bluuebunny/crossref_metadata_2025_split huggingface dataset:
How to scale-up: a comparative case study of scaling up a district health management strengthening intervention in Ghana, Malawi and Uganda
Authors: Bulthuis Susan , Kok Maryse , Onvlee Olivier , O’Byrne Thomasena , Amon Samuel , Namakula Justine , Chikaphupha Kingsley , Gerold Jana , Mansour Wesam , Raven Joanna , Broerse Jacqueline E. W. , Dieleman Marjolein 
Published: January 2023

Abstract
Background
The need to scale up public health interventions in low- and middle-income countries to ensure equitable and sustainable impact is widely acknowledged. However, there has been little understanding of how projects have sought to address the importance of scale-up in the design and implementation of their initiatives. This paper aims to gain insight into the facilitators of the scale-up of a district-level health management strengthening intervention in Ghana, Malawi and Uganda.

Methods
The study took a comparative case study approach with two rounds of data collection (2019 and 2021) in which a combination of different qualitative methods was applied. Interviews and group discussions took place with district, regional and national stakeholders who were involved in the implementation and scale-up of the intervention.

Results
A shared vision among the different stakeholders about how to institutionalize the intervention into the existing system facilitated scale-up. The importance of champions was also identified, as they influence buy-in from key decision makers, and when decision makers are convinced, political and financial support for scale-up can increase. In two countries, a specific window of opportunity facilitated scale-up. Taking a flexible approach towards scale-up, allowing adaptations of the intervention and the scale-up strategy to the context, was also identified as a facilitator. The context of decentralization and the politics and power relations between stakeholders involved also influenced scale-up.

Conclusions
Despite the identification of the facilitators of the scale-up, full integration of the intervention into the health system has proven challenging in all countries. Approaching scale-up from a systems change perspective could be useful in future scale-up efforts, as it focuses on sustainable systems change at scale (e.g. improving district health management) by testing a combination of interventions that could contribute to the envisaged change, rather than horizontally scaling up and trying to embed one particular intervention in the system.
Predictors of delayed Anti-Retroviral Therapy initiation among adults referred for HIV treatment in Uganda: a cross-sectional study
Authors: Kiyingi Micheal , Nankabirwa Joaniter I. , Sekaggya-Wiltshire Christine , Nangendo Joan , Kiweewa John M. , Katahoire Anne R. , Semitala Fred C. 
Published: January 2023

Abstract
Background
Uganda’s current guidelines recommend immediate initiation of Anti-Retroviral Therapy (ART) for persons living with HIV in order to reduce HIV/AIDS related morbidity and mortality. However, not all eligible PLHIV initiate ART within the recommended time following HIV diagnosis. We assessed the prevalence and factors associated with delayed ART initiation among PLHIV referred for ART initiation, five years since rolling out the test and treat guidelines.

Methods
In this cross-sectional study, we enrolled adult patients referred to Mulago Immune Suppressive Syndrome (Mulago ISS) clinic for ART initiation from January 2017 to May 2021. We collected data on socio-demographics, HIV diagnosis and referral circumstances, and time to ART initiation using a questionnaire. The outcome of interest was proportion of patients that delayed ART, defined as spending more than 30 days from HIV diagnosis to ART initiation. We performed multivariable logistic regression and identified significant factors.

Results
A total of 312 patients were enrolled of which 62.2% were female. The median (inter-quartile range [IQR]) age and baseline CD4 count of the patients were 35 (28–42) years and 315 (118.8–580.5) cells/μL respectively. Forty-eight (15.4%) patients delayed ART initiation and had a median (IQR) time to ART of 92 (49.0–273.5) days. The factors associated with delayed ART initiation were; 1) having had the HIV diagnosis made from a private health facility versus public, (adjusted odds ratio [aOR] = 2.4 (95% confidence interval [CI] 1.1–5.5); 2) initial denial of positive HIV test results, aOR = 5.4 (95% CI: 2.0–15.0); and, 3) having not received a follow up phone call from the place of HIV diagnosis, aOR = 2.8 (95% CI: 1.2–6.8).

