bluuebunny/crossref_metadata_2025 huggingface dataset:
The Blood Line: Racialized Boundary Making and Citizenship among Native Nations
Authors: Rodriguez-Lonebear Desi
Published: January 2021

Blood informs a central racial ideology in the United States that has historically been used to racialize many different groups. American Indians (AIs) are the only population in the United States for whom the racial logic of blood remains codified as a means of conferring collective belonging. This article explores how AI blood quantum persists as both a race-making and nation-making instrument. I ask two research questions: How does blood quantum persist as a metric of tribal citizenship? Are tribal citizenship criteria connected to contemporary demographic, geographic, political, and economic forces? I first extend racial formation theory to describe blood quantum as a “racial project” in its use to both construct tribal identities in explicitly racial ways and determine access to political, social, and material resources. I also consider how the sovereign right of Native nations to confer tribal citizenship is evident in the observed variation among citizenship rules. Using data from more than 80 percent of AI Native nations in the contiguous United States, I employ a multinomial regression model to evaluate tribal citizenship variation. I have two central findings: (1) although tribal citizenship criteria are starting to depart from the racializing policies of the settler-colonial state, blood quantum thresholds remain particularly durable; and (2) variation in tribal citizenship criteria is meaningful by geographic region, tribal governance status, and Indian gaming. Against a backdrop of growing racial diversity in the United States, I discuss implications of the blood line on tribal citizenship boundaries and tribal sovereignty.
High School Band Directors’ Perceptions and Applications of Democratic Rehearsal Procedures in Concert Band Rehearsals
Authors: Scherer Alec D.
Published: January 2021

The purpose of this study was to examine inservice high school band directors’ perceptions and applications of democratic rehearsal procedures in concert band rehearsals. Respondents ( N = 216) were members of the National Association for Music Education who were currently teaching concert band at the high school level. Respondents indicated that “identify and describe opportunities for individual and ensemble performance improvement” and “student-led sectionals” were considered the most important democratic rehearsal procedures for their students to experience. These same procedures were also the most frequently used democratic rehearsal procedures. Analysis of open-ended responses revealed that respondents believed student ownership, student engagement, and student growth as musicians and leaders were advantages to implementing democratic rehearsal procedures. Potential disadvantages included issues related to student ability, rehearsal time limitations, unfamiliar classroom dynamics, and availability of classroom resources. Implications for music teachers are discussed.
Specifications of the variant curation guidelines for ITGA2B/ITGB3: ClinGen Platelet Disorder Variant Curation Panel
Authors: Ross Justyne E. , Zhang Bing M. , Lee Kristy , Mohan Shruthi , Branchford Brian R. , Bray Paul , Dugan Stefanie N. , Freson Kathleen , Heller Paula G. , Kahr Walter H. A. , Lambert Michele P. , Luchtman-Jones Lori , Luo Minjie , Perez Botero Juliana , Rondina Matthew T. , Ryan Gabriella , Westbury Sarah , Bergmeier Wolfgang , Di Paola Jorge
Published: January 2021

Accurate and consistent sequence variant interpretation is critical to the correct diagnosis and appropriate clinical management and counseling of patients with inherited genetic disorders. To minimize discrepancies in variant curation and classification among different clinical laboratories, the American College of Medical Genetics and Genomics (ACMG), along with the Association for Molecular Pathology (AMP), published standards and guidelines for the interpretation of sequence variants in 2015. Because the rules are not universally applicable to different genes or disorders, the Clinical Genome Resource (ClinGen) Platelet Disorder Expert Panel (PD-EP) has been tasked to make ACMG/AMP rule specifications for inherited platelet disorders. ITGA2B and ITGB3, the genes underlying autosomal recessive Glanzmann thrombasthenia (GT), were selected as the pilot genes for specification. Eight types of evidence covering clinical phenotype, functional data, and computational/population data were evaluated in the context of GT by the ClinGen PD-EP. The preliminary specifications were validated with 70 pilot ITGA2B/ITGB3 variants and further refined. In the final adapted criteria, gene- or disease-based specifications were made to 16 rules, including 7 with adjustable strength; no modification was made to 5 rules; and 7 rules were deemed not applicable to GT. Employing the GT-specific ACMG/AMP criteria to the pilot variants resulted in a reduction of variants classified with unknown significance from 29% to 20%. The overall concordance with the initial expert assertions was 71%. These adapted criteria will serve as guidelines for GT-related variant interpretation to increase specificity and consistency across laboratories and allow for better clinical integration of genetic knowledge into patient care.
Two sides of the same coin? A review of the similarities and differences between idiopathic pulmonary fibrosis and rheumatoid arthritis-associated interstitial lung disease
Authors: Matson Scott , Lee Joyce , Eickelberg Oliver
Published: January 2021

Rheumatoid arthritis associated interstitial lung disease (RA-ILD) and idiopathic pulmonary fibrosis (IPF) are distinct diseases; however, they share several clinical, radiographic and genetic features. For instance, usual interstitial pneumonia (UIP), which is an ILD pattern required for a diagnosis of IPF, is also the most common ILD pattern in RA-ILD. The presence of UIP in RA-ILD is a poor prognostic sign with outcomes similar to those seen in IPF. The recent finding of a shared genetic susceptibility between IPF and RA-ILD has sparked additional interest in this relationship. This review outlines these similarities and differences in clinical presentation, appearance and outcomes in RA-ILD and IPF.

