bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intravenous immunoglobulin therapy in adult patients with idiopathic chronic cardiomyopathy and cardiac parvovirus B19 persistence: a prospective, double‐blind, randomized, placebo‐controlled clinical trial
Authors: Hazebroek Mark R. , Henkens Michiel T.H.M. , Raafs Anne G. , Verdonschot Job A.J. , Merken Jort J. , Dennert Robert M. , Eurlings Casper , Abdul Hamid Myrurgia A. , Wolffs Petra F.G. , Winkens Bjorn , Brunner‐La Rocca Hans‐Peter , Knackstedt Christian , van Paassen Pieter , van Empel Vanessa P.M. , Heymans Stephane R.B. 
Published: December 2020

AimsPrevious uncontrolled studies suggested a possible benefit of intravenous immunoglobulin (IVIg) in parvovirus B19 (B19V)‐related dilated cardiomyopathy (DCM). This randomized, double‐blind, placebo‐controlled, single‐centre trial investigated the benefits of IVIg beyond conventional therapy in idiopathic chronic DCM patients with B19V persistence.Methods and resultsFifty patients (39 men; mean age 54 ± 11 years) with idiopathic chronic (>6 months) DCM on optimal medical therapy, left ventricular ejection fraction (LVEF) <45%, and endomyocardial biopsy (EMB) B19V load of >200 copies/µg DNA were blindly randomized to either IVIg (n = 26, 2 g/kg over 4 days) or placebo (n = 24). The primary outcome was change in LVEF at 6 months after randomization. Secondary outcomes were change in functional capacity assessed by 6‐min walk test (6MWT), quality of life [Minnesota Living with Heart Failure Questionnaire (MLHFQ)], left ventricular end‐diastolic volume (LVEDV), and EMB B19V load at 6 months after randomization. LVEF significantly improved in both IVIg and placebo groups (absolute mean increase 5 ± 9%, P = 0.011 and 6 ± 10%, P = 0.008, respectively), without a significant difference between groups (P = 0.609). Additionally, change in 6MWT [median (interquartile range) IVIg 36 (13;82) vs. placebo 32 (5;80) m; P = 0.573], MLHFQ [IVIg 0 (−7;5) vs. placebo −2 (−6;6), P = 0.904] and LVEDV (IVIg −16 ± 49 mL/m2 vs. placebo −29 ± 40 mL/m2; P = 0.334) did not significantly differ between groups. Moreover, despite increased circulating B19V antibodies upon IVIg administration, reduction in cardiac B19V did not significantly differ between groups.ConclusionIntravenous immunoglobulin therapy does not significantly improve cardiac systolic function or functional capacity beyond standard medical therapy in patients with idiopathic chronic DCM and cardiac B19V persistence.Clinical Trial Registration: ClinicalTrials.gov ID NCT00892112.
Mismatch repair protein loss in cutaneous head and neck squamous cell carcinoma
Authors: Vasan Kartik , Anand Sunaina , Satgunaseelan Laveniya , Asher Rebecca , Low Hubert , Palme Carsten E. , Lee Jenny H. , Clark Jonathan R. , Gupta Ruta 
Published: December 2020

AbstractBackgroundThe treatment of advanced cutaneous head and neck cutaneous squamous cell carcinomas (HNcSCC) results in significant morbidity. Recently, immune checkpoint inhibitor treatment has been approved for DNA mismatch repair (MMR) deficient patients in a histology‐agnostic manner. This study aims to evaluate the incidence of MMR deficiency in advanced HNcSCC and its association with clinicopathologic factors.MethodsThe cohort included 176 consecutive HNcSCC cases treated with curative intent. Immunohistochemistry for MMR proteins (hMLH1, hMSH2, hMSH6, and hPMS2) was performed. Clinicopathological and survival data was collected prospectively.ResultsThe incidence of MMR protein deficiency was 9.1%. There was no association between age, incidence of metachronous malignancies, clinicopathological factors, or survival outcomes.ConclusionA higher incidence of MMR deficiency was observed in this cohort of advanced HNcSCC. The lack of association with young age at onset or increased incidence of metachronous malignancies suggests that MMR deficiency is likely to be sporadic in HNcSCC.
Levodopa–carbidopa intrajejunal infusion in Parkinson’s disease: untangling the role of age
Authors: Morgante Francesca , Oppo Valentina , Fabbri Margherita , Olivola Enrica , Sorbera Chiara , De Micco Rosa , Ielo Giovanna Chiara , Colucci Fabiana , Bonvegna Salvatore , Novelli Alessio , Modugno Nicola , Sensi Mariachiara , Zibetti Maurizio , Lopiano Leonardo , Tessitore Alessandro , Pilleri Manuela , Cilia Roberto , Elia Antonio E. , Eleopra Roberto , Ricciardi Lucia , Cossu Giovanni 
Published: December 2020

