bluuebunny/crossref_metadata_2025_split huggingface dataset:
Artificial escape from XCI by DNA methylation editing of the CDKL5 gene
Authors: Halmai Julian A N M , Deng Peter , Gonzalez Casiana E , Coggins Nicole B , Cameron David , Carter Jasmine L , Buchanan Fiona K B , Waldo Jennifer J , Lock Samantha R , Anderson Johnathon D , O’Geen Henriette , Segal David J , Nolta Jan , Fink Kyle D 
Published: December 2019

AbstractA significant number of X-linked genes escape from X chromosome inactivation and are associated with a distinct epigenetic signature. One epigenetic modification that strongly correlates with X-escape is reduced DNA methylation in promoter regions. Here, we created an artificial escape by editing DNA methylation on the promoter of CDKL5, a gene causative for an infantile epilepsy, from the silenced X-chromosomal allele in human neuronal-like cells. We identify that a fusion of the catalytic domain of TET1 to dCas9 targeted to the CDKL5 promoter using three guide RNAs causes significant reactivation of the inactive allele in combination with removal of methyl groups from CpG dinucleotides. Strikingly, we demonstrate that co-expression of TET1 and a VP64 transactivator have a synergistic effect on the reactivation of the inactive allele to levels &gt;60% of the active allele. We further used a multi-omics assessment to determine potential off-targets on the transcriptome and methylome. We find that synergistic delivery of dCas9 effectors is highly selective for the target site. Our findings further elucidate a causal role for reduced DNA methylation associated with escape from X chromosome inactivation. Understanding the epigenetics associated with escape from X chromosome inactivation has potential for those suffering from X-linked disorders.
Crystal structure of human cytoplasmic tRNAHis-specific 5′-monomethylphosphate capping enzyme
Authors: Liu Yining , Martinez Anna , Yamashita Seisuke , Tomita Kozo 
Published: December 2019

AbstractBCDIN3 domain containing RNA methyltransferase, BCDIN3D, monomethylates the 5′-monophosphate of cytoplasmic tRNAHis with a G−1:A73 mispair at the top of an eight-nucleotide-long acceptor helix, using S-adenosyl-l-methionine (SAM) as a methyl group donor. In humans, BCDIN3D overexpression is associated with the tumorigenic phenotype and poor prognosis in breast cancer. Here, we present the crystal structure of human BCDIN3D complexed with S-adenosyl-l-homocysteine. BCDIN3D adopts a classical Rossmann-fold methyltransferase structure. A comparison of the structure with that of the closely related methylphosphate capping enzyme, MePCE, which monomethylates the 5′-γ-phosphate of 7SK RNA, revealed the important residues for monomethyl transfer from SAM onto the 5′-monophosphate of tRNAHis and for tRNAHis recognition by BCDIN3D. A structural model of tRNAHis docking onto BCDIN3D suggested the molecular mechanism underlying the different activities between BCDIN3D and MePCE. A loop in BCDIN3D is shorter, as compared to the corresponding region that forms an α-helix to recognize the 5′-end of RNA in MePCE, and the G−1:A73 mispair in tRNAHis allows the N-terminal α-helix of BCDIN3D to wedge the G−1:A73 mispair of tRNAHis. As a result, the 5′-monophosphate of G−1 of tRNAHis is deep in the catalytic pocket for 5′-phosphate methylation. Thus, BCDIN3D is a tRNAHis-specific 5′-monomethylphosphate capping enzyme that discriminates tRNAHis from other tRNA species, and the structural information presented in this study also provides the molecular basis for the development of drugs against breast cancers.
Eosinophil count and mortality risk in incident hemodialysis patients
Authors: Kang Duk-Hee , Lee Yuji , Kleine Carola Ellen , Lee Yong Kyu , Park Christina , Hsiung Jui-Ting , Rhee Connie M , Kovesdy Csaba P , Kalantar-Zadeh Kamyar , Streja Elani 
Published: December 2019