In addition, this review highlights previous research in molecular biomarkers in both conditions, exploring areas of overlap and distinction. This focus on biomarkers in IPF and RA-ILD aims to highlight potential areas of discovery and clues to a potential shared pathobiology through investigation of novel molecular markers or the repurposing of biomarkers from one condition to the other.

The drive to better understand RA-ILD by leveraging our knowledge of IPF is underscored by our divergent treatment paradigms for these conditions and the concern for potential harm. As a result of advancing our understanding of the links between IPF and RA-ILD, current strategies for diagnosis, screening and treatment of ILD may fundamentally change in the coming years. Until then, clinicians face difficult clinical questions regarding the co-management of the articular disease and the ILD in RA.
Targeting cystic fibrosis inflammation in the age of CFTR modulators: focus on macrophages
Authors: Gillan Jonathan L. , Davidson Donald J. , Gray Robert D.
Published: January 2021

Cystic fibrosis (CF) is a life-shortening, multi-organ, autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The most prominent clinical manifestation in CF is the development of progressive lung disease characterised by an intense, chronic inflammatory airway response that culminates in respiratory failure and, ultimately, death. In recent years, a new class of therapeutics that have the potential to correct the underlying defect in CF, known as CFTR modulators, have revolutionised the field. Despite the exciting success of these drugs, their impact on airway inflammation, and its long-term consequences, remains undetermined. In addition, studies querying the absolute requirement for infection as a driver of CF inflammation have challenged the traditional consensus on CF pathogenesis, and also emphasise the need to prioritise complementary anti-inflammatory treatments in CF. Macrophages, often overlooked in CF research despite their integral role in other chronic inflammatory pathologies, have increasingly become recognised as key players in the initiation, perpetuation and resolution of CF lung inflammation, perhaps as a direct result of CFTR dysfunction. These findings suggest that macrophages may be an important target for novel anti-inflammatory interventional strategies to effectively treat CF lung function decline. This review will consider evidence for the efficacy of anti-inflammatory drugs in the treatment of CF, the potential role of macrophages, and the significance of targeting these pathways at a time when rectifying the basic defect in CF, through use of novel CFTR modulator therapies, is becoming increasingly viable.
New bronchoscopic treatment modalities for patients with chronic bronchitis
Authors: Hartman Jorine E. , Garner Justin L. , Shah Pallav L. , Slebos Dirk-Jan
Published: January 2021

Chronic bronchitis is a chronic, progressive disease that is difficult to treat. Despite much effort, patients remain highly symptomatic. Currently, a number of innovative bronchoscopic treatments for this disease are under investigation. Liquid nitrogen metered cryospray, bronchial rheoplasty and balloon desobstruction all aim to destroy the hyperplastic goblet cells and excess submucous glands using different strategies. These therapies are in an early phase of clinical research and larger randomised controlled trials are needed to confirm the pilot data available and to evaluate the treatment durability. The fourth technique, targeted lung denervation (TLD), aims to decrease the release of acetylcholine, which regulates smooth muscle tone and mucus production by ablating the parasympathetic nerves running alongside the main bronchi. Evaluation of this treatment is at a more advanced stage and promising effects on exacerbation frequency have been shown. However, confirmation of the benefit in improvement in chronic bronchitis symptoms is still needed.
Hiccups and psychosis: two atypical presentations of COVID-19
Authors: Alvarez-Cisneros Teresa , Lara-Reyes Aldo , Sansón-Tinoco Stephanie
Published: January 2021

The WHO defines a possible case of COVID-19 as a person experiencing fever, cough, shortness of breath, and neurological signs including anosmia, ageusia, or dysgeusia. However, experiences from hospitals all over the world have shown that presentations vary widely. Some atypical presentations include cardiac, gastrointestinal, neurological, and cutaneous and while some are driven by the inflammatory response, others are a consequence of the hypercoagulable state. In our emergency department in a private hospital in Mexico City, we received two patients with very different symptoms on the same shift. Two previously healthy men in their 40s presented to the ER with very atypical manifestations of COVID-19. Neither of them complained of fever, cough, or shortness of breath. The first referred a 3-day history of hiccups that had not resolved with metoclopramide. The second presented with an acute episode of altered mental status. While the first case revealed lung involvement of the disease, the second case had a clean chest CT scan. These cases are relevant as manifestations of COVID-19 vary widely, especially in previously healthy young adults.
Doppler ultrasound and contrast-enhanced ultrasound in detection of stent stenosis after iliac vein stenting
Authors: Liu Hong , Wang Jing , Zhao Yu , Chen Zheng , Wang Dong , Wei Miao , Lv Fajin , Ye Xiaoping
Published: January 2021

Background

To compare the diagnostic accuracy of Doppler ultrasound (DUS) with contrast-enhanced ultrasound (CEUS) for detection of iliac vein stent stenosis using multidetector computed tomography venography (MDCTV) as the reference method.

Methods

Patients with iliac vein obstructive disease treated with nitinol stents (Smart Control, Cordis, USA) between January 2016 and December 2017 were consecutively included in this study. DUS, CEUS, and MDCTV were carried out in all patients within one week of each other at 1 year post stenting to investigate the presence of stent compression and in-stent restenosis (ISR).

