bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigation of a family affected by early-onset osteoarthritis – proposal of a clinical pathway and bioinformatics pipeline for the investigation of cases of familial OA
Authors: Deveza Leticia A. , Zankl Andreas , Hunter David J. 
Published: July 2023

Abstract
Background
Familial cases of early-onset osteoarthritis (OA) are rare although the exact prevalence is unknown. Early recognition of underlying OA-associated disorders is vital for targeted treatment, when available, and genetic counselling, in case of skeletal dysplasias. Currently, there is no clear guidance on how best to investigate families affected by early-onset OA.

Methods
We investigated a family with multiple members affected by early-onset OA (age at onset ≤ 40 years). Clinical and demographic characteristics were collected, followed by laboratory investigations screening for a range of potential OA-associated disorders, and whole genome sequencing in selected individuals.

Results
Seventeen members of the family were included (7 affected and 10 non-affected). There was an even split between the two sexes and two participants were under 18 years old. No pattern of abnormality was seen in the laboratory investigation that could explain the OA phenotype in the family. Whole-genome sequencing was perfomed in one participant and analysed for likely pathogenic variants in genes known to be associated with skeletal dysplasias. A heterozygous variant in the COL2A1 gene was identified (p.Arg519Cys). Confirmatory tests were performed in five additional participants (four affected and one unaffected).

Conclusion
The methodology used in this study, including the clinical pathway and bioinformatics pipeline, could be applied to other families affected by early-onset OA.
Differences in medical education before, during, and in the post-peak period of the COVID-19 pandemic—exploring senior medical students’ attitudes
Authors: Vaca-Cartagena Bryan F. , Quishpe-Narváez Erika , Cartagena Ulloa Heidi , Estévez-Chávez Jenny Paola 
Published: July 2023

Abstract
Background
The burden that COVID-19 has brought to the economy, healthcare systems, and education is unmatched. Public health and social measures were implemented to halt transmission. Thus, social gathering and in-person learning, core aspects of medical education, were interrupted. Studies have documented the detrimental impact students graduating during the pandemic have had on their confidence and skills. However, data comparing pre-pandemic, pandemic, and post-peak students still lack. This study aimed to identify senior medical students' attitudes regarding their education and compare them according to the three previously described periods.

Methods
In this cross-sectional study, the survey employed was designed based on a previous questionnaire and applied to senior medical students before graduating between January 2018 and June 2022. Answers were collected using a three-point Likert scale and Yes/No questions. Associations between variables were examined using Chi-squared, Fisher’s Exact tests, and ANOVA, employing logistic regression to calculate odds ratio (OR) when appropriate.

Results
A total of 679 responses were analyzed. Most students (59%) were women. Up to 383, 241, and 55 senior medical students answered the survey before, during, and in the post-peak period of the COVID-19 pandemic, respectively. There was a staggering decrease in the percentage of students in the post-peak compared to the pre-pandemic period that considered certain factors such as being taught about the doctor-patient relationship (62% vs 75%), practicing teamwork (33% vs 54%), preclinical & clinical subjects (44% vs 63%), and being taught to conduct research (22% vs 32%) as “very useful” to their professional traineeship. There was a significant difference between pre-pandemic, pandemic, and post-peak students when asked if the study curriculum accomplished the goal of training a professional with integrity (89% vs 66% vs 64%, p < 0.001), respectively. In a multivariate analysis graduating during the pandemic (OR 3.92; 95% CI, 2.58–5.94) and in the post-peak period (OR 4.24; 95% CI, 2.23–8.07) were independent factors for the appreciation that the study curriculum did not meet its objective.

