bluuebunny/crossref_metadata_2025 huggingface dataset:
Studying SARS-CoV-2 vaccine hesitancy among health professionals in Tunisia
Authors: Zammit Nawel , Gueder Amani El , Brahem Aïcha , Ayouni Imen , Ghammam Rim , Fredj Sihem Ben , Sridi Chaima , Chouchene Asma , Kalboussi Houda , Maalel Olfa El , Chatti Souhaeil , Maatoug Jihene , Ghannem Hassen , Mrizak Néjib
Published: April 2022

Background

People's lives were seriously affected by the emergence and the spread of the COVID-19 disease. Several vaccines were developed in record time to overcome this pandemic. However, putting an end to this public health problem requires substantial vaccination coverage rate. This latter depends on the acceptance of these vaccines especially by health professionals; the leaders of the current war against COVID-19. In fact, they have a central role in promoting vaccination against the SARS-CoV-2. In the developed countries, hesitancy rates towards these vaccines among health professionals vary from 4.3% to 72%. In the developing countries, few studies focused on this issue.

Objective

To estimate the prevalence and the predictors of SARS-CoV-2 vaccine hesitancy among the Tunisian health professionals.

Methods

A cross-sectional study was led online between the 7th and the 21th of January 2021 among Tunisian health professionals. At least 460 participants were required. Snowball sampling method served to recruit participants. Data were collected using a pre-established and pre-tested questionnaire recorded in a free Google form. The link of the questionnaire was disseminated online to be self-administered anonymously to the participants. The generated online Google Sheet was uploaded and exported to SPSS software for analysis.

Results

Of the 546 responses, 493 were retained. The mean age of participants was 37.4 (± 9.5) years. Females represented 70.2% of participants. Social media represented the most frequently used source of information about COVID-19. The prevalence of SARS-CoV-2 vaccine hesitancy among participants was 51.9% (95% CI: 47.5–56.3)). Female sex, working far from the capital and having concerns about the vaccines components predicted more hesitancy among participants. In contrast, the use of the national COVID-19 information website predicted less hesitancy among them.

Conclusions

The current Tunisian communication plan about COVID-19 vaccines must be reinforced. Social media represent a cost effective communication channel that can serve to reassure Tunisian health professionals regarding the safety of COVID-19 vaccines. Special interest should be paid to females, paramedical professionals and those working far from the capital.
Measuring treatment attrition at various stages of engagement in Opioid Agonist Treatment in Ontario Canada using a cascade of care framework
Authors: Tahsin Farah , Morin Kristen A. , Vojtesek Frank , Marsh David C.
Published: April 2022

Background

The cascade of care framework is an effective way to measure attrition at various stages of engagement in Opioid Agonist Treatment (OAT). The primary objective of the study was to describe the cascade of care for patients who have accessed OAT from a network of specialized addiction clinics in Ontario, Canada. The secondary objectives were to evaluate correlates associated with retention in OAT at various stages and the impact of patients’ location of the residence on retention in OAT.

Design

A multi-clinic retrospective cohort study was conducted using electronic medical record (EMR) data from the largest network of OAT clinics in Canada (70 clinics) from 2014 to 2020. Study participants included all patients who received OAT from the network of clinics during the study period.

Measurements

In this study, four stages of the cascade of care framework were operationalized to identify treatment engagement patterns, including patients retained within 90 days, 90 to 365 days, one to 2 years, and more than 2 years. Correlates associated with OAT retention for 90 days, 90 to 365 days, 1 to 2 years, and more than 2 years were also evaluated and compared across rural and urban areas in northern and southern Ontario.

Results

A total of 32,487 patients were included in the study. Compared to patients who were retained in OAT for 90 days, patients who were retained for 90 to 365 days, 1 to 2 years, or more than 2 years were more likely to have a higher number of treatment attempts, a higher number of average monthly urine drug screening and a lower proportion of positive urine drug screening results for other drug use.

Conclusion

Distinct sociodemographic and clinical factors are likely to influence treatment retention at various stages of engagement along the OAT continuum. Research is required to determine if tailored strategies specific to people at different stages of retention have the potential to improve outcomes of OAT.
miR-489-3p promotes malignant progression of non-small cell lung cancer through the inactivation of Wnt/β-catenin signaling pathway via regulating USP48
Authors: Zhang Pei , Li Li , Wang Bing , Ran Xu , Yang Shengrong , Luo Yujie , Li Yunhe , Wang Zhenghong , Liu Yi , Zhu Bing
Published: April 2022

Background

Non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer globally, with average age of cancer patients becoming younger gradually. It is of significance to gain a comprehensive understanding of molecular mechanism underlying NSCLC.

