bluuebunny/crossref_metadata_2025_split huggingface dataset:
Does a new case-based payment system promote the construction of the ordered health delivery system? Evidence from a pilot city in China
Authors: Shi Huanyu , Cheng Zhichao , Liu Zhichao , Zhang Yang , Zhang Peng 
Published: March 2024

Abstract
Background
The construction of the ordered health delivery system in China aims to enhance equity and optimize the efficient use of medical resources by rationally allocating patients to different levels of medical institutions based on the severity of their condition. However, superior hospitals have been overcrowded, and primary healthcare facilities have been underutilized in recent years. China has developed a new case-based payment method called “Diagnostic Intervention Package” (DIP). The government is trying to use this economic lever to encourage medical institutions to actively assume treatment tasks consistent with their functional positioning and service capabilities.

Methods
This study takes Tai’an, a DIP pilot city, as a case study and uses an interrupted time series analysis to analyze the impact of DIP reform on the case severity and service scope of medical institutions at different levels.

Results
The results show that after the DIP reform, the proportion of patients receiving complicated procedures (tertiary hospitals: β3 = 0.197, P < 0.001; secondary hospitals: β3 = 0.132, P = 0.020) and the case mix index (tertiary hospitals: β3 = 0.022, P < 0.001; secondary hospitals: β3 = 0.008, P < 0.001) in tertiary and secondary hospitals increased, and the proportion of primary-DIP-groups cases decreased (tertiary hospitals: β3 = -0.290, P < 0.001; secondary hospitals: β3 = -1.200, P < 0.001), aligning with the anticipated policy objectives. However, the proportion of patients receiving complicated procedures (β3 = 0.186, P = 0.002) and the case mix index (β3 = 0.002, P < 0.001) in primary healthcare facilities increased after the reform, while the proportion of primary-DIP-groups cases (β3 = -0.515, P = 0.005) and primary-DIP-groups coverage (β3 = -2.011, P < 0.001) decreased, which will reduce the utilization efficiency of medical resources and increase inequity.

Conclusion
The DIP reform did not effectively promote the construction of the ordered health delivery system. Policymakers need to adjust economic incentives and implement restraint mechanisms to regulate the behavior of medical institutions.
A novel pan-PI3K inhibitor KTC1101 synergizes with anti-PD-1 therapy by targeting tumor suppression and immune activation
Authors: Peng Xin , Huang Xin , Lulu Talal Ben , Jia Wenqing , Zhang Shaolu , Cohen Limor , Huang Shengfan , Fan Jindian , Chen Xi , Liu Shanshan , Wang Yongzhe , Wang Kailin , Isoyama Sho , Dan Shingo , Wang Feng , Zhang Zhe , Elkabets Moshe , Kong Dexin 
Published: March 2024

Abstract
Background
Phosphoinositide 3-kinases (PI3Ks) are critical regulators of diverse cellular functions and have emerged as promising targets in cancer therapy. Despite significant progress, existing PI3K inhibitors encounter various challenges such as suboptimal bioavailability, potential off-target effects, restricted therapeutic indices, and cancer-acquired resistance. Hence, novel inhibitors that overcome some of these challenges are needed. Here, we describe the characterization of KTC1101, a novel pan-PI3K inhibitor that simultaneously targets tumor cell proliferation and the tumor microenvironment. Our studies demonstrate that KTC1101 significantly increases the anti-PD-1 efficacy in multiple pre-clinical mouse models.

Methods
KTC1101 was synthesized and characterized employing chemical synthesis, molecular modeling, Nuclear Magnetic Resonance (NMR), and mass spectrometry. Its target specificity was confirmed through the kinase assay, JFCR39 COMPARE analysis, and RNA-Seq analysis. Metabolic stability was verified via liver microsome and plasma assays, pharmacokinetics determined by LC–MS/MS, and safety profile established through acute toxicity assays to determine the LD50. The antiproliferative effects of KTC1101 were evaluated in a panel of cancer cell lines and further validated in diverse BALB/c nude mouse xenograft, NSG mouse xenograft and syngeneic mouse models. The KTC1101 treatment effect on the immune response was assessed through comprehensive RNA-Seq, flow cytometry, and immunohistochemistry, with molecular pathways investigated via Western blot, ELISA, and qRT-PCR.

