bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploring mechanisms of ventricular enlargement in idiopathic normal pressure hydrocephalus: a role of cerebrospinal fluid dynamics and motile cilia
Authors: Yamada Shigeki , Ishikawa Masatsune , Nozaki Kazuhiko 
Published: April 2021

AbstractIdiopathic normal pressure hydrocephalus (iNPH) is considered an age-dependent chronic communicating hydrocephalus associated with cerebrospinal fluid (CSF) malabsorption; however, the aetiology of ventricular enlargement in iNPH has not yet been elucidated. There is accumulating evidence that support the hypothesis that various alterations in CSF dynamics contribute to ventricle dilatation in iNPH. This review focuses on CSF dynamics associated with ventriculomegaly and summarises the current literature based on three potential aetiology factors: genetic, environmental and hydrodynamic. The majority of gene mutations that cause communicating hydrocephalus were associated with an abnormal structure or dysfunction of motile cilia on the ventricular ependymal cells. Aging, alcohol consumption, sleep apnoea, diabetes and hypertension are candidates for the risk of developing iNPH, although there is no prospective cohort study to investigate the risk factors for iNPH. Alcohol intake may be associated with the dysfunction of ependymal cilia and sustained high CSF sugar concentration due to uncontrolled diabetes increases the fluid viscosity which in turn increases the shear stress on the ventricular wall surface. Sleep apnoea, diabetes and hypertension are known to be associated with the impairment of CSF and interstitial fluid exchange. Oscillatory shear stress to the ventricle wall surfaces is considerably increased by reciprocating bidirectional CSF movements in iNPH. Increased oscillatory shear stress impedes normal cilia beating, leading to motile cilia shedding from the ependymal cells. At the lack of ciliary protection, the ventricular wall is directly exposed to increased oscillatory shear stress. Additionally, increased oscillatory shear stress may be involved in activating the flow-mediated dilation signalling of the ventricular wall. In conclusion, as the CSF stroke volume at the cerebral aqueduct increases, the oscillatory shear stress increases, promoting motor cilia shedding and loss of ependymal cell coverage. These are considered to be the leading causes of ventricular enlargement in iNPH.
Identifying potential treatment effect modifiers of the effectiveness of chiropractic care to infants with colic through prespecified secondary analyses of a randomised controlled trial
Authors: Holm Lise Vilstrup , Vach Werner , Jarbøl Dorte Ejg , Christensen Henrik Wulff , Søndergaard Jens , Hestbæk Lise 
Published: April 2021

AbstractBackgroundA recent trial identified large variation in effect of chiropractic care for infantile colic. Thus, identification of possible effect modifiers could potentially enhance the clinical reasoning to select infants with excessive crying for chiropractic care. Therefore, the aim of this study is to identify potential treatment effect modifiers which might influence the effect of chiropractic care for excessive crying in infancy.MethodsDesign: Prespecified secondary analyses of data from a randomised controlled trial. The analyses are partly confirmative and partly exploratory.Setting: Four chiropractic clinics in Denmark.Participants: Infants aged 2–14 weeks with unexplained excessive crying. Of the 200 infants randomised (1:1), 103 were assigned to a chiropractic care group and 97 to a control group.Intervention: Infants in the intervention group received chiropractic care for 2 weeks, while the control group was not treated.Main analyses: The outcome was change in daily hours of crying. Fifteen baseline variables and 6 general variables were selected as potential effect modifiers, and indices based on these were constructed. Factor analyses, latent class analyses and prognosis were used to construct other potentially modifying variables. Finally, an attempt at defining a new index aiming at optimal prediction of the treatment effect was made. The predictive value for all resulting variables were examined by considering the difference in mean change in crying time between the two treatment groups, stratified by the values of the candidate variables, i.e. interaction analyses.ResultsNone of the predefined items or indices were shown to be useful in identifying colicky infants with potentially larger gain from manual therapy. However, more baseline hours of crying (p = 0.029), short duration of symptoms (p = 0.061) and young age (p = 0.089) were all associated with an increased effect on the outcome of hours of crying.ConclusionMusculoskeletal indicators were not shown to be predictive of an increased benefit for colicky infants from chiropractic treatment. However, increased benefit was associated with early treatment and a high level of baseline crying, suggesting that the most severely affected infants have the greatest potential of benefiting from manual therapy. This finding requires validation by future studies.Trial registrationClinical TrialsNCT02595515, registered 2 November 2015.
The multi-domain responder index: a novel analysis tool to capture a broader assessment of clinical benefit in heterogeneous complex rare diseases
Authors: Tandon P. K. , Kakkis Emil D. 
Published: April 2021

