bluuebunny/crossref_metadata_2025_split huggingface dataset:
Migraines and keloids: a 15-year Taiwan claim database analysis
Authors: Lu Ying-Yi , Qin Hao , Lu Chun-Ching , Wu Ming-Kung , Zhang Cong-Liang , Wu Chieh-Hsin 
Published: February 2021

AbstractBackgroundFibroproliferative lesions with intractable pruritus, pain and hyperesthesia that cause uncontrolled scar growth are known as keloids. Migraines are common upsetting headache disorders characterised by frequent recurrence and attacks aggravated by physical activity. Both keloids and migraines can cause physical exhaustion and discomfort in patients; they have similar pathophysiological pathways, that is, the transforming growth factor-β1 gene and neurogenic inflammation.ObjectiveTo investigate subsequent development of migraines in patients with keloids.MethodsData were retrieved from the Taiwan National Health Insurance Research Database. The keloids group included patients aged 20 years and older with a recent diagnosis of keloids(n=9864). The non-keloids group included patients without keloids matched for gender and age at 1–4 ratio (n=39 456). Migraine risk between groups was measured by Cox proportional hazards regression models. Incidence rates and hazard ratios were calculated.ResultsDuring the study period, 103 keloids patients and 323 non-keloids patients developed migraines. The keloids patients had a 2.29-fold greater risk of developing migraines compared with the non-keloids group after adjustment for covariates (1.81 vs 0.55 per 1000 person-years, respectively). In the keloids group, female or patients younger than 50 years were prone to developing migraines.ConclusionThe higher tendency to develop migraines in the keloids group in comparison with the non-keloids group suggests that keloids could be a predisposing risk factor for migraine development in adults. Keloids patients who complain of headaches should be examined for migraines.
Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial
Authors: Lopes Maria Isabel , Bonjorno Leticia P , Giannini Marcela C , Amaral Natalia B , Menezes Pamella Indira , Dib Saulo Musse , Gigante Samara Libich , Benatti Maira N , Rezek Uebe C , Emrich-Filho Laerte L , Sousa Betania A A , Almeida Sergio C L , Luppino Assad Rodrigo , Veras Flavio P , Schneider Ayda , Rodrigues Tamara S , Leiria Luiz O S , Cunha Larissa D , Alves-Filho Jose C , Cunha Thiago M , Arruda Eurico , Miranda Carlos H , Pazin-Filho Antonio , Auxiliadora-Martins Maria , Borges Marcos C , Fonseca Benedito A L , Bollela Valdes R , Del-Ben Cristina M , Cunha Fernando Q , Zamboni Dario S , Santana Rodrigo C , Vilar Fernando C , Louzada-Junior Paulo , Oliveira Rene D R 
Published: February 2021

ObjectiveTo evaluate whether the addition of colchicine to standard treatment for COVID-19 results in better outcomes.DesignWe present the results of a randomised, double-blinded, placebo-controlled clinical trial of colchicine for the treatment of moderate to severe COVID-19, with 75 patients allocated 1:1 from 11 April to 30 August 2020. Colchicine regimen was 0.5 mg thrice daily for 5 days, then 0.5 mg twice daily for 5 days. The primary endpoints were the need for supplemental oxygen, time of hospitalisation, need for admission and length of stay in intensive care unit and death rate.ResultsSeventy-two patients (36 for placebo and 36 for colchicine) completed the study. Median (and IQR) time of need for supplemental oxygen was 4.0 (2.0–6.0) days for the colchicine group and 6.5 (4.0–9.0) days for the placebo group (p<0.001). Median (IQR) time of hospitalisation was 7.0 (5.0–9.0) days for the colchicine group and 9.0 (7.0–12.0) days for the placebo group (p=0.003). At day 2, 67% versus 86% of patients maintained the need for supplemental oxygen, while at day 7, the values were 9% versus 42%, in the colchicine and the placebo groups, respectively (log rank; p=0.001). Two patients died, both in placebo group. Diarrhoea was more frequent in the colchicine group (p=0.26).ConclusionColchicine reduced the length of both, supplemental oxygen therapy and hospitalisation. The drug was safe and well tolerated. Once death was an uncommon event, it is not possible to ensure that colchicine reduced mortality of COVID-19.Trial registration numberRBR-8jyhxh.
Using molecular testing and whole-genome sequencing for tuberculosis diagnosis in a low-burden setting: a cost-effectiveness analysis using transmission-dynamic modelling
Authors: Mugwagwa Tendai , Abubakar Ibrahim , White Peter J 
Published: February 2021