Results

The study included 139 patients (87 females; mean age 58 ± 15 years). For detecting stent compression, the kappa coefficient between the ultrasound modality of gray-scale imaging and MDCTV was 0.901, indicating very good agreement between these two modalities. ISR was detected in 50, 61, and 65 patients by DUS, CEUS, and MDCTV, respectively. DUS and CEUS (kappa = 0.449) and DUS and MDCTV (kappa = 0.516) had moderate agreement for ISR diagnosis, while for which CEUS and MDCTV (kappa 0.884) had very good agreement. The sensitivity and specificity of DUS and CEUS for diagnosing ISR were 63.1% and 90.8%, 87.8% and 97.3%, respectively.

Conclusions

CEUS is probably superior to DUS in terms of diagnostic accuracy for the follow-up of patients with iliac vein stent stenosis.
Optimization of pediatric CT scans in a developing country
Authors: Kamdem Fotso Eddy , Ngano Samba Odette , Alla Takam Clemence , Fotue Alain Jervé , Abogo Serge , Fai Cornellius Lukong
Published: January 2021

Background

The purpose of this study was to assess scan parameters and to propose strategies to optimize the examinations of children (from 0 to 15 years old) on adult scanners in developing countries.

Methods

A study was done in 2015 and 2018 on 312 pediatric patients to verify improved practices. The study of 2015 ended with proposed strategies. Dose and scan parameters were available for prospective dose analysis. These strategies were implemented in a study of 2018.

Results

Amount the CT examinations study in this paper, the common was head trauma (90 %). For every pediatric CT scan in 2015, a kV of 120 was used in the various hospitals. The mAs ranged from 57.75 to 283.33, slice thicknesses from 1.25 to 2.5 mm and pitch from 0.525 to 1.375 mm. In the study of 2018, implementing the strategy defined in the methodology and proposed in 2015: CTDIVoldecreased by 21.27 % for children < 1 year, 31.97 % for children 1–4 years, 17 % for children 5–9 years. DLP also decreased by 25.14 %, 36.29 % and 19.85 % for children < 1 year, 1–4 years and 5–9 years respectively. Children were exposed to ionizing radiation on machines designed for adults, but now the doses received by children are reduced.

Conclusions

The reduction of doses during the pediatric CT examination is possible with the introduction of new optimization protocols or the acquisition of a new machine with a pediatric protocol.
Home was not a safe haven: women’s experiences of intimate partner violence during the COVID-19 lockdown in Nigeria
Authors: Fawole Olufunmilayo I. , Okedare Omowumi O. , Reed Elizabeth
Published: January 2021

Background

Emergency situations, including epidemics, increase incidence of violence against women, especially intimate partner violence (IPV). This paper describes specific scenarios of IPV reported by women during the COVID-19 pandemic in Nigeria to provide insight for policy and programmatic efforts.

Methods

This paper draws on seven de-identified case reports from organisations serving women experiencing IPV as well as media coverage of IPV cases in Nigeria, between April and May, 2020.

Results

In most cases, reports identified IPV that was occurring prior to the lockdown, but increased in severity or involved new types of violence during the lockdown. The case scenarios included descriptions of many forms of IPV commonly reported, including physical, economic, psychological and sexual violence, often concurrently. Several women also reported threats of being thrown out of their homes by perpetrators, which threatens women’s ability to protect themselves from exposure to COVID-19, but could also leave women stranded with no access to transportation, social services, or other resources during the lockdown. Several women also reported IPV that involved custody of children, as well as IPV that disrupted women’s income generation. IPV was also reported in relation to economic stressors associated with the lockdown. Reports highlight how the lockdown disrupted women’s social support, hindering accessibility of formal and informal sources of help.

Conclusion

The lockdowns in Nigeria may have inadvertently placed women already experiencing partner violence at risk for experiencing more severe violence, new challenges to cope with violent experiences, and other forms of violence, including violence that used the lockdown as a way to threaten women’s security and ability to protect themselves from the virus. Hence, there is need for innovative approaches to support victims, with emphasis on ways in which perpetrators of IPV may be using the threat of COVID-19 to further gain power and control over partners.
Intellectual capital-based performance improvement: a study in healthcare sector
Authors: Alfiero Simona , Brescia Valerio , Bert Fabrizio
Published: January 2021

Background

Knowledge resources are in most productive sectors distinctive in terms of competitiveness. Still, in the health sector, they can have an impact on the health of the population, help make the organisations more efficient and can help improve decision-making processes. The purpose of this paper is to investigate the Intellectual Capital impact on healthcare organization’ performance in the Italian healthcare system.

Methods

The theoretical framework linked to intellectual Capital in the health sector and the performance evaluation related to efficiency supports the analysis carried out in two stages to determine the right placement of resources and the exogenous variables that influence performance level. The evaluation of the impact of the ICs on performance is determined through the Data envelopment analysis. The incidence of the exogenous variables has been established through linear regression.

Results

Empirical results in Italy show some IC components influence organization ‘performance (Essential Levels of Assistance) and could be used for defining the policy of allocation of resources in healthcare sector. The efficiency of 16 regions considered in 2016 based on Slack-Based-Model constant returns-to-scale (SBM-CRS) and Slack-Based-Model variable returns-to-scale (SBM-VRS) identifies a different ability to balance IC and performance. Current healthcare expenditure and the number of residents is correlated with the identified efficiency and performance levels.