Conclusions
The pandemic has hindered medical education. Students’ appreciation of their instruction has deteriorated. Urgent interventions that halt the negative impact on training, ensure readiness for future problems and improve schooling worldwide are needed.
Prognostic models for breast cancer: based on logistics regression and Hybrid Bayesian Network
Authors: Su Fan , Chao Jianqian , Liu Pei , Zhang Bowen , Zhang Na , Luo Zongyu , Han Jiaying 
Published: July 2023

AbstractBackgroundTo construct two prognostic models to predict survival in breast cancer patients; to compare the efficacy of the two models in the whole group and the advanced human epidermal growth factor receptor-2-positive (HER2+) subgroup of patients; to conclude whether the Hybrid Bayesian Network (HBN) model outperformed the logistics regression (LR) model.MethodsIn this paper, breast cancer patient data were collected from the SEER database. Data processing and analysis were performed using Rstudio 4.2.0, including data preprocessing, model construction and validation. The L_DVBN algorithm in Julia0.4.7 and bnlearn package in R was used to build and evaluate the HBN model. Data with a diagnosis time of 2018(n = 23,384) were distributed randomly as training and testing sets in the ratio of 7:3 using the leave-out method for model construction and internal validation. External validation of the model was done using the dataset of 2019(n = 8128). Finally, the late HER2 + patients(n = 395) was selected for subgroup analysis. Accuracy, calibration and net benefit of clinical decision making were evaluated for both models.ResultsThe HBN model showed that seventeen variables were associated with survival outcome, including age, tumor size, site, histologic type, radiotherapy, surgery, chemotherapy, distant metastasis, subtype, clinical stage, ER receptor, PR receptor, clinical grade, race, marital status, tumor laterality, and lymph node. The AUCs for the internal validation of the LR and HBN models were 0.831 and 0.900; The AUCs for the external validation of the LR and HBN models on the whole population were 0.786 and 0.871; the AUCs for the external validation of the two models on the subgroup population were 0.601 and 0.813.ConclusionThe accuracy, net clinical benefit, and calibration of the HBN model were better than LR model. The predictive efficacy of both models decreased and the difference was greater in advanced HER2 + patients, which means the HBN model had higher robustness and more stable predictive performance in the subgroup.
Opinion research among Russian Physicians on the application of technologies using artificial intelligence in the field of medicine and health care
Authors: Orlova I.A. , Akopyan Zh.A. , Plisyuk A.G. , Tarasova E.V. , Borisov E.N. , Dolgushin G.O. , Khvatova E.I. , Grigoryan M.A. , Gabbasova L.A. , Kamalov A.A. 
Published: July 2023

Abstract
Background
To date, no opinion surveys has been conducted among Russian physicians to study their awareness about artificial intelligence. With a survey, we aimed to evaluate the attitudes of stakeholders to the usage of technologies employing AI in the field of medicine and healthcare and identify challenges and perspectives to introducing AI.

Methods
We conducted a 12-question online survey using Google Forms. The survey consisted of questions related to the recognition of AI and attitudes towards it, the direction of development of AI in medicine and the possible risks of using AI in medicine.

Results
301 doctors took part in the survey. 107 (35.6%) responded that they are familiar with AI. The vast majority of participants considered AI useful in the medical field (85%). The advantage of AI was associated with the ability to analyze huge volumes of clinically relevant data in real time (79%). Respondents highlighted areas where AI would be most useful—organizational optimization (74%), biopharmaceutical research (67%), and disease diagnosis (52%). Among the possible problems when using AI, they noted the lack of flexibility and limited application on controversial issues (64% and 60% of respondents). 56% believe that AI decision making will be difficult if inadequate information is presented for analysis. A third of doctors fear that specialists with little experience took part in the development of AI, and 89% of respondents believe that doctors should participate in the development of AI for medicine and healthcare. Only 20 participants (6.6%) responded that they agree that AI can replace them at work. At the same time, 76% of respondents believe that in the future, doctors using AI will replace those who do not.

Conclusions
Russian doctors are for AI in medicine. Most of the respondents believe that AI will not replace them in the future and will become a useful tool. First of all, for optimizing organizational processes, research and diagnostics of diseases.

