bluuebunny/crossref_metadata_2025_split huggingface dataset:
User-driven design of child restraint information to reduce errors in use: a pilot randomised controlled trial
Authors: Hall Alexandra B , Ho Catherine , Albanese Bianca , Keay Lisa , Hunter Kate , Charlton Judith , Hayen Andrew , Bilston Lynne E , Brown Julie 
Published: September 2019

BackgroundIncorrect use of child restraints is a long-standing problem that increases the risk of injury in crashes. We used user-centred design to develop prototype child restraint instructional materials. The objective of this study was to evaluate these materials in terms of comprehension and errors in the use of child restraints. The relationship between comprehension and errors in use was also explored.MethodsWe used a parallel-group randomised controlled trial in a laboratory setting. The intervention group (n=22) were provided with prototype materials and the control group (n=22) with existing instructional materials for the same restraint. Participants installed the restraint in a vehicle buck, secured an appropriately sized mannequin in the restraint and underwent a comprehension test. Our primary outcome was overall correct use, and our secondary outcomes were (1) comprehension score and (2) percent errors in the installation trial.ResultsThere was 27% more overall correct use (p=0.042) and a higher mean comprehension score in the intervention group (mean 17, 95% CI 16 to 18) compared with the control group (mean 12, 95% CI 10 to 14, p<0.001). The mean error percentage in the control group was 23% (95% CI 16% to 31%) compared with 14% in the intervention group (95% CI 8% to 20%, p=0.056). For every one point increase in comprehension, there was an almost 2% (95% CI −2.7% to −1.0%) reduction in errors (y=45.5–1.87x, p value for slope <0.001).ConclusionsConsumer-driven design of informational materials can increase the correct use of child restraints. Targeting improved comprehension of informational materials may be an effective mechanism for reducing child restraint misuse.
Microsatellite instability detection using a large next-generation sequencing cancer panel across diverse tumour types
Authors: Pang Jiuhong , Gindin Tatyana , Mansukhani Mahesh , Fernandes Helen , Hsiao Susan 
Published: September 2019

AimMicrosatellite instability (MSI), a hallmark of DNA mismatch repair deficiency, is a key molecular biomarker with multiple clinical implications including the selection of patients for immunotherapy, identifying patients who may have Lynch syndrome and predicting prognosis in patients with colorectal tumours. Next-generation sequencing (NGS) provides the opportunity to interrogate large numbers of microsatellite loci concurrently with genomic variants. We sought to develop a method to detect MSI that would not require paired normal tissue and would leverage the sequence data obtained from a broad range of tumours tested using our 467-gene NGS Columbia Combined Cancer Panel (CCCP).MethodsAltered mononucleotide and dinucleotide microsatellite loci across the CCCP region of interest were evaluated in clinical samples encompassing a diverse range of tumour types. The number of altered loci was used to develop a decision tree classifier model trained on the retrospectively collected cohort of 107 clinical cases sequenced by the CCCP assay.ResultsThe classifier was able to correctly classify all cases and was then used to analyse a test set of clinical cases (n=112) and was able to correctly predict their MSI status with 100% sensitivity and specificity. Analysis of recurrently altered loci identified alterations in genes involved in DNA repair, signalling and transcriptional regulation pathways, many of which have been implicated in MSI tumours.ConclusionThis study highlights the utility of this approach, which should be applicable to laboratories performing similar testing.
Physical and psychosocial work exposures as risk factors for disability retirement due to a shoulder lesion
Authors: Sirén Maria , Viikari-Juntura Eira , Arokoski Jari , Solovieva Svetlana 
Published: September 2019

