bluuebunny/crossref_metadata_2025_split huggingface dataset:
A pragmatic randomized trial of a primary care antimicrobial stewardship intervention in Ontario, Canada
Authors: McIsaac Warren , Kukan Sahana , Huszti Ella , Szadkowski Leah , O’Neill Braden , Virani Sophia , Ivers Noah , Lall Rosemarie , Toor Navsheer , Shah Mruna , Alvi Ruby , Bhatt Aashka , Nakamachi Yoshiko , Morris Andrew M. 
Published: September 2021

Abstract
Background
More than 90% of antibiotics are prescribed in primary care, but 50% may be unnecessary. Reducing unnecessary antibiotic overuse is needed to limit antimicrobial resistance. We conducted a pragmatic trial of a primary care provider-focused antimicrobial stewardship intervention to reduce antibiotic prescriptions in primary care.

Methods
Primary care practitioners from six primary care clinics in Toronto, Ontario were assigned to intervention or control groups to evaluate the effectiveness of a multi-faceted intervention for reducing antibiotic prescriptions to adults with respiratory and urinary tract infections. The intervention included provider education, clinical decision aids, and audit and feedback of antibiotic prescribing. The primary outcome was total antibiotic prescriptions for these infections. Secondary outcomes were delayed prescriptions, prescriptions longer than 7 days, recommended antibiotic use, and outcomes for individual infections. Generalized estimating equations were used to estimate treatment effects, adjusting for clustering by clinic and baseline differences.

Results
There were 1682 encounters involving 54 primary care providers from January until May 31, 2019. In intervention clinics, the odds of any antibiotic prescription was reduced 22% (adjusted Odds Ratio (OR) = 0.78; 95% Confidence Interval (CI) = 0.64.0.96). The odds that a delay in filling a prescription was recommended was increased (adjusted OR=2.29; 95% CI=1.37, 3.83), while prescription durations greater than 7 days were reduced (adjusted OR=0.24; 95% CI=0.13, 0.43). Recommended antibiotic use was similar in control (85.4%) and intervention clinics (91.8%, p=0.37).

Conclusions
A community-based, primary care provider-focused antimicrobial stewardship intervention was associated with a reduced likelihood of antibiotic prescriptions for respiratory and urinary infections, an increase in delayed prescriptions, and reduced prescription durations.

Trial registration
clinicaltrials.gov (NCT03517215).
A CTLA-4 blocking strategy based on Nanobody in dendritic cell-stimulated cytokine-induced killer cells enhances their anti-tumor effects
Authors: Wang Wu , Wang Xi , Yang Wenli , Zhong Kai , He Na , Li Xuexia , Pang Yanyang , Lu Zi , Liu Aiqun , Lu Xiaoling 
Published: September 2021

Abstract
Background
Cytokine-induced killer cells induced with tumor antigen-pulsed dendritic cells (DC-CIK) immunotherapy is a promising strategy for the treatment of malignant tumors. However, it sefficacy is restricted by the immunosuppression, which is mediated by the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) pathway. In order to overcome the negative co-stimulation from these T cells, we screened a nanobody targeted for CTLA-4 (Nb36) and blocked the CTLA-4 signaling with Nb36.

Methods
Peripheral blood mononuclear cells (PBMCs) were collected from healthy donors to beused to induce CIK cells in vitro, after which they were co-cultured with DC cells that had received tumor antigens. In addition, we tested whether blocking CTLA-4 signaling with Nb36 could promote in vitro DC-CIK cells proliferation, pro-inflammatory cytokine production and cytotoxicity, or not. For the in vivo experiments, we constructed a subcutaneously transplanted tumor model and placed it in NOD/SCID mice to verify the anti-tumor effect of this therapy.

Results
After stimulation with Nb36, the DC-CIK cells presented enhanced proliferation and production of IFN-γ in vitro, which strengthened the killing effect on the tumor cells. For the in vivo experiments, it was found that Nb36-treated DC-CIK cells significantly inhibited the growth of subcutaneously transplanted livercancer tumors, as well as reduced the tumor weight and prolonged the survival of tumor-bearing NOD/SCID mice.

