bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rationale and design of the CORE (COrticosteroids REvised) study: protocol
Authors: Stam Suzanne P , Vulto Annet , Vos Michel J , Kerstens Michiel N , Rutgers Abraham , Kema Ido , Touw Daan J , Bakker Stephan JL , van Beek André P 
Published: May 2022

IntroductionCorticosteroids are an important pillar in many anti-inflammatory and immunosuppressive treatment regimens and are available in natural and synthetic forms, which are considered equipotent if clinical bioequivalence data are used. Current clinical bioequivalence data are however based on animal studies or studies with subjective endpoints. Furthermore, advancement in steroid physiology with regard to metabolism, intracellular handling and receptor activation have not yet been incorporated. Therefore, this study aims to re-examine the clinical bioequivalence and dose effects of the most widely used synthetic corticosteroids, prednisolone and dexamethasone.Methods and analysisIn this double-blind, randomised cross-over clinical trial, 24 healthy male and female volunteers aged 18–75 years, will be included. All volunteers will randomly receive either first a daily dose of 7.5 mg prednisolone for 1 week, immediately followed by a daily dose of 30 mg prednisolone for 1 week, or first a presumed clinical bioequivalent dose of 1.125 mg dexamethasone per day, immediately followed by 4.5 mg of dexamethasone per day for 1 week. After a wash-out period of 4–8 weeks, the other treatment will be applied. The primary study endpoint is the difference in free cortisol excretion in 24 hours urine. Secondary endpoints will include differences in immunological parameters, blood pressure and metabolic measurements.Ethics and disseminationThis study has been approved by the Medical Ethics Committee of the University Medical Center Groningen (METC 2020.398). The results of this study will be submitted for publication in peer-reviewed journals.Trial registration numberClinicalTrials.gov (Identifier: NCT04733144), and in the Dutch trial registry (NL9138).
Research on microstructure and interface bonding of high volume fraction SiCp/Al composite
Authors: Zhang Zhenggui , Cai Jiaxin , Wang Quanzhao 
Published: May 2022

Taking the high volume fraction SiCp/6061Al-based composite material prepared by the powder metallurgy method under different sintering temperatures and holding times as the research object, the microstructure and interface actions are investigated by X-ray diffractometer, scanning electron microscope, transmission electron microscope, etc. The results show that as the sintering temperature increases, the interface reaction between SiC and Al intensifies, producing brittle phase Al4C3 and MgAl2O4 and MgO interface products. The nucleation and growth of Al4C3 are controlled by the sintering temperature and time. When preparing large-size workpieces with high volume fraction SiCp/6061Al-based composite materials, the sintering temperature should be controlled below [Formula: see text]C, and the holding time should not exceed 24 h.
Impact of Nodal Metastases in HPV-Negative Oropharyngeal Cancer
Authors: Chang Clifford M. , Chen Michelle M. , Bellile Emily L. , Rozek Laura S. , Carey Thomas E. , Spector Matthew E. , Wolf Gregory T. , Taylor Jeremy MG , Chinn Steven B. 
Published: May 2022

Abstract

Background:
The updated American Joint Committee on Cancer (AJCC) 8th Edition staging manual restructured nodal classification and staging by placing less prognostic emphasis on nodal metastases for human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC). However, there was no change for HPV-negative OPSCC. The purpose of our study is to examine the impact of nodal metastases on survival in HPV-negative OPSCC.

Methods:
HPV-negative OPSCC was queried from the National Cancer Database (NCDB) and Surveillance, Epidemiology and End Results program (SEER) databases. Univariable and multivariable models were utilized to determine the impact of nodal status on overall survival. These patients were reclassified according to AJCC 8 HPV-positive criteria (TNM8+) and risk stratification was quantified with C-statistic.

Results:
There were 11,147 cases of HPV-negative OPSCC in the NCDB and 3,613 cases in SEER that were included in the nodal classification analysis. Unlike nonoropharyngeal malignancies, increased nodal stage is not clearly associated with survival for patients with OPSCC independent of HPV status. When the TNM8+ was applied to HPV-negative patients, there was improved concordance in the NCDB cohort, 0.561 (plus minus) 0.004 to 0.624 (plus minus) 0.004 (difference +0.063) and the SEER cohort, 0.561 (plus minus) 0.008 to 0.625 (plus minus) 0.008 (difference +0.065).

Conclusions:
We demonstrated a reduced impact of nodal metastasis on OPSCC survival, independent of HPV status and specific to OPSCC.