Results
KTC1101 demonstrated strong inhibition of cancer cell growth in vitro and significantly impeded tumor progression in vivo. It effectively modulated the Tumor Microenvironment (TME), characterized by increased infiltration of CD8+ T cells and innate immune cells. An intermittent dosing regimen of KTC1101 enhanced these effects. Notably, KTC1101 synergized with anti-PD-1 therapy, significantly boosting antitumor immunity and extending survival in preclinical models.

Conclusion
KTC1101's dual mechanism of action—directly inhibiting tumor cell growth and dynamically enhancing the immune response— represents a significant advancement in cancer treatment strategies. These findings support incorporating KTC1101 into future oncologic regimens to improve the efficacy of immunotherapy combinations.
Injectable Bombyx mori (B. mori) silk fibroin/MXene conductive hydrogel for electrically stimulating neural stem cells into neurons for treating brain damage
Authors: Yang Zhangze , You Yuxin , Liu Xiangyu , Wan Quan , Xu Zongpu , Shuai Yajun , Wang Jie , Guo Tingbiao , Hu Jiaqi , Lv Junhui , Zhang Meng , Yang Mingying , Mao Chuanbin , Yang Shuxu 
Published: March 2024

AbstractBrain damage is a common tissue damage caused by trauma or diseases, which can be life-threatening. Stem cell implantation is an emerging strategy treating brain damage. The stem cell is commonly embedded in a matrix material for implantation, which protects stem cell and induces cell differentiation. Cell differentiation induction by this material is decisive in the effectiveness of this treatment strategy. In this work, we present an injectable fibroin/MXene conductive hydrogel as stem cell carrier, which further enables in-vivo electrical stimulation upon stem cells implanted into damaged brain tissue. Cell differentiation characterization of stem cell showed high effectiveness of electrical stimulation in this system, which is comparable to pure conductive membrane. Axon growth density of the newly differentiated neurons increased by 290% and axon length by 320%. In addition, unfavored astrocyte differentiation is minimized. The therapeutic effect of this system is proved through traumatic brain injury model on rats. Combined with in vivo electrical stimulation, cavities formation is reduced after traumatic brain injury, and rat motor function recovery is significantly promoted.
Graphical Abstract
Clinical and genetic interpretation of uncertain DMD missense variants: evidence from mRNA and protein studies
Authors: Xie Zhiying , Liu Chang , Yu Haiyan , Xie Zhihao , Sun Chengyue , Zhu Ying , Hu Xiaoyu , Bai Li , Wei Luhua , Sun Peng , Lu Yanyu , Lu Yunlong , Zhao Yawen , Zhang Wei , Wang Zhaoxia , Meng Lingchao , Yuan Yun 
Published: March 2024

Abstract
Background
Pathogenic missense variants in the dystrophin (DMD) gene are rarely reported in dystrophinopathies. Most DMD missense variants are of uncertain significance and their pathogenicity interpretation remains complicated. We aimed to investigate whether DMD missense variants would cause aberrant splicing and re-interpret their pathogenicity based on mRNA and protein studies.

Methods
Nine unrelated patients who had an elevated serum creatine kinase level with or without muscle weakness were enrolled. They underwent a detailed clinical, imaging, and pathological assessment. Routine genetic testing and muscle-derived mRNA and protein studies of dystrophin and sarcoglycan genes were performed in them.

Results
Three of the 9 patients presented with a Duchenne muscular dystrophy (DMD) phenotype and the remaining 6 patients had a suspected diagnosis of Becker muscular dystrophy (BMD) or sarcoglycanopathy based on their clinical and pathological characteristics. Routine genetic testing detected only 9 predicted DMD missense variants in them, of which 6 were novel and interpreted as uncertain significance. Muscle-derived mRNA studies of sarcoglycan genes didn’t reveal any aberrant transcripts in them. Dystrophin mRNA studies confirmed that 3 predicted DMD missense variants (c.2380G > C, c.4977C > G, and c.5444A > G) were in fact splicing and frameshift variants due to aberrant splicing. The 9 DMD variants were re-interpreted as pathogenic or likely pathogenic based on mRNA and protein studies. Therefore, 3 patients with DMD splicing variants and 6 patients with confirmed DMD missense variants were diagnosed with DMD and BMD, respectively.