ObjectiveTo assess the longitudinal associations of physical and psychosocial exposures with disability retirement due to a shoulder lesion.MethodsIn a nationwide register-based study, we followed 1 135 654 wage earners aged 30–59 years for the occurrence of disability retirement due to a shoulder lesion. The occupational exposures were assessed with job exposure matrices. We used a competing risk regression model to estimate HRs and their 95% CIs and to test for the association between the exposures and the outcome. We also calculated the attributable fraction of disability retirement due to occupational exposures.ResultsA total of 2472 persons had full disability retirement due to a shoulder lesion during the follow-up. Physically heavy work showed the strongest association with the outcome in both genders, in men with an HR of 2.90 (95% CI 2.37 to 3.55) and in women with an HR of 3.21 (95% CI 2.80 to 3.90). Of the specific physical exposures, working with hands above shoulder level was statistically significantly associated with disability retirement in men. When all physical exposures were taken into consideration, 46% and 41% of disability retirement due to a shoulder lesion were attributed to physical work load factors in men and women, respectively. In addition, 49% (men) and 35% (women) of disability retirement were attributed to psychosocial work-related factors.ConclusionsOur findings suggest that a considerable proportion of disability retirement due to a shoulder lesion could be prevented by reducing physical and psychosocial exposures at work to a low level.
How does an incomplete sky coverage affect the Hubble Constant variance?
Authors: Bengaly Carlos A. P. , Andrade Uendert , Alcaniz Jailson S. 
Published: September 2019

Abstract
We address the $$\simeq 4.4\sigma $$≃4.4σ tension between local and the CMB measurements of the Hubble Constant using simulated Type Ia Supernova (SN) data-sets. We probe its directional dependence by means of a hemispherical comparison through the entire celestial sphere as an estimator of the $$H_0$$H0 cosmic variance. We perform Monte Carlo simulations assuming isotropic and non-uniform distributions of data points, the latter coinciding with the real data. This allows us to incorporate observational features, such as the sample incompleteness, in our estimation. We obtain that this tension can be alleviated to $$3.4\sigma $$3.4σ for isotropic realizations, and $$2.7\sigma $$2.7σ for non-uniform ones. We also find that the $$H_0$$H0 variance is largely reduced if the data-sets are augmented to 4 and 10 times the current size. Future surveys will be able to tell whether the Hubble Constant tension happens due to unaccounted cosmic variance, or whether it is an actual indication of physics beyond the standard cosmological model.
N6-Methyladenosine Modulates Nonsense-Mediated mRNA Decay in Human Glioblastoma
Authors: Li Fuxi , Yi Yang , Miao Yanyan , Long Wenyong , Long Teng , Chen Siyun , Cheng Weisheng , Zou Changye , Zheng Yueyuan , Wu Xingui , Ding Junjun , Zhu Kaiyu , Chen Delin , Xu Qiongcong , Wang Jinkai , Liu Qing , Zhi Feng , Ren Jian , Cao Qi , Zhao Wei 
Published: September 2019

Abstract

The N6-methyladenosine (m6A) modification influences various mRNA metabolic events and tumorigenesis, however, its functions in nonsense-mediated mRNA decay (NMD) and whether NMD detects induced carcinogenesis pathways remain undefined. Here, we showed that the m6A methyltransferase METTL3 sustained its oncogenic role by modulating NMD of splicing factors and alternative splicing isoform switches in glioblastoma (GBM). Methylated RNA immunoprecipitation-seq (MeRIP-seq) analyses showed that m6A modification peaks were enriched at metabolic pathway–related transcripts in glioma stem cells (GSC) compared with neural progenitor cells. In addition, the clinical aggressiveness of malignant gliomas was associated with elevated expression of METTL3. Furthermore, silencing METTL3 or overexpressing dominant-negative mutant METTL3 suppressed the growth and self-renewal of GSCs. Integrated transcriptome and MeRIP-seq analyses revealed that downregulating the expression of METTL3 decreased m6A modification levels of serine- and arginine-rich splicing factors (SRSF), which led to YTHDC1-dependent NMD of SRSF transcripts and decreased SRSF protein expression. Reduced expression of SRSFs led to larger changes in alternative splicing isoform switches. Importantly, the phenotypes mediated by METTL3 deficiency could be rescued by downregulating BCL-X or NCOR2 isoforms. Overall, these results establish a novel function of m6A in modulating NMD and uncover the mechanism by which METTL3 promotes GBM tumor growth and progression.

