bluuebunny/crossref_metadata_2025_split huggingface dataset:
What factors are associated with the research productivity of primary care researchers in Canada? A qualitative study
Authors: Aggarwal Monica , Hutchison Brian , Wong Sabrina T. , Katz Alan , Slade Steve , Snelgrove Deirdre 
Published: March 2024

Abstract
Background
Research evidence to inform primary care policy and practice is essential for building high-performing primary care systems. Nevertheless, research output relating to primary care remains low worldwide. This study describes the factors associated with the research productivity of primary care researchers.

Methods
A qualitative, descriptive key informant study approach was used to conduct semi-structured interviews with twenty-three primary care researchers across Canada. Qualitative data were analyzed using reflexive thematic analysis.

Results
Twenty-three primary care researchers participated in the study. An interplay of personal (psychological characteristics, gender, race, parenthood, education, spousal occupation, and support), professional (mentorship before appointment, national collaborations, type of research, career length), institutional (leadership, culture, resources, protected time, mentorship, type), and system (funding, systematic bias, environment, international collaborations, research data infrastructure) factors were perceived to be associated with research productivity. Research institutes and mentors facilitated collaborations, and mentors and type of research enabled funding success. Jurisdictions with fewer primary care researchers had more national collaborations but fewer funding opportunities. The combination of institutional, professional, and system factors were barriers to the research productivity of female and/or racialized researchers.

Conclusions
This study illuminates the intersecting and multifaceted influences on the research productivity of primary care researchers. By exploring individual, professional, institutional, and systemic factors, we underscore the pivotal role of diverse elements in shaping RP. Understanding these intricate influencers is imperative for tailored, evidence-based interventions and policies at the level of academic institutions and funding agencies to optimize resources, promote fair evaluation metrics, and cultivate inclusive environments conducive to diverse research pursuits within the PC discipline in Canada.
“We have to change our mindsets”: a qualitative study of barriers and facilitators in research collaboration across integrated care system organisations
Authors: Gidlow Christopher J. , Sams Lorna , Buckless Kim , Ellis Naomi J. , Duffy Helen C. , Lambley-Burke Ruth , Campbell Paul , Cooke Alison , Dziedzic Krysia , Brookes Matthew , Chockalingam Nachiappan , Devall Pam , Mallen Christian 
Published: March 2024

AbstractThe introduction of Integrated Care Systems (ICS) in England aimed to increase joint planning and delivery of health and social care, and other services, to better meet the needs of local communities. There is an associated duty to undertake collaborative research across ICS partners to inform this new integrated approach, which might be challenging given that organisations span health, local authority, voluntary and community sector, and research. This study aimed to explore the appetite for collaborative Research and Innovation (R&I) across ICSs, potential barriers and solutions. This qualitative study involved semi-structured interviews with 24 stakeholders who held senior positions within organisations across two ICS areas (Staffordshire and Stoke-on-Trent; Shropshire, Telford and Wrekin). Interview transcripts were analysed using inductive and deductive analysis, first mapping to the Theoretical Domains Framework (TDF), then considering key influences on organisational behaviour in terms of Capability, Opportunity and Motivation from the COM-B Behaviour Change Wheel. There were fundamental limitations on organisational opportunities for collaborative R&I: a historical culture of competition (rather than collaboration), a lack of research culture and prioritisation, compounded by a challenging adverse economic environment. However, organisations were motivated to undertake collaborative R&I. They recognised the potential benefits (e.g., skill-sharing, staff development, attracting large studies and funding), the need for collaborative research that mirrors integrated care, and subsequent benefits for care recipients. Related barriers included negative experiences of collaboration, fear of failing and low confidence. Capability varied across organisations in terms of research skills and confidence, which reflected the range of partners (from local authorities to NHS Trusts, primary care, and academic institutions). These findings indicate a need to shift from a culture of competition to collaboration, and to help organisations across ICS to prioritise research, and share resources and skills to mitigate the limiting effects of a constrained economic environment. This could be further explored using a systems change approach, to develop the collaborative research efforts alongside the overarching move towards integrated care.
Engineering Escherichia coli for increased Und-P availability leads to material improvements in glycan expression technology
Authors: Kay Emily J. , Dooda Manoj K. , Bryant Joseph C. , Reid Amanda J. , Wren Brendan W. , Troutman Jerry M. , Jorgenson Matthew A. 
Published: March 2024