Conclusions

This paper embeds an innovative link between healthcare performance, in term of efficiency and IC which aligns resource management with future strategy. The study provides a new decision-making approach.
Correction to: Cost-effectiveness of rapid diagnostic tests, compared to microscopic tests, for the diagnosis and treatment of gestational malaria in Colombia from an institutional perspective
Authors: Restrepo-Posada Deisy Cristina , Carmona-Fonseca Jaime , Cardona-Arias Jaiberth Antonio
Published: January 2021

An amendment to this paper has been published and can be accessed via the original article.
The use of dried tube specimens of Plasmodium falciparum in an external quality assessment programme to evaluate health worker performance for malaria rapid diagnostic testing in healthcare centres in Togo
Authors: Dorkenoo Ameyo M. , Kouassi Kafui Codjo , Koura Adjane K. , Adams Martin L. , Gbada Komivi , Katawa Gnatoulma , Yakpa Kossi , Charlebois Remi , Milgotina Ekaterina , Merkel Michele O. , Aidoo Michael
Published: January 2021

Background

The use of rapid diagnostic tests (RDTs) to diagnose malaria is common in sub-Saharan African laboratories, remote primary health facilities and in the community. Currently, there is a lack of reliable methods to ascertain health worker competency to accurately use RDTs in the testing and diagnosis of malaria. Dried tube specimens (DTS) have been shown to be a consistent and useful method for quality control of malaria RDTs; however, its application in National Quality Management programmes has been limited.

Methods

A Plasmodium falciparum strain was grown in culture and harvested to create DTS of varying parasite density (0, 100, 200, 500 and 1000 parasites/µL). Using the dried tube specimens as quality control material, a proficiency testing (PT) programme was carried out in 80 representative health centres in Togo. Health worker competency for performing malaria RDTs was assessed using five blinded DTS samples, and the DTS were tested in the same manner as a patient sample would be tested by multiple testers per health centre.

Results

All the DTS with 100 parasites/µl and 50% of DTS with 200 parasites/µl were classified as non-reactive during the pre-PT quality control step. Therefore, data from these parasite densities were not analysed as part of the PT dataset. PT scores across all 80 facilities and 235 testers was 100% for 0 parasites/µl, 63% for 500 parasites/µl and 93% for 1000 parasites/µl. Overall, 59% of the 80 healthcare centres that participated in the PT programme received a score of 80% or higher on a set of 0, 500 and 1000 parasites/ µl DTS samples. Sixty percent of health workers at these centres recorded correct test results for all three samples.

Conclusions

The use of DTS for a malaria PT programme was the first of its kind ever conducted in Togo. The ease of use and stability of the DTS illustrates that this type of samples can be considered for the assessment of staff competency. The implementation of quality management systems, refresher training and expanded PT at remote testing facilities are essential elements to improve the quality of malaria diagnosis.
Urban poverty and nutrition challenges associated with accessibility to a healthy diet: a global systematic literature review
Authors: Vilar-Compte Mireya , Burrola-Méndez Soraya , Lozano-Marrufo Annel , Ferré-Eguiluz Isabel , Flores Diana , Gaitán-Rossi Pablo , Teruel Graciela , Pérez-Escamilla Rafael
Published: January 2021

Background

There is an increasing global trend towards urbanization. In general, there are less food access issues in urban than rural areas, but this “urban advantage” does not benefit the poorest who face disproportionate barriers to accessing healthy food and have an increased risk of malnutrition.

Objectives

This systematic literature review aimed to assess urban poverty as a determinant of access to a healthy diet, and to examine the contribution of urban poverty to the nutritional status of individuals.

Methods

Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) methodology, our review included quantitative and qualitative studies published in English or in Spanish between 2000 and 2019. The articles were eligible if they focused on nutrition access (i.e. access to a healthy diet) or nutrition outcomes (i.e., anemia, overweight and obesity, micronutrient deficiency, micronutrient malnutrition) among urban poor populations. Articles were excluded if they did not meet pre-established criteria. The quality of the quantitative studies was assessed by applying Khan et al.’s methodology. Similarly, we assessed the quality of qualitative articles through an adapted version of the National Institute for Health and Care Excellence (NICE) methodology checklist. Finally, we systematically analyzed all papers that met the inclusion criteria based on a qualitative content and thematic analysis.

Results

Of the 68 papers included in the systematic review, 55 used quantitative and 13 used qualitative methods. Through the analysis of the literature we found four key themes: (i) elements that affect access to healthy eating in individuals in urban poverty, (ii) food insecurity and urban poverty, (iii) risk factors for the nutritional status of urban poor and (iv) coping strategies to limited access to food. Based on the systematization of the literature on these themes, we then proposed a conceptual framework of urban poverty and nutrition.

Conclusions

This systematic review identified distinct barriers posed by urban poverty in accessing healthy diets and its association with poorer nutrition outcomes, hence, questioning the “urban advantage”. A conceptual framework emerging from the existing literature is proposed to guide future studies and policies.