Significance:
These findings establish the oncogenic role of m6A writer METTL3 in glioblastoma stem cells.
Infiltrating Myeloid Cells Drive Osteosarcoma Progression via GRM4 Regulation of IL23
Authors: Kansara Maya , Thomson Kristian , Pang Puiyi , Dutour Aurelie , Mirabello Lisa , Acher Francine , Pin Jean-Philippe , Demicco Elizabeth G. , Yan Juming , Teng Michele W.L. , Smyth Mark J. , Thomas David M. 
Published: September 2019

AbstractThe glutamate metabotropic receptor 4 (GRM4) locus is linked to susceptibility to human osteosarcoma, through unknown mechanisms. We show that Grm4−/− gene–targeted mice demonstrate accelerated radiation-induced tumor development to an extent comparable with Rb1+/− mice. GRM4 is expressed in myeloid cells, selectively regulating expression of IL23 and the related cytokine IL12. Osteosarcoma-conditioned media induce myeloid cell Il23 expression in a GRM4-dependent fashion, while suppressing the related cytokine Il12. Both human and mouse osteosarcomas express an increased IL23:IL12 ratio, whereas higher IL23 expression is associated with worse survival in humans. Consistent with an oncogenic role, Il23−/− mice are strikingly resistant to osteosarcoma development. Agonists of GRM4 or a neutralizing antibody to IL23 suppressed osteosarcoma growth in mice. These findings identify a novel, druggable myeloid suppressor pathway linking GRM4 to the proinflammatory IL23/IL12 axis.Significance:Few novel systemic therapies targeting osteosarcoma have emerged in the last four decades. Using insights gained from a genome-wide association study and mouse modeling, we show that GRM4 plays a role in driving osteosarcoma via a non–cell-autonomous mechanism regulating IL23, opening new avenues for therapeutic intervention.See related commentary by Jones, p. 1484.This article is highlighted in the In This Issue feature, p. 1469
Genetic Mosaicism in Calmodulinopathy
Authors: Wren Lisa M. , Jiménez-Jáimez Juan , Al-Ghamdi Saleh , Al-Aama Jumana Y. , Bdeir Amnah , Al-Hassnan Zuhair N. , Kuan Jyn L. , Foo Roger Y. , Potet Franck , Johnson Christopher N. , Aziz Miriam C. , Carvill Gemma L. , Kaski Juan-Pablo , Crotti Lia , Perin Francesca , Monserrat Lorenzo , Burridge Paul W. , Schwartz Peter J. , Chazin Walter J. , Bhuiyan Zahurul A. , George Alfred L. 
Published: September 2019

Background:
CaM (calmodulin) mutations are associated with congenital arrhythmia susceptibility (calmodulinopathy) and are most often de novo. In this report, we sought to broaden the genotype-phenotype spectrum of calmodulinopathies with 2 novel calmodulin mutations and to investigate mosaicism in 2 affected families.

Methods:
CaM mutations were identified in 4 independent cases by DNA sequencing. Biochemical and electrophysiological studies were performed to determine functional consequences of each mutation.

Results:

Genetic studies identified 2 novel CaM variants (
CALM3
-E141K in 2 cases;
CALM1
-E141V) and one previously reported CaM pathogenic variant (
CALM3
-D130G) among 4 probands with shared clinical features of prolonged QTc interval (range 505–725 ms) and documented ventricular arrhythmia. A fatal outcome occurred for 2 of the cases. The parents of all probands were asymptomatic with normal QTc duration. However, 2 of the families had multiple affected offspring or multiple occurrences of intrauterine fetal demise. The mother from the family with recurrent intrauterine fetal demise exhibited the
CALM3
-E141K mutant allele in 25% of next-generation sequencing reads indicating somatic mosaicism, whereas
CALM3
-D130G was present in 6% of captured molecules of the paternal DNA sample, also indicating mosaicism. Two novel mutations (E141K and E141V) impaired Ca
2+
binding affinity to the C-domain of CaM. Human-induced pluripotent stem cell-derived cardiomyocytes overexpressing mutant or wild-type CaM showed that both mutants impaired Ca
2+
-dependent inactivation of L-type Ca
2+
channels and prolonged action potential duration.