Methods

Quantitative polymerase chain reaction (qPCR) and western blot were applied to measure RNA and protein levels separately. Functional assays and western blot were performed to determine the effects of miR-489-3p and USP48 on cell growth, migration and epithelial-mesenchymal transition (EMT) in NSCLC. TOP/FOP flash luciferase reporter assay was carried out to detect the activity of Wnt pathway. Besides, qPCR, RNA pulldown and luciferase reporter assays were conducted to probe into the target gene of miR-489-3p. Immunoprecipitation-western blot (IP-western blot) analysis was implemented to assess the effect of USP48 on the ubiquitination of β-catenin.

Results

miR-489-3p hampers NSCLC cell proliferation, migration and EMT in vitro and NSCLC tumorigenesis and metastasis in vivo. Additionally, miR-489-3p inactivates Wnt/β-catenin signaling pathway and regulates USP48 to inhibit the ubiquitination of β-catenin. Moreover, USP48 propels the development of NSCLC cells.

Conclusions

The current study demonstrated that miR-489-3p promotes the malignant progression of NSCLC cells via targeting USP48, which might offer a new perspective into NSCLC treatment.

Graphical abstract
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

Malaria 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

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

Albumin-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

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

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

Background

Physically 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).

Methods

This 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).

Results

Eleven 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.

Conclusion

This 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

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

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

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.
Transparency in quality of radiotherapy for breast cancer in the Netherlands: a national registration of radiotherapy-parameters
Authors: Maliko Nansi , Stam Marcel R. , Boersma Liesbeth J. , Vrancken Peeters Marie-Jeanne T. F. D. , Wouters Michel W. J. M. , KleinJan Eline , Mulder Maurice , Essers Marion , Hurkmans Coen W. , Bijker Nina
Published: April 2022

Background

Radiotherapy (RT) is part of the curative treatment of approximately 70% of breast cancer (BC) patients. Wide practice variation has been reported in RT dose, fractionation and its treatment planning for BC. To decrease this practice variation, it is essential to first gain insight into the current variation in RT treatment between institutes. This paper describes the development of the NABON Breast Cancer Audit-Radiotherapy (NBCA-R), a structural nationwide registry of BC RT data of all BC patients treated with at least surgery and RT.

Methods

A working group consisting of representatives of the BC Platform of the Dutch Radiotherapy Society selected a set of dose volume parameters deemed to be surrogate outcome parameters, both for tumour control and toxicity. Two pilot studies were carried out in six RT institutes. In the first pilot study, data were manually entered into a secured web-based system. In the second pilot study, an automatic Digital Imaging and Communications in Medicine (DICOM) RT upload module was created and tested.

Results

The NBCA-R dataset was created by selecting RT parameters describing given dose, target volumes, coverage and homogeneity, and dose to organs at risk (OAR). Entering the data was made mandatory for all Dutch RT departments. In the first pilot study (N = 1093), quite some variation was already detected. Application of partial breast irradiation varied from 0 to 17% between the 6 institutes and boost to the tumour bed from 26.5 to 70.2%. For patients treated to the left breast or chest wall only, the average mean heart dose (MHD) varied from 0.80 to 1.82 Gy; for patients treated to the breast/chest wall only, the average mean lung dose (MLD) varied from 2.06 to 3.3 Gy. In the second pilot study 6 departments implemented the DICOM-RT upload module in daily practice. Anonymised data will be available for researchers via a FAIR (Findable, Accessible, Interoperable, Reusable) framework.

Conclusions

We have developed a set of RT parameters and implemented registration for all Dutch BC patients. With the use of an automated upload module registration burden will be minimized. Based on the data in the NBCA-R analyses of the practice variation will be done, with the ultimate aim to improve quality of BC RT.

Trial registration Retrospectively registered.
High-mobility group box chromosomal protein-1 deletion alleviates osteoporosis in OVX rat model via suppressing the osteoclastogenesis and inflammation
Authors: Yu Haotao , Zhou Wei , Zhong Zhihong , Qiu Ruixin , Chen Guoquan , Zhang Ping
Published: April 2022

Background

Osteoporosis is a skeletal metabolic disease that constitutes a great threaten to human health. However, there is currently no gold standard for its treatment. High-mobility group box chromosomal protein-1 (HMGB-1) has been reported to play an important role in various orthopedic diseases. Till now, its role in osteoporosis remains elusive.

