tbuckley/cabot-search huggingface dataset:
Phase I First-in-Human Dose Escalation Study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms
Authors: David P. Steensma, Martin Wermke, Virginia M. Klimek, Peter L. Greenberg, Patricia Font, Rami S. Komrokji, Jay Yang, Andrew M. Brunner, Hetty E. Carraway, Lionel Ades, Aref Al-Kali, Juan M. Alonso-Dominguez, Ana Alfonso-Piérola, Catherine C. Coombs, H. Joachim Deeg, Ian Flinn, James M. Foran, Guillermo Garcia-Manero, Michael B. Maris, Malgorzata McMasters, Jean-Baptiste Micol, Jaime Perez De Oteyza, Felicitas Thol, Eunice S. Wang, Justin M. Watts, Justin Taylor, Richard Stone, Vikram Gourineni, Alyssa J. Marino, Huilan Yao, Benoit Destenaves, Xiaobin Yuan, Kun Yu, Sara Dar, Lernik Ohanjanian, Keisuke Kuida, Jianjun Xiao, Catherine Scholz, Antonio Gualberto, Uwe Platzbecker
Journal: Leukemia (2021)

Abstract We conducted a phase I clinical trial of H3B-8800, an oral small molecule that binds Splicing Factor 3B1 (SF3B1), in patients with MDS, CMML, or AML. Among 84 enrolled patients (42 MDS, 4 CMML and 38 AML), 62 were red blood cell (RBC) transfusion dependent at study entry. Dose escalation cohorts examined two once-daily dosing regimens: schedule I (5 days on/9 days off, range of doses studied 1–40 mg, n = 65) and schedule II (21 days on/7 days off, 7–20 mg, n = 19); 27 patients received treatment for ≥180 days. The most common treatment-related, treatment-emergent adverse events included diarrhea, nausea, fatigue, and vomiting. No complete or partial responses meeting IWG criteria were observed; however, RBC transfusion free intervals &gt;56 days were observed in nine patients who were transfusion dependent at study entry (15%). Of 15 MDS patients with missense SF3B1 mutations, five experienced RBC transfusion independence (TI). Elevated pre-treatment expression of aberrant transcripts of Transmembrane Protein 14C ( TMEM14C ), an SF3B1 splicing target encoding a mitochondrial porphyrin transporter, was observed in MDS patients experiencing RBC TI. In summary, H3B-8800 treatment was associated with mostly low-grade TAEs and induced RBC TI in a biomarker-defined subset of MDS.
Comparison of COVID-19 Vaccine Approvals at the US Food and Drug Administration, European Medicines Agency, and Health Canada
Authors: Mark P. Lythgoe, Paul Middleton
Journal: JAMA Network Open (2021)

This qualitative improvement study investigates COVID-19 vaccine approvals at 3 medicine regulatory agencies in the US, EU, and Canada, characterizing and contrasting regulatory review times, and analyzing the clinical evidence supporting authorization.
Abstract 255: Role of Connexin 43 in Muscular Dystrophy Cardiomyopathy
Authors: J. Patrick Gonzalez, Jayalakshmi Ramachandran, Chifei Kang, Lai-Hua Xie, Natalia Shirokova, Jorge Contreras, Diego Fraidenraich
Journal: Circulation Research (2016)