AbstractIn traditional clinical trial design, efficacy is typically assessed using a single primary endpoint in a randomized controlled trial to detect an expected treatment effect of a therapy in a narrowly selected patient population. This accepted paradigm is based on clinical evaluations that may not actually capture the breadth of the impact of a disease, which is especially true in the setting of complex, multisystem, rare diseases with small, extremely heterogeneous patient populations. The multi-domain responder index (MDRI) is a novel approach that accommodates complex and heterogeneous disease manifestations and evaluates a broad array of clinical disease without impairing the power or rigor of a study to fully understand a treatment. The MDRI sums the scores corresponding to clinically significant thresholds of change for each component domain in each individual patient, capturing the mean clinically meaningful change across multiple domains within individuals. This novel approach combines and then sums the results of independent domain endpoint responder analyses into one responder score to provide a broad basis for the assessment of efficacy. The impact of a treatment across multiple, physiologically independent domains, can be assessed clinically, reducing the adverse impact of heterogeneity on trial outcomes and allowing eligibility criteria to enroll a wider range of patients, ultimately resulting in efficacy and safety assessments of a therapy across a broad group of heterogeneous patients in rare disease programs.Trial registration The following studies are referenced within this manuscript (CLINICALTRIALS.GOV registration numbers): NCT00912925; NCT00146770; NCT00067470; NCT00104234; NCT00069641; NCT02230566; NCT02377921; NCT02432144.
CAR-T cells and BiTEs in solid tumors: challenges and perspectives
Authors: Edeline Julien , Houot Roch , Marabelle Aurélien , Alcantara Marion 
Published: April 2021

AbstractChimeric antigen receptor (CAR)-modified T cells and BiTEs are both immunotherapies which redirect T cell specificity against a tumor-specific antigen through the use of antibody fragments. They demonstrated remarkable efficacy in B cell hematologic malignancies, thus paving the way for their development in solid tumors. Nonetheless, the use of such new drugs to treat solid tumors is not straightforward. So far, the results from early phase clinical trials are not as impressive as expected but many improvements are under way. In this review we present an overview of the clinical development of CAR-T cells and BiTEs targeting the main antigens expressed by solid tumors. We emphasize the most frequent hurdles encountered by either CAR-T cells or BiTEs, or both, and summarize the strategies that have been proposed to overcome these obstacles.
Personalized genome structure via single gamete sequencing
Authors: Lyu Ruqian , Tsui Vanessa , McCarthy Davis J. , Crismani Wayne 
Published: April 2021

AbstractGenetic maps have been fundamental to building our understanding of disease genetics and evolutionary processes. The gametes of an individual contain all of the information required to perform a de novo chromosome-scale assembly of an individual’s genome, which historically has been performed with populations and pedigrees. Here, we discuss how single-cell gamete sequencing offers the potential to merge the advantages of short-read sequencing with the ability to build personalized genetic maps and open up an entirely new space in personalized genetics.
Diaphragmatic paralysis, respiratory function, and postoperative pain after interscalene brachial plexus block with a reduced dose of 10 ml levobupivacaine 0.25% versus a 20 ml dose in patients undergoing arthroscopic shoulder surgery: study protocol for the randomized controlled double-blind REDOLEV study
Authors: Oliver-Fornies P. , Ortega Lahuerta J. P. , Gomez Gomez R. , Gonzalo Pellicer I. , Oliden Gutierrez L. , Viñuales Cabeza J. , Gallego Ligorit L. , Orellana Melgar C. E. 
Published: April 2021

Abstract
Background
Arthroscopic shoulder surgery causes severe postoperative pain. An interscalene brachial plexus block provides adequate analgesia, but unintended spread of the local anesthetic administered may result in a phrenic nerve block, usually associated with a nonnegligible incidence of acute hemidiaphragmatic paralysis.
The main purpose of this trial will be to analyze the incidence of hemidiaphragmatic paralysis ensuing after interscalene brachial plexus block in patients undergoing arthroscopic shoulder surgery administered a standard volume (20 ml) vs. a low volume (10 ml) of levobupivacaine 0.25%.