Methods

Rats underwent ovariectomy (OVX) were used to construct a postmenopausal model of osteoporosis. Then, rats were divided into sham groups without OVX surgery, OVX model group, HMGB-1 knockdown (HMGB-1 KD) OVX model groups. The expression of HMGB1 was evaluated by qRT-PCR and western blotting. Subsequently, the changes of trabeculae were evaluated by micro-computed tomography (CT) assay. Skeletal necrosis and metabolism were further analyzed by hematoxylin–eosin (HE) staining, Alcian blue staining and Masson’s trichrome staining. The contents of serum alkaline phosphatase (ALP) and osteocalcin were detected by ELISA assay. Expression of osteoclast-associated receptor (OSCAR) and tartrate-resistant acid phosphatase (TRAP) were determined to investigate the effects of HMGB-1 loss on osteoclastogenesis.

Results

Single HMGB-1 deletion exerted no significant effect on rat trabeculae, serum ALP and osteocalcin. Noticeably, HMGB1 knockdown dramatically ameliorated OVX-induced changes in above indexes. Trabeculae structures of OVX rats were sparse with disorder arrangement, which were greatly recovered after HMGB-1 deletion. Enhanced osteoclastogenesis was observed in OVX rats by increasing number of TRAP + cells and expression of TRAP and OSCAR, and loss of HMGB1 ameliorated osteoclastogenesis in OVA rats. Moreover, HMGB-1 deletion antagonized OVX-evoked downregulation of osteoblast activity markers osterix (OSX), collagen type I alpha 1(COL1A1) and distal-less homeobox 2 (DLX2) protein. Furthermore, loss of HMGB-1 attenuated fluctuation of inflammatory factors in OVX rats. Additionally, HMGB-1 deficiency inhibited OVX-evoked activation of the Toll-like receptor (TLR) 4/NF-κB signaling pathway. Moreover, reactivating the TLR4 signaling further aggravated OVX-induced osteoporosis, which was reversed by HMGB1 knockdown.

Conclusion

HMGB-1 deletion alleviated OVX-triggered osteoporosis by suppressing osteoclastogenesis and inflammatory disorder via the inhibition of the TLR4 signaling. Therefore, HMGB-1 may be a promising therapeutic target for osteoporosis.
Clinical characteristics of multicentric reticulohistiocytosis and distinguished features from rheumatoid arthritis: a single-center experience in China
Authors: Zou Xiao-juan , Qiao Lin , Li Feng , Chen Hua , Yang Yun-jiao , Xu Dong , Zheng Wen-Jie , Jiang Zhen-yu , Wang Li , Wu Qing-jun , Zhang Feng-Chun
Published: April 2022

Objective

To investigate the clinical features of multicentric reticulohistiocytosis (MRH).

Methods

The clinical manifestations, laboratory examination results and histologic characteristics of eleven patients with MRH were collected and compared with those of 33 patients with rheumatoid arthritis.

Results

In total, 72.7% of the MRH patients were women. The median age was 46 years (range 33–84 years). Diagnosed by specific pathologic features, all MRH patients exhibited cutaneous involvement. The dorsa of the hands, arms, face and auricle were the most commonly affected areas. Nodules were also located on the legs, scalp, trunk, neck, and even the hypoglossis and buccal mucosa. Ten MRH patients (90.9%) had symmetric polyarthritis. Compared with rheumatoid arthritis (RA) patients, MRH patients were more likely to have distal interphalangeal joint (DIP) involvement (63.6% vs 24.2%, P = 0.017) and less likely to have elbow (36.4% vs 72.7%, P = 0.003), ankle (45.5% vs 93.9%, P < 0.001) and metacarpophalangeal joint (MCP) (36.4% vs 78.8%, P = 0.009) involvement. Positivity for rheumatoid factor (RF) (36.4% vs 84.6%, P = 0.001) and anti-CCP antibody (9.1% vs 81.8%, P = 0.000), as well as the median RF titer [43.8 (31.7–61.0) vs 175.4 (21.3–940.3), P = 0.021], in MRH patients was lower than in RA patients. Elevation of the erythrocyte sedimentation rate (ESR) was also less common in MRH patients than in RA patients (36.4% vs 72.7%, P = 0.030). After treatment with median- to large-dose corticosteroids and disease-modifying antirheumatic drugs, 8 patients achieved complete remission and 2 patients partial remission (skin lesions ameliorated, joint lesions not ameliorated).