Abstract
Objectives
Levodopa–Carbidopa Intrajejunal gel (LCIG) infusion is an effective intervention for people with advanced Parkinson’s disease (PD). Although age may not be a limiting factor for LCIG implant, no data are available on late elderly PD (LE-PD) subjects. In this cross-sectional, we aimed to demonstrate if older age may impact on quality of life (QoL), motor and non-motor symptoms severity, and profile of side effects in PD treated with LCIG.

Methods
Out of 512 PD subjects treated with LCIG at 9 Italian PD centers, we selected 25 LE-PD defined as age ≥ 80 years at last follow-up who were available to attend the study visit. Twenty-five PD patients (Control-PD, defined as age < 75 years at last follow-up) matched to LE-PD by disease and LCIG duration served as control group. The following motor and non-motor variables were ascertained: quality of life (PDQ-8), time spent in ON, wearing-off Questionnaire, Unified PD Rating Scale, freezing of gait questionnaire, Parkinson’s disease sleep scale-2, Non Motor Symptoms Scale (NMSS), and MOCA.

Results
No statistically significant differences were found between LE-PD and Control-PD on PDQ-8 and several motor and non-motor variables. LE-PD had less frequent and milder impulsive–compulsive behaviors and milder dyskinesia. At multivariable regression, worse quality of life was associated with UPDRS-III and NMSS scores but not to age at study visit and age at LICG implant. Rate of adverse effects was similar in both groups. Drop-out rate calculated in the whole PD cohort was comparable between the two groups.

Conclusion
Our data provide evidence that valuable LCIG infusion might be achieved in late elderly PD.
Statistics of Nascent and Mature RNA Fluctuations in a Stochastic Model of Transcriptional Initiation, Elongation, Pausing, and Termination
Authors: Filatova Tatiana , Popovic Nikola , Grima Ramon 
Published: December 2020

AbstractRecent advances in fluorescence microscopy have made it possible to measure the fluctuations of nascent (actively transcribed) RNA. These closely reflect transcription kinetics, as opposed to conventional measurements of mature (cellular) RNA, whose kinetics is affected by additional processes downstream of transcription. Here, we formulate a stochastic model which describes promoter switching, initiation, elongation, premature detachment, pausing, and termination while being analytically tractable. We derive exact closed-form expressions for the mean and variance of nascent RNA fluctuations on gene segments, as well as of total nascent RNA on a gene. We also obtain exact expressions for the first two moments of mature RNA fluctuations and approximate distributions for total numbers of nascent and mature RNA. Our results, which are verified by stochastic simulation, uncover the explicit dependence of the statistics of both types of RNA on transcriptional parameters and potentially provide a means to estimate parameter values from experimental data.
Harnessing Local and Transnational Communities in the Global Protection of Underwater Cultural Heritage
Authors: Martin Josh B. 
Published: December 2020

Abstract‘Communities’ – whether local, regional, or transnational – can provide an essential force in the protection of our global underwater cultural heritage (UCH). As an issue of low political concern, with its protection vulnerable to externalities and compliance weaknesses, UCH forms an ideal test case for exploring governance solutions without reliance on the state. It is also an area where communities are increasingly integrated within governance models. This article examines the theoretical justification for reducing reliance on top-down laws to protect natural and cultural heritage, exploring Ostromian arguments for greater community self- and co-regulation. Using this theoretical framework, it highlights numerous advantages of community-oriented governance in the management of a complex global concern, such as UCH protection, and underscores the role and importance of the appropriate design of meta-regulation in steering communities towards wider public objectives. The article also identifies where communities or ‘networks’ have provided important additional protection for UCH, and discusses further policy mechanisms – such as community buy-in, incentivization, and self-regulation – which could help to facilitate community-led governance in the future.
On the rise of discourse markers
Authors: Heine Bernd , Kaltenböck Gunther , Kuteva Tania , Long Haiping 
Published: December 2020