Impact:
We demonstrate, for the first time that when nodal staging is deemphasized as a part of overall staging, we see improved concordance and risk stratification for HPV-negative OPSCC. The exact mechanism of this differential impact remains unknown but offers a novel area of study.
PLGA–Nano-Encapsulated Disulfiram Inhibits Hypoxia-Induced NF-κB, Cancer Stem Cells, and Targets Glioblastoma In Vitro and In Vivo
Authors: Kannappan Vinodh , Liu Ying , Wang Zhipeng , Azar Karim , Kurusamy Sathishkumar , Kilari Rajagopal S. , Armesilla Angel L. , Morris Mark R. , Najlah Mohammad , Liu Peng , Bian Xiu-Wu , Wang Weiguang 
Published: May 2022

Abstract
Glioblastoma stem cell (GSC) is the major cause of glioblastoma multiforme (GBM) chemotherapy failure. Hypoxia is one of the determinants of GSC. NF-κB plays a pivotal link between hypoxia and cancer stem cells (CSCs). Disulfiram, an antialcoholism drug, has very strong NF-κB–inhibiting and anti-CSC activity. In this study, the in vitro anti-GSC activity of disulfiram and in vivo anti-GBM efficacy of poly lactic–co-glycolic acid nanoparticle-encapsulated disulfiram (DS-PLGA) were examined. We attempt to elucidate the molecular network between hypoxia and GSCs and also examined the anti-GSC activity of disulfiram in vitro and in vivo. The influence of GSCs and hypoxia on GBM chemoresistance and invasiveness was studied in hypoxic and spheroid cultures. The molecular regulatory roles of NF-κB, hypoxia-inducible factor-1α (HIF1α), and HIF2α were investigated using stably transfected U373MG cell lines. The hypoxia in neurospheres determines the cancer stem cell characteristics of the sphere-cultured GBM cell lines (U87MG, U251MG, U373MG). NF-κB is located at a higher hierarchical position than HIF1α/HIF2α in hypoxic regulatory network and plays a key role in hypoxia-induced GSC characters. DS inhibits NF-κB activity and targets hypoxia-induced GSCs. It showed selective toxicity to GBM cells, eradicates GSCs, and blocks migration and invasion at very low concentrations. DS-PLGA efficaciously inhibits orthotopic and subcutaneous U87MG xenograft in mouse models with no toxicity to vital organs.
Arrhythmogenic Right Ventricular Cardiomyopathy Prevalence and Arrhythmic Outcomes in At-Risk Family Members: A Systematic Review and Meta-Analysis
Authors: Sharma Apurva , Bosman Laurens P. , Tichnell Crystal , Nanavati Julie , Murray Brittney , Nonyane Bareng A.S. , Tandri Harikrishna , Calkins Hugh , James Cynthia A. 
Published: May 2022

Background:
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a complex cardiomyopathy with autosomal dominant inheritance and age-related incomplete penetrance, characterized by a high risk of sudden cardiac death. Recent professional consensus guidelines recommend clinical cardiac lifelong serial screening for at-risk family members refined only by age, but family genotype might influence necessary screening. Although numerous studies report prevalence of disease and arrhythmia in family members and explore predictors of penetrance and arrhythmic risk, a systematic review consolidating this evidence is lacking.

Methods:
We searched Medline (PubMed), Embase, The Cochrane Library, and Web of Science for studies that reported prevalence of (1) diagnosis of ARVC per 2010 Task Force Criteria and/or (2) sustained ventricular arrhythmias (VA) in at least 10 family members of definite patients with ARVC.

Results:

We identified 41 studies, including 36 that reported diagnosis by Task Force Criteria and 22 VA. Meta-analysis of 1359 family members, from 13 unique cohorts showed an average prevalence estimate of 25% for diagnosis as per Task Force Criteria (95% CI, 0.15–0.35, I
2
=
96.44%). Overall prevalence of VA among gene-positive family members was 18% (95% CI, 0.13–0.23, I
2
=33.25%) in 7 independent studies (n=597). Family genotype was a significant risk factor for diagnosis of both ARVC (odds ratio, 6.91 [95% CI, 1.27–37.70];
P
=0.0005) and VA (odds ratio, 13.62 [95% CI, 0.91–204.13];
P
=0.06). Male gender was not associated with disease prevalence (odds ratio, 1.18 [95% CI, 0.72–1.95];
P
=0.42) or VA (odds ratio, 0.81 [95% CI, 0.51–1.29];
P
=0.91).