Trial registration
This study was approved by the Local Ethics Committee of the Lomonosov Moscow State University Medical Research and Education Center (IRB00010587).
Identification of residues critical for the extension of Munc18-1 domain 3a
Authors: Wang Xianping , Gong Jihong , Zhu Le , Chen Huidan , Jin Ziqi , Mo Xiaoqiang , Wang Shen , Yang Xiaofei , Ma Cong 
Published: July 2023

Abstract
Background
Neurotransmitter release depends on the fusion of synaptic vesicles with the presynaptic membrane and is mainly mediated by SNARE complex assembly. During the transition of Munc18-1/Syntaxin-1 to the SNARE complex, the opening of the Syntaxin-1 linker region catalyzed by Munc13-1 leads to the extension of the domain 3a hinge loop, which enables domain 3a to bind SNARE motifs in Synaptobrevin-2 and Syntaxin-1 and template the SNARE complex assembly. However, the exact mechanism of domain 3a extension remains elusive.

Results
Here, we characterized residues on the domain 3a hinge loop that are crucial for the extension of domain 3a by using biophysical and biochemical approaches and electrophysiological recordings. We showed that the mutation of residues T323/M324/R325 disrupted Munc13-1-mediated SNARE complex assembly and membrane fusion starting from Munc18-1/Syntaxin-1 in vitro and caused severe defects in the synaptic exocytosis of mouse cortex neurons in vivo. Moreover, the mutation had no effect on the binding of Synaptobrevin-2 to isolated Munc18-1 or the conformational change of the Syntaxin-1 linker region catalyzed by the Munc13-1 MUN domain. However, the extension of the domain 3a hinge loop in Munc18-1/Syntaxin-1 was completely disrupted by the mutation, leading to the failure of Synaptobrevin-2 binding to Munc18-1/Syntaxin-1.

Conclusions
Together with previous results, our data further support the model that the template function of Munc18-1 in SNARE complex assembly requires the extension of domain 3a, and particular residues in the domain 3a hinge loop are crucial for the autoinhibitory release of domain 3a after the MUN domain opens the Syntaxin-1 linker region.
Adenosine metabolized from extracellular ATP ameliorates organ injury by triggering A2BR signaling
Authors: Kelestemur Taha , Németh Zoltán H. , Pacher Pal , Beesley Jennet , Robson Simon C. , Eltzschig Holger K. , Haskó György 
Published: July 2023

Abstract
Background
Trauma and a subsequent hemorrhagic shock (T/HS) result in insufficient oxygen delivery to tissues and multiple organ failure. Extracellular adenosine, which is a product of the extracellular degradation of adenosine 5’ triphosphate (ATP) by the membrane-embedded enzymes CD39 and CD73, is organ protective, as it participates in signaling pathways, which promote cell survival and suppress inflammation through adenosine receptors including the A2BR. The aim of this study was to evaluate the role of CD39 and CD73 delivering adenosine to A2BRs in regulating the host’s response to T/HS.

Methods
T/HS shock was induced by blood withdrawal from the femoral artery in wild-type, global knockout (CD39, CD73, A2BR) and conditional knockout (intestinal epithelial cell-specific deficient VillinCre-A2BRfl/fl) mice. At 3 three hours after resuscitation, blood and tissue samples were collected to analyze organ injury.

Results
T/HS upregulated the expression of CD39, CD73, and the A2BR in organs. ATP and adenosine levels increased after T/HS in bronchoalveolar lavage fluid. CD39, CD73, and A2BR mimics/agonists alleviated lung and liver injury. Antagonists or the CD39, CD73, and A2BR knockout (KO) exacerbated lung injury, inflammatory cytokines, and chemokines as well as macrophage and neutrophil infiltration and accumulation in the lung. Agonists reduced the levels of the liver enzymes aspartate transferase and alanine transaminase in the blood, whereas antagonist administration or CD39, CD73, and A2BR KO enhanced enzyme levels. In addition, intestinal epithelial cell-specific deficient VillinCre-A2BRfl/fl mice showed increased intestinal injury compared to their wild-type VillinCre controls.

