bluuebunny/crossref_metadata_2025_split huggingface dataset:
Coordinating health workforce management in a devolved context: lessons from Kenya
Authors: Thuku Mathew Kariuki , Muriuki Janet , Adano Ummuro , Oyucho Linet , Nelson David 
Published: March 2020

Abstract
Introduction
In 2013, Kenya fully and rapidly devolved health services to 47 county governments under its new constitution. It soon became evident that the coordination mechanism to manage the health workforce at a county level was inadequate. This case study describes how Kenya created an inter-county, multi-stakeholder human resources for health (HRH) coordination framework that promotes consensus, commitment, and cooperation in devolved HR management.

Case presentation
Through USAID funding, IntraHealth International built the health workforce management capacity of county governments by strengthening coordination mechanisms at the national and county levels. Informed by stakeholder mapping, Kenya’s 47 counties were grouped into nine clusters with similar geographic contexts and HRH challenges. Inter-county cluster HRH stakeholder coordination forums are hosted by a rotating county-led secretariat and meet quarterly to address gaps, share successes and challenges, and track implementation of action plans. They link to the national level for capacity building, policy formulation, HRH regulation, and provision of standards. Counties have assumed ownership of the forums and contributed about US$85000 to date toward expenses.

Conclusions
As a mechanism for transforming Kenya’s national HRH agenda into action at the county level, the HRH coordination framework has been instrumental in (1) expediting development, customization, and dissemination of policies, (2) enabling national HRH officers to mentor their county counterparts, and (3) providing collaborative platforms for multiple stakeholders to resolve HRH challenges and harmonize HR practices nationwide. Successes catalyzed through the inter-county forums include hiring over 20 000 health workers to address shortages; expanding the national HR information system to all 47 counties; developing guidelines for sharing specialist providers; and establishing professionalized HRH units in all 47 counties.
Kenya has made great strides in strengthening its health system through the HRH coordination framework, which supports standardization of county health operations with national goals while enabling national policy to address HRH gaps in the counties. Transitioning to fully local funding of inter-county forums is important for sustaining progress.
How does integrated knowledge translation (IKT) compare to other collaborative research approaches to generating and translating knowledge? Learning from experts in the field
Authors: Nguyen Tram , Graham Ian D. , Mrklas Kelly J. , Bowen Sarah , Cargo Margaret , Estabrooks Carole A. , Kothari Anita , Lavis John , Macaulay Ann C. , MacLeod Martha , Phipps David , Ramsden Vivian R. , Renfrew Mary J. , Salsberg Jon , Wallerstein Nina 
Published: March 2020

AbstractBackgroundResearch funders in Canada and abroad have made substantial investments in supporting collaborative research approaches to generating and translating knowledge as it is believed to increase knowledge use. Canadian health research funders have advocated for the use of integrated knowledge translation (IKT) in health research, however, there is limited research around how IKT compares to other collaborative research approaches. Our objective was to better understand how IKT compares with engaged scholarship, Mode 2 research, co-production and participatory research by identifying the differences and similarities among them in order to provide conceptual clarity and reduce researcher and knowledge user confusion about these common approaches.MethodsWe employed a qualitative descriptive method using interview data to better understand experts’ perspectives and experiences on collaborative research approaches. Participants’ responses were analysed through thematic analysis to elicit core themes. The analysis was centred around the concept of IKT, as it is the most recent approach; IKT was then compared and contrasted with engaged scholarship, Mode 2 research, co-production and participatory research. As this was an iterative process, data triangulation and member-checking were conducted with participants to ensure accuracy of the emergent themes and analysis process.ResultsDifferences were noted in the orientation (i.e. original purpose), historical roots (i.e. disciplinary origin) and partnership/engagement (i.e. role of partners etc.). Similarities among the approaches included (1) true partnerships rather than simple engagement, (2) focus on essential components and processes rather than labels, (3) collaborative research orientations rather than research methods, (4) core values and principles, and (5) extensive time and financial investment. Core values and principles among the approaches included co-creation, reciprocity, trust, fostering relationships, respect, co-learning, active participation, and shared decision-making in the generation and application of knowledge. All approaches require extensive time and financial investment to develop and maintain true partnerships.ConclusionsThis qualitative study is the first to systematically synthesise experts’ perspectives and experiences in a comparison of collaborative research approaches. This work contributes to developing a shared understanding of collaborative research approaches to facilitate conceptual clarity in use, reporting, indexing and communication among researchers, trainees, knowledge users and stakeholders to advance IKT and implementation science.
Wnt5a-induced M2 polarization of tumor-associated macrophages via IL-10 promotes colorectal cancer progression
Authors: Liu Qing , Yang Chaogang , Wang Shuyi , Shi Dongdong , Wei Chen , Song Jialin , Lin Xiaobin , Dou Rongzhang , Bai Jian , Xiang Zhenxian , Huang Sihao , Liu Keshu , Xiong Bin 
Published: March 2020