Conclusions:
The prevalence of ARVC and VA in at-risk family members differs significantly based on family genotype. Although recent recommendations provide a guideline based only on age, we propose screening every 1 to 2 years for gene-positive family members and every 3 to 5 years for first-degree relatives of gene-elusive cases, as long as they are asymptomatic and not athletes.
Mitochondrial Sirtuin-3 (SIRT3) Prevents Doxorubicin-Induced Dilated Cardiomyopathy by Modulating Protein Acetylation and Oxidative Stress
Authors: Tomczyk Mateusz M. , Cheung Kyle G. , Xiang Bo , Tamanna Nahid , Fonseca Teixeira Ana L. , Agarwal Prasoon , Kereliuk Stephanie M. , Spicer Victor , Lin Ligen , Treberg Jason , Tong Qiang , Dolinsky Vernon W. 
Published: May 2022

Background:
High doses of doxorubicin put cancer patients at risk for developing dilated cardiomyopathy. Previously, we showed that doxorubicin treatment decreases SIRT3 (sirtuin 3), the main mitochondrial deacetylase and increases protein acetylation in rat cardiomyocytes. Here, we hypothesize that SIRT3 expression can attenuate doxorubicin induced dilated cardiomyopathy in vivo by preventing the acetylation of mitochondrial proteins.

Methods:
Nontransgenic, M3-SIRT3 (truncated SIRT3; short isoform), and M1-SIRT3 (full-length SIRT3; mitochondrial localized) transgenic mice were treated with doxorubicin for 4 weeks (8 mg/kg body weight per week). Echocardiography was performed to assess cardiac structure and function and validated by immunohistochemistry and immunofluorescence (n=4–10). Mass spectrometry was performed on cardiac mitochondrial peptides in saline (n=6) and doxorubicin (n=5) treated hearts. Validation was performed in doxorubicin treated primary rat and human induced stem cell derived cardiomyocytes transduced with adenoviruses for M3-SIRT3 and M1-SIRT3 and deacetylase deficient mutants (n=4–10).

Results:
Echocardiography revealed that M3-SIRT3 transgenic mice were partially resistant to doxorubicin induced changes to cardiac structure and function whereas M1-SIRT3 expression prevented cardiac remodeling and dysfunction. In doxorubicin hearts, 37 unique acetylation sites on mitochondrial proteins were altered. Pathway analysis revealed these proteins are involved in energy production, fatty acid metabolism, and oxidative stress resistance. Increased M1-SIRT3 expression in primary rat and human cardiomyocytes attenuated doxorubicin-induced superoxide formation, whereas deacetylase deficient mutants were unable to prevent oxidative stress.

Conclusions:
Doxorubicin reduced SIRT3 expression and markedly affected the cardiac mitochondrial acetylome. Increased M1-SIRT3 expression in vivo prevented doxorubicin-induced cardiac dysfunction, suggesting that SIRT3 could be a potential therapeutic target for mitigating doxorubicin-induced dilated cardiomyopathy.
Blood Pressure and Glycemic Control Among Ambulatory US Adults With Heart Failure: National Health and Nutrition Examination Survey 2001 to 2018
Authors: Rethy Leah , Vu Thanh-Huyen T. , Shah Nilay S. , Carnethon Mercedes R. , Lagu Tara , Huffman Mark D. , Yancy Clyde W. , Lloyd-Jones Donald M. , Khan Sadiya S. 
Published: May 2022

Background:
Multisociety guidelines recommend a goal systolic blood pressure (BP) <130 mm Hg and a hemoglobin A1c (HbA1c) <8% in patients with heart failure (HF), regardless of ejection fraction. Few studies have described BP and glycemic control in ambulatory patients with HF and racial and ethnic disparities in this subset of the population.

Methods:
We evaluated prevalence of uncontrolled BP and HbA1c in non-Hispanic Black, non-Hispanic White, and Mexican American adults aged ≥20 years with self-reported HF (National Health and Nutrition Examination Surveys: 2001–2018). Prevalence ratios (95% CI) for uncontrolled BP and HbA1c were calculated by race and ethnicity and adjusted for sex, age, treatment, and socioeconomic status. In secondary analyses, we examined trends in the prevalence of uncontrolled BP and HbA1c.