Methods
This will be a prospective double-blind randomized controlled single-center two-arm comparative trial. Forty-eight patients will be included. The primary goal will be to ultrasonographically determine the incidence of hemidiaphragmatic paralysis by calculating the diaphragmatic thickness ratio in each group. The secondary goals will be to compare the two arms in terms of (1) decrease in forced vital capacity and (2) in forced expiratory volume at 1 s by spirometry; (3) decrease in diaphragmatic excursion by ultrasound; (4) 24-h total intravenous morphine consumption; (5) time to first opioid request of a patient-controlled analgesia pump; and (6) postoperative complications.

Discussion
This trial will demonstrate that a low-volume interscalene brachial plexus block decreases hemidiaphragmatic paralysis following arthroscopic shoulder surgery according to spirometry and ultrasound measurements and does not provide inferior postoperative analgesia to the standard volume, as measured by opioid requirements.

Trial registration
EudraCT and Spanish Trial Register (REec) registration number: 2019-003855-12 (registered on 7 January 2020). ClinicalTrials.gov identification number: NCT04385966 (retrospectively registered on 8 May 2020). Ethics Committee approval: EC19/093 (18 December 2019).
Mitochondrial protein CMPK2 regulates IFN alpha-enhanced foam cell formation, potentially contributing to premature atherosclerosis in SLE
Authors: Lai Jenn-Haung , Hung Li-Feng , Huang Chuan-Yueh , Wu De-Wei , Wu Chien-Hsiang , Ho Ling-Jun 
Published: April 2021

Abstract
Background
Premature atherosclerosis occurs in patients with SLE; however, the mechanisms remain unclear. Both mitochondrial machinery and proinflammatory cytokine interferon alpha (IFN-α) potentially contribute to atherogenic processes in SLE. Here, we explore the roles of the mitochondrial protein cytidine/uridine monophosphate kinase 2 (CMPK2) in IFN-α-mediated pro-atherogenic events.

Methods
Foam cell measurements were performed by oil red O staining, Dil-oxLDL uptake and the BODIPY approach. The mRNA and protein levels were measured by qPCR and Western blotting, respectively. Isolation of CD4+ T cells and monocytes was performed with monoclonal antibodies conjugated with microbeads. Manipulation of protein expression was conducted by either small interference RNA (siRNA) knockdown or CRISPR/Cas9 knockout. The expression of mitochondrial reactive oxygen species (mtROS) was determined by flow cytometry and confocal microscopy.

Results
IFN-α enhanced oxLDL-induced foam cell formation and Dil-oxLDL uptake by macrophages. In addition to IFN-α, several triggers of atherosclerosis, including thrombin and IFN-γ, can induce CMPK2 expression, which was elevated in CD4+ T cells and CD14+ monocytes isolated from SLE patients compared to those isolated from controls. The analysis of cellular subfractions revealed that CMPK2 was present in both mitochondrial and cytosolic fractions. IFN-α-induced CMPK2 expression was inhibited by Janus kinase (JAK)1/2 and tyrosine kinase 2 (Tyk2) inhibitors. Both the knockdown and knockout of CMPK2 attenuated IFN-α-mediated foam cell formation, which involved the reduction of scavenger receptor class A (SR-A) expression. CMPK2 also regulated IFN-α-enhanced mtROS production and inflammasome activation.