Abstract
Background
Tumor-associated macrophages (TAMs) in the tumor microenvironment influence tumor initiation, invasion and metastasis. Several studies have shown that Wnt5a is mainly expressed in the tumor stroma, especially in TAMs. However, whether Wnt5a regulates the polarization and biological function of TAMs in colorectal cancer (CRC) is incompletely understood.

Methods
Immunofluorescence staining was performed to detect CD68 and Wnt5a expression in colorectal tissues from patients (63 CRC specimens VS 20 normal tissues). RT-qPCR, flow cytometry, ELISA and inhibitors were carried out to explore the role of Wnt5a in the polarization of TAMs. Clone formation and transwell assays were performed to determine the effects of Wnt5a–treated macrophages on tumor proliferation, migration and invasion in vitro. Finally, a xenograft model was applied to confirm the effects of Wnt5a+ TAMs on CRC tumorigenesis.

Results
We found that high Wnt5a+CD68+/CD68+ TAMs ratio was significantly associated with poor prognosis in CRC patients and Wnt5a+ TAM was an M2-like TAM subtype. Subsequently, we found that Wnt5a induced macrophages to secrete IL-10, which then acted as an autocrine cytokine to induce M2 polarization of these macrophages. IL-10 neutralizing antibody completely reversed the pro-M2 effect of Wnt5a. Mechanistically, the CaKMII-ERK1/2-STAT3 pathway was required for Wnt5a-mediated IL-10 expression in macrophages. Furthermore, Wnt5a-induced M2 macrophages promoted CRC cells proliferation, migration and invasion; knockdown of Wnt5a in TAMs significantly impaired the pro-tumor functions of TAMs.

Conclusions
Our data indicate that Wnt5a could induce M2 polarization of TAMs by regulating CaKMII-ERK1/2-STAT3 pathway–mediated IL-10 secretion, ultimately promoting tumor growth and metastasis of CRC.
Exosomal KRAS mutation promotes the formation of tumor-associated neutrophil extracellular traps and causes deterioration of colorectal cancer by inducing IL-8 expression
Authors: Shang Anquan , Gu Chenzheng , Zhou Chen , Yang Yibao , Chen Chen , Zeng Bingjie , Wu Junlu , Lu Wenying , Wang Weiwei , Sun Zujun , Li Dong 
Published: March 2020

AbstractBackgroundColorectal cancer (CRC) remains one of the leading causes of cancer-related death. The current study aimed to elucidate the mechanism by which exosomes carrying KRAS mutant contribute to neutrophil recruitment as well as the formation of the neutrophil extracellular trap (NET) in CRC.MethodsAPC-WT and APC-KRASG12Dmouse models were initially developed. Peripheral blood, spleen, bone marrow (BM) and mesenteric lymph nodes (mLN) were isolated to detect neutrophil content. Then, APC-WT and APC-KRASG12Dmice were injected with exosomes isolated from APC-WT and APC-KRASG12Dmice. The ratio of neutrophils, NETs formation and IL-8 protein content were subsequently quantified in colon tissues. DKs-8 (wild type) and DKO-1 (KRAS mutant) cells were employed for in vitro experimentation. Then, DKs-8 cells were cultured with exosome-treated PMA stimulated neutrophil-forming NETs culture medium, with cell viability, invasion, migration, and adhesion evaluated.ResultsCompared with APC-WT mice, the numbers of polyps and neutrophils in the peripheral blood, spleen and mLNs were increased in APC-KRASG12Dmice, accompanied with increased NET formation, IL-8 expression and exosomes. Meanwhile, IL-8 upregulation, neutrophil recruitment and NET formation were observed in the mice injected with exosomes derived from APC-KRASG12D. The in vitro investigation results revealed that more NETs were formed in the presence of DKO-1-Exos, which were inhibited by DNAse. In addition, DKs-8- and DKO-1 cells-derived exosomes could adhere to NETs under static conditions in vitro. Exosomal KRAS mutants were noted to exert stimulatory effects on the IL-8 production and NET formation to promote the growth of CRC cells.ConclusionThe results provide evidence suggesting that exosomes may transfer mutant KRAS to recipient cells and trigger increases in IL-8 production, neutrophil recruitment and formation of NETs, eventually leading to the deterioration of CRC.
Upregulation of microRNA-328-3p by hepatitis B virus contributes to THLE-2 cell injury by downregulating FOXO4
Authors: Fu Xiaoyu , Ouyang Yi , Mo Juan , Li Ronghua , Fu Lei , Peng Shifang 
Published: March 2020