Systematic review registration

PROSPERO Registration number: CRD42018089788.
A multicentric quality-control study of exercise Doppler echocardiography of the right heart and the pulmonary circulation. The RIGHT Heart International NETwork (RIGHT-NET)
Authors:   On behalf of the RIGHT Heart International NETwork (RIGHT-NET) Investigators, Ferrara Francesco , Gargani Luna , Contaldi Carla , Agoston Gergely , Argiento Paola , Armstrong William F. , Bandera Francesco , Cademartiri Filippo , Citro Rodolfo , Cittadini Antonio , Cocchia Rosangela , D’Alto Michele , D’Andrea Antonello , Douschan Philipp , Ghio Stefano , Grünig Ekkehard , Guazzi Marco , Guida Stefania , Kasprzak Jaroslaw D. , Kolias Theodore John , Limongelli Giuseppe , Marra Alberto Maria , Mazzola Matteo , Mauro Ciro , Moreo Antonella , Pieri Francesco , Pratali Lorenza , Pugliese Nicola Riccardo , Raciti Mauro , Ranieri Brigida , Rudski Lawrence , Saggar Rajan , Salzano Andrea , Serra Walter , Stanziola Anna Agnese , Vannan Mani , Voilliot Damien , Vriz Olga , Wierzbowska-Drabik Karina , Naeije Robert , Bossone Eduardo
Published: January 2021

Purpose

This study was a quality-control study of resting and exercise Doppler echocardiography (EDE) variables measured by 19 echocardiography laboratories with proven experience participating in the RIGHT Heart International NETwork.

Methods

All participating investigators reported the requested variables from ten randomly selected exercise stress tests. Intraclass correlation coefficients (ICC) were calculated to evaluate the inter-observer agreement with the core laboratory. Inter-observer variability of resting and peak exercise tricuspid regurgitation velocity (TRV), right ventricular outflow tract acceleration time (RVOT Act), tricuspid annular plane systolic excursion (TAPSE), tissue Doppler tricuspid lateral annular systolic velocity (S’), right ventricular fractional area change (RV FAC), left ventricular outflow tract velocity time integral (LVOT VTI), mitral inflow pulsed wave Doppler velocity (E), diastolic mitral annular velocity by TDI (e’) and left ventricular ejection fraction (LVEF) were measured.

Results

The accuracy of 19 investigators for all variables ranged from 99.7 to 100%. ICC was > 0.90 for all observers. Inter-observer variability for resting and exercise variables was for TRV = 3.8 to 2.4%, E = 5.7 to 8.3%, e’ = 6 to 6.5%, RVOT Act = 9.7 to 12, LVOT VTI = 7.4 to 9.6%, S’ = 2.9 to 2.9% and TAPSE = 5.3 to 8%. Moderate inter-observer variability was found for resting and peak exercise RV FAC (15 to 16%). LVEF revealed lower resting and peak exercise variability of 7.6 and 9%.

Conclusions

When performed in expert centers EDE is a reproducible tool for the assessment of the right heart and the pulmonary circulation.
Reduction of miR-744 delivered by NSCLC cell-derived extracellular vesicles upregulates SUV39H1 to promote NSCLC progression via activation of the Smad9/BMP9 axis
Authors: Gao Liming , Tian Qi , Wu Tong , Shi Shanshan , Yin Xiaobo , Liu Lijie , Zheng Lei , Wang Ping , Tian Yaling , Xu Shufeng
Published: January 2021

Background

Non-small cell lung cancer (NSCLC) is a common type of lung cancer. Extracellular vehicles (EVs) are nano-sized particles containing proteins, lipids, and miRNAs secreted by various cells, which play important roles in the development of lung cancer by regulating a wide range of signaling pathways. This study focused on elucidating a potential mechanism by which EVs promote the development of NSCLC.

Methods

Expression levels of miR-744, SUV39H1, Smad9, and BMP4 in clinical tissue samples of NSCLC patients and cell lines were quantified by RT-qPCR and/or western blot analysis. The interaction between SUV39H1 and miR-744 was identified by dual-luciferase reporter assay. miR-744, SUV39H1, and BMP4 expression levels were modulated in A549 and H460 cells, in order to evaluate their effects on cell proliferation, colony formation and cell cycle. A NSCLC xenograft mouse model was used to verify the in vitro findings. NSCLC cell-derived EVs and normal bronchial epithelial cell-derived EVs were isolated and their roles in NSCLC development were evaluated in vivo and in vitro.

Results

miR-744 expression was lower in cancer cell-derived derived EVs than in normal lung epithelial cell-derived EVs. Reduced miR-744 expression in EVs upregulated SUV39H1 in NSCLC cells and further increased BMP4 levels to promote NSCLC development. BMP4 was upregulated in NSCLC cells upon suppression of Smad9 mediated by SUV39H1. Reduced miR-744 expression transferred from cancer cell-derived EVs into NSCLC cells enhanced cancer development.

Conclusion

Overall, our findings unveiled a mechanism whereby miR-744 delivered by NSCLC-derived EVs upregulated SUV39H1, activating the Smad9/BMP9 axis and thus promoted cancer development.
Peripherally misfolded proteins exacerbate ischemic stroke-induced neuroinflammation and brain injury
Authors: Liu Yanying , Subedi Kalpana , Baride Aravind , Romanova Svetlana , Callegari Eduardo , Huber Christa C. , Wang Xuejun , Wang Hongmin
Published: January 2021

Background

Protein aggregates can be found in peripheral organs, such as the heart, kidney, and pancreas, but little is known about the impact of peripherally misfolded proteins on neuroinflammation and brain functional recovery following ischemic stroke.