Conclusions:

We report 2 families with somatic mosaicism associated with arrhythmogenic calmodulinopathy, and demonstrate dysregulation of L-type Ca
2+
channels by 2 novel CaM mutations affecting the same residue. Parental mosaicism should be suspected in families with unexplained fetal arrhythmia or fetal demise combined with a documented CaM mutation.
Islamic Ecumenism in the Early Political Thought of Muḥammad Ḥusayn Faḍlallāh
Authors: Ali Nabil Hage 
Published: September 2019

AbstractBetween the late 1960s and early 1970s, political-economic turmoil led not only to the exodus of religious scholars and students from Iraq to Lebanon but also to the transnationalization of their activism. As they settled in Lebanon, these activists circulated key Islamist concepts that transcended religious factionalism. This article examines the early 1970s’ political thought of the Lebanese intellectual Muḥammad Ḥusayn Faḍlallāh (d. 2010), a prominent returning cleric from Iraq, intervening in discussions on the formative ideas of the Shiʿi Islamic movement in Lebanon. Furthermore, an analysis of concepts in Faḍlallāh’s works highlights a climate of intellectual openness and Islamic ecumenism. Linking the development of Faḍlallāh’s ecumenical thinking to the formation of overlapping spaces of activism in a context of secular-religious encounters in Iraq from the 1950s, this article also contributes to the scholarship that argues against the assumption that sectarianism, involving Sunni and Shiʿi Muslims, has existed since the onset of political discord in early Islam.
Examination of Nudging Schemes in the Simulation of Meteorology for Use in Air Quality Experiments: Application in the Great Lakes Region
Authors: Odman M. Talat , White Andrew T. , Doty Kevin , McNider Richard T. , Pour-Biazar Arastoo , Qin Momei , Hu Yongtao , Knipping Eladio , Wu Y. , Dornblaser Bright 
Published: September 2019

AbstractHigh levels of ozone have been observed along the shores of Lake Michigan for the last 40 years. Models continue to struggle in their ability to replicate ozone behavior in the region. In the retrospective way in which models are used in air quality regulation development, nudging or four-dimensional data assimilation (FDDA) of the large-scale environment is important for constraining model forecast errors. Here, paths for incorporating large-scale meteorological conditions but retaining model mesoscale structure are evaluated. For the July 2011 case studied here, iterative FDDA strategies did not improve mesoscale performance in the Great Lakes region in terms of diurnal trends or monthly averaged statistics, with overestimations of nighttime wind speed remaining as an issue. Two vertical nudging strategies were evaluated for their effects on the development of nocturnal low-level jets (LLJ) and their impacts on air quality simulations. Nudging only above the planetary boundary layer, which has been a standard option in many air quality simulations, significantly dampened the amplitude of LLJ relative to nudging only above a height of 2 km. While the LLJ was preserved with nudging only above 2 km, there was some deterioration in wind performance when compared with profiler networks above the jet between 500 m and 2 km. In examining the impact of nudging strategies on air quality performance of the Community Multiscale Air Quality model, it was found that performance was improved for the case of nudging above 2 km. This result may reflect the importance of the LLJ in transport or perhaps a change in mixing in the models.
The Horizontal Spectrum of Vertical Velocities near the Tropopause from Global to Gravity Wave Scales
Authors: Schumann Ulrich 
Published: September 2019

Abstract
Vertical motions are fundamental for atmospheric dynamics. Compared to horizontal motions, the horizontal spectrum of vertical velocity w is less well known. Here, w spectra are related to spectra of horizontal motions in the free atmosphere near the tropopause from global to gravity wave scales. At large scales, w is related to vertically averaged horizontal divergent motions by continuity. At small scales, the velocity energy spectra reach anisotropy as in stably stratified turbulence. Combining these limits approximates the w spectrum from global to small scales. The w spectrum is flat at large scales when the divergent spectrum shows a −2 slope, reaches a maximum at mesoscales after transition to −5/3 slopes, and then approaches a fraction of horizontal kinetic energy. The ratio of vertical kinetic energy to potential energy increases quadratically with wavenumber at large scales. It exceeds unity at small scales in stratified turbulence. Global and regional simulations and two recent aircraft measurement field campaigns support these relationships within 30% deviations. Energy exchange between horizontal and vertical motions may contribute to slope changes in the spectra. The model allows for checking measurement validity. Isotropy at large and small scales varies between the datasets. The fraction of divergent energy is 40%–70% in the measurements, with higher values in the stratosphere. Spectra above the tropopause are often steeper over mountains than over oceans, partly with two −5/3 subranges. A total of 80% of w variance near the tropopause occurs at scales between about 0.5 and 80 km.
Probabilistic Skill of Subseasonal Surface Temperature Forecasts over North America
Authors: Vigaud N. , Tippett M. K. , Yuan J. , Robertson A. W. , Acharya N. 
Published: September 2019

