bluuebunny/crossref_metadata_2025_split huggingface dataset:
Implementing Monte Carlo tests with p‐value buckets
Authors: Gandy Axel , Hahn Georg , Ding Dong 
Published: November 2019

AbstractSoftware packages usually report the results of statistical tests using p‐values. Users often interpret these values by comparing them with standard thresholds, for example, 0.1, 1, and 5%, which is sometimes reinforced by a star rating (***, **, and *, respectively). We consider an arbitrary statistical test whose p‐value p is not available explicitly, but can be approximated by Monte Carlo samples, for example, by bootstrap or permutation tests. The standard implementation of such tests usually draws a fixed number of samples to approximate p. However, the probability that the exact and the approximated p‐value lie on different sides of a threshold (the resampling risk) can be high, particularly for p‐values close to a threshold. We present a method to overcome this. We consider a finite set of user‐specified intervals that cover [0, 1] and that can be overlapping. We call these p‐value buckets. We present algorithms that, with arbitrarily high probability, return a p‐value bucket containing p. We prove that for both a bounded resampling risk and a finite runtime, overlapping buckets need to be employed, and that our methods both bound the resampling risk and guarantee a finite runtime for such overlapping buckets. To interpret decisions with overlapping buckets, we propose an extension of the star rating system. We demonstrate that our methods are suitable for use in standard software, including for low p‐value thresholds occurring in multiple testing settings, and that they can be computationally more efficient than standard implementations.
Neonatal care bundles are associated with a reduction in the incidence of intraventricular haemorrhage in preterm infants: a multicentre cohort study
Authors: de Bijl-Marcus Karen , Brouwer Annemieke Johanna , De Vries Linda S , Groenendaal Floris , Wezel-Meijler Gerda van 
Published: November 2019

ObjectiveTo investigate the effect of a nursing intervention bundle, applied during the first 72 hours of life, on the incidence of germinal matrix-intraventricular haemorrhage (GMH-IVH) in very preterm infants.DesignMulticentre cohort study.SettingTwo Dutch tertiary neonatal intensive care units.PatientsThe intervention group consisted of 281 neonates, whereas 280 infants served as historical controls (gestational age for both groups <30 weeks).InterventionsAfter a training period, the nursing intervention bundle was implemented and applied during the first 72 hours after birth. The bundle consisted of maintaining the head in the midline, tilting the head of the incubator and avoidance of flushing/rapid withdrawal of blood and sudden elevation of the legs.Main outcome measuresThe incidence of GMH-IVH occurring and/or increasing after the first ultrasound (but within 72 hours), cystic periventricular leukomalacia and/or in-hospital death was the primary composite outcome measure. Logistic regression analysis was used to explore differences between groups.ResultsThe nursing intervention bundle was associated with a lower risk of developing a GMH-IVH (any degree), cystic periventricular leukomalacia and/or mortality (adjusted OR 0.42, 95% CI 0.27 to 0.65). In the group receiving the bundle, also severe GMH-IVH, cystic periventricular leukomalacia and/or death were less often observed (adjusted OR 0.54, 95% CI 0.33 to 0.91).ConclusionsThe application of a bundle of nursing interventions is associated with reduced risk of developing a new/progressive (severe) GMH-IVH, cystic periventricular leukomalacia and/or mortality in very preterm infants when applied during the first 72 hours postnatally.
Adverse differences in cardiometabolic risk factor levels between individuals with pre-diabetes and normal glucose metabolism are more pronounced in women than in men: the Maastricht Study
Authors: de Ritter Rianneke , Sep Simone J S , van der Kallen Carla J H , Schram Miranda T , Koster Annemarie , Kroon Abraham A , van Greevenbroek Marleen M J , Eussen Simone J P M , Dagnelie Pieter C , de Jong Marit , Vos Rimke C , Woodward Mark , Bots Michiel L , Peters Sanne A E , Stehouwer Coen D A 
Published: November 2019