Methods

Here, we studied the ischemia/reperfusion (I/R) induced brain injury in mice with cardiomyocyte-restricted overexpression of a missense (R120G) mutant small heat shock protein, αB-crystallin (CryABR120G), by examining neuroinflammation and brain functional recovery following I/R in comparison to their non-transgenic (Ntg) littermates. To understand how peripherally misfolded proteins influence brain functionality, exosomes were isolated from CryABR120G and Ntg mouse blood and were used to treat wild-type (WT) mice and primary cortical neuron-glia mix cultures. Additionally, isolated protein aggregates from the brain following I/R were isolated and subjected to mass-spectrometric analysis to assess whether the aggregates contained the mutant protein, CryABR120G. To determine whether the CryABR120G misfolding can self-propagate, a misfolded protein seeding assay was performed in cell cultures.

Results

Our results showed that CryABR120G mice exhibited dramatically increased infarct volume, delayed brain functional recovery, and enhanced neuroinflammation and protein aggregation in the brain following I/R when compared to the Ntg mice. Intriguingly, mass-spectrometric analysis of the protein aggregates isolated from CryABR120G mouse brains confirmed presence of the mutant CryABR120G protein in the brain. Importantly, intravenous administration of WT mice with the exosomes isolated from CryABR120G mouse blood exacerbated I/R-induced cerebral injury in WT mice. Moreover, incubation of the CryABR120G mouse exosomes with primary neuronal cultures induced pronounced protein aggregation. Transduction of CryABR120G aggregate seeds into cell cultures caused normal CryAB proteins to undergo dramatic aggregation and form large aggregates, suggesting self-propagation of CryABR120G misfolding in cells.

Conclusions

These results suggest that peripherally misfolded proteins in the heart remotely enhance neuroinflammation and exacerbate brain injury following I/R likely through exosomes, which may represent an underappreciated mechanism underlying heart-brain crosstalk.
Molecular characterization of a complex small supernumerary marker chromosome derived from chromosome 18p: an addition to the literature
Authors: Marchina Eleonora , Forti Michela , Tonelli Mariella , Maccarini Stefania , Malvestiti Francesca , Piantoni Chiara , Filippini Elena , Fazzi Elisa , Borsani Giuseppe
Published: January 2021

Background

Small supernumerary marker chromosomes (sSMC) are a heterogeneous group of structurally abnormal chromosomes, with an incidence of 0,044% in newborns that increases up to almost 7 times in developmentally retarded patients. sSMC from all 24 chromosome have been described, most of them originate from the group of the acrocentric, with around half deriving from the chromosome 15. Non-acrocentric sSMC are less common and, in the 30 percent of the cases, are associated with phenotypic effect. Complex sSMC consist of chromosomal material derived from more than one chromosome. Genotype–phenotype correlations in patients with sSMC are difficult to assess. Clinical features depend on factors such as its size, genetic content, the involvement of imprinted genes which may be influenced by uniparental disomy and the level of mosaicism. Trisomy of the short arm of chromosome 18 (18p) is an infrequent finding and does not appear to be associated with a specific syndrome. However, mild intellectual disability with or without other anomalies is reported in almost one-third of the patients.

Case presentation

Here we present clinical and molecular characterization of a new case of de novo complex sSMC consisting of the entire short arm of chromosome 18p associated with a centromere of either chromosome 13 or 21, evidenced in a 5-year-old boy during diagnostic workup for moderate intellectual disability and dysmorphisms. To date, only seven cases of isolated trisomy 18p due to a sSMC have been reported, three of which have been characterized by array CGH. In two of them the breakpoints and the size of the duplication have been described. In the manuscript we also reviewed cases reported in the DECIPHER database carrying similar duplication and also considered smaller duplications within the region of interest, in order to evaluate the presence of critical regions implicated in the pathological phenotype.

Conclusions

Our case provides additional information about phenotypic effects of pure trisomy 18p, confirms chromosomal microarray analysis as gold standard to characterize complex sSMC, and supplies additional elements for genetic counselling.
Identification of a small molecule as inducer of ferroptosis and apoptosis through ubiquitination of GPX4 in triple negative breast cancer cells
Authors: Ding Yahui , Chen Xiaoping , Liu Can , Ge Weizhi , Wang Qin , Hao Xin , Wang Mengmeng , Chen Yue , Zhang Quan
Published: January 2021

Background

TNBC is the most aggressive breast cancer with higher recurrence and mortality rate than other types of breast cancer. There is an urgent need for identification of therapeutic agents with unique mode of action for overcoming current challenges in TNBC treatment.

Methods

Different inhibitors were used to study the cell death manner of DMOCPTL. RNA silencing was used to evaluate the functions of GPX4 in ferroptosis and apoptosis of TNBC cells and functions of EGR1 in apoptosis. Immunohistochemical assay of tissue microarray were used for investigating correlation of GPX4 and EGR1 with TNBC. Computer-aided docking and small molecule probe were used for study the binding of DMOCPTL with GPX4.

Results

DMOCPTL, a derivative of natural product parthenolide, exhibited about 15-fold improvement comparing to that of the parent compound PTL for TNBC cells. The cell death manner assay showed that the anti-TNBC effect of DMOCPTL mainly by inducing ferroptosis and apoptosis through ubiquitination of GPX4. The probe of DMOCPTL assay indicated that DMOCPTL induced GPX4 ubiquitination by directly binding to GPX4 protein. To the best of our knowledge, this is the first report of inducing ferroptosis through ubiquitination of GPX4. Moreover, the mechanism of GPX4 regulation of apoptosis is still obscure. Here, we firstly reveal that GPX4 regulated mitochondria-mediated apoptosis through regulation of EGR1 in TNBC cells. Compound 13, the prodrug of DMOCPTL, effectively inhibited the growth of breast tumor and prolonged the lifespan of mice in vivo, and no obvious toxicity was observed.