Results:

Uncontrolled BP was present in 48% (95% CI, 49%–56%) of adults with HF (representing 2.3 million people). Non-Hispanic Black participants had a higher prevalence of uncontrolled BP compared with non-Hispanic White participants (53% [48%–58%] compared with 47% [43%–51%],
P
<0.05). In adjusted models, non-Hispanic Black participants were 1.19 (1.02–1.39) times more likely to have uncontrolled BP than non-Hispanic White participants. Overall, uncontrolled HbA1c was found in 8% (6%, 10%) with no differences by race and ethnicity. Prevalence of uncontrolled BP improved over time but uncontrolled risk factors remained high—2017 to 2018: 41% (36%, 47%) and 7% (5%, 12%) had uncontrolled BP and HbA1c, respectively.

Conclusions:
We document an unacceptably high prevalence of uncontrolled BP and HbA1c in a nationally representative, ambulatory HF sample with significant differences in BP control by race and ethnicity.
Association Between Atrial Uptake on Cardiac Scintigraphy With Technetium-99m-Pyrophosphate Labeled Bone-Seeking Tracers and Atrial Fibrillation
Authors: Hussain Muzna , Krywanczyk Alison , Donnellan Eoin , Martyn Trejeeve , Hassan Ossama Abou , Alkharabsheh Saqer , Watson Chris , Tang W.H. , Kwon Deborah , Cremer Paul , Cheng Feixiong , Kanj Mohamed , Griffin Brian , Tan Carmela , Rodriguez E. Rene , Hanna Mazen , Jaber Wael , Collier Patrick 
Published: May 2022

Background:
Transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized disease, in which atrial fibrillation (AF) has been shown to be prevalent. Cardiac scintigraphy with technetium-99m-pyrophosphate (99mTc-PyP) labeled bone-seeking tracers is used to noninvasively make the diagnosis of ATTR-CA, based on ventricular myocardial uptake. Assessment of atrial wall uptake (AU) on 99mTc-PyP is currently not used in the clinical setting

Methods:
We analyzed a cohort of patients referred for 99mTc-PyP scan at a tertiary center to explore AU and associations between any and incident AF, ATTR-CA, and all-cause mortality.

Results:

Among 580 patients included, 296 patients (51%) had a diagnosis of AF; 164 patients (28%) had scans consistent with ATTR-CA while 117 patients (20%) had AU. Of 117 patients with AU, 107 (91%) had any AF. In contrast, of 463 patients without AU 191(41%) had any AF. Of those with AU, 59/117(50%) patients had a 99mTc-PyP diagnosis of ATTR-CA while 58/117(50%) patients did not have such a diagnosis (
P
=1.00). Patients with AU had significantly more any AF (hazard ratio [HR], 1.03 [95% CI, 1.02–1.04];
P
<0.001), independent of ATTR-CA diagnosis and sex. On multivariable Cox proportional hazards analyses adjusting for age, AU, ATTR-CA diagnosis, sex, smoking, hypertension, diabetes, left ventricular ejection fraction, and coronary artery disease, both age (HR, 1.03 [95% CI, 1.02–1.04];
P
<0.0001) and AU (HR, 2.68 [95% CI, 2.11–3.41];
P
<0.0001) were independently associated with the development of any AF. Freedom from incident AF at 1-year was significantly lower in patients with AU, both in patients with and without ATTR-CA respectively (HR, 2.27 [95% CI, 1.37–3.78];
P
<0.0001 versus HR, 2.21 [95% CI, 1.46–3.34];
P
<0.0001).

Conclusions:
In a consecutive cohort of patients undergoing 99mTc-PyP scans, 20% had AU, which was statistically associated with any AF, independently of ATTR-CA diagnosis and sex. AU was associated with significantly lower freedom from incident AF at 1-year. Overlooking AU on 99mTc-PyP scans could potentially miss an earlier disease manifestation, or an additional risk factor for any/incident AF.
Global Impact of Different Blood Pressure Thresholds in 4 021 690 Participants of the May Measurement Month Initiative
Authors: Nolde Janis M. , Beaney Thomas , Carnagarin Revathy , Schutte Aletta E. , Poulter Neil R. , Schlaich Markus P. 
Published: May 2022

Background:
Influential guidelines currently define hypertension at different thresholds of blood pressure (BP). The global May Measurement Month initiative provides a unique opportunity to estimate the potential consequences of universal lowering of BP thresholds on the prevalence of hypertension based on a large, real-world, patient-level data set.

Methods:
The average of the second and third of 3 attended BP readings after 5 minutes of rest from 4 021 690 standardized, opportunistic BP screenings in various settings of the 2017 to 2019 May Measurement Month initiatives from 104 countries were analyzed to assess the demographic and phenotypic impact of 3 defined BP thresholds.