ObjectiveTo investigate whether adverse differences in levels of cardiovascular risk factors in women than men, already established when comparing individuals with and without diabetes, are also present before type 2 diabetes onset.Research design and methodsIn a population-based cohort study of individuals aged 40-75 years (n=3410; 49% women, 29% type 2 diabetes (oversampled by design)), we estimated associations with cardiometabolic and lifestyle risk factors of (1) pre-diabetes and type 2 diabetes (reference category: normal glucose metabolism) and (2) among non-diabetic individuals, of continuous levels of hemoglobin A1c (HbA1c). Age-adjusted sex differences were analyzed using linear and logistic regression models with sex interaction terms.ResultsIn pre-diabetes, adverse differences in cardiometabolic risk factors were greater in women than men for systolic blood pressure (difference, 3.02 mm Hg; 95% CI:−0.26 to 6.30), high-density lipoprotein (HDL) cholesterol (difference, −0.10 mmol/L; 95% CI: −0.18 to −0.02), total-to-HDL cholesterol ratio (difference, 0.22; 95% CI: −0.01 to 0.44), triglycerides (ratio: 1.11; 95% CI: 1.01 to 1.22), and inflammation markers Z-score (ratio: 1.18; 95% CI: 0.98 to 1.41). In type 2 diabetes, these sex differences were similar in direction, and of greater magnitude. Additionally, HbA1c among non-diabetic individuals was more strongly associated with several cardiometabolic risk factors in women than men: per one per cent point increase, systolic blood pressure (difference, 3.58 mm Hg; 95% CI: −0.03 to 7.19), diastolic blood pressure (difference, 2.10 mm Hg; 95% CI: −0.02 to 4.23), HDL cholesterol (difference, −0.09 mmol/L; 95% CI: −0.19 to 0.00), and low-density lipoprotein cholesterol (difference, 0.26 mmol/L; 95% CI: 0.05 to 0.47). With regard to lifestyle risk factors, no consistent pattern was observed.ConclusionOur results are consistent with the concept that the more adverse changes in cardiometabolic risk factors in women (than men) arise as a continuous process before the onset of type 2 diabetes.
Paramedics and serious illness: communication training
Authors: Pease Nikki Jane , Sundararaj Jenifer Jeba , O'Brian Edward , Hayes Joanne , Presswood Edward , Buxton Samantha 
Published: November 2019

ObjectivesThe need to empower Ambulance Service staff at the point of delivery of end of life care (EoLC) is crucial. We describe the delivery, outcomes and potential impact of the Serious Illness Conversation project delivered to Welsh Ambulance Service Trust (WAST) staff. Over an 18-month period, 368 WAST staff attended face-to-face teaching, which included serious illness conversation communication skills, symptom control and ‘shared decision making’.MethodData collected from WAST staff were used to gain insight on perception of their role and challenges within the context of EoLC, understand the impact of teaching on self-confidence and identify impact on the wider service. A mixed methods approach was used for data analysis.ResultsWAST staff view themselves in several important roles, acting as ‘facilitators’ to patient-centred, seamless care, providing support, liaison between services and practical help in patient care at the end of life. The difficult questions and situations pertaining to EoLC were related to discussions on death and dying and managing expectation. The predominant barriers identified related to communication. Quantitative outcomes on the six communication domains indicate statistically significant improvement in self-assessed confidence. The overall impact to the wider ambulance service suggests a trend towards better use of resources.ConclusionThe perceived roles and challenges identified by paramedics can help in customising training objectives. The initial outcomes from the ongoing project with WAST demonstrate increased confidence in handling communication issues. Initial successive surveys suggest teaching is making a real life impact on patient care at end of life.
Distributed Edge Coloring and a Special Case of the Constructive Lovász Local Lemma
Authors: Chang Yi-Jun , He Qizheng , Li Wenzheng , Pettie Seth , Uitto Jara 
Published: November 2019

The complexity of distributed edge coloring depends heavily on the
palette size
as a function of the maximum degree Δ. In this article, we explore the complexity of edge coloring in the LOCAL model in different palette size regimes. Our results are as follows.