Conclusion
In conclusion, the CD39-CD73-A2BR axis protects against T/HS-induced multiple organ failure.
BID expression determines the apoptotic fate of cancer cells after abrogation of the spindle assembly checkpoint by AURKB or TTK inhibitors
Authors: Bertran-Alamillo Jordi , Giménez-Capitán Ana , Román Ruth , Talbot Sara , Whiteley Rebecca , Floc’h Nicolas , Martínez-Pérez Elizabeth , Martin Matthew J. , Smith Paul D. , Sullivan Ivana , Terp Mikkel G. , Saeh Jamal , Marino-Buslje Cristina , Fabbri Giulia , Guo Grace , Xu Man , Tornador Cristian , Aguilar-Hernández Andrés , Reguart Noemí , Ditzel Henrik J. , Martínez-Bueno Alejandro , Nabau-Moretó Núria , Gascó Amaya , Rosell Rafael , Pease J. Elizabeth , Polanska Urszula M. , Travers Jon , Urosevic Jelena , Molina-Vila Miguel A. 
Published: July 2023

Abstract
Background
Drugs targeting the spindle assembly checkpoint (SAC), such as inhibitors of Aurora kinase B (AURKB) and dual specific protein kinase TTK, are in different stages of clinical development. However, cell response to SAC abrogation is poorly understood and there are no markers for patient selection.

Methods
A panel of 53 tumor cell lines of different origins was used. The effects of drugs were analyzed by MTT and flow cytometry. Copy number status was determined by FISH and Q-PCR; mRNA expression by nCounter and RT-Q-PCR and protein expression by Western blotting. CRISPR-Cas9 technology was used for gene knock-out (KO) and a doxycycline-inducible pTRIPZ vector for ectopic expression. Finally, in vivo experiments were performed by implanting cultured cells or fragments of tumors into immunodeficient mice.

Results
Tumor cells and patient-derived xenografts (PDXs) sensitive to AURKB and TTK inhibitors consistently showed high expression levels of BH3-interacting domain death agonist (BID), while cell lines and PDXs with low BID were uniformly resistant. Gene silencing rendered BID-overexpressing cells insensitive to SAC abrogation while ectopic BID expression in BID-low cells significantly increased sensitivity. SAC abrogation induced activation of CASP-2, leading to cleavage of CASP-3 and extensive cell death only in presence of high levels of BID. Finally, a prevalence study revealed high BID mRNA in 6% of human solid tumors.

Conclusions
The fate of tumor cells after SAC abrogation is driven by an AURKB/ CASP-2 signaling mechanism, regulated by BID levels. Our results pave the way to clinically explore SAC-targeting drugs in tumors with high BID expression.
Biodegradable FePS3 nanoplatform for efficient treatment of osteosarcoma by combination of gene and NIR-II photothermal therapy
Authors: Luo Tingting , Jiang Mingyang , Cheng Ziqiang , Lin Yuntao , Chen Yuling , Zhang Zhenyu , Zhou Jian , Zhou Wenhua , Yu Xue-Feng , Li Shuchun , Geng Shengyong , Yang Hongyu 
Published: July 2023

AbstractAs a common tumor with high incidence, osteosarcoma possesses extremely poor prognosis and high mortality. Improving the survival of osteosarcoma patients is still a great challenge due to the precipice of advancement in treatment. In this study, a combination strategy of gene therapy and photothermal therapy (PTT) is developed for efficient treatment of osteosarcoma. Two-dimensional (2D) FePS3 nanosheets are synthesized and functionalized by poly-L-lysine-PEG-folic acid (PPF) to fabricate a multifunctional nanoplatform (FePS@PPF) for further loading microRNAs inhibitor, miR-19a inhibitor (anti-miR-19a). The photothermal conversion efficiency of FePS@PPF is up to 47.1% under irradiation by 1064 nm laser. In vitro study shows that anti-miR-19a can be efficiently internalized into osteosarcoma cells through the protection and delivery of FePS@PPF nanaocarrier, which induces up-regulation of PTEN protein and down-regulation p-AKT protein. After intravenous injection, the FePS@PPF nanoplatform specifically accumulates to tumor site of osteosarcoma-bearing mice. The in vitro and in vivo investigations reveal that the combined PTT-gene therapy displays most significant tumor ablation compared with monotherapy. More importantly, the good biodegradability promotes FePS@PPF to be cleared from body avoiding potential toxicity of long-term retention. Our work not only develops a combined strategy of NIR-II PTT and gene therapy mediated by anti-miR-19a/FePS@PPF but also provides insights into the design and applications of other nanotherapeutic platforms.
Advancing health through evidence assisted decisions with health policy and systems research program: a qualitative evaluation of a national health research grant management process in the Philippines
Authors: Sales Reneepearl Kim , Reyes-Ramos Gladys Kaye , de Veyra Chiqui , Gascon Gabrielle , Barraca Vianka , Garcia Gillian , Yap Maria Eufemia 
Published: July 2023

