bluuebunny/crossref_metadata_2025_split huggingface dataset:
Re-orienting anti-malarial drug development to better serve pregnant women
Authors: El Gaaloul Myriam , Tornesi Belen , Lebus Flynn , Reddy David , Kaszubska Wiweka 
Published: April 2022

AbstractMalaria is one of the most serious infectious diseases affecting predominantly low- and middle-income countries, where pregnant women are among the populations at risk. There are limited options to prevent or treat malaria in pregnancy, particularly in the first trimester, and existing ones may not work optimally in areas where the threat of drug resistance is rising. As malaria elimination is a key goal of the global health community, the inclusion of pregnant women in the adult population to protect from malaria will be key to achieving success. New, safe, and effective options are needed but it can take decades of evidence-gathering before a medicine is recommended for use in pregnancy. This is because pregnant women are typically not included in pre-registration clinical trials due to fear of causing harm. Data to support dosing and safety in pregnancy are subsequently collected in post-licensure studies. There have been growing calls in recent years that this practice needs to change, amplified by the COVID-19 pandemic and increasing public awareness that newly developed medicines generally cannot be administered to pregnant women from the onset. The development of new anti-malarials should ensure that data informing their use in pregnancy and breastfeeding are available earlier. To achieve this, a mindset change and a different approach to medications for pregnant women are needed. Changes in non-clinical, translational, and clinical approaches in the drug development pathway, in line with recent recommendations from the regulatory bodies are proposed in this Comment. The new approach applies to any malaria-endemic region, regardless of the type of Plasmodium responsible for malaria cases. By incorporating intentional and systematic data collection from pre-registration stages of development through post-licensure, it will be possible to inform on the benefit/risk balance of a new anti-malarial earlier and help ensure that the needs of pregnant individuals are addressed in a more timely and equitable manner in the future.
Air pollution and biomarkers of cardiovascular disease and inflammation in the Malmö Diet and Cancer cohort
Authors: Azzouz Mehjar , Xu Yiyi , Barregard Lars , Fagerberg Björn , Zöller Bengt , Molnár Peter , Oudin Anna , Spanne Mårten , Engström Gunnar , Stockfelt Leo 
Published: April 2022

Abstract
Introduction
Air pollution is associated with increased risk of cardiovascular disease, possibly through chronic systemic inflammation that promotes the progression of atherosclerosis and the risk of cardiovascular events. This study aimed to investigate the associations between air pollution and established biomarkers of inflammation and cardiovascular disease.

Methods
The Cardiovascular Subcohort of the Malmö Diet and Cancer cohort includes 6103 participants from the general population of Malmö, Sweden. The participants were recruited 1991–1994. Annual mean residential exposure to particulate matter < 2.5 and < 10 μm (PM2.5 and PM10), and nitrogen oxides (NOx) at year of recruitment were assigned from dispersion models. Blood samples collected at recruitment, including blood cell counts, and biomarkers (lymphocyte- and neutrophil counts, C-reactive protein (CRP), soluble urokinase-type plasminogen activator receptor (suPAR), lipoprotein-associated phospholipase A2 (Lp-PLA2), ceruloplasmin, orosomucoid, haptoglobin, complement-C3, and alpha-1-antitrypsin) were analyzed. Multiple linear regression models were used to investigate the cross-sectional associations between air pollutants and biomarkers.

Results
The mean annual exposure levels in the cohort were only slightly or moderately above the new WHO guidelines of 5 μg/m3 PM2.5 (10.5 μg/m3 PM2.5). Residential PM2.5 exposure was associated with increased levels of ceruloplasmin, orosomucoid, C3, alpha-1-antitrypsin, haptoglobin, Lp-PLA2 and the neutrophil-lymphocyte ratio. Ceruloplasmin, orosomucoid, C3 and alpha-1-antitrypsin were also positively associated with PM10. There were no associations between air pollutants and suPAR, leukocyte counts or CRP. The associations between particles and biomarkers were still significant after removing outliers and adjustment for CRP levels. The associations were more prominent in smokers.