Conclusions

These findings firstly revealed novel manner to induce ferroptosis through ubiquitination of GPX4 and provided mechanism for GPX4 inducing mitochondria-mediated apoptosis through up-regulation of EGR1 in TNBC cells. Moreover, compound 13 deserves further studies as a lead compound with novel mode of action for ultimate discovery of effective anti-TNBC drug.
Lnc-GULP1–2:1 affects granulosa cell proliferation by regulating COL3A1 expression and localization
Authors: Yao Guidong , Kong Yue , Yang Guang , Kong Deqi , Xu Yijiang , He Jiahuan , Xu Ziwen , Bai Yucheng , Fan Huiying , He Qina , Sun Yingpu
Published: January 2021

Backgrounds

Long non-coding RNA is a novel group of non-protein coding transcripts over 200 nt in length. Recent studies have found that they are widely involved in many pathological and physiological processes. In our previous study, we found that lnc-GULP1–2:1 was significantly down-regulated in the ovarian cortical tissue of patients with primary ovarian insufficiency and predicted that lnc-GULP1–2:1 has a regulatory effect on COL3A1.

Results

In this study, we found that lnc-GULP1–2:1 was mainly localized in the cytoplasm of luteinized granulosa cells. The expression of lnc-GULP1–2:1 was lower in patients with diminished ovarian reserve but substantially elevated in patients with polycystic ovary syndrome. Overexpression of lnc-GULP1–2:1 in KGN cells significantly inhibited cell proliferation, likely through cell cycle related genes CCND2 and p16. Moreover, lnc-GULP1–2:1 expression was positively correlated with the level of COL3A in luteinized granulosa cells from patients with different ovarian functions as well as in multiple cell lines. Overexpression of lnc-GULP1–2:1 in KGN cells promoted the expression of COL3A1 and its translocation into the nucleus. Consistently, silencing COL3A1 in KGN cells also significantly inhibited cell proliferation.

Conclusions

Lnc-GULP1–2:1 affects the proliferation of granulosa cells by regulating the expression and localization of COL3A1 protein, and may participate in the regulation of ovarian follicle development. This study will provide new insight into molecular mechanisms underlying ovarian follicular development, which will help generate novel diagnostic and therapeutic strategies for diseases related to ovarian follicular development disorders.
Semi-elemental versus polymeric formula for enteral nutrition in brain-injured critically ill patients: a randomized trial
Authors: Carteron Laurent , Samain Emmanuel , Winiszewski Hadrien , Blasco Gilles , Balon Anne-Sophie , Gilli Camille , Piton Gael , Capellier Gilles , Pili-Floury Sebastien , Besch Guillaume
Published: January 2021

Background

The properties of semi-elemental enteral nutrition might theoretically improve gastrointestinal tolerance in brain-injured patients, known to suffer gastroparesis. The purpose of this study was to compare the efficacy and tolerance of a semi-elemental versus a polymeric formula for enteral nutrition (EN) in brain-injured critically ill patients.

Methods

Prospective, randomized study including brain-injured adult patients [Glasgow Coma Scale (GCS) ≤ 8] with an expected duration of mechanical ventilation > 48 h. Intervention: an enteral semi-elemental (SE group) or polymeric (P group) formula. EN was started within 36 h after admission to the intensive care unit and was delivered according to a standardized nurse-driven protocol. The primary endpoint was the percentage of patients who received both 60% of the daily energy goal at 3 days and 100% of the daily energy goal at 5 days after inclusion. Tolerance of EN was assessed by the rate of gastroparesis, vomiting and diarrhea.

Results

Respectively, 100 and 95 patients were analyzed in the SE and P groups: Age (57[44–65] versus 55[40–65] years) and GCS (6[3–7] versus 5[3–7]) did not differ between groups. The percentage of patients achieving the primary endpoint was similar (46% and 48%, respectively; relative risk (RR) [95% confidence interval (CI)] = 1.05 (0.78–1.42); p = 0.73). The mean daily energy intake was, respectively, 20.2 ± 6.3 versus 21.0 ± 6.5 kcal/kg/day (p = 0.42). Protein intakes were 1.3 ± 0.4 versus 1.1 ± 0.3 g/kg/day (p < 0.0001). Respectively, 18% versus 12% patients presented gastroparesis (p = 0.21), and 16% versus 8% patients suffered from diarrhea (p = 0.11). No patient presented vomiting in either group.

Conclusion

Semi-elemental compared to polymeric formula did not improve daily energy intake or gastrointestinal tolerance of enteral nutrition.

Trial registration

EudraCT/ID-RCB 2012-A00078-35 (registered January 17, 2012).
Evaluation of convalescent plasma versus standard of care for the treatment of COVID-19 in hospitalized patients: study protocol for a phase 2 randomized, open-label, controlled, multicenter trial
Authors: Diago-Sempere Elena , Bueno José Luis , Sancho-López Aránzazu , Rubio Elena Múñez , Torres Ferrán , de Molina Rosa Malo , Fernández-Cruz Ana , de Diego Isabel Salcedo , Velasco-Iglesias Ana , Payares-Herrera Concepción , Flecha Inmaculada Casas , Avendaño-Solà Cristina , Palomino Rafael Duarte , Ramos-Martínez Antonio , Ruiz-Antorán Belén
Published: January 2021

Background

COVID-19 is a respiratory disease caused by a novel coronavirus (SARS-CoV-2) and causes substantial morbidity and mortality. At the time this clinical trial was planned, there were no available vaccine or therapeutic agents with proven efficacy, but the severity of the condition prompted the use of several pharmacological and non-pharmacological interventions.