Abstract
Background
Bacterial surface glycans are assembled by glycosyltransferases (GTs) that transfer sugar monomers to long-chained lipid carriers. Most bacteria employ the 55-carbon chain undecaprenyl phosphate (Und-P) to scaffold glycan assembly. The amount of Und-P available for glycan synthesis is thought to be limited by the rate of Und-P synthesis and by competition for Und-P between phosphoglycosyl transferases (PGTs) and GTs that prime glycan assembly (which we collectively refer to as PGT/GTs). While decreasing Und-P availability disrupts glycan synthesis and promotes cell death, less is known about the effects of increased Und-P availability.

Results
To determine if cells can maintain higher Und-P levels, we first reduced intracellular competition for Und-P by deleting all known non-essential PGT/GTs in the Gram-negative bacterium Escherichia coli (hereafter called ΔPGT/GT cells). We then increased the rate of Und-P synthesis in ΔPGT/GT cells by overexpressing the Und-P(P) synthase uppS from a plasmid (puppS). Und-P quantitation revealed that ΔPGT/GT/puppS cells can be induced to maintain 3-fold more Und-P than wild type cells. Next, we determined how increasing Und-P availability affects glycan expression. Interestingly, increasing Und-P availability increased endogenous and recombinant glycan expression. In particular, ΔPGT/GT/puppS cells could be induced to express 7-fold more capsule from Streptococcus pneumoniae serotype 4 than traditional E. coli cells used to express recombinant glycans.

Conclusions
We demonstrate that the biotechnology standard bacterium E. coli can be engineered to maintain higher levels of Und-P. The results also strongly suggest that Und-P pathways can be engineered to increase the expression of potentially any Und-P-dependent polymer. Given that many bacterial glycans are central to the production of vaccines, diagnostics, and therapeutics, increasing Und-P availability should be a foremost consideration when designing bacterial glycan expression systems.
Promoting collateral formation in type 2 diabetes mellitus using ultra-small nanodots with autophagy activation and ROS scavenging
Authors: Wang Yixuan , Li Feifei , Mao Linshuang , Liu Yu , Chen Shuai , Liu Jingmeng , Huang Ke , Chen Qiujing , Wu Jianrong , Lu Lin , Zheng Yuanyi , Shen Weifeng , Ying Tao , Dai Yang , Shen Ying 
Published: March 2024

Abstract
Background
Impaired collateral formation is a major factor contributing to poor prognosis in type 2 diabetes mellitus (T2DM) patients with atherosclerotic cardiovascular disease. However, the current pharmacological treatments for improving collateral formation remain unsatisfactory. The induction of endothelial autophagy and the elimination of reactive oxygen species (ROS) represent potential therapeutic targets for enhancing endothelial angiogenesis and facilitating collateral formation. This study investigates the potential of molybdenum disulfide nanodots (MoS2 NDs) for enhancing collateral formation and improving prognosis.

Results
Our study shows that MoS2 NDs significantly enhance collateral formation in ischemic tissues of diabetic mice, improving effective blood resupply. Additionally, MoS2 NDs boost the proliferation, migration, and tube formation of endothelial cells under high glucose/hypoxia conditions in vitro. Mechanistically, the beneficial effects of MoS2 NDs on collateral formation not only depend on their known scavenging properties of ROS (H2O2, •O2-, and •OH) but also primarily involve a molecular pathway, cAMP/PKA-NR4A2, which promotes autophagy and contributes to mitigating damage in diabetic endothelial cells.

Conclusions
Overall, this study investigated the specific mechanism by which MoS2 NDs mediated autophagy activation and highlighted the synergy between autophagy activation and antioxidation, thus suggesting that an economic and biocompatible nano-agent with dual therapeutic functions is highly preferable for promoting collateral formation in a diabetic context, thus, highlighting their therapeutic potential.

