bluuebunny/crossref_metadata_2025_split huggingface dataset:
PC4 serves as a negative regulator of skin wound healing in mice
Authors: Liao Fengying , Chen Long , Luo Peng , Jiang Zhongyong , Chen Zelin , Wang Ziwen , Zhang Chi , Wang Yu , He Jintao , Wang Qing , Wang Yawei , Liu Lang , Huang Yu , Wang Huilan , Jiang Qingzhi , Luo Min , Gan Yibo , Liu Yunsheng , Wang Yang , Wu Jie , Xie Wentao , Cheng Zhuo , Dai Yali , Li Jialun , Liu Zujuan , Yang Fan , Shi Chunmeng 
Published: April 2020

Abstract

Background
Human positive cofactor 4 (PC4) was initially characterized as a multifunctional transcriptional cofactor, but its role in skin wound healing is still unclear. The purpose of this study was to explore the role of PC4 in skin wound healing through PC4 knock-in mouse model.

Methods
A PC4 knock-in mouse model (PC4+/+) with a dorsal full-thickness wound was used to investigate the biological functions of PC4 in skin wound healing. Quantitative PCR, Western blot analysis and immunohistochemistry were performed to evaluate the expression of PC4; Sirius red staining and immunofluorescence were performed to explore the change of collagen deposition and angiogenesis. Proliferation and apoptosis were detected using Ki67 staining and TUNEL assay. Primary dermal fibroblasts were isolated from mouse skin to perform cell scratch experiments, cck-8 assay and colony formation assay.

Results
The PC4+/+ mice were fertile and did not display overt abnormalities but showed an obvious delay in cutaneous healing of dorsal skin. Histological staining showed insufficient re-epithelialization, decreased angiogenesis and collagen deposition, increased apoptosis and decreased cell proliferation in PC4+/+ skin. Our data also showed decreased migration rate and proliferation ability in cultured primary fibroblasts from PC4+/+ mice in vitro.

Conclusions
This study suggests that PC4 might serve as a negative regulator of skin wound healing in mice.
Renewal and Differentiation of GCD Necklace Olfactory Sensory Neurons
Authors: Bloom Maria Lissitsyna , Johnston Lucille B , Datta Sandeep Robert 
Published: April 2020

AbstractBoth canonical olfactory sensory neurons (OSNs) and sensory neurons belonging to the guanylate cyclase D (GCD) “necklace” subsystem are housed in the main olfactory epithelium, which is continuously bombarded by toxins, pathogens, and debris from the outside world. Canonical OSNs address this challenge, in part, by undergoing renewal through neurogenesis; however, it is not clear whether GCD OSNs also continuously regenerate and, if so, whether newborn GCD precursors follow a similar developmental trajectory to that taken by canonical OSNs. Here, we demonstrate that GCD OSNs are born throughout adulthood and can persist in the epithelium for several months. Phosphodiesterase 2A is upregulated early in the differentiation process, followed by the sequential downregulation of β-tubulin and the upregulation of CART protein. The GCD and MS4A receptors that confer sensory responses upon GCD neurons are initially expressed midway through this process but become most highly expressed once CART levels are maximal late in GCD OSN development. GCD OSN maturation is accompanied by a horizontal migration of neurons toward the central, curved portions of the cul-de-sac regions where necklace cells are concentrated. These findings demonstrate that—like their canonical counterparts—GCD OSNs undergo continuous renewal and define a GCD-specific developmental trajectory linking neurogenesis, maturation, and migration.
Discriminative Ability and Reliability of Transesophageal Echocardiography in Characterizing Cases of Cardiac Device Lead Vegetations Versus Noninfectious Echodensities
Authors: George Merit P , Esquer Garrigos Zerelda , Vijayvargiya Prakhar , Anavekar Nandan S , Luis Sushil Allen , Wilson Walter R , Baddour Larry M , Sohail M Rizwan 
Published: April 2020

Abstract

Background
Approximately one-third of cases of cardiovascular implantable electronic device (CIED) infection present as CIED lead infection. The precise transesophageal echocardiographic (TEE) definition and characterization of “vegetation” associated with CIED lead infection remain unclear.

Methods
We identified a sample of 25 consecutive cases of CIED lead infection managed at our institution between January 2010 and December 2017. Cases of CIED lead infection were classified using standardized definitions. Similarly, a sample of 25 noninfected patients who underwent TEE that showed a defined lead echodensity during the study period was included as a control group. TEEs were reviewed by 2 independent echocardiologists who were blinded to all linked patient demographic, clinical, and microbiological information. Reported echocardiographic variables of the infected vs noninfected cases were compared, and the overall diagnostic performance was analyzed.