Conclusions
The study suggests that CMPK2 plays contributing roles in the pro-atherogenic effects of IFN-α.
An EPIC predictor of gestational age and its application to newborns conceived by assisted reproductive technologies
Authors: Haftorn Kristine L. , Lee Yunsung , Denault William R. P. , Page Christian M. , Nustad Haakon E. , Lyle Robert , Gjessing Håkon K. , Malmberg Anni , Magnus Maria C. , Næss Øyvind , Czamara Darina , Räikkönen Katri , Lahti Jari , Magnus Per , Håberg Siri E. , Jugessur Astanand , Bohlin Jon 
Published: April 2021

Abstract
Background
Gestational age is a useful proxy for assessing developmental maturity, but correct estimation of gestational age is difficult using clinical measures. DNA methylation at birth has proven to be an accurate predictor of gestational age. Previous predictors of epigenetic gestational age were based on DNA methylation data from the Illumina HumanMethylation 27 K or 450 K array, which have subsequently been replaced by the Illumina MethylationEPIC 850 K array (EPIC). Our aims here were to build an epigenetic gestational age clock specific for the EPIC array and to evaluate its precision and accuracy using the embryo transfer date of newborns from the largest EPIC-derived dataset to date on assisted reproductive technologies (ART).

Methods
We built an epigenetic gestational age clock using Lasso regression trained on 755 randomly selected non-ART newborns from the Norwegian Study of Assisted Reproductive Technologies (START)—a substudy of the Norwegian Mother, Father, and Child Cohort Study (MoBa). For the ART-conceived newborns, the START dataset had detailed information on the embryo transfer date and the specific ART procedure used for conception. The predicted gestational age was compared to clinically estimated gestational age in 200 non-ART and 838 ART newborns using MM-type robust regression. The performance of the clock was compared to previously published gestational age clocks in an independent replication sample of 148 newborns from the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restrictions (PREDO) study—a prospective pregnancy cohort of Finnish women.

Results
Our new epigenetic gestational age clock showed higher precision and accuracy in predicting gestational age than previous gestational age clocks (R2 = 0.724, median absolute deviation (MAD) = 3.14 days). Restricting the analysis to CpGs shared between 450 K and EPIC did not reduce the precision of the clock. Furthermore, validating the clock on ART newborns with known embryo transfer date confirmed that DNA methylation is an accurate predictor of gestational age (R2 = 0.767, MAD = 3.7 days).

Conclusions
We present the first EPIC-based predictor of gestational age and demonstrate its robustness and precision in ART and non-ART newborns. As more datasets are being generated on the EPIC platform, this clock will be valuable in studies using gestational age to assess neonatal development.
Assessment and management of disease burden and quality of life in patients with hereditary angioedema: a consensus report
Authors: Bork Konrad , Anderson John T. , Caballero Teresa , Craig Timothy , Johnston Douglas T. , Li H. Henry , Longhurst Hilary J. , Radojicic Cristine , Riedl Marc A. 
Published: April 2021

AbstractBackgroundHereditary angioedema (HAE) is a rare disease characterized by unpredictable, potentially life-threatening attacks, resulting in significant physical and emotional burdens for patients and families. To optimize care for patients with HAE, an individualized management plan should be considered in partnership with the physician, requiring comprehensive assessment of the patient’s frequency and severity of attacks, disease burden, and therapeutic control. Although several guidelines and consensus papers have been published concerning the diagnosis and treatment of HAE, there has been limited specific clinical guidance on the assessment of disease burden and quality of life (QoL) in this patient population. Practical guidance is critical in supporting effective long-term clinical management of HAE and improving patient outcomes. The objective of this review is to provide evidence-based guidelines for an individualized assessment of disease burden and QoL in patients with HAE.MethodsA consensus meeting was held on February 29, 2020, consisting of 9 HAE experts from the United States and Europe with extensive clinical experience in the treatment of HAE. Consensus statements were developed based on a preliminary literature review and discussions from the consensus meeting.ResultsFinal statements reflect the consensus of the expert panel and include the assessment of attack severity, evaluation of disease burden, and long-term clinical management of HAE caused by C1-esterase inhibitor deficiency. Patient-reported outcome measures for assessing HAE attack severity and frequency are available and valuable tools; however, attack frequency and severity are insufficient markers of disease severity unless they are evaluated in the broader context of the effect on an individual patient’s QoL. QoL assessments should be individualized for each patient and minimally, they should address the interference of HAE with work, school, social, family, and physical activity, along with access to and burden of HAE treatment. Advances in HAE therapies offer the opportunity for comprehensive, individualized treatment plans, allowing patients to achieve minimal attack burden with reduced disease and treatment burden.ConclusionThis consensus report builds on existing guidelines by expanding the assessment of disease burden and QoL measures for patients with HAE.
Genome-wide identification of the GATA transcription factor family and their expression patterns under temperature and salt stress in Aspergillus oryzae
Authors: Jiang Chunmiao , Lv Gongbo , Ge Jinxin , He Bin , Zhang Zhe , Hu Zhihong , Zeng Bin 
Published: April 2021