Graphical Abstract
Comparative effectiveness and safety of DOACs vs. VKAs in treatment of left ventricular thrombus- a meta-analysis update
Authors: Hu Tong , Chen Changli , Maduray Kellina , Han Wenqiang , Chen Tongshuai , Zhong Jingquan 
Published: March 2024

Abstract
Background and objective
Left ventricular thrombus (LVT) formation in patients with acute myocardial infarction (AMI) or cardiomyopathies is not uncommon. The optimal oral anticoagulation therapy for resolving LVT has been under intense debate. Vitamin K antagonists (VKAs) remain the anticoagulant of choice for this condition, according to practice guidelines. Evidence supporting the use of direct oral anticoagulants (DOACs) in the management of LVT continues to grow. We performed a systematic review and meta-analysis to compare the efficacy and safety of DOACs versus VKAs.

Methods
A comprehensive literature search was carried out in PubMed, Cochrane Library, Web of Science, Embase, and Scopus databases in July 2023. The efficacy outcomes of this study were thrombus resolution, ischemic stroke, systemic embolism, stroke/systemic embolism, all-cause mortality, and adverse cardiovascular events. The safety outcomes were any bleeding, major bleeding, and intracranial hemorrhage. A total of twenty-seven eligible studies were included in the meta-analysis. Data were analyzed utilizing Stata software version 15.1.

Results
There was no significant difference between DOACs and VKAs with regard to LVT resolution (RR = 1.00, 95% CI 0.95–1.05, P = 0.99). In the overall analysis, DOACs significantly reduced the risk of stroke (RR = 0.74, 95% CI 0.57–0.96, P = 0.021), all-cause mortality (RR = 0.70, 95% CI 0.57–0.86, P = 0.001), any bleeding (RR = 0.75, 95% CI 0.61–0.92, P = 0.006) and major bleeding (RR = 0.67, 95% CI 0.52–0.85, P = 0.001) when compared to VKAs. Meanwhile, in the sub-analysis examining randomized controlled trials (RCTs), the aforementioned outcomes no longer differed significantly between the DOACs and VKAs groups. The incidences of systemic embolism (RR = 0.81, 95% CI 0.54–1.22, P = 0.32), stroke/systemic embolism (RR = 0.85, 95% CI 0.72–1.00, P = 0.056), intracranial hemorrhage (RR = 0.59, 95% CI 0.23–1.54, P = 0.28), and adverse cardiovascular events (RR = 0.99, 95% CI 0.63–1.56, P = 0.92) were comparable between the DOACs and VKAs groups. A subgroup analysis showed that patients treated with rivaroxaban had a significantly lower risk of stroke (RR = 0.24, 95% CI 0.08–0.72, P = 0.011) than those in the VKAs group.

Conclusion
With non-inferior efficacy and superior safety, DOACs are promising therapeutic alternatives to VKAs in the treatment of LVT. Further robust investigations are warranted to confirm our findings.
Epigenetic remodeling to improve the efficacy of immunotherapy in human glioblastoma: pre-clinical evidence for development of new immunotherapy approaches
Authors: Lofiego Maria Fortunata , Piazzini Francesca , Caruso Francesca Pia , Marzani Francesco , Solmonese Laura , Bello Emma , Celesti Fabrizio , Costa Maria Claudia , Noviello Teresa , Mortarini Roberta , Anichini Andrea , Ceccarelli Michele , Coral Sandra , Di Giacomo Anna Maria , Maio Michele , Covre Alessia ,   The EPigenetic Immune-oncology Consortium Airc (EPICA) investigators
Published: March 2024

Abstract
Background
Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor, that is refractory to standard treatment and to immunotherapy with immune-checkpoint inhibitors (ICI). Noteworthy, melanoma brain metastases (MM-BM), that share the same niche as GBM, frequently respond to current ICI therapies. Epigenetic modifications regulate GBM cellular proliferation, invasion, and prognosis and may negatively regulate the cross-talk between malignant cells and immune cells in the tumor milieu, likely contributing to limit the efficacy of ICI therapy of GBM. Thus, manipulating the tumor epigenome can be considered a therapeutic opportunity in GBM.