Abstract
Background
Health policy and systems research (HPSR) has influenced Philippine policies, including tobacco control, mental health, and COVID-19. The Department of Health (DOH) Philippines and Philippine Council for Health Research and Development (PCHRD) launched the Advancing Health through Evidence-Assisted Decisions (AHEAD) with HPSR program in 2017, aiming to build a community of researchers and decision-makers committed to evidence production and utilization. Research systems employ grant management processes for transparency and accountability in research funding, preventing waste, fraud, and misuse of funds.

Methods
This study evaluated AHEAD-HPSR's grant management using surveys, interviews, and focus groups to document (1) grant administration processes implemented by DOH and PCHRD, and (2) experiences of grantees, program managers, staff, and policymakers. Data were initially analyzed through the USA Grant Accountability Office’s Federal Grant Life Cycle, with new themes created as they emerged. The study identified processes and gaps in the research grant life cycle stages: design/redesign, pre-award, award, implementation, closeout, and research dissemination and utilization.

Results
Identification of research areas for the grant are identified using national and departmental research priorities. While Calls for Proposals are posted publicly, researchers that have previously worked with policymakers are contacted directly to submit proposals. The evaluation found that research is delayed by bureaucracies in grant administration, particularly in financial reporting and ethics review processes. Complying with the terminal financial report was identified as the most challenging part of the grant process due to immense auditing requirements. Grantees recommend the simplification of bureaucracy for fund release to enable them to focus on research work.

Conclusion
This study contributes to the limited literature on health research grant management in developing countries. Valuable information and recommendations were contributed by stakeholders in this evaluation. These are manifestations of a continuing interest and desire to make health policy and systems research in the Philippines more robust and relevant. It is imperative for the program to continually evolve and build systems most applicable to its multidisciplinary context.
Transfer of patient’s peripheral blood mononuclear cells (PBMCs) disrupts blood–brain barrier and induces anti-NMDAR encephalitis: a study of novel humanized PBMC mouse model
Authors: Shu Yaqing , Peng Fuhua , Zhao Bingchu , Liu Chunxin , Li Qihui , Li Huilu , Wang Yuge , Jiang Yanjun , Lu Tingting , Wang Qin , Sun Jian , Feng Huiyu , Lu Zhengqi , Liu Xiaodong , Wang Jie , Qiu Wei 
Published: July 2023

Abstract
Background
Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe autoimmune neuropsychiatric disease. Brain access of anti-NMDAR autoantibody through the blood–brain barrier (BBB) is essential for pathogenesis. Most previous animal models limit the investigation of etiologies of BBB damage in patients.

Methods
In this study, we established a novel humanized mouse model of anti-NMDAR encephalitis by intraperitoneal injection of patients’ peripheral blood mononuclear cells (PBMCs) into BALB/c Rag2−/−Il2rg−/−SirpαNODFlk2−/− mice.

Results
We found that engraftment of patients’ PBMCs not only produced potent anti-GluN1 autoantibodies, but also disrupted BBB integrity to allow brain access of autoantibodies, resulting in a hyperactive locomotor phenotype, anxiety- and depressive-like behaviors, cognitive deficits, as well as functional changes in corresponding brain regions. Transcriptome analysis suggested an exaggerated immune response and impaired neurotransmission in the mouse model and highlighted Il-1β as a hub gene implicated in pathological changes. We further demonstrated that Il-1β was produced by endothelial cells and disrupted BBB by repressing tight junction proteins. Treatment with Anakinra, an Il-1 receptor antagonist, ameliorated BBB damage and neuropsychiatric behaviors.

Conclusions
Our study provided a novel and clinically more relevant humanized mouse model of anti-NMDAR encephalitis and revealed an intrinsic pathogenic property of the patient’s lymphocytes.