Conclusion
Long-term residential exposure to moderate levels of particulate air pollution was associated with several biomarkers of inflammation and cardiovascular disease. This supports inflammation as a mechanism behind the association between air pollution and cardiovascular disease.
Preclinical safety and hepatotoxicity evaluation of biomineralized copper sulfide nanoagents
Authors: Xia Ya-Nan , Zu He , Guo Haoxiang , Jiang Tianyan , Yang Siqi , Yu Huan , Zhang Shaodian , Ding Heng , Li Xiaoyu , Wang Yangyun , Wang Yong , Zhang Leshuai W. 
Published: April 2022

AbstractAlbumin-biomineralized copper sulfide nanoparticles (Cu2−xS NPs) have attracted much attention as an emerging phototheranostic agent due to their advantages of facile preparation method and high biocompatibility. However, comprehensive preclinical safety evaluation is the only way to meet its further clinical translation. We herein evaluate detailedly the safety and hepatotoxicity of bovine serum albumin-biomineralized Cu2−xS (BSA@Cu2−xS) NPs with two different sizes in rats. Large-sized (LNPs, 17.8 nm) and small-sized (SNPs, 2.8 nm) BSA@Cu2−xS NPs with great near-infrared absorption and photothermal conversion efficiency are firstly obtained. Seven days after a single-dose intravenous administration, SNPs distributed throughout the body are cleared primarily through the feces, while a large amount of LNPs remained in the liver. A 14-day subacute toxicity study with a 28-day recovery period are conducted, showing long-term hepatotoxicity without recovery for LNPs but reversible toxicity for SNPs. Cellular uptake studies indicate that LNPs prefer to reside in Kupffer cells, leading to prolonged and delayed hepatotoxicity even after the cessation of NPs administration, while SNPs have much less Kupffer cell uptake. RNA-sequencing analysis for gene expression indicates that the inflammatory pathway, lipid metabolism pathway, drug metabolism-cytochrome P450 pathway, cholesterol/bile acid metabolism pathway, and copper ion transport/metabolism pathway are compromised in the liver by two sizes of BSA@Cu2−xS NPs, while only SNPs show a complete recovery of altered gene expression after NPs discontinuation. This study demonstrates that the translational feasibility of small-sized BSA@Cu2−xS NPs as excellent nanoagents with manageable hepatotoxicity.
Graphical Abstract
Health-related quality of life among Chinese patients with Crohn’s disease: a cross-sectional survey using the EQ-5D-5L
Authors: Gao Ziyun , Wang Pei , Hong Jie , Yan Yuqing , Tong Tianying , Wu Bin , Hu Jun , Wang Zhenhua 
Published: April 2022

Abstract
Background
Crohn’s disease (CD) is a chronic disease that may have an adverse impact on health-related quality of life (HRQoL). This study aimed to describe the HRQoL of CD patients and assess correlating factors using the EQ-5D-5L in China.

Methods
We recruited CD patients at Shanghai Renji Hospital from October 2018 to May 2019. The data collected included demographic and clinical information, medical expenditures, and EQ-5D-5L questionnaire responses. The chi-square test or Fisher’s exact test was applied to analyse the proportion of patients in subgroups at each level. After the selection of correlating variables by univariate analysis, multivariate regression analyses were used to explore the correlating factors of HRQoL in CD patients.

Results
A total of 202 CD inpatients with a mean disease duration of 3.3 years were enrolled in the study. A total of 71.8% of patients were males, and 49.5% of patients were aged between 30 and 49 years. The average EQ-5D-5L utility score was 0.85, with a standard deviation (SD) of 0.12. Males, ileum lesions, remission status, and lower expenditure predicted higher EQ-5D-5L scores. In each EQ-5D-5L dimension, the proportion of patients differed significantly by gender, disease activity and location subgroup. In the multivariate regression models, being in an active CD state and using antibiotics had significantly adverse impacts on HRQoL (p < 0.05).