Lower Bounds:
First, we simplify the
round elimination
technique of Brandt et al. [16] and prove that (2Δ −2)-edge coloring requires Ω (log
Δ
log
n
) time with high probability and Ω (log
Δ
n
) time deterministically,
even on trees
. Second, we show that a natural approach to computing (Δ +1)-edge colorings (Vizing’s theorem), namely, extending an arbitrary partial coloring by iteratively recoloring subgraphs, requires Ω (Δ log
n
) time.

Upper Bounds on General Graphs:
We give a randomized edge coloring algorithm that can use palette sizes as small as Δ + Õ(√Δ), which is a natural barrier for randomized approaches. The running time of our (1+ϵ)Δ-edge coloring algorithm is usually dominated by
O
(\log ϵ
−1
) calls to a distributed Lovász local lemma (LLL) algorithm. For example, using the Chung-Pettie-Su LLL algorithm, we compute a (1+ϵ)Δ-edge coloring in
O
(log
n
) time when ϵ ≥ (log
3
Δ) / √ Δ , or
O
(log
Δ
n
) + (log log
n
)

3 +
o
(1)

time when ϵ = Ω (1). When Δ is sublogarithmic in
n
the performance is improved with the Ghaffari-Harris-Kuhn LLL algorithm.

Upper Bounds on Trees:
We show that the Ω (log
Δ
log
n
) lower bound can be nearly matched on trees. To establish this result, we develop a new distributed Lovász local lemma algorithm for
tree-structured dependency graphs
, which arise naturally from
O
(1)-round probabilistic algorithms run on trees. Specifically, our (1+ϵ)Δ-edge coloring algorithm for trees takes
O
(log (1 / ϵ)) ⋅ max { log log
n
\ log log log
n
, log
log Δ
log
n
} time when ϵ ≥ (log
3
Δ) / √ Δ, or
O
(max { log log
n
\ log log log
n
, log
Δ
log
n
}) time when ϵ = Ω (1).
Clinical Evolution of Epithelial–Mesenchymal Transition in Human Carcinomas
Authors: Navas Tony , Kinders Robert J. , Lawrence Scott M. , Ferry-Galow Katherine V. , Borgel Suzanne , Hollingshead Melinda G. , Srivastava Apurva K. , Alcoser Sergio Y. , Makhlouf Hala R. , Chuaqui Rodrigo , Wilsker Deborah F. , Konaté Mariam M. , Miller Sarah B. , Voth Andrea Regier , Chen Li , Vilimas Tomas , Subramanian Jyothi , Rubinstein Lawrence , Kummar Shivaani , Chen Alice P. , Bottaro Donald P. , Doroshow James H. , Parchment Ralph E. 
Published: November 2019

Abstract

The significance of the phenotypic plasticity afforded by epithelial–mesenchymal transition (EMT) for cancer progression and drug resistance remains to be fully elucidated in the clinic. We evaluated epithelial–mesenchymal phenotypic characteristics across a range of tumor histologies using a validated, high-resolution digital microscopic immunofluorescence assay (IFA) that incorporates β-catenin detection and cellular morphology to delineate carcinoma cells from stromal fibroblasts and that quantitates the individual and colocalized expression of the epithelial marker E-cadherin (E) and the mesenchymal marker vimentin (V) at subcellular resolution (“EMT-IFA”). We report the discovery of β-catenin+ cancer cells that coexpress E-cadherin and vimentin in core-needle biopsies from patients with various advanced metastatic carcinomas, wherein these cells are transitioning between strongly epithelial and strongly mesenchymal-like phenotypes. Treatment of carcinoma models with anticancer drugs that differ in their mechanism of action (the tyrosine kinase inhibitor pazopanib in MKN45 gastric carcinoma xenografts and the combination of tubulin-targeting agent paclitaxel with the BCR-ABL inhibitor nilotinib in MDA-MB-468 breast cancer xenografts) caused changes in the tumor epithelial–mesenchymal character. Moreover, the appearance of partial EMT or mesenchymal-like carcinoma cells in MDA-MB-468 tumors treated with the paclitaxel–nilotinib combination resulted in upregulation of cancer stem cell (CSC) markers and susceptibility to FAK inhibitor. A metastatic prostate cancer patient treated with the PARP inhibitor talazoparib exhibited similar CSC marker upregulation. Therefore, the phenotypic plasticity conferred on carcinoma cells by EMT allows for rapid adaptation to cytotoxic or molecularly targeted therapy and could create a form of acquired drug resistance that is transient in nature.