Duchenne muscular dystrophy (DMD) is caused by an X-linked mutation that leads to the absence of dystrophin, resulting in life-threatening arrhythmogenesis and associated heart failure. The downstream events that lead to cardiomyopathy are largely unexplored. We unveiled a novel role for the gap junction protein connexin43 (Cx43) in maintaining cardiac conduction and ultimately in preventing heart failure from occurring in DMD. In mild mdx and severe mdx:utr mouse models of DMD, and human DMD tissues, Cx43 was found to be aberrantly upregulated and mislocalized to lateral sides of cardiomyocytes, with an abnormal phosphorylation pattern. We found that a triplet of serine residues, which plays a key role in a variety of cardiac pathologies, was hypophosphorylated in mdx relative to wild-type hearts. Electrocardiography on isoproterenol (Iso) challenged mice showed that both DMD mouse models developed arrhythmias and died within 24 hours, while wild-type mice were free of pathology. Administering peptide mimetic inhibitors of lateralized Cx43 channels prior to Iso challenge protected mdx mice from arrhythmogenesis and death. Cx43 copy number reduction in mdx:Cx43(+/-) mice not only ameliorated acute but also chronic, long-term symptoms of cardiomyopathy in mdx mice. Overall, our findings suggest that Cx43 lateralization contributes significantly to DMD cardiomyopathy and that selective inhibition of misplaced, upregulated channels may provide substantial benefit.
Reappearance of C-Peptide During the Third Trimester of Pregnancy in Type 1 Diabetes: Pancreatic Regeneration or Fetal Hyperinsulinism?
Authors: Claire L. Meek, Richard A. Oram, Timothy J. McDonald, Denice S. Feig, Andrew T. Hattersley, Helen R. Murphy
Journal: Diabetes Care (2021)

OBJECTIVE We assessed longitudinal patterns of maternal C-peptide concentration to examine the hypothesis of β-cell regeneration in pregnancy with type 1 diabetes. RESEARCH DESIGN AND METHODS C-peptide was measured on maternal serum samples from 127 participants (12, 24, and 34 weeks) and cord blood during the Continuous Glucose Monitoring in Women With Type 1 Diabetes in Pregnancy Trial (CONCEPTT). C-peptide was measured using a highly sensitive direct and solid-phase competitive electrochemiluminescent immunoassay. RESULTS Three discrete patterns of maternal C-peptide trajectory were identified: pattern 1, undetectable throughout pregnancy, n = 74 (58%; maternal C-peptide &amp;lt;3 pmol/L); pattern 2, detectable at baseline, n = 22 (17%; maternal C-peptide 7–272 pmol/L at baseline); and pattern 3, undetectable maternal C-peptide at 12 and 24 weeks, which first became detectable at 34 weeks, n = 31 (24%; maternal C-peptide 4–26 pmol/L at 34 weeks). Baseline characteristics and third trimester glucose profiles of women with pattern 1 and pattern 3 C-peptide trajectories were similar, but women in pattern 3 had suboptimal glycemia (50% time above range) at 24 weeks’ gestation. Offspring of women with pattern 3 C-peptide trajectories had elevated cord blood C-peptide (geometric mean 1,319 vs. 718 pmol/L; P = 0.007), increased rates of large for gestational age (90% vs. 60%; P = 0.002), neonatal hypoglycemia (42% vs. 14%; P = 0.001), and neonatal intensive care admission (45% vs. 23%; P = 0.023) compared with pattern 1 offspring. CONCLUSIONS First maternal C-peptide appearance at 34 weeks was associated with midtrimester hyperglycemia, elevated cord blood C-peptide, and high rates of neonatal complications. This suggests transfer of C-peptide from fetal to maternal serum and is inconsistent with pregnancy-related β-cell regeneration.
Abstract 52: Isolation, Characterization and Partial Direct Differentiation of Patient Derived Human Primary Cardiac and Placental Fibroblasts From Surgical Discard Tissue into Induced Mesoderm Progenitor Cell
Authors: Pouya Sadeghi Pour, Costanza Emanueli, Massimo Caputo, Gianni Angelini
Journal: Circulation Research (2016)