Conclusions
CD may have a significant negative impact on HRQoL in Chinese CD patients. Being in an active phase of the disease and using antibiotics were identified as affecting HRQoL.
Identification of a pyroptosis-related lncRNA risk model for predicting prognosis and immune response in colon adenocarcinoma
Authors: Tan Yuying , Lu Liqing , Liang Xujun , Chen Yongheng 
Published: April 2022

Abstract
Background
Colon adenocarcinoma (COAD) is one of the most common malignant tumors and is diagnosed at an advanced stage with a poor prognosis worldwide. Pyroptosis is involved in the initiation and progression of tumors. This research focused on constructing a pyroptosis-related ceRNA network to generate a reliable risk model for risk prediction and immune infiltration analysis of COAD.

Methods
Transcriptome data, miRNA-sequencing data, and clinical information were downloaded from the TCGA database. First, differentially expressed mRNAs (DEmRNAs), miRNAs (DEmiRNAs), and lncRNAs (DElncRNAs) were identified to construct a pyroptosis-related ceRNA network. Second, a pyroptosis-related lncRNA risk model was developed applying univariate Cox regression analysis and least absolute shrinkage and selection operator method (LASSO) regression analysis. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses were utilized to functionally annotate RNAs contained in the ceRNA network. In addition, Kaplan-Meier analysis, receiver operating characteristic (ROC) curves, univariate and multivariate Cox regression, and nomogram were applied to validate this risk model. Finally, the relationship of this risk model with immune cells and immune checkpoint blockade (ICB)-related genes was analyzed.

Results
A total of 5373 DEmRNAs, 1159 DElncRNAs, and 355 DEmiRNAs were identified. A pyroptosis-related ceRNA regulatory network containing 132 lncRNAs, 7 miRNAs, and 5 mRNAs was constructed, and a ceRNA-based pyroptosis-related risk model including 11 lncRNAs was built. The tumor tissues were classified into high- and low-risk groups according to the median risk score. Kaplan-Meier analysis showed that the high-risk group had a shorter survival time; ROC analysis, independent prognostic analysis, and nomogram further indicated the risk model was a significant independent prognostic factor what had an excellent ability to predict patients’ risk. Moreover, immune infiltration analysis indicated that the risk model was related to immune infiltration cells (i.e., B cell naïve, T cell follicular helper, macrophage M1) and ICB-related genes (i.e., PD-1, CTLA4, HAVCR2).

Conclusions
This pyroptosis-related lncRNA risk model possessed good prognostic value, and the ability to predict the outcome of ICB immunotherapy in COAD.
Identifying essential implementation strategies: a mixed methods process evaluation of a multi-strategy policy implementation intervention for schools
Authors: Lane Cassandra , Naylor Patti-Jean , Shoesmith Adam , Wolfenden Luke , Hall Alix , Sutherland Rachel , Nathan Nicole 
Published: April 2022