Conclusions
Our findings demonstrated that in response to CTLA-4 specific nanobody stimulation, DC-CIK cells exhibited a better anti-tumor effect. In fact, this Nb-based CTLA-4 blocking strategy achieved an anti-tumor efficacy close to that of monoclonal antibodies. Our findings suggest that DC-CIK cells + Nb36 have the potential to treat malignant tumors through in vivo adoptive therapy.
Infrequent RAS mutation is not associated with specific histological phenotype in gliomas
Authors: Makino Yasuhide , Arakawa Yoshiki , Yoshioka Ema , Shofuda Tomoko , Minamiguchi Sachiko , Kawauchi Takeshi , Tanji Masahiro , Kanematsu Daisuke , Nonaka Masahiro , Okita Yoshiko , Kodama Yoshinori , Mano Masayuki , Hirose Takanori , Mineharu Yohei , Miyamoto Susumu , Kanemura Yonehiro 
Published: September 2021

Abstract
Background
Mutations in driver genes such as IDH and BRAF have been identified in gliomas. Meanwhile, dysregulations in the p53, RB1, and MAPK and/or PI3K pathways are involved in the molecular pathogenesis of glioblastoma. RAS family genes activate MAPK through activation of RAF and PI3K to promote cell proliferation. RAS mutations are a well-known driver of mutation in many types of cancers, but knowledge of their significance for glioma is insufficient. The purpose of this study was to reveal the frequency and the clinical phenotype of RAS mutant in gliomas.

Methods
This study analysed RAS mutations and their clinical significance in 242 gliomas that were stored as unfixed or cryopreserved specimens removed at Kyoto University and Osaka National Hospital between May 2006 and October 2017. The hot spots mutation of IDH1/2, H3F3A, HIST1H3B, and TERT promoter and exon 2 and exon 3 of KRAS, HRAS, and NRAS were analysed with Sanger sequencing method, and 1p/19q codeletion was analysed with multiplex ligation-dependent probe amplification. DNA methylation array was performed in some RAS mutant tumours to improve accuracy of diagnosis.

Results
RAS mutations were identified in four gliomas with three KRAS mutations and one NRAS mutation in one anaplastic oligodendroglioma, two anaplastic astrocytomas (IDH wild-type in each), and one ganglioglioma. RAS-mutant gliomas were identified with various types of glioma histology.

Conclusion
RAS mutation appears infrequent, and it is not associated with any specific histological phenotype of glioma.
Ontario adults’ health behaviors, mental health, and overall well-being during the COVID-19 pandemic
Authors: Shillington Katie J. , Vanderloo Leigh M. , Burke Shauna M. , Ng Victor , Tucker Patricia , Irwin Jennifer D. 
Published: September 2021

Abstract
Background
Public health measures such as physical distancing and work-from-home initiatives have been implemented to slow the spread of COVID-19. These measures may also be associated with unhealthy lifestyle behaviors, which could be particularly problematic for those already at highest risk for losing years of healthy life due to chronic disease (i.e., 30–59-year-olds). The purpose of this paper is two-fold: (1) to provide an overview of Ontario adults’ health behaviors (i.e., physical activity, sedentary behaviors, and dietary intake), mental health, and well-being during the first few months of the COVID-19 pandemic (April–July 2020); and (2) to explore the difference between physical activity and various health behaviors (i.e., well-being, mental health, and dietary intake).

Methods
As a part of a larger, longitudinal study, participants completed an online survey that included demographic information, the Global Physical Activity Questionnaire, Starting the Conversation, the Mental Health Inventory, and the Personal Wellbeing Index-Adult. Data analyses involved computing measures of central tendency and dispersion for demographic characteristics and tools followed by descriptive statistics. Separate independent t-tests were conducted to investigate the difference between physical activity status and well-being, mental health, and dietary intake.

Results
A total of 2157 Ontarians completed an online survey. Descriptive statistics indicated that respondents met physical activity and sedentary behavior guidelines, reported double the amount of recommended recreational screen time, practiced moderately healthy dietary behaviors, experienced mental health problems, and scored below “normal” in some well-being domains.