AbstractBackgroundEosinophils are traditionally known as moderators of allergic reactions; however, they have now emerged as one of the principal immune-regulating cells as well as predictors of vascular disease and mortality in the general population. Although eosinophilia has been demonstrated in hemodialysis (HD) patients, associations of eosinophil count (EOC) and its changes with mortality in HD patients are still unknown.MethodsIn 107 506 incident HD patients treated by a large dialysis organization during 2007–11, we examined the relationships of baseline and time-varying EOC and its changes (ΔEOC) over the first 3 months with all-cause mortality using Cox proportional hazards models with three levels of hierarchical adjustment.ResultsBaseline median EOC was 231 (interquartile range 155–339) cells/μL and eosinophilia (&gt;350 cells/μL) was observed in 23.4% of patients. There was a gradual increase in EOC over time after HD initiation with a median ΔEOC of 5.1 (IQR −53–199) cells/μL, which did not parallel the changes in white blood cell count. In fully adjusted models, mortality risk was highest in subjects with lower baseline and time-varying EOC (&lt;100 cells/μL) and was also slightly higher in patients with higher levels (≥550 cells/μL), resulting in a reverse J-shaped relationship. The relationship of ΔEOC with all-cause mortality risk was also a reverse J-shape where both an increase and decrease exhibited a higher mortality risk.ConclusionsBoth lower and higher EOCs and changes in EOC over the first 3 months after HD initiation were associated with higher all-cause mortality in incident HD patients.
Intracranial Atherosclerosis: A Disease of Functional, not Anatomic Stenosis? How Trans-Stenotic Pressure Gradients Can Help Guide Treatment
Authors: Zanaty Mario , Rossen James D , Roa Jorge A , Nakagawa Daichi , Hudson Joseph S , Kasab Sami Al , Limaye Kaustubh , Asi Khaled , Dandapat Sudeepta , Jabbour Pascal , Samaniego Edgar A , Hasan David M 
Published: December 2019

Abstract

Background
Most trials have assessed intracranial atherosclerotic disease (ICAD) severity based on angiographic stenosis. However, anatomic stenosis might not accurately identify the actual state of functional post-stenotic flow limitation.

Objective
To investigate whether angiographic stenosis correlates with physiologic distal flow limitation, measured as trans-stenotic pressure gradients, in ICAD patients.

Methods
In patients referred for endovascular treatment of anterior circulation symptomatic ICAD who failed maximal medical therapy (MMT) per SAMMPRIS (Stenting versus Aggressive Medical Therapy for Intracranial Arterial Stenosis) criteria, angiographic luminal diameters and percentages of stenosis were correlated with trans-stenotic pressure gradients, calculated as distal/proximal pressure ratios (DPPR) and proximal minus distal pressure gradients (PDPG), by way of Spearman correlation coefficients.

Results
Nine patients (3 men, 6 women) were evaluated. Atherosclerotic lesions’ locations included internal carotid artery in 5 subjects (2 cavernous, 3 supraclinoid) and proximal middle cerebral artery (M1) in 4 patients. Mean percentage of stenosis was 80 ± 8% (range 75%-94%). Minimal lumen diameter at the most stenotic ICAD site ranged from 0.2 to 0.9 mm (0.59 ± 0.41 mm). DPPR ranged from 0.38 to 0.63 (0.56 ± 0.14). PDPG ranged from 35 to 57 mm Hg (50 ± 8 mm Hg). Spearman coefficients showed no correlation between DPPR or PDPG and angiographic minimal luminal diameters or percentages of stenosis. There were no procedural complications related to trans-stenotic pressure measurements.

CONCLUSION
Angiographic stenosis does not reflect the physiologic severity of distal flow limitation in patients with ICAD. Hemodynamic assessment using trans-stenotic pressure ratios and gradients may serve as a more reliable predictive biomarker for MMT failure and response to revascularization.
The AtHB1 Transcription Factor Controls the miR164-CUC2 Regulatory Node to Modulate Leaf Development
Authors: Miguel Virginia N , Manavella Pablo A , Chan Raquel L , Capella Mat�as 
Published: December 2019

Abstract
The presence of small tooth-like indentations, or serrations, characterizes leaf margins of Arabidopsis thaliana plants. The NAC family member CUP-SHAPED COTYLEDON 2 (CUC2), which undergoes post-transcriptional gene silencing by three micro-RNA genes (MIR164A, B and C), controls the extension of leaf serration. Here, we analyzed the role of AtHB1, a transcription factor (TF) belonging to the homeodomain-leucine zipper subfamily I, in shaping leaf margins. Using mutants with an impaired silencing pathway as background, we obtained transgenic plants expressing AtHB1 over 100 times compared to controls. These plants presented an atypical developmental phenotype characterized by leaves with deep serration. Transcript measurements revealed that CUC2 expression was induced in plants overexpressing AtHB1 and repressed in athb1 mutants, indicating a positive regulation exerted by this TF. Moreover, molecular analyses of AtHB1 overexpressing and mutant plants revealed that AtHB1 represses MIR164 transcription. We found that overexpression of MIR164B was able to reverse the serration phenotype of plants overexpressing AtHB1. Finally, chromatin immunoprecipitation assays revealed that AtHB1 was able to bind in vivo the promoter regions of all three MIR164 encoding loci. Altogether, our results indicate that AtHB1 directly represses MIR164 expression to enhance leaf serration by increasing CUC2 levels.
A Systematic Literature Review of Spine Neurostimulation Therapies for the Treatment of Pain
Authors: Deer Timothy R , Grider Jay S , Lamer Tim J , Pope Jason E , Falowski Steven , Hunter Corey W , Provenzano David A , Slavin Konstantin V , Russo Marc , Carayannopoulos Alexios , Shah Jay M , Harned Michael E , Hagedorn Jonathan M , Bolash Robert B , Arle Jeff E , Kapural Leo , Amirdelfan Kasra , Jain Sameer , Liem Liong , Carlson Jonathan D , Malinowski Mark N , Bendel Markus , Yang Ajax , Aiyer Rohit , Valimahomed Ali , Antony Ajay , Craig Justin , Fishman Michael A , Al-Kaisy Adnan A , Christelis Nick , Rosenquist Richard W , Levy Robert M , Mekhail Nagy 
Published: December 2019