Methods
Microarray transcriptional and methylation profiles, followed by gene set enrichment and IPA analyses, were performed to study the differences in the constitutive expression profiles of GBM vs MM-BM cells, compared to the extracranial MM cells and to investigate the modulatory effects of the DNA hypomethylating agent (DHA) guadecitabine among the different tumor cells. The prognostic relevance of DHA-modulated genes was tested by Cox analysis in a TCGA GBM patients’ cohort.

Results
The most striking differences between GBM and MM-BM cells were found to be the enrichment of biological processes associated with tumor growth, invasion, and extravasation with the inhibition of MHC class II antigen processing/presentation in GBM cells. Treatment with guadecitabine reduced these biological differences, shaping GBM cells towards a more immunogenic phenotype. Indeed, in GBM cells, promoter hypomethylation by guadecitabine led to the up-regulation of genes mainly associated with activation, proliferation, and migration of T and B cells and with MHC class II antigen processing/presentation. Among DHA-modulated genes in GBM, 7.6% showed a significant prognostic relevance. Moreover, a large set of immune-related upstream-regulators (URs) were commonly modulated by DHA in GBM, MM-BM, and MM cells: DHA-activated URs enriched for biological processes mainly involved in the regulation of cytokines and chemokines production, inflammatory response, and in Type I/II/III IFN-mediated signaling; conversely, DHA-inhibited URs were involved in metabolic and proliferative pathways.

Conclusions
Epigenetic remodeling by guadecitabine represents a promising strategy to increase the efficacy of cancer immunotherapy of GBM, supporting the rationale to develop new epigenetic-based immunotherapeutic approaches for the treatment of this still highly deadly disease.
Prevalence and genotype distribution of HPV infections among women in Chengdu,China
Authors: Zhang Junying , Zha Tianzhi , Wang Xuemei , He Weijun 
Published: March 2024

Abstract
Background
Human papilloma virus (HPV) infection among female is the cause of cervical cancer and genital warts. In China, the HPV vaccination rate and the target population screening rate among females are low, and the aims of this study on the genotype distribution and prevalence of HPV infection were to provide more targeted strategies for the prevention and treatment of cervical cancer and HPV-related diseases.

Methods
Polymerase chain reaction-reverse dot blot (PCR-RDB) was adopted for HPV genotyping test, the prevalence and 23 genotypes distribution of HPV infections among 181,705 women in Chengdu from 2013 to 2020 were analysed.

Results
The overall prevalence rate of HPV infection among 181,705 cases was 23.28%, the prevalence of HR-HPV at the age group < 20 years, 60–69 years and ≥ 70 years were higher than the overall prevalence.The prevalence of HPV showed a bimodal U-shaped curve with age; the first and second peak common occurred among females < 20 years old (42.97%) and 60–69 years old (37.56%), respectively.The top five genotypes of HPV infection among females in Chengdu were HPV52/16/58/81/53. Single infection (73.26%) was the main HPV infection pattern, followed by double infection (19.17%) and multiple infection (7.57%), the infection rate of HPV showed a gradual declined as the patterns of HPV coinfections increased, low-risk and high-risk coinfection was higher in low-risk HPV infection (43.68%) and lower in high-risk HPV infection (13.59%). The prevalence of genotypes − 6 and − 81 infection was the second highest at the age group of 20 and 40–59, respectively, while the prevalence of HPV16 was the highest at the age group of ≥ 70 among 23 genotypes among the 181,705 women.

Conclusions
The prevalence of HPV infections among women in Chengdu is higher than domestic certain developed citys, among the five vaccines available, nonavalent vaccine is more suitable for Chengdu females. For young females prioritizing vaccination is essential in the current context.Double screening for HPV DNA is important in middle-aged women (30–49 years), and screening should not be lacking in older women (> 65 years). Additionally,for patients with genital warts, it is necessary to screen for high-risk HPV infection and provide appropriate management and treatment. Given the limitations of this study, future HPV research should aim to achieve full coverage of the target population, and our studies should also include cellular or pathological data of HPV-positive cases, vaccination rates, and various lifestyle details.
Traditional knowledge of animal-derived medicines used by Gelao community in Northern Guizhou, China
Authors: Liu Xiaoqi , Li Shuo , Feng Yi , Chen Xingxing , Ma Yuhan , Xiao Hai , Zhao Yongxia , Liu Sha , Zheng Guishen , Yang Xiujuan , Wu Faming , Xie Jian 
Published: March 2024

Abstract
Introduction
This study aims to document and preserve the traditional medicinal knowledge of the Gelao community in Northern Guizhou, China, providing valuable insights for modern pharmacological research and the development of these traditional remedies.