Conclusion
As the end of the COVID-19 pandemic is currently unknown, its associated restrictions and society changes may influence adults’ behaviors in both the short- and longer-term. As such, our findings might provide immediate insight into the development of timely and evidence-informed health promotion and disease prevention strategies for Canadians, which could support adults’ health behaviors, mental health, and well-being during the COVID-19 pandemic and other, future pandemics.
Evaluation of the standard procedure for treatment of periprosthetic joint infections of total knee and hip arthroplasty: a comparison of the 2015 and 2020 census in total joint replacement centres in Germany
Authors: Osmanski-Zenk Katrin , Klinder Annett , Rimke Christina , Wirtz Dieter C. , Lohmann Christoph H. , Haas Holger , Kladny Bernd , Mittelmeier Wolfram 
Published: September 2021

Abstract
Background
There are different procedures for both, the diagnosis and the therapy of a periprosthetic joint infection (PJI), however, national or international guidelines for a standardised treatment regime are still lacking. The present paper evaluates the use of the predominant treatment protocols for PJI in certified total joint replacement centres (EPZ) in Germany based on an EndoCert questionnaire.

Materials and methods
The questionnaire was developed in cooperation with the EndoCert Certification Commission to survey the treatment protocols for septic revision arthroplasties in EPZ. Questions targeted the various treatment options including prosthesis preserving procedures (DAIR - Debridement, antibiotics, irrigation, and retention of the prosthesis), one-stage revision, two-stage revision, removal of the endoprosthesis and diagnostic sampling prior to re-implantation. All certified EPZ participated (n = 504) and the results from the current survey in 2020 were compared to data from a previous analysis in 2015.

Results
The number of centres that performed DAIR up to a maximum of 4 weeks and more than 10 weeks after index surgery decreased since 2015, while the number of centres that provided a one-stage revision as a treatment option increased (hip: + 6.3%; knee: + 6.6%). The majority of the centres (73.2%) indicated a 4–8 week period as the preferred interval between prosthesis removal and re-implantation in two-stage revision in hip as well as knee revisions. Centres with a higher number of revision surgeries (> 200 revisions/year), opted even more often for the 4–8 week period (92.3%). In two-stage revision the use of metal-based spacers with/without reinforcement with antibiotic-containing cement as an interim placeholder was significantly reduced in 2020 compared to 2015. There was also a clear preference for cemented anchoring in two-stage revision arthroplasty in the knee in 2020, whereas the majority of hip replacements was cementless. Additionally, in 2020 the number of samples for microbiological testing during the removal of the infected endoprosthesis increased and 72% of the centres took five or more samples. Overall, the number of EPZ with a standardised protocol for the procedure expanded from 2015 to 2020.

Conclusion
While there was a trend towards standardised therapeutic algorithms for PJI with more uniform choices among the centres in 2020 compared to 2015, the treatment often remains an individual decision. However, since a consistent treatment regime is of vital importance with an expected rise of total numbers of revision arthroplasties, uniform definitions with regard to comparability and standardisation are necessary for the further development of the EndoCert system.
Privacy and artificial intelligence: challenges for protecting health information in a new era
Authors: Murdoch Blake 
Published: September 2021

Abstract
Background
Advances in healthcare artificial intelligence (AI) are occurring rapidly and there is a growing discussion about managing its development. Many AI technologies end up owned and controlled by private entities. The nature of the implementation of AI could mean such corporations, clinics and public bodies will have a greater than typical role in obtaining, utilizing and protecting patient health information. This raises privacy issues relating to implementation and data security.

Main body
The first set of concerns includes access, use and control of patient data in private hands. Some recent public–private partnerships for implementing AI have resulted in poor protection of privacy. As such, there have been calls for greater systemic oversight of big data health research. Appropriate safeguards must be in place to maintain privacy and patient agency. Private custodians of data can be impacted by competing goals and should be structurally encouraged to ensure data protection and to deter alternative use thereof. Another set of concerns relates to the external risk of privacy breaches through AI-driven methods. The ability to deidentify or anonymize patient health data may be compromised or even nullified in light of new algorithms that have successfully reidentified such data. This could increase the risk to patient data under private custodianship.