BackgroundDespite progress in TB control in low-burden countries like England and Wales, there are still diagnostic delays. Molecular testing and/or whole-genome sequencing (WGS) provide more rapid diagnosis but their cost-effectiveness is relatively unexplored in low-burden settings.MethodsAn integrated transmission-dynamic health economic model is used to assess the cost-effectiveness of using WGS to replace culture-based drug-sensitivity testing, versus using molecular testing versus combined use of WGS and molecular testing, for routine TB diagnosis. The model accounts for the effects of faster appropriate treatment in reducing transmission, benefiting health and reducing future treatment costs. Cost-effectiveness is assessed using incremental net benefit (INB) over a 10-year horizon with a quality-adjusted life-year valued at £20 000, and discounting at 3.5% per year.ResultsWGS shortens the time to drug sensitivity testing and treatment modification where necessary, reducing treatment and hospitalisation costs, with an INB of £7.1 million. Molecular testing shortens the time to TB diagnosis and treatment. Initially, this causes an increase in annual costs of treatment, but averting transmissions and future active TB disease subsequently, resulting in cost savings and health benefits to achieve an INB of £8.6 million (GeneXpert MTB/RIF) or £11.1 million (Xpert-Ultra). Combined use of Xpert-Ultra and WGS is the optimal strategy we consider, with an INB of £16.5 million.ConclusionRoutine use of WGS or molecular testing is cost-effective in a low-burden setting, and combined use is the most cost-effective option. Adoption of these technologies can help low-burden countries meet the WHO End TB Strategy milestones, particularly the UK, which still has relatively high TB rates.
Therapeutic Controversies in the Medical Management of Valvular Heart Disease
Authors: Barry Arden R. , Wang Erica H. Z. 
Published: February 2021

Objective: To evaluate the evidence for common therapeutic controversies in the medical management of valvular heart disease (VHD). Data Sources: A literature search of PubMed (inception to December 2020) was performed using the terms angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and aortic stenosis (AS); and adrenergic β-antagonists and aortic valve regurgitation (AR) or mitral stenosis (MS). Study Selection and Data Extraction: Randomized controlled trials (RCTs) and meta-analyses conducted in humans and published in English that reported ≥1 clinical outcome were included. Data Synthesis: Nine articles were included: 3 RCTs and 1 meta-analysis for ACE inhibitors/ARBs in AS, 1 RCT for β-blockers in AR, and 4 RCTs for β-blockers in MS. Evidence suggests that ACE inhibitors/ARBs do not increase the risk of adverse outcomes in patients with AS but may delay valve replacement. β-Blockers do not appear to worsen outcomes in patients with chronic AR and may improve left-ventricular function in patients with a reduced ejection fraction. β-Blockers do not improve and may actually worsen exercise tolerance in patients with MS in sinus rhythm. Relevance to Patient Care and Clinical Practice: ACE inhibitors/ARBs and β-blockers can likely be safely used in patients with AS or AR, respectively, who have a compelling indication. There is insufficient evidence to recommend routine use of β-blockers in patients with MS without atrial fibrillation. Conclusions: Common beliefs about the medical treatment of VHD are not supported by high-quality data. There remains a need for larger-scale RCTs in the medical management of VHD.
The moral responsibility of governments and individuals in the context of the coronavirus pandemic
Authors: Nihlén Fahlquist Jessica 
Published: February 2021

Aim: Not only is the coronavirus pandemic about science and facts, it also raises a number of ethical questions. Some of the most important questions in this context are related to responsibility. First, what is a government’s primary responsibility? Second, how should both the government and individuals consider personal moral responsibility in this context? Method: This paper uses conceptual and normative analysis to address responsibility in the context of the pandemic. The paper also refers to reports published by the German Ethics Council, the Malaysian Bioethics Community and the Swedish National Council on Medical Ethics. Results: The primary responsibility of governments is to create a balance between individual values and rights, one hand, and the health of the population, on the other. There are good reasons to conceive of individual responsibility as a virtue, having to do with the development of crucial character traits and habits. The responsibility of governments is connected to individual responsibility through the values of trust and solidarity. Conclusions: Governments need to communicate clearly (a) how they balance conflicts between collective health and individual rights and values and (b) what the chosen strategy entails in terms of collective and individual responsibility. Success requires attention to ethical values from all involved. Individuals will need to develop new character traits to help manage this pandemic and to prevent new ones. Governments must facilitate the development of such character traits by building trust and solidarity with and among citizens.
A Novel Lncrna, Lncery, Interacts with Wdr82 to Regulate Erythroid Differentiation By Promoting Globin Gene Transcription
Authors: Yang Shangda , Sun Guohuan , Wu Peng , Kuang Yijin , Chen Cong , Zheng Zhaofeng , Gu Quan , Zhu Caiying , Gou Fanglin , Yang Zining , Zhao Xiangnan , Yang Liu , Lu Shihong , Lihong Shi , Lv Xue , Dong Fang , Shi Lihong , Ng Lai Guang , Liu Jing , Cheng Hui , Cheng Tao 
Published: February 2021

