (SC) if the predicted 911 to ED arrival time was &lt;30 min. A maximum sample size of 24 was planned. The study required exception from informed consent. The primary outcomes were the proportion of patients with 911 to ED arrival &lt;30 min and ED arrival to ECPR flow &lt;30 min. Results: Out of 156 cardiac arrest runs, 15 participants (10%) were randomized prior to ending the trial for slow accrual. Five of 12 patients randomized to expedited transport had an ED arrival time of &lt;30 min (mean 32.5+7.1). All ECPR eligible patients were cannulated, 3 of 5 receiving ECPR had flow initiated &lt;30 min of ED arrival (mean 32.4+10.9), and 7 were ECPR ineligible. One patient (randomized to SC) survived to 30 days, and no patients in either group survived with a good neurological outcome. Conclusions: EROCA demonstrated a functional model for selecting patients with refractory OHCA for ET in an ECPR capable system but did not meet predefined time-interval targets. These results provide important insight into the feasibility of ECPR clinical trials and clinical practice based on selected target intervals.
Abstract 14721: Impact of Covid-19 on Cardiology Consultation in Tertiary Care Hospital of a Developing Country
Authors: ghufran adnan, Osman Faheem, Maria Khan, Pirbhat Shams, Jamshed Ali
Journal: Circulation (2020)

Introduction: COVID-19 pandemic has overwhelmed the healthcare system of Pakistan. There has been observation regarding changes in pattern of patient presentation to emergency department (ED) for all diseases particularly cardiovascular. The aim of the study is to investigate these changes in cardiology consultations and compare pre-COVID-19 and COVID-19 era. Hypothesis: There is a significant difference in cardiology consultations during COVID era as compared to non-COVID era. Method: We collected data retrospectively of consecutive patients who visited emergency department (ED) during March-April 2019 (non-COVID era) and March-April 2020 (COVID era). Comparison has been made to quantify the differences in clinical characteristics, locality, admission, type, number, and reason of Cardiology consults generated. Results: We calculated the difference of 1351 patients between COVID and non-COVID era in terms of cardiology consults generated from Emergency department, using Chi-square test. Out of which 880 (59%) are male with mean age of 61(SD=15). Analysis shows pronounced augmentation in number of comorbidities [Hypertension(6%), Chronic kidney disease (6%), Diabetes (5%)] but there was 36% drop in total cardiology consultations and 43% reduction rate in patient’s ED visit from other cities during COVID era. There was 60% decrease in acute coronary syndrome presentation in COVID era, but fortuitously drastic increase (30%) in type II myocardial injury has been noted. Conclusion: There is a remarkable decline observed in patients presenting with cardiac manifestations during COVID era. Lack in timely care could have a pernicious impact on outcomes, global health care organizations should issue directions to adopt telemedicine services in underprivileged areas to provide timely care to cardiac patients.