Conclusion
There was significant delay of ART initiation among referred PLHIV within 5 years after the rollout of test and treat guidelines in Uganda. Health system challenges in the continuity of HIV care services negatively affects timely ART initiation among referred PLHIV in Uganda.
Real-time forecasting the trajectory of monkeypox outbreaks at the national and global levels, July–October 2022
Authors: Bleichrodt Amanda , Dahal Sushma , Maloney Kevin , Casanova Lisa , Luo Ruiyan , Chowell Gerardo 
Published: January 2023

Abstract
Background
Beginning May 7, 2022, multiple nations reported an unprecedented surge in monkeypox cases. Unlike past outbreaks, differences in affected populations, transmission mode, and clinical characteristics have been noted. With the existing uncertainties of the outbreak, real-time short-term forecasting can guide and evaluate the effectiveness of public health measures.

Methods
We obtained publicly available data on confirmed weekly cases of monkeypox at the global level and for seven countries (with the highest burden of disease at the time this study was initiated) from the Our World in Data (OWID) GitHub repository and CDC website. We generated short-term forecasts of new cases of monkeypox across the study areas using an ensemble n-sub-epidemic modeling framework based on weekly cases using 10-week calibration periods. We report and assess the weekly forecasts with quantified uncertainty from the top-ranked, second-ranked, and ensemble sub-epidemic models. Overall, we conducted 324 weekly sequential 4-week ahead forecasts across the models from the week of July 28th, 2022, to the week of October 13th, 2022.

Results
The last 10 of 12 forecasting periods (starting the week of August 11th, 2022) show either a plateauing or declining trend of monkeypox cases for all models and areas of study. According to our latest 4-week ahead forecast from the top-ranked model, a total of 6232 (95% PI 487.8, 12,468.0) cases could be added globally from the week of 10/20/2022 to the week of 11/10/2022. At the country level, the top-ranked model predicts that the USA will report the highest cumulative number of new cases for the 4-week forecasts (median based on OWID data: 1806 (95% PI 0.0, 5544.5)). The top-ranked and weighted ensemble models outperformed all other models in short-term forecasts.

Conclusions
Our top-ranked model consistently predicted a decreasing trend in monkeypox cases on the global and country-specific scale during the last ten sequential forecasting periods. Our findings reflect the potential impact of increased immunity, and behavioral modification among high-risk populations.
Molecular subtypes based on cuproptosis-related genes and tumor microenvironment infiltration characteristics in pancreatic adenocarcinoma
Authors: Li Jian , Yin Jingyang , Li Wenhua , Wang Huaizhi , Ni Bing 
Published: January 2023

Abstract
Background
Multiple molecular subtypes with distinct clinical outcomes in pancreatic adenocarcinoma (PAAD) have been identified in recent years. Cuproptosis is a new form of cell death that likely involved in tumor progression. However, the cuproptosis-related molecular subtypes as well as its mediated tumor microenvironment (TME) cell infiltration characteristics largely remain unclear.

Methods
Expression profiles of 10 cuproptosis-related genes (CRGs) and their association with patient survival, TME, cancer stemness and drug resistance were studied in 33 cancer types using the TCGA pan-cancer data. Using 437 PAAD samples from five cohorts (TCGA-PAAD cohort and four GEO cohorts), we explored the molecular subtypes mediated by CRGs, along with the associated TME cell infiltration. Unsupervised methods were utilized to perform cuproptosis subtype clustering. The cuproptosis score was constructed using the COX regression model with least absolute shrinkage and selection operator regression (LASSO) algorithm to quantify the cuproptosis characteristics of a single tumor.

Results
The expression of 10 CRGs varies in different cancer types with striking inter- and intra- cancer heterogeneity. We integrated the genomic profiling of the CRGs and identified three distinct cuproptosis subtypes, and found that multi-layer CRG alterations were correlated with patient prognosis and TME cell infiltration characteristics. In addition, a cuproptosis score signature was constructed to predict prognosis, and its clinical impacts were characterized in the TCGA-PAAD cohort. The cuproptosis signature was significantly associated with prognosis, tumor subtypes, CD8 T-cell infiltration, response to immune checkpoint inhibitors (ICIs) and chemotherapeutic drug sensitivity. Furthermore, the expression patterns of CRGs in pancreatic cancer cells and normal controls were validated, which was almost consistent with the results from the public database. The expression level and prognostic predictive capability of DLAT were verified in 97 PAAD patients from our patient cohort.