Abstract
Background
Hepatitis B virus (HBV) remains a major cause of chronic hepatitis and hepatocellular carcinoma, and miRNAs play important roles in HBV pathogenesis. Our previous study has shown that miR-328-3p is upregulated in HBV-infected patients and serves as a potent predictor for the prognosis of HBV-related liver failure.

Methods
Here, the role of miR-328-3p in modulating cell injury in HBV-infected liver cells THLE-2 was investigated in detail. MiR-328-3p expression was examined using qRT-PCR. The levels of pro-inflammatory cytokines were measured using ELISA. HBV RNA and HBV DNA levels were quantified. The interactions between STAT3 and miR-328-3p promoter as well as miR-328-3p and FOXO4 were analyzed using chromatin immunoprecipitation (CHIP) assay and luciferase reporter assay, respectively. THLE-2 cell injury was evaluated by examining cell viability and apoptosis.

Results
HBV promoted expression of miR-328-3p through the STAT3 signal pathway and that increasingly expressed miR-328-3p downregulated its target FOXO4, leading to the promotion of cell injury in HBV-infected liver cells THLE-2.

Conclusion
These data demonstrate that HBV-STAT3-miR-328-3p-FOXO4 regulation pathway may play an important role in the pathogenesis of HBV infection.
Serum choline is associated with hepatocellular carcinoma survival: a prospective cohort study
Authors: Liu Zhao-Yan , Yishake Dinuerguli , Fang Ai-Ping , Zhang Dao-Ming , Liao Gong-Cheng , Tan Xu-Ying , Zhang Yao-Jun , Zhu Hui-Lian 
Published: March 2020

Abstract
Background
Higher choline and betaine levels have been linked to lower risk of liver cancer, whereas existing data in relation to hepatocellular carcinoma (HCC) prognosis are scarce. Our objective was to examine the associations of the serum choline and betaine with HCC survival.

Methods
866 newly diagnosed HCC patients were enrolled in the Guangdong Liver Cancer Cohort. Serum choline and betaine were assessed using high-performance liquid chromatography with online electro-spray ionization tandem mass spectrometry. Liver cancer-specific survival (LCSS) and overall survival (OS) were calculated. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs).

Results
Serum choline levels were associated with better LCSS (T3 vs. T1: HR = 0.69, 95% CI: 0.51–0.94; P-trend < 0.05) and OS (T3 vs. T1: HR = 0.73, 95% CI: 0.54–0.99; P-trend < 0.05). The associations were significantly modified by C-reactive protein (CRP) levels but not by other selected prognostic factors including sex, age, etc. The favorable associations between serum choline and LCSS and OS were only existed among patients with CRP ≥3.0 mg/L. No significant associations were found between serum betaine levels and either LCSS or OS.

Conclusions
This study revealed that higher serum choline levels were associated with better HCC survival, especially in HCC patients with systemic inflammation status. No significant associations were found between serum betaine and HCC survival. Our findings suggest the benefits of choline on HCC survival.

Trial registration
The Guangdong Liver Cancer Cohort was registered at clinicaltrials.gov as NCT03297255.
Crucial role of androgen receptor in resistance and endurance trainings-induced muscle hypertrophy through IGF-1/IGF-1R- PI3K/Akt- mTOR pathway
Authors: YIN Lijun , LU Lin , LIN Xiaojing , WANG Xiaohui 
Published: March 2020

Abstract
Background
Androgen receptor (AR) has been reported to play vital roles in exercise-induced increase of muscle mass in rats, but needs to be further verified and the mechanism behind remains unclear. As AR target genes, insulin growth factor-1 (IGF-1) and IGF-1 receptor (IGF-1R) promote muscle hypertrophy through activating PI3K/Akt- mammalian target of rapamycin (mTOR) pathway, a classic pathway of muscle hypertrophy. So the main purpose of this study was using AR antagonist flutamide to demonstrate AR’s effect on training-induced muscle hypertrophy and its possible mechanism: IGF-1/IGF-1R- PI3K/Akt- mTOR pathway?