Conclusions
We are currently in a familiar situation in which regulation and oversight risk falling behind the technologies they govern. Regulation should emphasize patient agency and consent, and should encourage increasingly sophisticated methods of data anonymization and protection.
Domiciliary dentistry clinics: a multiple case study in the province of Quebec, Canada
Authors: Makansi N. , Rousseau J. , Bedos C. ,   ACE-Dent Research Group, Gauthier Linda , Morissette Laurent , Ducharme Isabelle , Savage Claire , Esfandiari Shahrokh , Hovey Richard , Macdonald Mary Ellen , Nicolau Belinda , Lévesque Martine , Farrell Kim , Thomson Tammy , Apelian Nareg , Brondani Mario , Girard Félix , Dawson Aimée , Vergnes Jean-Noel , Blaizot Alessandra 
Published: September 2021

AbstractBackgroundThe demand for more flexible and person-centered models of oral healthcare delivery is increasing and while mobile and domiciliary dental services have the potential to increase access to oral healthcare among dependent elderly and people with disabilities; the uptake of this service model by dentists remains low. Therefore, the aim of this study was to understand how existing domiciliary dental services operate within a particular context.MethodsWe used a qualitative descriptive multiple case study design. We studied three independent domiciliary dentistry clinics in the province of Quebec, Canada. We completed observations of 27 domiciliary visits, four of which were in private homes and the remaining 23 in LTCFs. We also conducted semi-structured interviews with dental professionals, patients, and caregivers. We performed a qualitative content analysis using a deductive/inductive coding framework.ResultsWe presented a detailed description of the physical and service features of the studied cases. Physical features included the set-up of the mobile clinics, the portable equipment used, and the domiciliary locations of visits. For service features, we described the roles, attitudes, and interactions among those involved on both the providers’ and recipients’ sides, as well as, the logistical and financial aspect of the domiciliary dental services.ConclusionsDespite variations in setup and years of practice, the three mobile clinics had similar physical and service features. They also faced common logistic challenges but were able to provide services and respond to the high demand for domiciliary dental services. Additional research in different contexts would further contribute to building evidence-based models to help increase the uptake of this type of practice by current and future dental professionals.
Integrated early childhood development policy in Iran: a stakeholder analysis
Authors: Atashbahar Omolbanin , Sari Ali Akbari , Takian Amirhossein , Olyaeemanesh Alireza , Mohamadi Efat , Barakati Sayyed Hamed 
Published: September 2021

Abstract
Background
Many stakeholders are involved in the complicated process of policy making in integrated early childhood development (IECD). In other words, there are many challenges for IECD policy making in developing countries, including Iran. The aim of this study was to identify potential stakeholders and their interactions in IECD policy making in Iran.

Method
A mixed-methods study was conducted in two phases in 2018. First, forty semi-structured interviews and a review of IECD-related documents were conducted to identify potential stakeholders and their roles. Second, using a designed checklist, these stakeholders were assessed for power, interest, and position in IECD policy making. Then, a map of stakeholders and a three-dimensional stakeholder analysis figure were designed.

Results
The results of this study showed that various stakeholders, including governmental, semi-governmental, social, non-governmental and international organizations, potentially influence IECD policy in Iran. They were found to have diverse levels of power, interest and position in this regard, leading to their different impacts on the process. This diversity is assumed to have affected their levels of participation and support. Also, we found that the stakeholders with a high-power level do not have a high level of interest in, or support for, IECD policy. In general, organizational competition, complicated inter-sectoral nature of this process, insufficient budget, insufficient awareness about the importance of IECD, lack of priority given to IECD in relevant organizations, economical views rather than developmental perspectives, and lack of commitment among top managers are the reasons why this policy enjoys a low degree of support.

Conclusions
There are weaknesses in effective interactions and relationships among IECD policy stakeholders. This will lead to the lack of equal opportunities for optimal early childhood development. To improve this process, advocacy from high-level authorities of the organizations, negotiation with child-friendly groups, establishing a body to coordinate and oversee children’s affairs, using the capacity of non-governmental organizations, strengthening inter-sectoral collaboration by clarifying the roles and responsibilities of stakeholders and the relationships between them, and increasing public awareness can be helpful.
Insights into the evolutionary origin of the pineal color discrimination mechanism from the river lamprey
Authors: Wada Seiji , Kawano-Yamashita Emi , Sugihara Tomohiro , Tamotsu Satoshi , Koyanagi Mitsumasa , Terakita Akihisa 
Published: September 2021

Abstract
Background
Pineal-related organs in cyclostomes, teleosts, amphibians, and reptiles exhibit color opponency, generating antagonistic neural responses to different wavelengths of light and thereby sensory information about its “color”. Our previous studies suggested that in zebrafish and iguana pineal-related organs, a single photoreceptor cell expressing both UV-sensitive parapinopsin and green-sensitive parietopsin generates color opponency in a “one-cell system.” However, it remains unknown to what degree these opsins and the single cell-based mechanism in the pineal color opponency are conserved throughout non-mammalian vertebrates.