Results
Descriptions of lead echodensities were variable and there were no significant differences in median echodensity diameter or mobility between infected vs noninfected groups. Among infected cases, blinded echocardiogram reports by either reviewer correctly made a prediction of infection in 6 of 25 (24%). Interechocardiologist agreement was 68%. Sensitivity of blinded TEEs ranged from 31.5% to 37.5%.

Conclusions
Infectious vs noninfectious lead echodensities could not be reliably distinguished on the basis of size, mobility, and general shape descriptors obtained from a retrospective blinded TEE examination without knowledge of clinical and microbiological parameters. Therefore, a reanalysis of criteria used to support a diagnosis of CIED lead infection may be warranted.
Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients With COVID-19 (April 2020)
Authors: Bhimraj Adarsh , Morgan Rebecca L , Shumaker Amy Hirsch , Lavergne Valery , Baden Lindsey , Cheng Vincent Chi-Chung , Edwards Kathryn M , Gandhi Rajesh , Muller William J , O’Horo John C , Shoham Shmuel , Murad M Hassan , Mustafa Reem A , Sultan Shahnaz , Falck-Ytter Yngve 
Published: April 2020

Abstract

Background
There are many pharmacologic therapies that are being used or considered for treatment of coronavirus disease 2019 (COVID-19). There is a need for frequently updated practice guidelines on their use, based on critical evaluation of rapidly emerging literature. The objective was to develop evidence-based rapid guidelines intended to support patients, clinicians, and other healthcare professionals in their decisions about treatment and management of patients with COVID-19.

Methods
The Infectious Diseases Society of America (IDSA) formed a multidisciplinary guideline panel of infectious disease clinicians, pharmacists, and methodologists with varied areas of expertise. Process followed a rapid recommendation checklist. The panel prioritized questions and outcomes. Then a systematic review of the peer-reviewed and gray literature was conducted. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of evidence and make recommendations.

Results
The IDSA guideline panel agreed on 7 treatment recommendations and provided narrative summaries of other treatments undergoing evaluations.

Conclusions
The panel expressed the overarching goal that patients be recruited into ongoing trials, which would provide much-needed evidence on the efficacy and safety of various therapies for COVID-19, given that we could not make a determination whether the benefits outweigh harms for most treatments.
Development and Validation of the IBD-REFER Criteria: Early Referral for Suspected Inflammatory Bowel Diseases in Adults and Children
Authors: Atia Ohad , Shosberger Adi , Focht Gili , Ledder Oren , Lev-Tzion Raffi , Navon Dan , Assa Amit , Yerushalmi Baruch , Shaoul Ron , Shouval Dror S , Bar-Gil Shitrit Ariella , Koslowsky Benjamin , Dotan Iris , Kariv Revital , Lavon Eitan , Turner Dan 
Published: April 2020

AbstractBackgroundEarly treatment of inflammatory bowel disease (IBD) is associated with positive outcomes but a significant diagnostic delay has been reported in most countries.AimWe aimed to develop and validate IBD-REFER criteria, intended for primary care physicians, to screen patients at risk for IBD.MethodsA Delphi group of 10 experts generated a list of symptoms associated with the onset of IBD, supplemented by a review of the literature. The list was reduced in an iterative process and graded based on importance. For data-driven statistical formatting, the charts of 200 IBD (100 children, 100 adults) and 100 non-IBD controls but with gastrointestinal symptoms were reviewed. The IBD-REFER items were scored for each subject, as well as the contending Red Flag criteria from the International Organization for the Study of IBD. External validation was performed on additionally enrolled cohorts of 100 IBD patients and 50 controls.ResultsThe Delphi process retained 5 items as major criteria (≥1 item required for early referral) and 11 as minor (≥2 items required). Following the removal of uninformative items and further formatting in the data-driven stage, 10 core items were retained: 3 as major and 7 as minor. In the external validation, the final IBD-REFER criteria had a sensitivity/specificity of 98%/96% in adults and 96%/96% in children, significantly higher than achieved by the Red Flag criteria (71%/84% and 60%/88%, respectively; P &lt; 0.001).ConclusionThe IBD-REFER criteria may guide the selection of patients for expedited gastrointestinal investigation.
Economic Outcomes of Inflammatory Bowel Disease Patients Switching to a Second Anti-Tumor Necrosis Factor or Vedolizumab
Authors: Chiorean Michael , Afzali Anita , Cross Raymond K , Macaulay Dendy , Griffith Jenny , Wang Anthony , Garcia-Horton Viviana 
Published: April 2020