Conclusions
These findings may help understand the roles of CRGs in PAAD and the molecular characterization of cuproptosis subtypes. In addition, the cuproptosis score could serve as a promising biomarker for predicting prognosis and response to immunotherapy in PAAD patients.
Intestinal epithelium penetration of liraglutide via cholic acid pre-complexation and zein/rhamnolipids nanocomposite delivery
Authors: Bao Xiaoyan , Qian Kang , Xu Mengjiao , Chen Yi , Wang Hao , Pan Ting , Wang Zhengyi , Yao Ping , Lin Li 
Published: January 2023

AbstractBackgroundOral administration offered a painless way and improved compliance for diabetics. However, the emerging GLP-1 analog peptide drugs for diabetes primarily rely on the injection route, and the development of oral dosage forms was hampered by the low oral bioavailability due to the structural vulnerability to digestive enzymes and molecule impermeability in the gastrointestinal tract.ResultsIn this study, the non-covalent interaction between cholic acid (CA) and liraglutide (LIRA) was found and theoretically explained by molecular docking simulation. Formation of this physical complex of liraglutide and cholic acid (LIRA/CA Complex) reduced the self-aggregation of LIRA and accelerated intestinal epithelium penetration. By the anti-solvent method, LIRA/CA Complex was loaded into zein/rhamnolipids nanoparticles (LIRA/CA@Zein/RLs) with a loading efficiency of 76.8%. LIRA was protected from fast enzymatic degradation by the hydrophobic zein component. Meanwhile, Rhamnolipids, a glycolipid with surface activity, promoted endocytosis while also stabilizing the nanoparticles. The two components worked synergistically to ensure the delivery of LIRA/CA Complex to intestinal villi and improved oral absorption without disrupting tight junctions. LIRA/CA@Zein/RLs demonstrated a considerable intestinal epithelium absorption in mouse gastrointestinal section and a retentionin vivo over 24 h, resulting in a significant and long-lasting hypoglycemic effect in Type 2 diabetes mice.ConclusionThis study provided a promising oral delivery approach for LIRA and exhibited the potential for further translation into clinical application.
Therapeutic potential and mechanisms of mesenchymal stem cell-derived exosomes as bioactive materials in tendon–bone healing
Authors: Zou Jiaxuan , Yang Weinan , Cui Wushi , Li Congsun , Ma Chiyuan , Ji Xiaoxiao , Hong Jianqiao , Qu Zihao , Chen Jing , Liu An , Wu Haobo 
Published: January 2023

AbstractTendon–bone insertion (TBI) injuries, such as anterior cruciate ligament injury and rotator cuff injury, are the most common soft tissue injuries. In most situations, surgical tendon/ligament reconstruction is necessary for treating such injuries. However, a significant number of cases failed because healing of the enthesis occurs through scar tissue formation rather than the regeneration of transitional tissue. In recent years, the therapeutic potential of mesenchymal stem cells (MSCs) has been well documented in animal and clinical studies, such as chronic paraplegia, non-ischemic heart failure, and osteoarthritis of the knee. MSCs are multipotent stem cells, which have self-renewability and the ability to differentiate into a wide variety of cells such as chondrocytes, osteoblasts, and adipocytes. Numerous studies have suggested that MSCs could promote angiogenesis and cell proliferation, reduce inflammation, and produce a large number of bioactive molecules involved in the repair. These effects are likely mediated by the paracrine mechanisms of MSCs, particularly through the release of exosomes. Exosomes, nano-sized extracellular vesicles (EVs) with a lipid bilayer and a membrane structure, are naturally released by various cell types. They play an essential role in intercellular communication by transferring bioactive lipids, proteins, and nucleic acids, such as mRNAs and miRNAs, between cells to influence the physiological and pathological processes of recipient cells. Exosomes have been shown to facilitate tissue repair and regeneration. Herein, we discuss the prospective applications of MSC-derived exosomes in TBI injuries. We also review the roles of MSC–EVs and the underlying mechanisms of their effects on promoting tendon–bone healing. At last, we discuss the present challenges and future research directions.
Graphical Abstract
Output-orientated policy engagement: a model for advancing the use of epidemiological evidence in health policy
Authors: Banks Emily , Haynes Abby , Lovett Ray , Yadav Uday Narayan , Agostino Jason 
Published: January 2023