It has long been hypothesized that the use of convalescent plasma (CP) from infected patients who have developed an effective immune response is likely to be an option for the treatment of patients with a variety of severe acute respiratory infections (SARI) of viral etiology. The aim of this study is to assess the efficacy and safety of convalescent plasma in adult patients with severe COVID-19 pneumonia.

Methods/design

The ConPlas-19 study is a multicenter, randomized, open-label controlled trial. The study has been planned to include 278 adult patients hospitalized with severe COVID-19 infection not requiring mechanical ventilation (invasive or non-invasive). Subjects are randomly assigned in a 1:1 ratio (139 per treatment arm), stratified by center, to receive intravenously administered CP (single infusion) plus SOC or SOC alone, and are to be followed for 30 days. The primary endpoint of the study is the proportion of patients that progress to category 5, 6, or 7 (on the 7-point ordinal scale proposed by the WHO) at day 15. Interim analyses for efficacy and/or futility will be conducted once 20%, 40%, and 60% of the planned sample size are enrolled and complete D15 assessment.

Discussion

This clinical trial is designed to evaluate the efficacy and safety of passive immunotherapy with convalescent plasma for the treatment of adult patients hospitalized with COVID-19. The results of this study are expected to contribute to establishing the potential place of CP in the therapeutics for a new viral disease.

Trial registration

ClinicalTrials.gov NCT04345523. Registered on 30 March, 2020. First posted date: April 14, 2020.
The complexities of the diet-microbiome relationship: advances and perspectives
Authors: Leeming Emily R. , Louca Panayiotis , Gibson Rachel , Menni Cristina , Spector Tim D. , Le Roy Caroline I.
Published: January 2021

Personalised dietary modulation of the gut microbiota may be key to disease management. Current investigations provide a broad understanding of the impact of diet on the composition and activity of the gut microbiota, yet detailed knowledge in applying diet as an actionable tool remains limited. Further to the relative novelty of the field, approaches are yet to be standardised and extremely heterogeneous research outcomes have ensued. This may be related to confounders associated with complexities in capturing an accurate representation of both diet and the gut microbiota. This review discusses the intricacies and current methodologies of diet-microbial relations, the implications and limitations of these investigative approaches, and future considerations that may assist in accelerating applications. New investigations should consider improved collection of dietary data, further characterisation of mechanistic interactions, and an increased focus on -omic technologies such as metabolomics to describe the bacterial and metabolic activity of food degradation, together with its crosstalk with the host. Furthermore, clinical evidence with health outcomes is required before therapeutic dietary strategies for microbial amelioration can be made. The potential to reach detailed understanding of diet-microbiota relations may depend on re-evaluation, progression, and unification of research methodologies, which consider the complexities of these interactions.
Mode and dynamics of vanA-type vancomycin resistance dissemination in Dutch hospitals
Authors: Arredondo-Alonso Sergio , Top Janetta , Corander Jukka , Willems Rob J. L. , Schürch Anita C.
Published: January 2021

Background

Enterococcus faecium is a commensal of the gastrointestinal tract of animals and humans but also a causative agent of hospital-acquired infections. Resistance against glycopeptides and to vancomycin has motivated the inclusion of E. faecium in the WHO global priority list. Vancomycin resistance can be conferred by the vanA gene cluster on the transposon Tn1546, which is frequently present in plasmids. The vanA gene cluster can be disseminated clonally but also horizontally either by plasmid dissemination or by Tn1546 transposition between different genomic locations.

Methods

We performed a retrospective study of the genomic epidemiology of 309 vancomycin-resistant E. faecium (VRE) isolates across 32 Dutch hospitals (2012–2015). Genomic information regarding clonality and Tn1546 characterization was extracted using hierBAPS sequence clusters (SC) and TETyper, respectively. Plasmids were predicted using gplas in combination with a network approach based on shared k-mer content. Next, we conducted a pairwise comparison between isolates sharing a potential epidemiological link to elucidate whether clonal, plasmid, or Tn1546 spread accounted for vanA-type resistance dissemination.

Results

On average, we estimated that 59% of VRE cases with a potential epidemiological link were unrelated which was defined as VRE pairs with a distinct Tn1546 variant. Clonal dissemination accounted for 32% cases in which the same SC and Tn1546 variants were identified. Horizontal plasmid dissemination accounted for 7% of VRE cases, in which we observed VRE pairs belonging to a distinct SC but carrying an identical plasmid and Tn1546 variant. In 2% of cases, we observed the same Tn1546 variant in distinct SC and plasmid types which could be explained by mixed and consecutive events of clonal and plasmid dissemination.

Conclusions

In related VRE cases, the dissemination of the vanA gene cluster in Dutch hospitals between 2012 and 2015 was dominated by clonal spread. However, we also identified outbreak settings with high frequencies of plasmid dissemination in which the spread of resistance was mainly driven by horizontal gene transfer (HGT). This study demonstrates the feasibility of distinguishing between modes of dissemination with short-read data and provides a novel assessment to estimate the relative contribution of nested genomic elements in the dissemination of vanA-type resistance.