Methods
Forty-eight Sprague Dawley male rats aged 7 weeks were randomly divided into six groups: control (C), flutamide (F), resistance training (R), resistance training plus flutamide (R + F), endurance training (E), and endurance training plus flutamide (E + F) groups. Flutamide was used to block AR in rats. Rats in R and R + F groups fulfilled 3 weeks of ladder climbing with progressively increased load, while E and E + F rats completed 3-week moderate intensity aerobic exercise on a treadmill. The relative muscle mass (muscle mass/body weight) of rats was detected. Serum levels of testosterone and IGF-1 of rats were determined by ELISA, and mRNA levels of IGF-1R and mTOR in muscles by real-time PCR. Protein levels of AR, IGF-1, IGF-1R, mTOR, PI3K, Akt, p-PI3K and p-Akt in muscles were detected by Western blot.

Results
(1) The training-induced rise in the relative muscle mass and the expression levels of AR were only found in the gastrocnemius of R rats and in the soleus of E rats (selective muscle hypertrophy), which were blocked by flutamide. (2) Serum testosterone in the R and E rat were increased, and flutamide exerted no effect. (3) The levels of IGF-1, IGF-1R and mTOR as well as the activities of PI3K and Akt were enhanced selectively (in the gastrocnemius of R rats and in the soleus of E rats), which were reduced by flutamide. Conclusions: AR exerted an essential role in both resistance training and endurance training-induced muscle hypertrophy, which was mediated at least partly through IGF-1/IGF-1R- PI3K/Akt- mTOR pathway.
Laminin 221 fragment is suitable for the differentiation of human induced pluripotent stem cells into brain microvascular endothelial-like cells with robust barrier integrity
Authors: Aoki Hiromasa , Yamashita Misaki , Hashita Tadahiro , Iwao Takahiro , Matsunaga Tamihide 
Published: March 2020

Abstract
Background
In vitro blood–brain barrier (BBB) models using human induced pluripotent stem (iPS) cell-derived brain microvascular endothelial-like cells (iBMELCs) have been developed to predict the BBB permeability of drug candidates. For the differentiation of iBMELCs, Matrigel, which is a gelatinous protein mixture, is often used as a coating substrate. However, the components of Matrigel can vary among lots, as it is obtained from mouse sarcoma cells with the use of special technics and also contains various basement membranes. Therefore, fully defined substrates as substitutes for Matrigel are needed for a stable supply of iBMELCs with less variation among lots.

Methods
iBMELCs were differentiated from human iPS cells on several matrices. The barrier integrity of iBMELCs was evaluated based on transendothelial electrical resistance (TEER) values and permeability of fluorescein isothiocyanate-dextran 4 kDa (FD4) and Lucifer yellow (LY). Characterization of iBMELCs was conducted by RT-qPCR and immunofluorescence analysis. Functions of efflux transporters were defined by intracellular accumulation of the substrates in the wells of multiwell plates.

Results
iBMELCs differentiated on laminin 221 fragment (LN221F-iBMELCs) had higher TEER values and lower permeability of LY and FD4 as compared with iBMELCs differentiated on Matrigel (Matrigel-iBMELCs). Besides, the gene and protein expression levels of brain microvascular endothelial cells (BMEC)-related markers were similar between LN221F-iBMELCs and Matrigel-iBMELCs. Moreover, both Matrigel- and LN221F-iBMELCs had functions of P-glycoprotein and breast cancer resistance protein, which are essential efflux transporters for barrier functions of the BBB.