AbstractObjectiveTo conduct a systematic literature review of spinal cord stimulation (SCS) for pain.DesignGrade the evidence for SCS.MethodsAn international, interdisciplinary work group conducted literature searches, reviewed abstracts, and selected studies for grading. Inclusion/exclusion criteria included randomized controlled trials (RCTs) of patients with intractable pain of greater than one year’s duration. Full studies were graded by two independent reviewers. Excluded studies were retrospective, had small numbers of subjects, or existed only as abstracts. Studies were graded using the modified Interventional Pain Management Techniques–Quality Appraisal of Reliability and Risk of Bias Assessment, the Cochrane Collaborations Risk of Bias assessment, and the US Preventative Services Task Force level-of-evidence criteria.ResultsSCS has Level 1 evidence (strong) for axial back/lumbar radiculopathy or neuralgia (five high-quality RCTs) and complex regional pain syndrome (one high-quality RCT).ConclusionsHigh-level evidence supports SCS for treating chronic pain and complex regional pain syndrome. For patients with failed back surgery syndrome, SCS was more effective than reoperation or medical management. New stimulation waveforms and frequencies may provide a greater likelihood of pain relief compared with conventional SCS for patients with axial back pain, with or without radicular pain.
Conventional versus ultrasound treat to target: no difference in magnetic resonance imaging inflammation or joint damage over 2 years in early rheumatoid arthritis
Authors: Sundin Ulf , Aga Anna-Birgitte , Skare Øivind , Nordberg Lena B , Uhlig Till , Hammer Hilde B , van der Heijde Désirée , Kvien Tore K , Lillegraven Siri , Haavardsholm Espen A ,   the ARCTIC study group
Published: December 2019

Abstract

Objective
To investigate whether an ultrasound-guided treat-to-target strategy for early RA would lead to reduced MRI inflammation or less structural damage progression compared with a conventional treat-to-target strategy.

Methods
A total of 230 DMARD-naïve early RA patients were randomized to an ultrasound tight control strategy targeting DAS &lt;1.6, no swollen joints and no power Doppler signal in any joint or a conventional strategy targeting DAS &lt;1.6 and no swollen joints. Patients in both arms were treated according to the same DMARD escalation strategy. MRI of the dominant hand was performed at six time points over 2 years and scored according to the OMERACT RA MRI scoring system. A total of 218 patients had baseline and one or more follow-up MRIs and were included in the analysis. The mean MRI score change from baseline to each follow-up and the 2 year risk for erosive progression were compared between arms.

Results
MRI bone marrow oedema, synovitis and tenosynovitis improved over the first year and was sustained during the second year of follow-up, with no statistically significant differences between the ultrasound and the conventional arms at any time point. The 2 year risk for progression of MRI erosions was similar in both treatment arms: ultrasound arm 39%, conventional arm 33% [relative risk 1.16 (95% CI 0.81, 1.66), P = 0.40].

Conclusion
Incorporating ultrasound information in treatment decisions did not lead to reduced MRI inflammation or less structural damage compared with a conventional treatment strategy. The findings support that systematic use of ultrasound does not provide a benefit in the follow-up of patients with early RA.