AbstractBackgroundAnti-tumor necrosis factor (TNF) therapies have been the mainstay of inflammatory bowel disease (IBD) treatment for nearly 2 decades. Therapies with novel mechanisms of action have been recently developed. This study compared healthcare resource utilization (HRU) and costs incurred while switching from an initial anti-TNF to another anti-TNF versus switching to vedolizumab.MethodsAdults with IBD who switched from initial anti-TNF to another anti-TNF or vedolizumab were identified from Truven MarketScan claims database (January 1, 2000–September 30, 2017). Patient characteristics were assessed during the 6-month period before the initiation date of the switched-to treatment (index date). Adjusted analyses of all-cause and disease-related HRU and costs during the 6-month period after the index date (study period) were performed. Anti-TNF and vedolizumab switchers with Crohn’s disease (CD) and ulcerative colitis (UC) were separately compared.ResultsA total of 502 vedolizumab, 1708 adalimumab, 755 infliximab, and 703 other switchers with CD and 461, 428, 311, and 148 with UC, respectively, were identified. Patient demographics were similar across cohorts. Total all-cause costs were significantly higher for vedolizumab than adalimumab, infliximab, and certolizumab switchers in the CD cohort and adalimumab and infliximab in the UC cohort. In both cohorts, adalimumab and other switchers had fewer all-cause and IBD-related outpatient visits than vedolizumab switchers.ConclusionsCD/UC patients who switched to vedolizumab from initial anti-TNF had higher total and treatment costs than patients who switched to another anti-TNF, except for UC patients who switched to golimumab. Prospective studies should be conducted to confirm these findings.
Human influenza A virus causes myocardial and cardiac-specific conduction system infections associated with early inflammation and premature death
Authors: Filgueiras-Rama David , Vasilijevic Jasmina , Jalife Jose , Noujaim Sami F , Alfonso Jose M , Nicolas-Avila Jose A , Gutierrez Celia , Zamarreño Noelia , Hidalgo Andres , Bernabé Alejandro , Cop Christopher Pablo , Ponce-Balbuena Daniela , Guerrero-Serna Guadalupe , Calle Daniel , Desco Manuel , Ruiz-Cabello Jesus , Nieto Amelia , Falcon Ana 
Published: April 2020

Abstract

Aims
Human influenza A virus (hIAV) infection is associated with important cardiovascular complications, although cardiac infection pathophysiology is poorly understood. We aimed to study the ability of hIAV of different pathogenicity to infect the mouse heart, and establish the relationship between the infective capacity and the associated in vivo, cellular and molecular alterations.

Methods and results
We evaluated lung and heart viral titres in mice infected with either one of several hIAV strains inoculated intranasally. 3D reconstructions of infected cardiac tissue were used to identify viral proteins inside mouse cardiomyocytes, Purkinje cells, and cardiac vessels. Viral replication was measured in mouse cultured cardiomyocytes. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were used to confirm infection and study underlying molecular alterations associated with the in vivo electrophysiological phenotype. Pathogenic and attenuated hIAV strains infected and replicated in cardiomyocytes, Purkinje cells, and hiPSC-CMs. The infection was also present in cardiac endothelial cells. Remarkably, lung viral titres did not statistically correlate with viral titres in the mouse heart. The highly pathogenic human recombinant virus PAmut showed faster replication, higher level of inflammatory cytokines in cardiac tissue and higher viral titres in cardiac HL-1 mouse cells and hiPSC-CMs compared with PB2mut-attenuated virus. Correspondingly, cardiac conduction alterations were especially pronounced in PAmut-infected mice, associated with high mortality rates, compared with PB2mut-infected animals. Consistently, connexin43 and NaV1.5 expression decreased acutely in hiPSC-CMs infected with PAmut virus. YEM1L protease also decreased more rapidly and to lower levels in PAmut-infected hiPSC-CMs compared with PB2mut-infected cells, consistent with mitochondrial dysfunction. Human IAV infection did not increase myocardial fibrosis at 4-day post-infection, although PAmut-infected mice showed an early increase in mRNAs expression of lysyl oxidase.