Hematopoietic differentiation is controlled by both genetic and epigenetic regulators. Long non-coding RNAs (lncRNAs) have been demonstrated to be important for normal hematopoiesis, but their function in erythropoiesis needs to be further explored. Here, we profiled the transcriptome of 17 murine hematopoietic cell populations by deep sequencing and identified a novel lncRNA, that was highly expressed in erythroid-related progenitors and erythrocytes. For this reason, we named it lncEry. We also identified a novel lncEry isoform, which was the principal transcript and has not been reported before. Furthermore, we found that nearly 90% of lncEry molecules localized to the nucleus. Next, we performed knockdown and knockout assays to study the function of lncEry, and found that lncEry depletion impaired erythroid differentiation. RNA sequencing analysis showed that lncEry depletion decreased the expression of erythrocyte homeostasis or differentiation related genes, including globin genes, thus indicating its important role in regulating erythroid differentiation. Mechanistically, we performed RNA-pulldown assays and found that lncEry could interact with Wdr82, a component of the Set1A histone H3-Lys4 methyltransferase complex. In addition, a series of molecular assays indicated that lncEry could stabilize the localization of Set1A/Wdr82 complex to facilitate H3K4me3 on the promoter region of globin genes and participate in regulating erythropoiesis. These findings identify lncEry as an important player in the transcriptional regulation of globin genes to coordinate erythropoiesis.

Disclosures
No relevant conflicts of interest to declare.
Patterns and Growth of a Dedicated Pediatric Coagulation Consult Service in a Freestanding Children's Hospital
Authors: Carpenter Shannon L , Bilynsky Eryn , Wideman Dena , D'Agostino Kristina , Amos Lauren E , Sharma Mukta , Silvey Michael 
Published: February 2021

Introduction: At our freestanding pediatric hospital, a dedicated inpatient coagulation consult service has existed for 15 years. To our knowledge, this type of service is relatively unique in a pediatric hospital and provides an opportunity to objectively evaluate changes in coagulation consults in this patient population. Over the past decade, the increasing rate of thrombosis in hospitalized pediatric patients has been noted and more attention has been placed on preventing the occurrence of hospital-acquired venous thromboembolism. With concern over this increased incidence, more inpatients have been receiving prophylactic anticoagulation.
Methods: This is a secondary use of existing clinical care data study, involving review of the patients receiving a consult from the inpatient coagulation consult service. Average daily census was documented via a clinical tracking system. Data collection ranged from May 2011 to May 2020. Since 2013, number of distinct new consults (not repeat patients), and indication for consult have also been documented. These data were analyzed for trends in average census number and indication for consult. Additionally, the service requesting the consult is also reported.
Results: From May 2011 to May 2020, the average daily census for the coagulation consult service has increased from 4.5 to 34.4 patients. (Figure 1) The rate of consult request for prophylactic anticoagulation increased from 8 in 2013 to 82 in 2020, while thrombosis and bleeding referrals remained relatively stable. (Figure 2) Since 2013, the service with the most requests for prophylactic anticoagulation over the entire period was orthopedic surgery with 70, followed by the cardiovascular intensive care (31) and medical intensive care (28) units (ICU). There was an increase in the number of prophylactic anticoagulation consults from the ICUs over the course of the study. (Figure 3) In early 2020 a VTE risk stratification was instituted in the CVICU.
Conclusions: In this single institution, retrospective study, we noted an increase in number of consults for the coagulation service overall, and a larger increase in requests for consults for prophylactic anticoagulation. Further studies should be done to determine whether this increase in use of prophylactic anticoagulation exists at other pediatric hospitals and the impact on subsequent VTE development.