Trial registration number
Clinicaltrials.gov, http://clinicaltrials.gov, NCT01205854.
Screening for Hepatitis B Virus Infection in Pregnant Women: US Preventive Services Task Force Reaffirmation Recommendation Statement
Authors: Owens Douglas K. , Davidson Karina W. , Krist Alex H. , Barry Michael J. , Cabana Michael , Caughey Aaron B. , Doubeni Chyke A. , Epling John W. , Kemper Alex R. , Kubik Martha , Landefeld C. Seth , Mangione Carol M. , Pbert Lori , Silverstein Michael , Simon Melissa A. , Tseng Chien-Wen , Wong John B. 
Published: December 2019

(Abstracted from JAMA 2019;322(4):349–354)
In 2009, the US Preventive Services Task Force (USPSTF) recommended that pregnant women be screened for hepatitis B virus (HBV) infection. It cited strong evidence that the benefit of screening substantially outweighed the harm.
Sonographic Lower Uterine Segment Thickness After Prior Cesarean Section to Predict Uterine Rupture: A Systematic Review and Meta-analysis
Authors: Swift Brenna E. , Shah Prakesh S. , Farine Dan 
Published: December 2019

(Abstracted from Acta Obstet Gynecol Scand 2019;98:830–841)
Cesarean delivery rates in the United States were 32% in 2015. This high rate is coupled with dramatically decreased rates of trial of labor after cesareans (TOLACs) in recent years that may indicate fear of potential complications (such as uterine rupture).
Reduced Sensitivity to Anesthetic Agents upon Lesioning the Mesopontine Tegmental Anesthesia Area in Rats Depends on Anesthetic Type
Authors: Minert Anne , Baron Mark , Devor Marshall 
Published: December 2019

Abstract

Background
The brainstem mesopontine tegmental anesthesia area is a key node in circuitry responsible for anesthetic induction and maintenance. Microinjecting the γ-aminobutyric acid–mediated (GABAergic) anesthetic pentobarbital in this nucleus rapidly and reversibly induces general anesthesia, whereas lesioning it renders the animal relatively insensitive to pentobarbital administered systemically. This study investigated whether effects of lesioning the mesopontine tegmental anesthesia area generalize to other anesthetic agents.

Methods
Cell-selective lesions were made using ibotenic acid, and rats were later tested for changes in the dose–response relation to etomidate, propofol, alfaxalone/alfadolone, ketamine, and medetomidine delivered intravenously using a programmable infusion pump. Anesthetic induction for each agent was tracked using five behavioral endpoints: loss of righting reflex, criterion for anesthesia (score of 11 or higher), criterion for surgical anesthesia (score of 14 or higher), antinociception (loss of pinch response), and deep surgical anesthesia (score of 16).

Results
As reported previously for pentobarbital, on-target mesopontine tegmental anesthesia area lesions reduced sensitivity to the GABAergic anesthetics etomidate and propofol. The dose to achieve a score of 16 increased to 147 ± 50% of baseline in control animals ± SD (P = 0.0007; 7 lesioned rats and 18 controls) and 136 ± 58% of baseline (P = 0.010; 6 lesioned rats and 21 controls), respectively. In contrast, responsiveness to the neurosteroids alfaxalone and alfadolone remained unchanged compared with baseline (94 ± 24%; P = 0.519; 6 lesioned rats and 18 controls) and with ketamine increased slightly (90 ± 11%; P = 0.039; 6 lesioned rats and 19 controls). The non-GABAergic anesthetic medetomidine did not induce criterion anesthesia even at the maximal dose tested. The dose to reach the maximal anesthesia score actually obtained was unaffected by the lesion (112 ± 8%; P = 0.063; 5 lesioned rats and 18 controls).

Conclusions
Inability to induce anesthesia in lesioned animals using normally effective doses of etomidate, propofol, and pentobarbital suggests that the mesopontine tegmental anesthesia area is the effective target of these, but not necessarily all, GABAergic anesthetics upon systemic administration. Cortical and spinal functions are likely suppressed by recruitment of dedicated ascending and descending pathways rather than by direct, distributed drug action.

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New
Operative Versus Nonoperative Outcomes of Middle-Third Clavicle Fractures: A Systematic Review and Meta-Analysis
Authors: Amer Kamil , Smith Brendan , Thomson Jennifer E. , Congiusta Dominick , Reilly Mark C. , Sirkin Michael S. , Adams Mark R. 
Published: December 2019

Objectives:
Middle third clavicle fractures have long been managed conservatively with immobilization. Some patients, especially those with completely displaced or shortened clavicle fractures are now thought to have increased risk of nonunion or symptomatic malunion. The authors performed a meta-analysis to study the incidence of nonunion and symptomatic malunion and test the hypothesis that surgical fixation of these fractures significantly lowers the risk of these complications.