Significance:
Despite the role of EMT in metastasis and drug resistance, no standardized assessment of EMT phenotypic heterogeneity in human carcinomas exists; the EMT-IFA allows for clinical monitoring of tumor adaptation to therapy.
A Small-Molecule Inhibitor Targeting TRIP13 Suppresses Multiple Myeloma Progression
Authors: Wang Yingcong , Huang Jing , Li Bo , Xue Han , Tricot Guido , Hu Liangning , Xu Zhijian , Sun Xiaoxiang , Chang Shuaikang , Gao Lu , Tao Yi , Xu Hongwei , Xie Yongsheng , Xiao Wenqin , Yu Dandan , Kong Yuanyuan , Chen Gege , Sun Xi , Lian Fulin , Zhang Naixia , Wu Xiaosong , Mao Zhiyong , Zhan Fenghuang , Zhu Weiliang , Shi Jumei 
Published: November 2019

AbstractThe AAA-ATPase TRIP13 drives multiple myeloma progression. Here, we present the crystal structure of wild-type human TRIP13 at a resolution of 2.6 Å. A small-molecule inhibitor targeting TRIP13 was identified on the basis of the crystal structure. The inhibitor, designated DCZ0415, was confirmed to bind TRIP13 using pull-down, nuclear magnetic resonance spectroscopy, and surface plasmon resonance–binding assays. DCZ0415 induced antimyeloma activity in vitro, in vivo, and in primary cells derived from drug-resistant patients with myeloma. The inhibitor impaired nonhomologous end joining repair and inhibited NF-κB activity. Moreover, combining DCZ0415 with the multiple myeloma chemotherapeutic melphalan or the HDAC inhibitor panobinostat induced synergistic antimyeloma activity. Therefore, targeting TRIP13 may be an effective therapeutic strategy for multiple myeloma, particularly refractory or relapsed multiple myeloma.Significance:These findings identify TRIP13 as a potentially new therapeutic target in multiple myeloma.
Exploitation of CD133 for the Targeted Imaging of Lethal Prostate Cancer
Authors: Glumac Paige M. , Gallant Joseph P. , Shapovalova Mariya , Li Yingming , Murugan Paari , Gupta Shilpa , Coleman Ilsa M. , Nelson Peter S. , Dehm Scott M. , LeBeau Aaron M. 
Published: November 2019

Abstract

Purpose:
Aggressive variant prostate cancer (AVPC) is a nonandrogen receptor–driven form of disease that arises in men in whom standard-of-care therapies have failed. Therapeutic options for AVPC are limited, and the development of novel therapeutics is significantly hindered by the inability to accurately quantify patient response to therapy by imaging. Imaging modalities that accurately and sensitively detect the bone and visceral metastases associated with AVPC do not exist.

Experimental Design:
This study investigated the transmembrane protein CD133 as a targetable cell surface antigen in AVPC. We evaluated the expression of CD133 by microarray and IHC analysis. The imaging potential of the CD133-targeted IgG (HA10 IgG) was evaluated in preclinical prostate cancer models using two different imaging modalities: near-infrared and PET imaging.

Results:
Evaluation of the patient data demonstrated that CD133 is overexpressed in a specific phenotype of AVPC that is androgen receptor indifferent and neuroendocrine differentiated. In addition, HA10 IgG was selective for CD133-expressing tumors in all preclinical imaging studies. PET imaging with [89Zr]Zr-HA10 IgG revealed a mean %ID/g of 24.30 ± 3.19 in CD133-positive metastatic lesions as compared with 11.82 ± 0.57 in CD133-negative lesions after 72 hours (P = 0.0069). Ex vivo biodistribution showed similar trends as signals were increased by nearly 3-fold in CD133-positive tumors (P &lt; 0.0001).