Background: Human primary cells more closely mimic the physiological state of cells in vivo and generate more relevant data representing living systems. Access to the surgical discard tissue enables the possibility of patient derived, disease specific, cellular bio-bank. In achieving this goal, target cellular lines must be isolated, characterized and fully expanded under specific Standard Operating Procedures(SOP). In this project, we aim in achieving and implementing such goal for Fibroblasts derived from two distinct patient tissues. In parallel, in light of cardiac regenerative therapy, with reference to the published work on Cardiomyocyte Direct Differentiation on mouse fibroblasts into induced cardiomyocyte-like cells (iCMs) by transduction with MicroRNAs (1,133a, 208a and 499) we sought to determine whether primary human cardiac and placental fibroblasts could have the potential in direct differentiation to induced cardiomyocyte-like cells (iCM) through sequential administration of small molecule (ITD-1) in combination with MicroRNAs. Methods and Results: Primary right atrial appendage cardiac and smooth chorion laeve placental fibroblast isolates were generated from surgical discard patient derived tissues subjected for identification of the most efficient isolation method through available enzymatic and mechanical techniques. We have shown through FACS analysis that both groups extracellular marker expression can be limited to CD90+CD31-CD44+FBSP+ which constitutes the majority of cultured primary fibroblasts. Respectively, intercellular expression of DDR2+ VIM+ COL1+CD90+ markers was validated through immunofluorescence microscopy. Transcriptional profiling of Noted lines showed expression of Fibroblast specific genes at higher rate.Furthermore, sorted placental fibroblast isolates were subjected to (ITD-1)treatment and mature MicroRNA mimic cocktail. Transcriptional profiling analysis through RT-PCR concluded down regulation of most distinct fibroblast markers and partial expression of MESP1.
Abstract 10952: Myocardial Production of Follistatin-Like 1 is Associated With Left Ventricular Adverse Remodeling in Survivors of Acute Myocardial Infarction
Authors: Manabu Uematsu, Kazuto Nakamura, Takamitsu Nakamura, Toru Yoshizaki, Yosuke Watanabe, Juntaro Deyama, Kazuhiro Watanabe, Tsuyoshi Kobayashi, Daisuke Fujioka, Yukio Saito, Kenichi Kawabata, Jun-ei Obata, Kiyotaka Kugiyama
Journal: Circulation (2018)

Follistatin-like 1 (FSTL1) is expressed in infarcted myocardium. Experimental studies showed that FSTL1 exerts cardioprotective effects against ischemic injury. However, little is known in humans. ...
Abstract 15248: Tachycardia-Induced Incomplete Relaxation and Left Ventricular Volume Loss in Concentric Hypertrophy
Authors: Markus Meyer, Iwan Nyotowidjojo, Marc Tischler, Martin LeWinter
Journal: Circulation (2011)

Background: Concentric LV hypertrophy (LVH) is a precursor to heart failure with normal ejection fraction. We have shown that when isolated human LV myocardium from patients with LVH is electricall...
Association of Costs and Days at Home With Transfer Hospital in Home
Authors: Shubing Cai, Orna Intrator, Caitlin Chan, Laurence Buxbaum, Mary Ann Haggerty, Ciaran S. Phibbs, Edna Schwab, Bruce Kinosian
Journal: JAMA Network Open (2021)