AbstractGATA transcription factors (TFs) are involved in the regulation of growth processes and various environmental stresses. Although GATA TFs involved in abiotic stress in plants and some fungi have been analyzed, information regarding GATA TFs in Aspergillusoryzae is extremely poor. In this study, we identified and functionally characterized seven GATA proteins from A.oryzae 3.042 genome, including a novel AoSnf5 GATA TF with 20-residue between the Cys-X2-Cys motifs which was found in Aspergillus GATA TFs for the first time. Phylogenetic analysis indicated that these seven A. oryzae GATA TFs could be classified into six subgroups. Analysis of conserved motifs demonstrated that Aspergillus GATA TFs with similar motif compositions clustered in one subgroup, suggesting that they might possess similar genetic functions, further confirming the accuracy of the phylogenetic relationship. Furthermore, the expression patterns of seven A.oryzae GATA TFs under temperature and salt stresses indicated that A. oryzae GATA TFs were mainly responsive to high temperature and high salt stress. The protein–protein interaction network of A.oryzae GATA TFs revealed certain potentially interacting proteins. The comprehensive analysis of A. oryzae GATA TFs will be beneficial for understanding their biological function and evolutionary features and provide an important starting point to further understand the role of GATA TFs in the regulation of distinct environmental conditions in A.oryzae.
Evaluation of an oxygen‐dependent self‐inducible surfactin synthesis in B. subtilis by substitution of native promoter PsrfA by anaerobically active PnarG and PnasD
Authors: Hoffmann Mareen , Braig Alina , Fernandez Cano Luna Diana Stephanie , Rief Katharina , Becker Philipp , Treinen Chantal , Klausmann Peter , Morabbi Heravi Kambiz , Henkel Marius , Lilge Lars , Hausmann Rudolf 
Published: April 2021

AbstractA novel approach targeting self-inducible surfactin synthesis under oxygen-limited conditions is presented. Because both the nitrate (NarGHI) and nitrite (NasDE) reductase are highly expressed during anaerobic growth ofB. subtilis, the native promoter PsrfAof the surfactin operon in strainB. subtilisJABs24 was replaced by promoters PnarGand PnasDto induce surfactin synthesis anaerobically. Shake flask cultivations with varying oxygen availabilities indicated no significant differences in native PsrfAexpression. As hypothesized, activity of PnarGand PnasDincreased with lower oxygen levels and surfactin was not produced by PsrfA::PnarGas well as PsrfA::PnasDmutant strains under conditions with highest oxygen availability. PnarGshowed expressions similar to PsrfAat lowest oxygen availability, while maximum value of PnasDwas more than 5.5-fold higher. Although the promoter exchange PsrfA::PnarGresulted in a decreased surfactin titer at lowest oxygen availability, the strain carrying PsrfA::PnasDreached a 1.4-fold increased surfactin concentration with 696 mg/L and revealed an exceptional high overallYP/Xof 1.007 g/g. This value also surpassed theYP/Xof the reference strain JABs24 at highest and moderate oxygen availability. Bioreactor cultivations illustrated that significant cell lysis occurred when the process of “anaerobization” was performed too fast. However, processes with a constantly low agitation and aeration rate showed promising potential for process improvement, especially by employing the strain carrying PsrfA::PnasDpromoter exchange. Additionally, replacement of other native promoters by nitrite reductase promoter PnasDrepresents a promising tool for anaerobic-inducible bioprocesses inBacillus.