Conclusions:
To our knowledge, this is the first study to define CD133 as a targetable marker of AVPC. Similarly, we have developed a novel imaging agent, which is selective for CD133-expressing tumors, resulting in a noninvasive PET imaging approach to more effectively detect and monitor AVPC.
The YAP1 Signaling Inhibitors, Verteporfin and CA3, Suppress the Mesothelioma Cancer Stem Cell Phenotype
Authors: Kandasamy Sivaveera , Adhikary Gautam , Rorke Ellen A. , Friedberg Joseph S. , Mickle McKayla B. , Alexander H. Richard , Eckert Richard L. 
Published: November 2019

Abstract

Mesothelioma is an aggressive cancer that has a poor prognosis. Tumors develop in the mesothelial lining of the pleural and peritoneal cavities in response to asbestos exposure. Surgical debulking followed by chemotherapy is initially effective, but this treatment ultimately selects for resistant cells that form aggressive and therapy-resistant recurrent tumors. Mesothelioma cancer stem cells (MCS) are a highly aggressive subpopulation present in these tumors that are responsible for tumor maintenance and drug resistance. In this article, we examine the impact of targeting YAP1/TAZ/TEAD signaling in MCS cells. YAP1, TAZ, and TEADs are transcriptional mediators of the Hippo signaling cascade that activate gene expression to drive tumor formation. We show that two YAP1 signaling inhibitors, verteporfin and CA3, attenuate the MCS cell phenotype. Verteporfin or CA3 treatment reduces YAP1/TEAD level/activity to suppress MCS cell spheroid formation, Matrigel invasion, migration, and tumor formation. These agents also increase MCS cell apoptosis. Moreover, constitutively active YAP1 expression antagonizes inhibitor action, suggesting that loss of YAP1/TAZ/TEAD signaling is required for response to verteporfin and CA3. These agents are active against mesothelioma cells derived from peritoneal (epithelioid) and patient-derived pleural (sarcomatoid) mesothelioma, suggesting that targeting YAP1/TEAD signaling may be a useful treatment strategy.

Implications:
These studies suggest that inhibition of YAP1 signaling may be a viable approach to treating mesothelioma.
CRISPR-Mediated Activation of Endogenous Gene Expression in the Postnatal Heart
Authors: Schoger Eric , Carroll Kelli J. , Iyer Lavanya M. , McAnally John R. , Tan Wei , Liu Ning , Noack Claudia , Shomroni Orr , Salinas Gabriela , Groß Julia , Herzog Nicole , Doroudgar Shirin , Bassel-Duby Rhonda , Zimmermann Wolfram-H. , Zelarayán Laura C. 
Published: November 2019

Rationale:
Genome editing by CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 is evolving rapidly. Recently, second-generation CRISPR/Cas9 activation systems based on nuclease inactive dead (d)Cas9 fused to transcriptional transactivation domains were developed for directing specific guide (g)RNAs to regulatory regions of any gene of interest, to enhance transcription. The application of dCas9 to activate cardiomyocyte transcription in targeted genomic loci in vivo has not been demonstrated so far.

Objective:

We aimed to develop a mouse model for cardiomyocyte-specific, CRISPR-mediated transcriptional modulation, and to demonstrate its versatility by targeting
Mef2d
and
Klf15
loci (2 well-characterized genes implicated in cardiac hypertrophy and homeostasis) for enhanced transcription.