Abstract
The skill of surface temperature forecasts up to 4 weeks ahead is examined for weekly tercile category probabilities constructed using extended logistic regression (ELR) applied to three ensemble prediction systems (EPSs) from the Subseasonal-to-Seasonal (S2S) project (ECMWF, NCEP, and CMA), which are verified over the common period 1999–2010 and averaged with equal weighting to form a multimodel ensemble (MME). Over North America, the resulting forecasts are characterized by good reliability and varying degrees of sharpness. Skill decreases after two weeks and from winter to summer. Multimodel ensembling damps negative skill that is present in individual forecast systems, but overall, does not lead to substantial skill improvement compared to the best (ECMWF) model. Spatial pattern correction is implemented by projecting the ensemble mean temperatures neighboring each grid point onto Laplacian eigenfunctions, and then using those amplitudes as new predictors in the ELR. Forecasts and skill improve beyond week 2, when the ELR model is trained on spatially averaged temperature (i.e., the amplitude of the first Laplacian eigenfunction) rather than the gridpoint ensemble mean, but not at shorter leads. Forecasts are degraded when adding more Laplacian eigenfunctions that encode additional spatial details as predictors, likely due to the short reforecast sample size. Forecast skill variations with ENSO are limited, but MJO relationships are more pronounced, with the highest skill during MJO phase 3 up to week 3, coinciding with enhanced forecast probabilities of above-normal temperatures in winter.
A cautionary note: Toxicity of polyethylene glycol 200 injected intraperitoneally into mice
Authors: Thiele Wilko , Kyjacova Lenka , Köhler Almut , Sleeman Jonathan P 
Published: September 2019

The parenteral administration of hydrophobic substances in vivo requires the use of organic solvents to ensure sufficient solubility and avoid precipitation. Dimethyl sulfoxide is commonly used for this purpose. Based on the common assumption that polyethylene glycol (PEG) is non-toxic, our local regulatory authorities recently recommended the use of PEG instead. However, mice injected intraperitoneally (i.p.) with PEG 200 at a dose of 8 mL/kg (i.e. 9 g/kg) did not tolerate PEG 200 well, and half of the animals had to be euthanized. Our results demonstrate that although PEG 200 is generally considered to be harmless, it can be toxic when injected i.p. and is painful for the recipient mice. Nevertheless, it can be used as a solvent for repeated i.p. injections in mice at a dose of 2 mL/kg (i.e. 2.25 g/kg) without obvious signs of systemic toxicity.
Effects of ketamine in patients with treatment-refractory generalized anxiety and social anxiety disorders: Exploratory double-blind psychoactive-controlled replication study
Authors: Glue Paul , Neehoff Shona , Sabadel Amandine , Broughton Lucy , Le Nedelec Martin , Shadli Shabah , McNaughton Neil , Medlicott Natalie J 
Published: September 2019

Background: We previously reported that ketamine has anxiolytic effects in patients with treatment-resistant generalized anxiety and social anxiety disorders. Aims: The purpose of this study was to replicate our earlier report about ketamine‘s anxiolytic activity, using a more robust study design. Methods: This was a double-blind, psychoactive-controlled ascending dose study in 12 patients with treatment-resistant generalized anxiety and social anxiety disorders who were not currently depressed. Ascending doses of ketamine (0.25, 0.5, 1 mg/kg) were administered at weekly intervals, and midazolam 0.01 mg/kg, the control, was randomly inserted into the ketamine dose sequence. Assessments included ratings of anxiety and dissociation, safety and tolerability, and blood samples for ketamine pharmacokinetics and BDNF concentrations. Results: Improvements in anxiety ratings occurred within an hour of ketamine dosing, and persisted for up to 1 week. A dose-response profile was noted for anxiolytic effects, dissociative side effects, and changes in blood pressure and heart rate after ketamine dosing. Midazolam had minor brief effects on anxiety ratings. Ketamine was safe and well tolerated. Ketamine pharmacokinetics were correlated with dissociation ratings. Serum BDNF concentrations declined over time and were similar for all treatments. Conclusions: Ketamine may be a potential therapeutic option for patients with treatment-resistant generalized anxiety and social anxiety disorders.