Conclusion

Always pathologically diagnosed, MRH is a systemic disease involving RA-like erosive polyarthritis and a specific distribution of skin nodules characterized by "coral beads". More DIP involvement and less elbow, ankle and MCP involvement are seen in MRH than in RA. In addition, less positivity and lower-titer RF, uncommon presence of anti-CCP antibodies and ESR elevation may be helpful to distinguish MRH from RA.
Emerging role of RNA sensors in tumor microenvironment and immunotherapy
Authors: Yang Rui , Yu Sihui , Xu Tianhan , Zhang Jiawen , Wu Sufang
Published: April 2022

RNA sensors detect foreign and endogenous RNAs to protect the host by initiating innate and adaptive immune response. In tumor microenvironment (TME), activation of RNA sensors induces tumor-inhibitory cytotoxic T lymphocyte responses and inhibits the activity of immunosuppressive cells though stimulating type I IFN signaling pathway. These characteristics allow RNA sensors to be prospective targets in tumor immunotherapy. Therefore, a comprehensive understanding of the roles of RNA sensors in TME could provide new insight into the antitumor immunotherapy. Moreover, RNA sensors could be prominent triggering targets to synergize with immunotherapies. In this review, we highlight the diverse mechanisms of RNA sensors in cancer immunity and their emerging contributions in cancer immunotherapy, including monotherapy with RNA sensor agonists, as well as combination with chemotherapy, radiotherapy, immune checkpoint blockade or cancer vaccine.
Standardised data collection in prehospital critical care: a comparison of medical problem categories and discharge diagnoses
Authors: Tommila Miretta , Pappinen Jukka , Raatiniemi Lasse , Saviluoto Anssi , Toivonen Tuukka , Björkman Johannes , Nurmi Jouni
Published: April 2022

Background

Prehospital medical problem reporting is essential in the management of helicopter emergency medical services (HEMS) operations. The consensus-based template for reporting and documenting in physician-staffed prehospital services exists and the classification of medical problems presented in the template is widely used in research and quality improvement. However, validation of the reported prehospital medical problem is lacking. This study aimed to describe the in-hospital diagnoses, patient characteristics and medical interventions in different categories of medical problems.

Methods

This retrospective, observational registry study examined the 10 most common in-hospital International Statistical Classification of Disease (ICD-10) diagnoseswithin different prehospital medical problem categories, defined by the HEMS physician/paramedic immediately after the mission was completed. Data were gathered from a national HEMS quality registry and a national hospital discharge registry. Patient characteristics and medical interventions related to different medical problem categories are also described.

Results

A total of 33,844 patients were included in the analyses. All the medical problem categories included a broad spectrum of ICD-10 diagnoses (the number of diagnosis classes per medical problem category ranged from 73 to 403). The most frequent diagnoses were mainly consistent with the reported medical problems. Overlapping of ICD-10 diagnoses was mostly seen in two medical problem categories: stroke and acute neurology excluding stroke. Additionally, typical patient characteristics and disturbances in vital signs were related to adequate medical problem categories.

Conclusions

Medical problems reported by HEMS personnel have adequate correspondence to hospital discharge diagnoses. However, the classification of cerebrovascular accidents remains challenging.
Genome-wide and transcriptome-wide association studies of mammographic density phenotypes reveal novel loci
Authors: Chen Hongjie , Fan Shaoqi , Stone Jennifer , Thompson Deborah J. , Douglas Julie , Li Shuai , Scott Christopher , Bolla Manjeet K. , Wang Qin , Dennis Joe , Michailidou Kyriaki , Li Christopher , Peters Ulrike , Hopper John L. , Southey Melissa C. , Nguyen-Dumont Tu , Nguyen Tuong L. , Fasching Peter A. , Behrens Annika , Cadby Gemma , Murphy Rachel A. , Aronson Kristan , Howell Anthony , Astley Susan , Couch Fergus , Olson Janet , Milne Roger L. , Giles Graham G. , Haiman Christopher A. , Maskarinec Gertraud , Winham Stacey , John Esther M. , Kurian Allison , Eliassen Heather , Andrulis Irene , Evans D. Gareth , Newman William G. , Hall Per , Czene Kamila , Swerdlow Anthony , Jones Michael , Pollan Marina , Fernandez-Navarro Pablo , McConnell Daniel S. , Kristensen Vessela N. ,   NBCS Investigators, Rothstein Joseph H. , Wang Pei , Habel Laurel A. , Sieh Weiva , Dunning Alison M. , Pharoah Paul D. P. , Easton Douglas F. , Gierach Gretchen L. , Tamimi Rulla M. , Vachon Celine M. , Lindström Sara
Published: April 2022

Background

Mammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants.

Methods

We conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/BCAC consortia.

Results

We identified 28 genome-wide significant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype atp < 0.05. TWAS further identified two novel genes (SHOX2andCRISPLD2) whose genetically predicted expression was significantly associated with MD phenotypes.