Disclosures
Carpenter: CSL Behring: Research Funding; American Thrombosis and Hemostasis Network: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Honoraria; Kedrion: Honoraria; Novo Nordisk: Honoraria; Shire: Research Funding; Hemostasis & Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees; American Academy of Pediatrics: Other: PREP Heme/Onc editorial board.
Human Orthogonal IL-2/IL-2Rβ As a Tunable Approach to Enhance CD19-Speific CAR-T Cell Antitumor Activity
Authors: Zhang Qian , Hresko Morgan , Hollander Michael Jacob , Picton Lora , Su Leon , Nunez-Cruz Selene , Sockolosky Jonathan T , Garcia K.Christopher , Milone Michael C. 
Published: February 2021

Immunotherapy using T cells engineered with a chimeric antigen receptors (CAR) can produce deep and durable control of B-cell malignancies that is associated with the engraftment and persistence of the CAR T cells following adoptive transfer. Interleukin-2 (IL-2) is a central T cell cytokine that promotes T cell proliferation and effector function with a potential to enhance CAR T cell immunotherapy; however, the use of recombinant IL-2 to support T cell immunotherapy is limited by the significant toxicity associated with IL-2 infusion. Previous work has demonstrated the feasibility of engineering murine IL-2 and it's receptor to create an orthogonal (ortho) cytokine-receptor pair capable of delivering IL-2's signal without the associated toxicity (Sockolosky JT et al. Science 2018). In order to translate this novel approach to humans, we engineered a human orthogonal IL-2 (ortho-hIL-2) and human orthogonal IL-2Rβ (ortho-hIL-2Rβ) pair based upon similar mutations to those required in the murine system. We show that hoIL-2 induces JAK-STAT signaling and supports proliferation of the IL-2 dependent cutaneous T-cell lymphoma (CTCL) line, SeAx, and primary human CD8+ primary T cells when hoIL-2Rb is expressed in these cells. HoIL-2 at concentrations 1000-fold higher than wild-type IL-2 failed to induce signaling in the absence of the orthogonal receptor illustrating the high selectivity of ortho-hIL-2 for the ortho-hIL-2Rβ. Using a CD19-specific, 4-1BB-costimulated CAR T cell (CART19), we show that ortho-hIL-2 induced a dose-dependent increase in ortho-hIL-2Rβ CAR-T cell expansion and serum cytokines in vivo by as much as 1000-fold at 2 weeks following adoptive transfer into NSG mice bearing CD19+ Nalm6 leukemia xenografts and daily ortho-hIL-2 treatment. We further demonstrate that hoIL-2 can rescue the anti-leukemic effect of an otherwise suboptimal CAR T cell dose. In addition to augmenting initial CAR T cell engraftment and efficacy, we also show that ortho-hIL-2 administration initiated at the time of leukemic relapse following CAR T cell therapy can rescue an otherwise failed anti-leukemic response. In aggregate, these data demonstrate the ability of the human orthogonal IL-2 cytokine-receptor system to support T cell expansion in vivo and the potential of combining this approach with CAR T cell immunotherapy to augment the anti-tumor efficacy of engineered T cells.

Disclosures
Sockolosky: Synthekine Therapeutics: Current equity holder in private company. Garcia:Synthekine: Current equity holder in private company, Other: founder. Milone:Novartis: Patents & Royalties.
Systems-Level Analysis of the Immune Repertoire in Neutropenia Reveal Arrested NK Cell Differentiation and Exhaustion
Authors: Sohlberg Ebba , Pfefferle Aline , Ask Eivind Heggernes , Tschan-Plessl Astrid , Jacobs Benedikt , Lorenz Suzanne , Meinke Stephan , Hoglund Petter , Sundin Mikael , Karlsson Goran , Palmblad Jan , Malmberg Karl-Johan 
Published: February 2021