Conclusion
The fully defined substrate LN221F presents as an optimal coating matrix for differentiation of iBMELCs. The LN221F-iBMELCs had more robust barrier function for a longer period than Matrigel-iBMELCs with characteristics of BMECs. This finding will contribute the establishment of an iBMELC supply system for pharmacokinetic and pathological models of the BBB.
In vitro modeling of blood–brain barrier and interface functions in neuroimmune communication
Authors: Erickson Michelle A. , Wilson Miranda L. , Banks William A. 
Published: March 2020

AbstractNeuroimmune communication contributes to both baseline and adaptive physiological functions, as well as disease states. The vascular blood–brain barrier (BBB) and associated cells of the neurovascular unit (NVU) serve as an important interface for immune communication between the brain and periphery through the blood. Immune functions and interactions of the BBB and NVU in this context can be categorized into at least five neuroimmune axes, which include (1) immune modulation of BBB impermeability, (2) immune regulation of BBB transporters, secretions, and other functions, (3) BBB uptake and transport of immunoactive substances, (4) immune cell trafficking, and (5) BBB secretions of immunoactive substances. These axes may act separately or in concert to mediate various aspects of immune signaling at the BBB. Much of what we understand about immune axes has been from work conducted using in vitro BBB models, and recent advances in BBB and NVU modeling highlight the potential of these newer models for improving our understanding of how the brain and immune system communicate. In this review, we discuss how conventional in vitro models of the BBB have improved our understanding of the 5 neuroimmune axes. We further evaluate the existing literature on neuroimmune functions of novel in vitro BBB models, such as those derived from human induced pluripotent stem cells (iPSCs) and discuss their utility in evaluating aspects of neuroimmune communication.
A community–based system dynamics approach for understanding factors affecting mental Health and Health seeking behaviors in Beirut and Beqaa regions of Lebanon
Authors: Noubani Aya , Diaconu Karin , Ghandour Lilian , El Koussa Maria , Loffreda Giulia , Saleh Shadi 
Published: March 2020

Abstract
Background
Available evidence on mental health and psychosocial problems in Lebanon is limited. Recent quantitative data suggests a high prevalence among Syrian refugees and their Lebanese host communities, with significant treatment gaps in both populations. This study aims to determine how Lebanese host and Syrian refugee communities perceive mental health, and identify health seeking behaviors and barriers to health access in two contrasting contexts of fragility.

Methods
A comparative qualitative study design was adopted whereby a total of 36 semi-structured interviews with Lebanese host and Syrian refugees’ community members were conducted, followed by a series of four participatory group model building (GMB) sessions. Participants were recruited from two contrasting fragility contexts: Beirut and Beqaa regions. During these sessions, causal loop diagrams were elicited depicting shared understandings of factors prompting the onset of mental health and psychosocial issues; health seeking behaviors, pathways and elements affecting the rate of health improvement and maintenance were also identified.

Results
Community members in both settings had similar perceptions of factors contributing to mental health. Participants named long-term effects of exposure to wars, political and social effects of conflicts, and financial constraints at the household level as precipitating factors prompting the onset of mental health and psychosocial stressors. Gender and integration related challenges between communities were identified as factors that affect condition onset and associated care seeking. Pathways for health seeking were found to be shaped by trust, the advice and support of loved ones, and the need to ensure confidentiality of affected individuals. Recurrent themes in discussion highlighted major barriers to healthcare access including significant delays in health care seeking from the formal health system, widespread social stigma, prohibitive service costs, lack of health coverage, limited awareness of mental health service availability and limited trust in the quality of services available.

Conclusion
Mental health and psychosocial support strategies need to be gender- and integration-sensitive, primarily focused on condition prevention and awareness raising in order to strengthen health-seeking behaviors.
Recent advances in radiotherapy of breast cancer
Authors: Haussmann Jan , Corradini Stefanie , Nestle-Kraemling Carolin , Bölke Edwin , Njanang Freddy Joel Djiepmo , Tamaskovics Bálint , Orth Klaus , Ruckhaeberle Eugen , Fehm Tanja , Mohrmann Svjetlana , Simiantonakis Ioannis , Budach Wilfried , Matuschek Christiane 
Published: March 2020

AbstractRadiation therapy is an integral part of the multidisciplinary management of breast cancer. Regional lymph node irradiation in younger trials seems to provide superior target coverage as well as a reduction in long-term toxicity resulting in a small benefit in the overall survival rate. For partial breast irradiation there are now two large trials available which support the role of partial breast irradiation in low risk breast cancer patients. Multiple randomized trials have established that a sequentially applied dose to the tumor bed improves local control with the cost of worse cosmetic results.