Conclusions

Our findings provided novel insight into the genetic background of MD phenotypes, and further demonstrated their shared genetic basis with breast cancer.
A quasi-randomised controlled trial of online distribution of home-based hepatitis C self-testing for key populations in Malaysia: a study protocol
Authors: Shilton Sonjelle , Sem Xiaohui , Chan Huan-Keat , Chung Han Yang , Karunanithy Anu , Markby Jessica , Chan Po-Lin , Luhmann Niklas , Johnson Cheryl , Nabeta Pamela , Nasir Nazrila Hairizan Bt , Ongarello Stefano , Reipold Elena Ivanova , Hassan Muhammad Radzi Abu
Published: April 2022

Background

Malaysia has an estimated hepatitis C virus (HCV) prevalence of 1.9% among its adult population and a history of providing HCV treatment in the public sector. In 2019, Malaysia launched a 5-year national strategic plan for viral hepatitis control and has been expanding HCV testing and treatment to the primary care and community levels, while actively engaging key populations in services for hepatitis care. The Ministry of Health (MoH) is seeking to specifically understand how to better target HCV services at men who have sex with men (MSM); HCV self-testing could increase the uptake of HCV testing among this group.

Methods

We aim to integrate HCV antibody self-testing into an existing online platform used for HIV self-testing, to evaluate the acceptability and impact of an online HCV self-testing programme in Malaysia. This is a non-blinded parallel group quasi-randomised superiority study comparing HCV self-testing via an online distribution model with the standard care, which involves attending a clinic for facility-based HCV antibody testing (control, 2:1). Participants will be randomised to either the HCV self-testing via online distribution arm, in which either an oral fluid- or blood-based HCV self-test kit will be mailed to them, or the control arm, where they will be provided with information about the nearest centre with HCV testing. The primary outcome is the number and proportion of participants who report completion of testing. Secondary outcomes include the number and proportion of participants who (a) receive a positive result and are made aware of their status, (b) are referred to and complete HCV RNA confirmatory testing, and (c) start treatment. Acceptability, feasibility, attitudes around HCV testing, and cost will also be evaluated. The target sample size is 750 participants.

Discussion

This study is one of the first in the world to explore the real-world impact of HCV self-testing on key populations using online platforms and compare this with standard HCV testing services. The outcomes of this study will provide critical evidence about testing uptake, linkage to care, acceptability, and any social harms that may emerge due to HCV self-testing.

Trial registration

ClinicalTrials.gov NCT04982718
Transcranial direct current stimulation to modulate brain reactivity to food cues in overweight and obese adults: study protocol for a randomized controlled trial with fMRI (NeuroStim-Obesity)
Authors: Ghobadi-Azbari Peyman , Malmir Nastaran , Vartanian Meghedi , Mahdavifar-Khayati Rasoul , Robatmili Somaye , Hadian Venus , Derafsheh Sara , Nitsche Michael A. , Nosratabadi Masoud , Farhoudian Ali , Ekhtiari Hamed
Published: April 2022

Background

With increasing obese populations worldwide, developing interventions to modulate food-related brain processes and functions is particularly important. Evidence suggests that transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) may modulate the reward–control balance towards facilitation of cognitive control and possible suppression of reward-related mechanisms that drive food cue-induced craving. This protocol describes a clinical trial that investigates the neurocognitive mechanisms of action for tDCS to modulate food cue-reactivity and cravings in people with obesity.

Method

The NeuroStim-Obesity trial is a prospective, randomized, sham-controlled, double-blind single-session tDCS trial targeting food craving in those with obesity or overweighed. Once randomized, 64 adults with obesity or overweighed complete one session in which they receive either active or sham tDCS over the DLPFC (anode F4 and cathode F3, 2 mA intensity for 20 min). The primary outcome is change in neural response to the food cue-reactivity task in the ventral striatum after a single-session bilateral tDCS compared to sham stimulation. Secondary outcomes include changes in food craving evaluated by the Food Craving Questionnaire-State (FCQ-S). We will also explore the predictive role of brain structure and functional networks assessed by structural and functional magnetic resonance imaging (MRI) during both task performance and the resting-state that are acquired pre- and post-intervention to predict response to tDCS.

Discussion

The results will provide novel insight into neuroscience for the efficacy of tDCS and will advance the field towards precision medicine for obesity. Exploratory results will examine the potential predictive biomarkers for tDCS response and eventually provide personalized intervention for the treatment of obesity.

Trial registration

Iranian Registry of Clinical Trials (IRCT) IRCT20121020011172N4. Retrospectively registered on 4 June 2020