Methods:
A search was performed in the PubMed, Embase, and Cochrane Library databases for randomized clinical trials and quasi-experimental trials that compare outcomes of operative and nonoperative management for clavicle fractures that are fully (100%) displaced or have greater than 2 cm of shortening. Pooled patient data were used to construct forest plots for the meta-analysis.

Results:
Eleven studies including 497 patients who were treated and 457 patients treated conservatively were analyzed. Patients managed operatively had significantly lower relative risk of developing nonunion [0.17 (95% confidence interval 0.08–0.33)] and symptomatic malunion [0.13 (95% confidence interval 0.05–0.37)]. Plate fixation significantly reduced the risk of nonunion, but intramedullary nail fixation did not. There was no difference in Constant–Murley or DASH scores between the 2 treatment groups or in the rate of secondary operative procedures.

Conclusions:
Patients who undergo operative fixation of displaced middle-third clavicle fractures have a lower incidence of nonunion and symptomatic malunion. The clinical significance of this effect is uncertain, as functional scores were similar in both groups. Further research into the risk factors for nonunion and symptomatic malunion will be necessary to determine which patients benefit from operative fixation.

Level of Evidence:
Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.
Using Reflective Teaching Program to Explore Health-Promoting Behaviors in Nursing Students
Authors: CHANG Yi-Ya , CHEN Miao-Chuan 
Published: December 2019

ABSTRACT

Background
The attitudes of nurses toward health promotion affect patients. However, current classroom teaching does not provide nursing students with actual experiences. An experiential and reflective teaching design will help nursing students practice actual health behaviors and record their feelings. This will help nursing students better understand the difficulties and feelings experienced by nurses when encouraging patients to make behavioral changes in clinical settings.

Purpose
This study aimed to explore the experiences and factors affecting health-promoting learning with reflective teaching in nursing students.

Methods
This explorative study integrated the “reflective assessment, engagement, and action-reflection” strategy of reflective teaching into the standard health-promotion teaching curriculum to understand the experiences of nursing students when executing health-promoting behaviors. Fifty-seven second-year nursing students from a university in northern Taiwan participated in this course, which was conducted between September 2017 and January 2018. The data were collected from the contents of the reflective journals written by the nursing students and analyzed using thematic analysis.

Results
The three health-promoting behaviors performed by most of the students were regular exercise, balanced and healthy diet, and adequate daily water intake. The feelings experienced by the nursing students during the execution of health-promoting behaviors included easier said than done, compromise and adjustment, and continuation of health behaviors. Accommodation, peer encouragement, and support were important, facilitating factors of health-promoting behaviors in this study.

Conclusions/Implications for Practice
The results of this study may serve as a reference for nursing lecturers when employing reflective teaching in the classroom. Reflective teaching designs for actual experiences help nursing students experience the crucial factors and benefits of executing health-promoting behaviors.
Environmental exposures and the risk of inflammatory bowel disease: a case-control study from Saudi Arabia
Authors: Algethmi Wafaa , Baumann Cedric , Alnajjar Wed , Sroji Aaliah , Alsahafi Majid , Jawa Hani , Qari Yousef , Peyrin-Biroulet Laurent , Saadah Omar I. , Mosli Mahmoud 
Published: December 2019

Background and aims:
Environmental exposures play a key role in inflammatory bowel disease pathogenesis. The incidence of IBD has increased in the Arabic Peninsula with a disease phenotype that seems to differ from that of Western countries. We aimed to examine the association between environmental exposures and the risk of IBD in Saudi Arabia.

Patients and methods:
We performed a case-control study comparing Saudi individuals with confirmed IBD and healthy controls. All subjects completed a detailed questionnaire that included data on demographics, clinical characteristics, childhood exposures, socioeconomic exposures, and parent factors. Associations between risk factors and inflammatory bowel disease were investigated through univariate and multivariate regression analysis.

Results:
The analysis included 82 patients and 160 controls. According to multiple logistic regression analysis, holding a University/Master degree education level or a PhD degree reduced the risk of inflammatory bowel disease by 10-fold (odds ratio = 0.1, confidence interval = 0.1–0.3), receiving seven vaccines or more during childhood increased the risk of developing inflammatory bowel disease by nine-fold (odds ratio = 9.2, confidence interval = 2.9–29.4) and maternal use of oral contraceptives pills increased the risk by 11-fold (odds ratio = 11.4, confidence interval = 3.3–39.3).

Conclusion:
Inflammatory bowel disease occurrence was independently associated with education level, number of childhood vaccination, and maternal use of oral contraceptives pills in this population of inflammatory bowel disease patients. This is the first study examining environmental exposures as risk factors for inflammatory bowel disease in Saudi Arabia.