AbstractBackgroundPhysically Active Children in Education (PACE) is composed of eight implementation strategies that improves schools’ implementation of a government physical activity policy. A greater understanding of each discrete implementation strategy could inform improvements to PACE for delivery at-scale. This study aimed to: (A) measure the dose delivered, fidelity, adoption and acceptability of each strategy using quantitative data; (B) identify implementation barriers and facilitators using qualitative data; and (C) explore the importance of each strategy by integrating both data sets (mixed methods).MethodsThis study used data from a cluster randomised noninferiority trial comparing PACE with an adapted version (Adapted PACE) that was delivered with reduced in-person external support to reduce costs and increase scalability. Data were collected from both trials arms for between-group comparison. Descriptive statistics were produced using surveys of principals, in-school champions and teachers; and project records maintained by PACE project officers (objective A). Thematic analysis was performed using in-school champion and project officer interviews (objective B). Both data sets were integrated via a triangulation protocol and findings synthesized in the form of meta-inferences (objective C).ResultsEleven in-school champions and six project officers completed interviews; 33 principals, 51 in-school champions and 260 teachers completed surveys. Regardless of group allocation, implementation indicators were high for at least one component of each strategy: dose delivered =100%, fidelity ≥95%, adoption ≥83%, acceptability ≥50%; and several implementation barriers and facilitators were identified within three broad categories: external policy landscape, inner organizational structure/context of schools, and intervention characteristics and processes. All strategies were considered important as use varied by school, however support from a school executive and in-school champions’ interest were suggested as especially important for optimal implementation.ConclusionThis study highlights the importance of both executive support and in-school champions for successful implementation of school physical activity policies. In particular, identifying and supporting an in-school champion to have high power and high interest is recommended for future implementation strategies. This may reduce the need for intensive external support, thus improving intervention scalability.
miR-203, fine-tunning neuroinflammation by juggling different components of NF‐κB signaling
Authors: Li Shufang , Li Linpeng , Li Jieli , Liang Xiaosheng , Song Chao , Zou Yi 
Published: April 2022

Abstract
Background
miR-203 was first indicated in maintaining skin homeostasis and innate immunity. Aberrant expression of miR-203 was found associated with pathological progressions of immune disorders, cancers, as well as neurodegenerations. Recently, increasing data on miR-203 in regulating neuroinflammation and neuronal apoptosis has raised extensive concern about the biological function of this microRNA.

Methods
Mouse model with ectopic miR-203 expression in the hippocampus was constructed by stereotactic injection of lentiviral expression vector of pre-miR-203. Association of miR-203 and mRNA of Akirin2, as well as the competition for miR-203 targeting between Akirin2 3ʹUTR and another recently characterized miR-203 target, 14-3-3θ, was verified using Dual-Luciferase Reporter Gene Assay and western blot. Microglia activation and pro-inflammatory cytokines expression in the hippocampus of mice overexpressing miR-203 was evaluated using immunohistochemistry analysis and western blot. Neuronal cell death was monitored using anti-caspase 8 in immunohistochemistry as well as TUNEL assay. Cognition of mice was assessed with a behavior test battery consisting of nesting behavior test, Barnes maze and fear conditioning test.

Results
Akirin2, an activator of NF‐κB signaling, was identified as a direct target of miR-203. By also targeting 14-3-3θ, a negative regulator of NF‐κB signaling, miR-203 displayed an overall pro-inflammatory role both in vitro and in vivo. Promoted nuclear translocation of NF‐κB and increased expression of proinflammatory cytokines were observed in cultured BV2 cells transfected with miR-203 mimics. Microglia activation and upregulation of NF‐κB, IL-1β and IL-6 were observed in mouse hippocampus with overexpression of miR-203. In addition, promoted neuronal cell death in the hippocampus and impaired neuronal activities resulted in cognitive dysfunction of mice with ectopic miR-203 expression in the hippocampus.

Conclusion
A pro-inflammatory and neurodisruptive role of miR-203 was addressed based on our data in this study. Given the identification of Akirin2 as a direct target of miR-203 and the competition with 14-3-3θ for miR-203 targeting, together with the findings of other signaling molecules in NF‐κB pathway as targets of miR-203, we proposed that miR-203 was a master modulator, fine-tunning neuroinflammation by juggling different components of NF‐κB signaling.
Morphine-induced microglial immunosuppression via activation of insufficient mitophagy regulated by NLRX1
Authors: Peng Jialing , Pan Jingrui , Wang Hongxuan , Mo Jingjing , Lan Lihuan , Peng Ying 
Published: April 2022

Abstract
Background
Chronic morphine exposure induces immunosuppression in the peripheral and central nervous system, resulting in susceptibility of patients to invading pathogens. Mitophagy is a crucial regulator of inflammation, and dysregulated mitophagy may cause immunosuppression, but whether mitophagy is linked with morphine-induced immunosuppression in the brain remains unknown. NLRX1 is the only mitochondrially localized NOD family receptor protein which serves as a critical regulator in immunity and mitophagy activation, but it remains an enigma how NLRX1 functions in the crosstalk between microglial inflammatory defense and mitophagy in the presence of morphine.