Neutrophils are innate cells that have been suggested to play a critical role in terminal differentiation of NK cells. Whether this is a direct effect or a consequence of global immune changes with effects on NK cell homeostasis remains unknown. Here, we used high-resolution flow and mass cytometry to examine NK cell repertoires in 64 neutropenic patients and 27 healthy age- and gender-matched controls. A subgroup of neutropenic patients had lower frequencies and absolute numbers of NK cells, yet increased frequencies of CD56bright among NK cells (Figure 1A-C). Moreover, their CD56dim compartment was characterized by a block in differentiation, with a relative lack of NKG2A-CD57+KIR+ NK cells. In line with the differentiation arrest, no expansion of adaptive NK cells could be detected in CMV-seropositive patients from this subgroup. Furthermore, CD56dim NK cells showed increased frequencies of Ki-67+, Tim-3+ and TIGIT+ cells suggestive of activation and exhaustion (Figure 1D). The systemic imprint in the NK cell repertoire was associated with a blunted tumor target cell response with inefficient killing and a lower proportion of degranulating CD56dim cells (Figure 1E). RNA sequencing of the NK cell compartment further revealed that the differentiation arrest was linked to increased expression of transcription factors and genes involved in proliferation and cytokine signaling (Figure 1F). Serum protein profiling of 264 proteins showed upregulation of pathways related to apoptosis and cell turnover, as well as immune regulation and inflammation including higher levels of IL-10, IL-18 and IL-27 in these patients (Figure 1G-H). Notably, the majority of patients with perturbed NK cell compartment exhibited high-grade neutropenia, overall suggesting that the profoundly altered NK cell homeostasis was tightly connected to the severity of their underlying etiology (Figure 1I).

Disclosures
Meinke: XNK Therapeutics AB: Consultancy. Palmblad:Roche Sweden Inc: Speakers Bureau; Chieti Canada Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees. Malmberg:Vycellix: Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Consultancy, Patents & Royalties.
Prestack seismic inversion with structural constraints
Authors: Li Dong , Peng Suping , Zhang Rui , Guo Yinling , Lu Yongxu , Cui Xiaoqin 
Published: February 2021

Prestack seismic inversion usually suffers from a lower signal-to-noise ratio, which could result in unstable inversion results. The conventional multitrace lateral constrained inversion blurs steeply dipping layers, whereas the simple structural constrained inversion is affected by noise. To solve this issue, an inversion method with multiple constraints is proposed, which include (1) a local smoothing operator is used to suppress the inversion anomalies caused by data noise, (2) a difference operator is used to protect the stratum boundary, and (3) a structural dipping constraint is used to enhance the characterization of the possible dipping stratum. The multiconstraint inversion (MCI) method suppresses the inversion anomalies caused by data noise without blurring the stratum boundary. The effects of different constraints in the inversion process and the influence of noise on the inversion results are analyzed. In MCI, the regularization coefficient of each constraint operator is dynamically changed, thereby controlling the significance of each regularization term in the inversion. The proposed algorithm is tested on synthetic and field data, which demonstrate its effectiveness and improved accuracy on the inversion results.
Growth Hormone Pulses and Liver Gene Expression Are Differentially Regulated by the Circadian Clock Gene Bmal1
Authors: Schoeller Erica L , Tonsfeldt Karen J , Sinkovich McKenna , Shi Rujing , Mellon Pamela L 
Published: February 2021

Abstract
In this study, we found that loss of the circadian clock gene Bmal1 causes disruptions throughout the growth hormone (GH) axis, from hepatic gene expression to production of urinary pheromones and pheromone-dependent behavior. First, we show that Bmal1 knockout (KO) males elicit reduced aggressive responses from wild-type (WT) males and secrete lower levels of major urinary proteins (MUPs); however, we also found that a liver-specific KO of Bmal1 (liver-Bmal1-KO) produces a similar reduction in MUP secretion without a defect in aggressive behavior, indicating that the decrease in elicited aggression arises from another factor. We then shifted our investigation to determine the cause of MUP dysregulation in Bmal1 KO animals. Because the pulse pattern of GH drives sexually dimorphic expression of hepatic genes including MUPs, we examined GH pulsatility. We found that Bmal1 KO males have a female-like pattern of GH release, whereas liver-Bmal1-KO mice are not significantly different from either WT or Bmal1 KO. Since differential patterns of GH release regulate the transcription of many sexually dimorphic genes in the liver, we then examined hepatic gene transcription in Bmal1 KO and liver-Bmal1-KO mice. We found that while some female-predominant genes increase in the Bmal1 KO, there was no decrease in male-predominant genes, and little change in the liver-Bmal1-KO. We also found disrupted serum insulin growth factor 1 (IGF-1) and liver Igf1 messenger RNA in the Bmal1 KO mice, which may underlie the disrupted GH release. Overall, our findings differentiate between GH-pulse–driven and circadian-driven effects on hepatic genes, and the functional consequences of altered GH pulsatility.