<h3>Importance</h3> New Centers for Medicare &amp; Medicaid Services waivers created a payment mechanism for hospital at home services. Although it is well established that direct admission to hospital at home from the community as a substitute for hospital care provides superior outcomes and lower cost, the effectiveness of transfer hospital at home—that is, completing hospitalization at home—is unclear. <h3>Objective</h3> To evaluate the outcomes of the transfer component of a Veterans Affairs (VA) Hospital in Home program (T-HIH), taking advantage of natural geographical limitations in a program's service area. <h3>Design, Setting, and Participants</h3> In this quality improvement study, T-HIH was offered to veterans residing in Philadelphia, Pennsylvania, and their outcomes were compared with those of propensity-matched veterans residing in adjacent Camden, New Jersey, who were admitted to the VA hospital from 2012 to 2018. Data analysis was performed from October 2019 to May 2020. <h3>Intervention</h3> Enrollment in the T-HIH program. <h3>Main Outcomes and Measures</h3> The main outcomes were hospital length of stay, 30-day and 90-day readmissions, VA direct costs, combined VA and Medicare costs, mortality, 90-day nursing home use, and days at home after hospital discharge. An intent-to-treat analysis of cost and utilization was performed. <h3>Results</h3> A total of 405 veterans (mean [SD] age, 66.7 [0.83] years; 399 men [98.5%]) with medically complex conditions, primarily congestive heart failure and chronic obstructive pulmonary disease exacerbations (mean [SD] hierarchical condition categories score, 3.54 [0.16]), were enrolled. Ten participants could not be matched, so analyses were performed for 395 veterans (all of whom were men), 98 in the T-HIH group and 297 in the control group. For patients in the T-HIH group compared with the control group, length of stay was 20% lower (6.1 vs 7.7 days; difference, 1.6 days; 95% CI, −3.77 to 0.61 days), VA costs were 20% lower (−$5910; 95% CI, −$13 049 to $1229), combined VA and Medicare costs were 22% lower (−$7002; 95% CI, −$14 314 to $309), readmission rates were similar (23.7% vs 23.0%), the numbers of nursing home days were significantly fewer (0.92 vs 7.45 days; difference, −6.5 days; 95% CI, −12.1 to −0.96 days;<i>P</i> = .02), and the number of days at home was 18% higher (81.4 vs 68.8 days; difference, 12.6 days; 95% CI, 3.12 to 22.08 days;<i>P</i> = .01). <h3>Conclusions and Relevance</h3> In this study, T-HIH was significantly associated with increased days at home and less nursing home use but was not associated with increased health care system costs.
Allogeneic Hematopoietic Cell Transplantation Causes Accelerated Aging Both of the Hematopoietic and Somatic Systems
Authors: Moshe Yeshurun, Meir Lahav, Uri Rozovski, Einat Beery, Liat Shargian, Maya Moshe, Michal Navon Sela, Anat Peck, Iuliana Vaxman, Ofir Wolach, Pia Raanani, Orit Uziel
Journal: Blood (2017)
Disparities in Learning Mode Access Among K–12 Students During the COVID-19 Pandemic, by Race/Ethnicity, Geography, and Grade Level — United States, September 2020–April 2021
Authors: Emily Oster, Rebecca Jack, Clare Halloran, John Schoof, Diana McLeod, Haisheng Yang, Julie Roche, Dennis Roche
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

In response to the COVID-19 pandemic, schools across the United States began transitioning to virtual learning during spring 2020. However, schools' learning modes varied during the 2020-21 school year across states as schools transitioned at differing times back to in-person learning, in part reflecting updated CDC guidance. Reduced access to in-person learning is associated with poorer learning outcomes and adverse mental health and behavioral effects in children (1-3). Data on the learning modes available in 1,200 U.S. public school districts (representing 46% of kindergarten through grade 12 [K-12] public school enrollment) from all 50 states and the District of Columbia during September 2020-April 2021 were matched with National Center for Education Statistics (NCES) demographic data. Learning mode access was assessed for K-12 students during the COVID-19 pandemic, over time and by student race/ethnicity, geography, and grade level group. Across all assessed racial/ethnic groups, prevalence of virtual-only learning showed more variability during September-December 2020 but declined steadily from January to April 2021. During January-April 2021, access to full-time in-person learning for non-Hispanic White students increased by 36.6 percentage points (from 38.0% to 74.6%), compared with 31.1 percentage points for non-Hispanic Black students (from 32.3% to 63.4%), 23.0 percentage points for Hispanic students (from 35.9% to 58.9%) and 30.6 percentage points for students of other races/ethnicities (from 26.3% to 56.9%). In January 2021, 39% of students in grades K-5 had access to full-time in-person learning compared with 33% of students in grades 6-8 and 30% of students in grades 9-12. Disparities in full-time in-person learning by race/ethnicity existed across school levels and by geographic region and state. These disparities underscore the importance of prioritizing equitable access to this learning mode for the 2021-22 school year. To increase equitable access to full-time in-person learning for the 2021-22 school year, school leaders should focus on providing safety-optimized in-person learning options across grade levels. CDC's K-12 operational strategy presents a pathway for schools to safely provide in-person learning through implementing recommended prevention strategies, increasing vaccination rates for teachers and older students with a focus on vaccine equity, and reducing community transmission (4).
HIV Testing Trends Among Persons with Commercial Insurance or Medicaid — United States, 2014–2019
Authors: Kirk D. Henny, Weiming Zhu, Ya-lin A. Huang, Ashley Townes, Kevin P. Delaney, Karen W. Hoover
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