Conclusion
Human IAV can infect the heart and cardiac-specific conduction system, which may contribute to cardiac complications and premature death.
Intestinal CD14+ Macrophages Protect CD4+ T Cells From Activation-induced Cell Death via Exosomal Membrane TNF in Crohn’s Disease
Authors: Liu Huashan , Liang Zhenxing , Wang Fengwei , Zheng Xiaobin , Zeng Ziwei , He Xiaowen , Gao Xiang , Zhi Min , Wu Xiaojian , Wu Xianrui , Lan Ping 
Published: April 2020

AbstractBackground and aimsSustained activation of CD4+ T cells plays important roles in the pathogenesis of Crohn’s disease [CD]. Under physiologic conditions, activated T cells can be timely eliminated by a process termed activation-induced cell death [AICD], restraining T cell over-activation and preventing immunological destruction. We inquired whether defective AICD might explain CD4+ T cell over-activation in CD and investigated the underlying mechanisms.MethodsCD14+ macrophages [Mφ] and CD4+ T cells were isolated from intestinal tissues or peripheral blood of controls and CD patients. An ex vivo evaluation system was employed to simulate AICD and cell apoptosis was measured by flow cytometry.ResultsCD4+ T cells from CD patients fail to undergo AICD in the ex vivo system. Specifically, proinflammatory type 1 helper T [Th1] and type 17 helper T [Th17] cells, rather than immunosuppressive regulatory T [Treg] cells evade AICD in CD. CD14+ Mφ in the intestinal inflammatory microenvironment of CD promote AICD resistance in CD4+ T cells via a cell-to-cell contact-independent manner. Mechanistically, CD14+ Mφ released exosomes express membrane tumour necrosis factor [TNF] which engages TNFR2 on CD4+ T cells and triggers NF-κB signalling, thereby causing AICD resistance. Importantly, clinically applicable anti-TNF antibodies effectively blocked exosomal membrane TNF-induced CD4+ T cell AICD resistance.ConclusionsCD14+ Mφ participate in CD pathogenesis by inducing AICD resistance through release of exosomal membrane TNF to activate the TNFR2/NF-κB pathway in CD4+ T cells. These results present new insights into CD pathogenesis and extend mechanistic understanding of anti-TNF agents.Proposed modelCD14+ Mφ in the intestinal microenvironment of CD patients maintain the sustained activation of CD4+ T cells through exosomal membrane TNF to induce apoptosis resistance via TNFR2/NF-κB signalling, which could be effectively blocked by clinically applicable anti-TNF agents.
Identification of anticancer drugs associated with atrial fibrillation: analysis of the WHO pharmacovigilance database
Authors: Alexandre Joachim , Salem Joe-Elie , Moslehi Javid , Sassier Marion , Ropert Camille , Cautela Jennifer , Thuny Franck , Ederhy Stéphane , Cohen Ariel , Damaj Ghandi , Vilque Jean-Pierre , Plane Anne-Flore , Legallois Damien , Champ-Rigot Laure , Milliez Paul , Funck-Brentano Christian , Dolladille Charles 
Published: April 2020

Abstract

Aims
The explosion of novel anticancer therapies has meant emergence of cardiotoxicity signals including atrial fibrillation (AF). Reliable data concerning the liability of anticancer drugs in inducing AF are scarce. Using the World Health Organization individual case safety report database, VigiBase®, we aimed to determine the association between anticancer drugs and AF.

Methods and results
A disproportionality analysis evaluating the multivariable-adjusted reporting odds ratios for AF with their 99.97% confidence intervals was performed for 176 U.S. Food and Drug Administration (FDA)- or European Medicines Agency (EMA)-labelled anticancer drugs in VigiBase®, followed by a descriptive analysis of AF cases for the anticancer drugs identified in VigiBase®. ClinicalTrial registration number: NCT03530215. A total of 11 757 AF cases associated with at least one anticancer drug were identified in VigiBase® of which 95.8% were deemed serious. Nineteen anticancer drugs were significantly associated with AF of which 14 (74%) are used in haematologic malignancies and 9 (45%) represented new AF associations not previously confirmed in literature including immunomodulating agents (lenalidomide, pomalidomide), several kinase inhibitors (nilotinib, ponatinib, midostaurin), antimetabolites (azacytidine, clofarabine), docetaxel (taxane), and obinutuzumab, an anti-CD20 monoclonal antibody.

Conclusion
Although cancer malignancy itself may generate AF, we identified 19 anticancer drugs significantly associated with a significant increase in AF over-reporting. This pharmacovigilance study provides evidence that anticancer drugs themselves could represent independent risk factors for AF development. Dedicated prospective clinical trials are now required to confirm these 19 associations. This list of suspected anticancer drugs should be known by physicians when confronted to AF in cancer patients, particularly in case of haematologic malignancies.
Performance of the GRACE 2.0 score in patients with type 1 and type 2 myocardial infarction
Authors: Hung John , Roos Andreas , Kadesjö Erik , McAllister David A , Kimenai Dorien M , Shah Anoop S V , Anand Atul , Strachan Fiona E , Fox Keith A A , Mills Nicholas L , Chapman Andrew R , Holzmann Martin J 
Published: April 2020

Abstract

Aims
The Global Registry of Acute Coronary Events (GRACE) score was developed to evaluate risk in patients with myocardial infarction. However, its performance in type 2 myocardial infarction is uncertain.