Results
We found that in the lamprey pineal organ, the two opsins are conserved but that, in contrast to the situation in other vertebrate pineal-related organs, they are expressed in separate photoreceptor cells. Intracellular electrophysiological recordings demonstrated that the parietopsin-expressing photoreceptor cells with Go-type G protein evoke a depolarizing response to visible light. Additionally, spectroscopic analyses revealed that parietopsin with 11-cis 3-dehydroretinal has an absorption maximum at ~570 nm, which is in approximate agreement with the wavelength (~560 nm) that produces the maximum rate of neural firing in pineal ganglion cells exposed to visible light. The vesicular glutamate transporter is localized at both the parietopsin- and parapinopsin-expressing photoreceptor terminals, suggesting that both types of photoreceptor cells use glutamate as a transmitter. Retrograde tracing of the pineal ganglion cells revealed that the terminal of the parietopsin-expressing cells is located close enough to form a neural connection with the ganglion cells, which is similar to our previous observation for the parapinopsin-expressing photoreceptor cells and the ganglion cells. In sum, our observations point to a “two-cell system” in which parietopsin and parapinopsin, expressed separately in two different types of photoreceptor cells, contribute to the generation of color opponency in the pineal ganglion cells.

Conclusion
Our results indicate that the jawless vertebrate, lamprey, employs a system for color opponency that differes from that described previously in jawed vertebrates. From a physiological viewpoint, we propose an evolutionary insight, the emergence of pineal “one-cell system” from the ancestral “multiple (two)-cell system,” showing the opposite evolutionary direction to that of the ocular color opponency.
The stem rust fungus Puccinia graminis f. sp. tritici induces centromeric small RNAs during late infection that are associated with genome-wide DNA methylation
Authors: Sperschneider Jana , Jones Ashley W. , Nasim Jamila , Xu Bo , Jacques Silke , Zhong Chengcheng , Upadhyaya Narayana M. , Mago Rohit , Hu Yiheng , Figueroa Melania , Singh Karam B. , Stone Eric A. , Schwessinger Benjamin , Wang Ming-Bo , Taylor Jennifer M. , Dodds Peter N. 
Published: September 2021

Abstract
Background
Silencing of transposable elements (TEs) is essential for maintaining genome stability. Plants use small RNAs (sRNAs) to direct DNA methylation to TEs (RNA-directed DNA methylation; RdDM). Similar mechanisms of epigenetic silencing in the fungal kingdom have remained elusive.

Results
We use sRNA sequencing and methylation data to gain insight into epigenetics in the dikaryotic fungus Puccinia graminis f. sp. tritici (Pgt), which causes the devastating stem rust disease on wheat. We use Hi-C data to define the Pgt centromeres and show that they are repeat-rich regions (~250 kb) that are highly diverse in sequence between haplotypes and, like in plants, are enriched for young TEs. DNA cytosine methylation is particularly active at centromeres but also associated with genome-wide control of young TE insertions. Strikingly, over 90% of Pgt sRNAs and several RNAi genes are differentially expressed during infection. Pgt induces waves of functionally diversified sRNAs during infection. The early wave sRNAs are predominantly 21 nts with a 5′ uracil derived from genes. In contrast, the late wave sRNAs are mainly 22-nt sRNAs with a 5′ adenine and are strongly induced from centromeric regions. TEs that overlap with late wave sRNAs are more likely to be methylated, both inside and outside the centromeres, and methylated TEs exhibit a silencing effect on nearby genes.

Conclusions
We conclude that rust fungi use an epigenetic silencing pathway that might have similarity with RdDM in plants. The Pgt RNAi machinery and sRNAs are under tight temporal control throughout infection and might ensure genome stability during sporulation.