Methods and Results:

A mouse model expressing dCas9 with the VPR transcriptional transactivation domains under the control of the
Myh
(myosin heavy chain) 6 promoter was generated. These mice innocuously expressed dCas9 exclusively in cardiomyocytes. For initial proof-of-concept, we selected
Mef2d
, which when overexpressed, led to hypertrophy and heart failure, and
Klf15
, which is lowly expressed in the neonatal heart. The most effective gRNAs were first identified in fibroblast (C3H/10T1/2) and myoblast (C2C12) cell lines. Using an improved triple gRNA expression system (TRISPR [triple gRNA expression construct]), up to 3 different gRNAs were transduced simultaneously to identify optimal conditions for transcriptional activation. For in vivo delivery of the validated gRNA combinations, we employed systemic administration via adeno-associated virus serotype 9. On gRNA delivery targeting
Mef2d
expression, we recapitulated the anticipated cardiac hypertrophy phenotype. Using gRNA targeting
Klf15
, we could enhance its transcription significantly, although
Klf15
is physiologically silenced at that time point. We further confirmed specific and robust dCas9VPR on-target effects.

Conclusions:
The developed mouse model permits enhancement of gene expression by using endogenous regulatory genomic elements. Proof-of-concept in 2 independent genomic loci suggests versatile applications in controlling transcription in cardiomyocytes of the postnatal heart.
Long‐Term Outcome of Additional Superior Vena Cava to Septal Linear Ablation in Catheter Ablation of Atrial Fibrillation
Authors: Jin Moo‐Nyun , Lim Byounghyun , Yu Hee Tae , Kim Tae‐Hoon , Uhm Jae‐Sun , Joung Boyoung , Lee Moon‐Hyoung , Hwang Chun , Pak Hui‐Nam 
Published: November 2019

Background

We previously reported the benefit of linear ablation from the superior vena cava to the right atrial septum (
SVC
‐L) within a year after circumferential pulmonary vein isolation (
CPVI
) in patients with paroxysmal atrial fibrillation (
AF
). We explored the long‐term effects of
SVC
‐L and its potential related mechanisms.

Methods and Results

Among 2140 consecutive patients with
AF
ablation, we included 614 patients (73.3% male, aged 57.8±10.7 years, 13.7% with persistent
AF
) who did not undergo an extra–pulmonary vein left atrial ablation after propensity score matching; of those, 307 had additional
SVC
‐L and 307 had
CPVI
alone. We evaluated the heart rate variability and computational modeling study to explore mechanisms. Although the procedure time was longer in the
SVC
‐L group than the
CPVI
group (
P
<0.001), the complication rates did not differ (
P
=0.560). During 40.5±24.4 months of follow‐up, the rhythm outcome was significantly better in the
SVC
‐L group than the
CPVI
group (log rank,
P
<0.001). At 2‐year follow‐up of heart rate variability, a significantly higher mean heart rate (
P
=0.018) and a lower ratio of low/high‐frequency components (
P
=0.011) were found with
SVC
‐L than
CPVI
alone. In realistic in silico biatrial modeling, which reflected the electroanatomies of 10 patients,
SVC
‐L significantly reduced biatrial dominant frequency compared with
CPVI
alone (
P
<0.001) and increased
AF
termination and defragmentation rates (
P
=0.033).

Conclusions

SVC
‐L ablation in addition to
CPVI
significantly improved the long‐term rhythm outcome over 2 years after
AF
catheter ablation by mechanisms involving autonomic modulation and
AF
organization.
‘Every Frenchman Must Read This Book’: The Impact of Politics and Ideology on the Production, Translation and Dissemination of Hitler’s Mein Kampf in France, 1933-1939
Authors: Brouwer Aron 
Published: November 2019

Abstract
This article examines the political and ideological circumstances surrounding the two French translations of Adolf Hitler’s Mein Kampf during the 1930s. It focuses on the personal histories of the translation agents involved in the production, translation and dissemination of Mein Kampf—such as diplomats, politicians, investors, publishers, editors and translators. By uncovering and exposing their ideological attitudes, this study shows how Hitler’s book was altered, censored and repurposed in France to suit different political agendas. Consequently, it argues that the two French translations during the prewar period, entitled Mon Combat (1934) and Ma Doctrine (1938), should be regarded as historical artifacts in their own right, rather than mere reproductions.