Results:
The age- and sex-standardized median of the relative increase in rate of hypertension with a change of thresholds from ≥140/≥90 to ≥130/≥80 mm Hg was 72.3% (interquartile range, 59.3%–91.3%) among the participating countries. With a change from ≥140/≥90 to ≥120/≥70 mm Hg, the median range was 162.6% (interquartile range, 132.8%–202.6%). The increase in rate of hypertension was most pronounced in low-income (95.3% and 203.9%) and least pronounced in high-income countries (71.6% and 167.1%).

Conclusions:
The impact of a universal application of lower BP thresholds for the definition of hypertension would have an enormous impact on the prevalence of hypertension globally with large disparities between countries and substantial heterogeneity of demographic and phenotypic patterns, which should be confirmed in dedicated population studies. While focusing on lower BP targets may constitute an opportunity for early intervention, the potential socioeconomic consequences may pose unsurmountable obstacles for most health care systems worldwide.
Effect of Environmental Change Distribution on Artificial Life Simulations
Authors: Bullinaria John A. 
Published: May 2022

Abstract
It is already well known that environmental variation has a big effect on real evolution, and similar effects have been found in evolutionary artificial life simulations. In particular, a lot of research has been carried out on how the various evolutionary outcomes depend on the noise distributions representing the environmental changes, and how important it is for models to use inverse power-law distributions with the right noise colour. However, there are two distinct factors of relevance—the average total magnitude of change per unit time and the distribution of individual change magnitudes—and misleading results may emerge if those factors are not properly separated. This article makes use of an existing agent-based artificial life modeling framework to explore this issue using models previously tried and tested for other purposes. It begins by demonstrating how the total magnitude and distribution effects can easily be confused, and goes on to show how it is possible to untangle the influence of these interacting factors by using correlation-based normalization. It then presents a series of simulation results demonstrating that interesting dependencies on the noise distribution remain after separating those factors, but many effects involving the noise colour of inverse power-law distributions disappear, and very similar results arise across restricted-range white-noise distributions. The average total magnitude of change per unit time is found to have a substantial effect on the simulation outcomes, but the distribution of individual changes has very little effect. A robust counterexample is thereby provided to the idea that it is always important to use accurate environmental change distributions in artificial life models.
Input Legitimacy of Voluntary Sustainability Standards and Acceptance Among Southern Producers: A Qualitative Comparative Analysis
Authors: Schouten Greetje , Toonen Hilde M. , Leeuwerik Dorine 
Published: May 2022

Abstract
Voluntary standards are key instruments to address sustainability concerns in value chains. The legitimacy of these initiatives has been debated, particularly related to acceptance by Global South stakeholders. The governance literature has predominantly argued that initiatives employing democratic approaches to governance are more likely to increase their legitimacy. In this article, we use a configurational approach to test this proposition in relation to standard acceptance by southern producers. A qualitative comparative analysis of eight cases was carried out, linking three elements of input legitimacy (inclusion, participation, and accountability) to the outcome of standard uptake in the Global South. While our findings suggest that an inclusive governance structure is important, overall, they show no evidence to explain the presence or absence of standard acceptance in the Global South. We conclude that theoretical assumptions about democratic legitimacy cannot be confirmed and argue for further opening up the scholarly debate to include conceptualizations, methods, and approaches inclusive of different ways of creating and perceiving legitimacy.
Orchestrating Global Climate Governance Through Data: The UNFCCC Secretariat and the Global Climate Action Platform
Authors: Mai Laura , Elsässer Joshua Philipp 
Published: May 2022

AbstractSince the adoption of the Paris Agreement, the focus of the United Nations climate regime has shifted from forging consensus among national governments toward animating implementation activity across multiple levels. Based on a case study of the Global Climate Action Portal—an online database designed to document nonstate actor climate commitments and implementation efforts—we trace, conceptualize, and assess how the roles of data, data infrastructures, and actor constellations have changed as a result of this shift. We argue that in the pre-COP21 negotiation phase, the United Nations Climate Secretariat strategically used the database to orchestrate and leverage nonstate actor commitments to exert pressure on intergovernmental negotiations. By contrast, in the post-COP21 implementation phase, the Secretariat, in collaboration with climate data specialists, is seeking to develop the portal to track and animate implementation activity. Given these developments, we discuss the potential and limitations of data-driven climate governance and set out avenues for future research.