Methods
Our methodology encompassed a blend of literature review, community interviews, and participatory observation to delve into the traditional knowledge of animal-derived medicines among the Gelao community. We employed quantitative ethnological and ecological assessment techniques to evaluate the significance of these practices. Informed consent was secured before conducting interviews, with a focus on ascertaining the types of medicines familiar to the informants, including their local names, sources, methods of preparation, application techniques, diseases treated, frequency of use, and safety considerations.

Results
Our research cataloged 55 varieties of animal-derived medicines utilized by the Gelao people. Out of these, 34 originate from wild animals, mainly encompassing small insects, reptiles, and aquatic species; the remaining 21 are derived from domesticated animals, largely involving their tissues, organs, and various physiological or pathological by-products. These medicines are primarily applied in treating pediatric ailments (13 types), internal disorders (11 types), gynecological issues (3 types), dermatological problems (7 types), ENT conditions (3 types), trauma-related injuries (5 types), joint and bone ailments (5 types), infections (2 types), dental issues (2 types), and urolithiasis (1 type), with three types being used for other miscellaneous conditions. Commonly utilized medicines, such as honey, Blaps beetle, chicken gallstones, and snake-based products, are preferred for their availability, edibility, and safety within the Gelao communities.

Conclusion
The Gelao community’s traditional medicines represent a rich diversity of animal sources, showcasing extensive expertise and knowledge in their processing and clinical applications. This wealth of traditional knowledge offers novel perspectives for the contemporary pharmacological study and development of these remedies. Additionally, our research plays a crucial role in aiding the preservation and continuation of this invaluable cultural heritage.
Trachelogenin alleviates osteoarthritis by inhibiting osteoclastogenesis and enhancing chondrocyte survival
Authors: Jiang Tao , Zhang Jiahui , Ruan Beite , Xi Xiaobing , Yang Zhuo , Liu Jianmin , Zhao Hongyan , Xu Xing , Jiang Min 
Published: March 2024

Abstract
Background
Osteoarthritis (OA) is a prevalent global health concern associated with the loss of articular cartilage and subchondral bone. The lack of disease-modifying drugs for OA necessitates the exploration of novel therapeutic options. Our previous study has demonstrated that traditional Chinese medical herb Trachelospermum jasminoides (Lindl.) Lem. extract suppressed osteoclastogenesis and identified trachelogenin (TCG) as a representative compound. Here, we delved into TCG’s potential to alleviate OA.

Methods
We initially validated the in vivo efficacy of TCG in alleviating OA using a rat OA model. Subsequently, we isolated primary bone marrow-derived macrophages in vitro to investigate TCG's impact on osteoclastogenesis. We further employed a small molecule pull-down assay to verify TCG's binding target within osteoclasts. Finally, we isolated primary mouse chondrocytes in vitro to study TCG's regulatory effects and mechanisms on chondrocyte survival.

Results
TCG preserved subchondral bone integrity and protected articular cartilage in a rat OA model. Subsequently, in vitro experiments unveiled TCG's capability to inhibit osteoclastogenesis and function through binding to Ras association proximate 1 (Rap1) and inhibiting its activation. Further study demonstrated that TCG inhibited Rap1/integrin αvβ3/c-Src/Pyk2 signaling cascade, and consequently led to failed F-actin ring formation. Besides, TCG promoted the proliferation of mouse primary chondrocytes while suppressing apoptosis in vitro. This is attributed to TCG's ability to upregulate HIF1α, thereby promoting glycolysis.

Conclusion
TCG exerted inhibitory effects on osteoclastogenesis through binding to Rap1 and inhibiting Rap1 activation, consequently preventing subchondral bone loss. Moreover, TCG enhanced chondrocyte survival by upregulating HIF1α and promoting glycolysis. These dual mechanisms collectively provide a novel approach to prevented against cartilage degradation.