Abstract
Discourse markers exhibit a range of grammatical
properties that set them apart from many other lexical and
grammatical forms. A number of hypotheses have been proposed to
account for these properties. Most commonly, such accounts have
drawn on grammaticalization theory, less commonly also on the notion
of pragmaticalization. As argued in this paper, however, the rise of
discourse markers cannot be described exhaustively in terms of
parameters of grammaticalization or pragmaticalization. Looking at
the rise of two English and one French discourse marker, the paper
argues that this development is also shaped by a general strategy of
discourse processing called cooptation, which accounts for
properties of discourse markers that are beyond the scope of
grammaticalization theory. Thus, discourse markers are described
best as grammaticalized (paren)theticals.
On divergent paths and functions of ‘background’-based discourse
markers in Korean
Authors: Rhee Seongha , Koo Hyun Jung 
Published: December 2020

Abstract
This paper analyzes two polyfunctional discourse
markers (DMs) in Korean, kulssey and
kuntey, which share lexical and grammatical
sources, with the meaning of ‘at the time’ for
kulssey and ‘at the place’ for
kuntey. They denote the background of an
action/event (‘in such circumstances’), which is their primary
meaning when used as connective adverbs. Despite these source
commonalities, when they developed into DMs, their functional
differences are pronounced, only with a few shared functions. They
show a certain degree of positional preferences by function, but at
a more comprehensive level, left- and right-periphery do not show
rigid functional dichotomy with respect to subjectification and
intersubjectification, often hypothesized in the literature.
Instead, the role of prosody is more crucial.
On pragma-semantics of expressives
Authors: Zolyan Suren 
Published: December 2020

Abstract
Expressives can be understood as: (1) a
manifestation of speaker’s emotional or affective attitudes; (2) a
peculiar type of performatives; (3) a linguistic entity expressing
or displaying what is the case. The third conception is taken as the
basic one; we attempt to develop it, taking into account Bühler’s
representational theory of language and the theory of performatives
(Austin, Searle). Expressives are closely connected with behavioral
patterns, situations, and actions. An actualization of verbal
behavior (a performative component of expressives) meets its
counterpart in the verbalization of action (a descriptive
component). We suggest to describe pragma-semantics of expressives
as based on prototypical behavioural frames.
A just amazing marker in French: “Juste”
Authors: Do-Hurinville Danh-Thành 
Published: December 2020

Abstract

Juste belongs to those words (justement,
limite, grave, côté, question, niveau…) that today one
cannot do without, both in everyday conversation and in the media!
After pointing out that juste, from the Latin
justus, is a transcategorial unit par
excellence, as it can be an adjective, a noun, or an adverb, this
article deals with its recent adverbial use, identified orally in
the early 2000s, officially registered in Le Petit Robert de
la Langue Française in 2014. I propose that
juste is a metalinguistic marker which creates
double modalisation: it has scope both over an element X which can
be an extreme (non-gradable) adjective, a non-gradable noun phrase
(verb phrase or prepositional phrase), and over the utterance act.
This recent adverbial use of juste is analysed in
the following configurations: (1) juste and extreme
adjectives (extreme adjectives formed by the suffix
-issime, and extreme adjectives formed by the
private prefix -in); (2) juste and
non-gradable sequences [pas + gradable adjectives];
(3) juste and two non-gradable sequences
([très / trop + gradable
adjectives]; [super / hyper / ultra / supra / mega /
giga + gradable adjectives]); (4)
juste and non-gradable [noun / verb /
prepositional] phrases.
Folding Stability of Pax9 Intronic G-Quadruplex Correlates with Relative Molar Size in Eutherians
Authors: Jara-Espejo Manuel , Hawkins Melissa T R , Fogalli Giovani Bressan , Line Sergio Roberto Peres 
Published: December 2020