HIV testing is a critical component of effective HIV prevention and care.CDC recommends routine opt-out HIV testing in health care settings for all sexually active persons aged 13-64 years at least once in their lifetime and risk-based testing regardless of age for those who report behaviors associated with HIV acquisition (1).However, recent studies show low HIV testing rates in clinical settings; HIV testing rates at visits to physician offices did not increase during 2009-2016 (2).The objective of the current study is to estimate temporal trends in HIV testing among persons with commercial insurance or Medicaid from 2014 through 2019 and describe their demographic characteristics in 2019.Weighted data from the IBM MarketScan Commercial Claims and Encounters database* (commercial insurance) and from the Centers for Medicare & Medicaid Services (CMS) claims database † (Medicaid) were analyzed to estimate the proportions of persons with commercial insurance or Medicaid who received testing for HIV.Testing rates increased among male and nonpregnant female persons aged ≥13 years with either type of coverage.In 2019, only 4.0% of those with commercial insurance and 5.5% of those with Medicaid received testing for HIV.Testing rates were higher among non-Hispanic Black or African American (Black) persons and Hispanic or Latino (Hispanic) persons.Based on mathematical modeling studies, these annual testing rates would need to increase at least threefold and be sustained over several years (3,4) to achieve the Ending the HIV Epidemic (EHE) in the U.S. initiative goal of ≥95% of persons with HIV being aware of their infection by 2025.§ Interventions need to be implemented to increase routine and risk-based HIV testing in clinical settings to higher levels that can help reduce * https://www.ibm.com/products/marketscan-research-databases/databases
A Method for Overcoming Plasma Protein Inhibition of Tyrosine Kinase Inhibitors
Authors: David J. Young, Bao Nguyen, Li Li, Tomoyasu Higashimoto, Mark J. Levis, Jun O. Liu, Donald Small
Journal: Blood Cancer Discovery (2021)

Abstract FMS-like tyrosine kinase 3 (FLT3) is the most frequently mutated gene in acute myeloid leukemia and a target for tyrosine kinase inhibitors (TKI). FLT3 TKIs have yielded limited improvements to clinical outcomes. One reason for this is TKI inhibition by endogenous factors. We characterized plasma protein binding of FLT3 TKI, specifically staurosporine derivatives (STS-TKI) by alpha-1-acid glycoprotein (AGP), simulating its effects upon drug efficacy. Human AGP inhibits the antiproliferative activity of STS-TKI in FLT3/ITD-dependent cells, with IC50 shifts higher than clinically achievable. This is not seen with nonhuman plasma. Mifepristone cotreatment, with its higher AGP affinity, improves TKI activity despite AGP, yielding IC50s predicted to be clinically effective. In a mouse model of AGP drug inhibition, mifepristone restores midostaurin activity. This suggests combinatorial methods for overcoming plasma protein inhibition of existing TKIs for leukemia as well as providing a platform for investigating the drug–protein interaction space for developing more potent small-molecule agents. Significance: Our data provide a mechanism for the failure of some previous TKI clinical trials. The ability of mifepristone to disinhibit TKIs suggests an approach by which the combination of TKIs with already approved and well-tolerated drugs may restore TKI activity. This article is highlighted in the In This Issue feature, p. 403
Patient Rights to Publicity versus Provider Rights to Privacy: Striking a Balance When Blogging in the Medical Setting
Authors: Marleen Eijkholt, Marilyn Fisher, Jane Jankowski
Journal: The American Journal of Bioethics (2021)