AbstractBackgroundUse of epidemiological research in policy and practice is suboptimal, contributing to significant preventable morbidity and mortality. Barriers to the use of research evidence in policy include lack of research–policy engagement, lack of policy-relevant research, differences in policymaker and researcher practice norms, time constraints, difficulties in coordination, and divergent languages and reward systems.Approach and outcomesIn order to increase policy-relevant research and research uptake, we developed the output-orientated policy engagement (OOPE) model, in Australia. It integrates a foundational approach to engagement with cycles of specific activity focused around selected research outputs. Foundational elements include measures to increase recognition and valuing of policymaker expertise, emphasis on policy uptake, policy awareness of the research group’s work, regular policy engagement and policy-relevant capacity-building. Specific activities include (i) identification of an “output”—usually at draft stage—and program of work which are likely to be of interest to policymakers; (ii) initial engagement focusing on sharing “preview” evidence from this output, with an invitation to provide input into this and to advise on the broader program of work; and (iii) if there is sufficient interest, formation of a researcher–policy-maker partnership to shape and release the output, as well as inform the program of work. This cycle is repeated as the relationship continues and is deepened. As well as supporting policy-informed evidence generation and research-aware policymakers, the output-orientated model has been found to be beneficial in fostering the following: a pragmatic starting place for researchers, in often large and complex policy environments; purposeful and specific engagement, encouraging shared expectations; non-transactional engagement around common evidence needs, whereby researchers are not meeting with policymakers with the expectation of receiving funding; built-in translation; time and resource efficiency; relationship-building; mutual learning; policy-invested researchers and research-invested policy-makers; and tangible policy impacts. A case study outlines how the output-orientated approach supported researcher–policymaker collaboration to generate new evidence regarding Aboriginal and Torres Strait Islander cardiovascular disease risk and to apply this to national guidelines.ConclusionOutput-orientated policy engagement provides a potentially useful pragmatic model to catalyse and support partnerships between researchers and policymakers, to increase the policy-relevance and application of epidemiological evidence.
EREG is the core onco-immunological biomarker of cuproptosis and mediates the cross-talk between VEGF and CD99 signaling in glioblastoma
Authors: Zhou Yujie , Xiao Dongdong , Jiang Xiaobing , Nie Chuansheng 
Published: January 2023

AbstractBackgroundGlioma is the most prevalent primary tumor of the central nervous system. Glioblastoma multiforme (GBM) is the most malignant form of glioma with an extremely poor prognosis. A novel, regulated cell death form of copper-induced cell death called “cuproptosis” provides a new prospect for cancer treatment by regulating cuproptosis.MethodsData from bulk RNA sequencing (RNA-seq) analysis (The Cancer Genome Atlas cohort and Chinese Glioma Genome Atlas cohort) and single cell RNA-seq (scRNA-seq) analysis were integrated to reveal their relationships. A scoring system was constructed according to the cuproptosis-related gene expression, and core genes were experimentally verified using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blot (WB), immunohistochemistry (IHC), and immunofluorescence (IF). Moreover, cell counting kit-8 (CCK8), colony formation, 5-ethynyl-2’-deoxyuridine (EdU) incorporation, transwell, and flow cytometry cell cycle were performed to evaluate cell proliferation, invasion, and migration.ResultsThe Cuproptosis Activation Scoring (CuAS) Model has stable and independent prognostic efficacy, as verified by two CGGA datasets. Epiregulin (EREG), the gene of the model has the most contributions in the principal component analysis (PCA), is an onco-immunological gene that can affect immunity by influencing the expression of programmed death-ligand 1 (PD-L1) and mediate the process of cuproptosis by influencing the expression of ferredoxin 1 (FDX1). Single cell transcriptome analysis revealed that high CuAS GBM cells are found in vascular endothelial growth factor A (VEGFA) + malignant cells. Oligodendrocyte transcription factor 1 (OLIG1) + malignant is the original clone, and VEGF and CD99 are the differential pathways of specific cell communication between the high and low CuAS groups. This was also demonstrated by immunofluorescence in the tissue sections. Furthermore, CuAS has therapeutic potential for immunotherapy, and we predict that many drugs (methotrexate, NU7441, KU -0063794, GDC-0941, cabozantinib, and NVP-BEZ235) may be used in patients with high CuAS.ConclusionEREG is the core onco-immunological biomarker of CuAS and modulates the cross-talk between VEGF and CD99 signaling in glioblastoma, and CuAS may provide support for immunotherapy and chemotherapy.
Ethanol extract from Artemisia argyi leaves inhibits HSV-1 infection by destroying the viral envelope
Authors: Liu Ping , Zhong Lishan , Xiao Ji , Hu Yuze , Liu Tao , Ren Zhe , Wang Yifei , Zheng Kai 
Published: January 2023