AbstractEutherian dentition has been the focus of a great deal of studies in the areas of evolution, development, and genomics. The development of molar teeth is regulated by an antero-to-posterior cascade mechanism of activators and inhibitors molecules, where the relative sizes of the second (M2) and third (M3) molars are dependent of the inhibitory influence of the first molar (M1). Higher activator/inhibitor ratios will result in higher M2/M1 or M3/M1. Pax9 has been shown to play a key role in tooth development. We have previously shown that a G-quadruplex in the first intron of Pax9 can modulate the splicing efficiency. Using a sliding window approach with we analyzed the association of the folding energy (Mfe) of the Pax9 first intron with the relative molar sizes in 42 mammalian species, representing 9 orders. The Mfe of two regions located in the first intron of Pax9 were shown to be significantly associated with the M2/M1 and M3/M1 areas and mesiodistal lengths. The first region is located at the intron beginning and can fold into a stable G4 structure, whereas the second is downstream the G4 and 265 bp from intron start. Across species, the first intron of Pax9 varied in G-quadruplex structural stability. The correlations were further increased when the Mfe of the two sequences were added. Our results indicate that this region has a role in the evolution of the mammalian dental pattern by influencing the relative size of the molars.
Placebo Surgery Controlled Trials
Authors: Bunzli Samantha , Choong Emma , Shadbolt Cade , Wall Laura , Nelson Elizabeth , Schilling Chris , Wilding Helen , Lohmander L. Stefan , Balogh Zsolt J. , Paolucci Francesco , Clarke Philip , Choong Peter F. M. , Dowsey Michelle M. 
Published: December 2020

Objective:
To explore whether placebo surgery controlled trials achieve what they set out to do by investigating discrepancy between projected and actual design aspects of trials identified through systematic review methods.

Summary Background:
Interest in placebo surgery controlled trials is growing in response to concerns regarding unnecessary surgery and the societal cost of low-value healthcare. As questions about the justifiability of using placebo controls in surgery have been addressed, attention is now being paid to more practical concerns.

Methods:
Six databases were searched from inception - May 2020 (MEDLINE, Embase, Emcare, APA PsycInfo, CINAHL, Cochrane Library). Placebo surgery controlled trials with a published protocol were included. Three authors extracted “projected” design aspects from protocols and “actual” design aspects from main findings papers. Absolute and relative difference between projected and actual design aspects were presented for each trial. Trials were grouped according to whether they met their target sample size (“completed”) and were concluded in a timely fashion. Pairs of authors assessed risk of bias.

Results:
Of 24 trials with data available to analyse; 3 were completed and concluded within target timeframe; 10 were completed and concluded outside the target timeline; 4 were completed without clear target timeframes; 2 were incomplete and concluded within the target framework; 5 were incomplete and concluded outside the target timeline. Trials which reached the recruitment target underestimated trial duration by 88% and number of recruitment sites by 87%.

Conclusions:
Trialists need to factor additional time and sites into future placebo surgery controlled trials. A robust reporting framework of projected and actual trial design is imperative for trialists to learn from their predecessors.

Review Registration:
PROSPERO (CRD42019133296)
Influence of clinical characteristics and anti-cancer therapy on outcomes from SARS-CoV-2 infection: a systematic review and meta-analysis of 5,678 cancer patients
Authors: Chin Ik Shin , Galavotti Sara , Yip Kay Por , Curley Helen , Arnold Roland , Sharma-Oates Archana , Chegwidden Laura , Lee Siang Ing , Lee Lennard YW , Pinato David J. , Dettorre Gino M. , Palles Claire 
Published: December 2020

Abstract

Background
The COVID-19 pandemic started a healthcare crisis and heavily impacted cancer services.

Methods
Data from cohort studies of COVID-19 cancer patients published up until October 23rd 2020 from PubMed, PubMed Central, medRxiv and Google Scholar were reviewed. Meta-analyses using the random effects model was performed to assess the risk of death in cancer patients with COVID-19.

Results
Our meta-analyses including up to 5,678 patients from 13 studies showed that the following were all statistically significant risk factors for death following SARS-CoV-2 infection in cancer patients: age of 65 and above, presence of co-morbidities, cardiovascular disease, chronic lung disease, diabetes and hypertension. There was no evidence that patients who had received cancer treatment within 60 days of their COVID-19 diagnosis were at a higher risk of death, including patients who had recent chemotherapy.