The nurse asks the ethics consultant what can be done to stop the patient’s blogging. R.J.’s messages on the public forum are taking their toll on the care environment and the health care providers...
Intensive Medical Management to Prevent Large and Small Artery Atherothrombotic Stroke
Authors: Meng Lee, Bruce Ovbiagele, Jeffrey L. Saver
Journal: JAMA (2021)

This Viewpoint examines the potential of using newer strategies to prevent ischemic stroke due to large and small artery atherothrombosis, including agents to lower LDL cholesterol, as well as increase eicosapentaenoic acid levels, insulin sensitivity and synthesis, and folic acid levels.
Complement mediates binding and procoagulant effects of ultralarge HIT immune complexes
Authors: Sanjay Khandelwal, Ayiesha Barnes, Lubica Rauova, Amrita Sarkar, Ann H. Rux, Serge V. Yarovoi, S. Sergei Zaitsev, John D. Lambris, Sooho S. Myoung, Alexandra Johnson, Grace M. Lee, Madelaine Duarte, Mortimer Poncz, Gowthami M. Arepally, Douglas B. Cines
Journal: Blood (2021)
MyD88 signaling by neurons induces chemokines that recruit protective leukocytes to the virus-infected CNS
Authors: Luca Ghita, Julia Spanier, Chintan Chhatbar, Felix Mulenge, Andreas Pavlou, Pia-Katharina Larsen, Inken Waltl, Yvonne Lueder, Moritz Kohls, Klaus Jung, Sonja M. Best, Reinhold Förster, Martin Stangel, Dietmar Schreiner, Ulrich Kalinke
Journal: Science Immunology (2021)

During viral CNS infection, MyD88 signaling in infected neurons orchestrates recruitment of protective peripheral immune cells.
Mental health support after covid-19: closer relations between general practice, psychology, and occupational health
Authors: Woody Caan
Journal: BMJ (2021)

Thank you for your interest in spreading the word about The BMJ.NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address. Username * Your Email * Send To * You are going to email the following Mental health support after covid-19: closer relations between general practice, psychology, and occupational health Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Overexpression of BRD4 Is an Adverse Prognostic Factor in Acute Myeloid Leukemia
Authors: Hima Bansal, Steven Kornblau, Qiu Yihua, Kevin R Coombes, Subbarayalu Panneerdoss, Anand Karnad, Steven Weitman, Gail Tomlinson, Sanjay Bansal, Swami P. Iyer
Journal: Blood (2017)
Trend in mandatory immunisation coverage: linear and joinpoint regression approach, Serbia, 2000 to 2017
Authors: Marko Veljkovic, Goranka Loncarevic, Milena Kanazir, Darija Kisic-Tepavcevic, Tatjana Gazibara
Journal: Eurosurveillance (2021)

BackgroundAnalyses of temporal trends in immunisation coverage may help to identify problems in immunisation activities at specific points in time. These data are essential for further planning, meeting recommended indicators, monitoring, management and advocacy.AimThis study examined the trends of mandatory vaccination coverage in the period 2000-2017 in Serbia.MethodsData on completed immunisations were retrieved from annual national reports of the Institute of Public Health of Serbia during the period 2000-2017. To assess the trends of immunisation coverage, both linear and joinpoint regression analyses were performed. A probability p < 0.05 was considered significant.ResultsOver the period 2000-2017 linear regression analysis showed a significant decline in coverage with the primary vaccination against poliomyelitis, diphtheria, tetanus, pertussis and measles, mumps, rubella (MMR) (p ≤ 0.01). In the same period, coverage of all subsequent revaccinations significantly decreased, namely, first revaccination for pertussis (p < 0.01); first, second and third revaccination against diphtheria, tetanus and poliomyelitis (p < 0.01); and second dose against MMR before enrolment in elementary school (p < 0.05). Although linear regression analysis did not show change in vaccination coverage trend against tuberculosis (Bacillus Calmette-Guérin; BCG), hepatitis B (HepB3) in infants and diseases caused by