AbstractHerpes simplex virus type 1 (HSV-1) is a widely disseminated virus that establishes latency in the brain and causes occasional but fatal herpes simplex encephalitis. Currently, acyclovir (ACV) is the main clinical drug used in the treatment of HSV-1 infection, and the failure of therapy in immunocompromised patients caused by ACV-resistant HSV-1 strains necessitates the requirement to develop novel anti-HSV-1 drugs. Artemisia argyi, a Traditional Chinese Medicine, has been historically used to treat inflammation, bacterial infection, and cancer. In this study, we demonstrated the antiviral effect and mechanism of ethanol extract of A. argyi leaves (hereafter referred to as ‘AEE’). We showed that AEE at 10 μg/ml exhibits potent antiviral effects on both normal and ACV-resistant HSV-1 strains. AEE also inhibited the infection of HSV-2, rotavirus, and influenza virus. Transmission electron microscopy revealed that AEE destroys the membrane integrity of HSV-1 viral particles, resulting in impaired viral attachment and penetration. Furthermore, mass spectrometry assay identified 12 major components of AEE, among which two new flavones, deoxysappanone B 7,3ʹ-dimethyl ether, and 3,7-dihydroxy-3′,4ʹ-dimethoxyflavone, exhibited the highest binding affinity to HSV-1 glycoprotein gB at the surface site critical for gB–gH–gL interaction and gB-mediated membrane fusion, suggesting their involvement in inactivating virions. Therefore, A. argyi is an important source of antiviral drugs, and the AEE may be a potential novel antiviral agent against HSV-1 infection.
Short- and long-term polystyrene nano- and microplastic exposure promotes oxidative stress and divergently affects skin cell architecture and Wnt/beta-catenin signaling
Authors: Schmidt Anke , da Silva Brito Walison Augusto , Singer Debora , Mühl Melissa , Berner Julia , Saadati Fariba , Wolff Christina , Miebach Lea , Wende Kristian , Bekeschus Sander 
Published: January 2023

AbstractNano- and microplastic particles (NMP) are strong environmental contaminants affecting marine ecosystems and human health. The negligible use of biodegradable plastics and the lack of knowledge about plastic uptake, accumulation, and functional consequences led us to investigate the short- and long-term effects in freshly isolated skin cells from mice. Using fluorescent NMP of several sizes (200 nm to 6 µm), efficient cellular uptake was observed, causing, however, only minor acute toxicity as metabolic activity and apoptosis data suggested, albeit changes in intracellular reactive species and thiol levels were observed. The internalized NMP induced an altered expression of various targets of the nuclear factor-2-related transcription factor 2 pathway and were accompanied by changed antioxidant and oxidative stress signaling responses, as suggested by altered heme oxygenase 1 and glutathione peroxide 2 levels. A highly increased beta-catenin expression under acute but not chronic NMP exposure was concomitant with a strong translocation from membrane to the nucleus and subsequent transcription activation of Wnt signaling target genes after both single-dose and chronic long-term NMP exposure. Moreover, fibroblast-to-myofibroblast transdifferentiation accompanied by an increase of α smooth muscle actin and collagen expression was observed. Together with several NMP-induced changes in junctional and adherence protein expression, our study for the first time elucidates the acute and chronic effects of NMP of different sizes in primary skin cells' signaling and functional biology, contributing to a better understanding of nano- and microplastic to health risks in higher vertebrates.