Conclusions
Cancer patients are susceptible to severe COVID-19, especially older patients and patients with co-morbidities who will require close monitoring. Our findings support the continued administration of anti-cancer therapy during the pandemic. The analysis of chemotherapy was powered at 70% to detect an effect size of 1.2 but all other anti-cancer treatments had lower power. Further studies are required to better estimate their impact on the outcome of cancer patients.
Exploring test retest reliability and longitudinal stability of digital biomarkers for Parkinson’s disease in the m-Power dataset
Authors: Far Mehran Sahandi , Eickhoff Simon B. , Goñi María , Dukart Juergen 
Published: December 2020

AbstractBackgroundDigital biomarkers (DB) as captured using sensors embedded in modern smart devices are a promising technology for home-based symptom monitoring in Parkinson’s disease (PD).ObjectiveDespite extensive application in recent studies test-retest reliability and longitudinal stability of DB has not been well addressed in this context. We utilized the large-scale m-Power dataset to establish the test-retest reliability and longitudinal stability of gait, balance, voice and tapping tasks in an unsupervised and self-administered daily life setting in PD patients and healthy volunteers.MethodsIntraclass Correlation Coefficients (ICC) were computed to estimate the test-retest reliability of features that also differentiate between PD and healthy volunteers. In addition, we tested for longitudinal stability of DB measures in PD and HC as well as for their sensitivity to PD medication effects.ResultsAmong the features differing between PD and HC, only few tapping and voice features had good to excellent test-retest reliabilities and medium to large effect sizes. All other features performed poorly in this respect. Only few features were sensitive to medication effects. The longitudinal analyses revealed significant alterations over time across a variety of features and in particular for the tapping task.ConclusionsThese results indicate the need for further development of more standardized, sensitive and reliable DB for application in self-administered remote studies in PD patients. Motivational, learning and other confounds may cause a variation in performance that needs to be considered in DB longitudinal applications.
Vitamins D2and D3have overlapping but different effects on human gene expression revealed through analysis of blood transcriptomes in a randomised double-blind placebo-controlled food-fortification trial
Authors: Durrant Louise R. , Bucca Giselda , Hesketh Andrew , Möller-Levet Carla , Tripkovic Laura , Wu Huihai , Hart Kathryn H. , Mathers John C. , Elliott Ruan M. , Lanham-New Susan A. , Smith Colin P. 
Published: December 2020

AbstractFor the first time, we report the influence of vitamin D2and vitamin D3on genome-wide gene expression in whole blood from healthy women representing two ethnic groups, white European and South Asian. In this randomised placebo-controlled trial, participants were given daily physiological doses (15 µg) of either vitamin D2or D3for 12 weeks and changes in the transcriptome were compared relative to the transcriptome at baseline. While there was some overlap in the repertoire of differentially expressed genes after supplementation with each vitamin D source, most changes were specific to either vitamin D3or vitamin D2, suggesting that each form of the vitamin may have different effects on human physiology. Notably, following vitamin D3supplementation, the majority of changes in gene expression reflected a down-regulation in the activity of genes, many encoding components of the innate and adaptive immune systems. These are consistent with the emerging concept that vitamin D orchestrates a shift in the immune system towards a more tolerogenic status. Moreover, divergent changes were observed following supplementation with either vitamin D3or vitamin D2for gene expression associated with type 1 and type 2 interferon activity. This is particularly intriguing as interferons play a critical role in the innate response to infection and aberrant type 1 interferon signalling is implicated in severe COVID-19 disease. The observed differences in gene expression after supplementation with vitamin D2compared with vitamin D3warrant a more intensive investigation of the biological effects of the two forms of vitamin D on human physiology.Significance statementsThis study suggests that the influence of vitamins D2and D3on human physiology may not be the same, as deduced from differences in gene expression within whole blood.South Asian participants were found to respond differently to vitamin D supplementation at the transcriptome level from white Europeans.The differentially expressed immune pathways identified in this study are consistent with vitamin D orchestrating a more tolerogenic immune status and this could be relevant in the context of the severity of immune response to viral infections such as Covid-19.The potential relevance of this study to severe Covid-19 disease is highlighted by our observed enhancement of type 1 interferon signalling by vitamin D3, but not vitamin D2.