Methods and results
In two cohorts of consecutive patients with suspected acute coronary syndrome from 10 hospitals in Scotland (n = 48 282) and a tertiary care hospital in Sweden (n = 22 589), we calculated the GRACE 2.0 score to estimate death at 1 year. Discrimination was evaluated by the area under the receiver operating curve (AUC), and compared for those with an adjudicated diagnosis of type 1 and type 2 myocardial infarction using DeLong’s test. Type 1 myocardial infarction was diagnosed in 4981 (10%) and 1080 (5%) patients in Scotland and Sweden, respectively. At 1 year, 720 (15%) and 112 (10%) patients died with an AUC for the GRACE 2.0 score of 0.83 [95% confidence interval (CI) 0.82–0.85] and 0.85 (95% CI 0.81–0.89). Type 2 myocardial infarction occurred in 1121 (2%) and 247 (1%) patients in Scotland and Sweden, respectively, with 258 (23%) and 57 (23%) deaths at 1 year. The AUC was 0.73 (95% CI 0.70–0.77) and 0.73 (95% CI 0.66–0.81) in type 2 myocardial infarction, which was lower than for type 1 myocardial infarction in both cohorts (P &lt; 0.001 and P = 0.008, respectively).

Conclusion
The GRACE 2.0 score provided good discrimination for all-cause death at 1 year in patients with type 1 myocardial infarction, and moderate discrimination for those with type 2 myocardial infarction.

Trial registration
ClinicalTrials.gov number, NCT01852123.
Unraveling the regulation of sophorolipid biosynthesis in Starmerella bombicola
Authors: Lodens Sofie , Roelants Sophie L K W , Luyten Goedele , Geys Robin , Coussement Pieter , De Maeseneire Sofie L , Soetaert Wim 
Published: April 2020

ABSTRACT
Starmerella bombicola very efficiently produces the secondary metabolites sophorolipids (SLs). Their biosynthesis is not-growth associated and highly upregulated in the stationary phase. Despite high industrial and academic interest, the underlying regulation of SL biosynthesis remains unknown. In this paper, potential regulation of SL biosynthesis through the telomere positioning effect (TPE) was investigated, as the SL gene cluster is located adjacent to a telomere. An additional copy of this gene cluster was introduced elsewhere in the genome to investigate if this results in a decoy of regulation. Indeed, for the new strain, the onset of SL production was shifted to the exponential phase. This result was confirmed by RT-qPCR analysis. The TPE effect was further investigated by developing and applying a suitable reporter system for this non-conventional yeast, enabling non-biased comparison of gene expression between the subtelomeric CYP52M1- and the URA3 locus. This was done with a constitutive endogenous promotor (pGAPD) and one of the endogenous promotors of the SL biosynthetic gene cluster (pCYP52M1). A clear positioning effect was observed for both promotors with significantly higher GFP expression levels at the URA3 locus. No clear GFP upregulation was observed in the stationary phase for any of the new strains.
Shadow Economies and the Success of Economic Sanctions: Explaining Why Democratic Targets Are Disadvantaged
Authors: Early Bryan R , Peksen Dursun 
Published: April 2020

AbstractThe sanctions literature has identified numerous mechanisms by which the adverse economic effects of sanctions impact their success rate. This body of work, however, has mostly focused on targets’ formal economies and has thus overlooked whether sanctions-induced changes in shadow (also known as informal) economic activity influence sanctions’ effectiveness. In this article, we develop two rival arguments that can potentially explain how shadow sector growth affects sanctions’ outcomes. Our grievance mitigation theory argues that increased shadow sector activity decreases the political pressure on leaders to capitulate to sanctions, while our disadvantaged democracy theory asserts that shadow economies create budgetary resource demands and deficits that disproportionately hamper democratic targets’ ability to resist sanctions. We assess the empirical merits of the two theories using time-series cross-national data for 1950–2005. We find robust evidence that the growth of shadow economies increases the likelihood of sanctions’ success in democratic targets while not significantly affecting the success rate of sanctions against non-democratic regimes. Our findings shed new light on the processes by which the economic disruptions and hardships created by sanctions translate into pressure on targeted regimes to concede to sanctions.