Methods
Primary microglia and astrocytes, BV2 and MA cell lines were utilized. Mice were stimulated with repeated morphine treatment to mimic chronic morphine exposure, and activation of mitophagy, lysosomal functions, and inflammation were assayed in specific brain regions and immune organs with or without NLRX1-silencing.

Results
Morphine induced microglial mitophagy in a LC3 (microtubule-associated proteins light chain 3)-dependent manner, which was mediated by NLRX1. Contrastingly, morphine impaired lysosomal functions, including generation, acidification and mitophagosome–lysosome fusion, thus leading to insufficient mitophagy activation in microglia. NLRX1-silencing inhibited mitophagy activity and rescued lysosomal functions including generation and acidification in microglia. The NLRX1-mediated incomplete mitophagy in microglial cells contributed to immunosuppression and vulnerability towards pathogenic challenge after morphine treatment. In vivo, NLRX1-mediated microglial mitophagy activation by morphine was mainly located in the murine brain cortex, striatum, and cerebellum, where NLRX1 functioned as a negative immune regulator and facilitated septic shock. Collectively, microglial immune responses to septic shock were amenable to NLRX1 silencing in the brain with morphine treatment.

Conclusion
Morphine activated insufficient mitophagy in microglia which was regulated by NLRX1, ultimately leading to host immunosuppression and susceptible conditions in the brain.
Revisiting concepts of evidence in implementation science
Authors: Brownson Ross C. , Shelton Rachel C. , Geng Elvin H. , Glasgow Russell E. 
Published: April 2022

Abstract
Background
Evidence, in multiple forms, is a foundation of implementation science. For public health and clinical practice, evidence includes the following: type 1 evidence on etiology and burden; type 2 evidence on effectiveness of interventions; and type 3: evidence on dissemination and implementation (D&I) within context. To support a vision for development and use of evidence in D&I science that is more comprehensive and equitable (particularly for type 3 evidence), this article aims to clarify concepts of evidence, summarize ongoing debates about evidence, and provide a set of recommendations and tools/resources for addressing the “how-to” in filling evidence gaps most critical to advancing implementation science.

Main text
Because current conceptualizations of evidence have been relatively narrow and insufficiently characterized in our opinion, we identify and discuss challenges and debates about the uses, usefulness, and gaps in evidence for implementation science. A set of questions is proposed to assist in determining when evidence is sufficient for dissemination and implementation. Intersecting gaps include the need to (1) reconsider how the evidence base is determined, (2) improve understanding of contextual effects on implementation, (3) sharpen the focus on health equity in how we approach and build the evidence-base, (4) conduct more policy implementation research and evaluation, and (5) learn from audience and stakeholder perspectives. We offer 15 recommendations to assist in filling these gaps and describe a set of tools for enhancing the evidence most needed in implementation science.

Conclusions
To address our recommendations, we see capacity as a necessary ingredient to shift the field’s approach to evidence. Capacity includes the “push” for implementation science where researchers are trained to develop and evaluate evidence which should be useful and feasible for implementers and reflect community or stakeholder priorities. Equally important, there has been inadequate training and too little emphasis on the “pull” for implementation science (e.g., training implementers, practice-based research). We suggest that funders and reviewers of research should adopt and support a more robust definition of evidence. By critically examining the evolving nature of evidence, implementation science can better fulfill its vision of facilitating widespread and equitable adoption, delivery, and sustainment of scientific advances.