Conclusion
Our study highlights the importance of muscle biopsy and aberrant splicing for clinical and genetic interpretation of uncertain DMD missense variants.
Community-based rehabilitation for people with psychosocial disabilities in low- and middle-income countries: a systematic review of the grey literature
Authors: Butura Ana-Maria , Ryan Grace K. , Shakespeare Tom , Ogunmola Olusegun , Omobowale Olubukola , Greenley Rachel , Eaton Julian 
Published: March 2024

Abstract
Background
Community based rehabilitation (CBR) aims to promote the inclusion and participation of people with disabilities, particularly in low- and middle-income countries (LMICs). Yet people with psychosocial disabilities are often excluded from CBR programmes. The restrictive inclusion criteria used by previous reviews make it difficult to identify promising examples that could otherwise help to inform the uptake of CBR for people with psychosocial disabilities. We aim to address this gap using gold standard methods for the review and synthesis of grey literature on CBR for people with psychosocial disabilities in LMICs.

Methods
Our search strategy was developed in consultation with an expert advisory group and covered seven grey literature databases, two customised Google Advanced searches, 34 targeted websites and four key reports. A single reviewer screened the search results and extracted relevant data using a standardised format based on the World Health Organisation’s CBR matrix. The included programmes were then checked by a second reviewer with experience in CBR to ensure they met the review’s criteria. A narrative synthesis with summative content analysis was performed to synthesise the findings.

Results
The 23 CBR programmes identified for inclusion spanned 19 countries and were mostly located in either rural areas or urban areas where a large proportion of the population was living in poverty. 13 were classified as livelihood programmes, eight as empowerment programmes, seven as social programmes, seven as health programmes and four as education programmes. Only two addressed all five of these components. 12 of the included programmes reported challenges to implementation, with stigma and lack of resources emerging as two of the most prominent themes.

Conclusion
This grey literature review identified several CBR programmes and synthesised key learning that would have otherwise been missed by a more traditional review of the published literature. However, as evaluation by implementing organisations is not always conducted to a high standard, the quality of this evidence is generally poor. A flexible monitoring and evaluation framework for CBR programmes could help to reduce heterogeneity in terms of the quality and content of reporting.
11p13 microduplication: a differential diagnosis of Silver–Russell syndrome?
Authors: Amin Asmaa K. , Krause Jeremias , Eggermann Thomas 
Published: March 2024

Abstract
Background
Silver–Russel syndrome (SRS) is a congenital disorder which is mainly characterized by intrauterine and postnatal growth retardation, relative macrocephaly, and characteristic (facial) dysmorphisms. The majority of patients shows a hypomethylation of the imprinting center region 1 (IC1) in 11p15 and maternal uniparental disomy of chromosome 7 (upd(7)mat), but in addition a broad spectrum of copy number variations (CNVs) and monogenetic variants (SNVs) has been reported in this cohort. These heterogeneous findings reflect the clinical overlap of SRS with other congenital disorders, but some of the CNVs are recurrent and have therefore been suggested as SRS-associated loci. However, this molecular heterogeneity makes the decision on the diagnostic workup of patients with SRS features challenging.

Case presentation
A girl with clinical features of SRS but negatively tested for the IC1 hypomethylation and upd(7)mat was analyzed by whole genome sequencing in order to address both CNVs and SNVs in the same run. We identified a 11p13 microduplication affecting a region overlapping with a variant reported in a previously published patient with clinical features of Silver–Russel syndrome.

Conclusions
The identification of a 11p13 microduplication in a patient with SRS features confirms the considerable contribution of CNVs to SRS-related phenotypes, and it strengthens the evidence for a 11p13 microduplication syndrome as a differential diagnosis SRS. Furthermore, we could confirm that WGS is a valuable diagnostic tool in patients with SRS and related disorders, as it allows CNVs and SNV detection in the same run, thereby avoiding a time-consuming diagnostic testing process.
Unraveling the molecular mechanisms of lymph node metastasis in ovarian cancer: focus on MEOX1
Authors: Li Jiajia , Sun Yihua , Zhi Xiuling , Sun Yating , Abudousalamu Zulimire , Lin Qianhan , Li Bin , Yao Liangqing , Chen Mo 
Published: March 2024

Abstract
Background
Lymph node metastasis (LNM) is a major factor contributing to the high mortality rate of ovarian cancer, making the treatment of this disease challenging. However, the molecular mechanism underlying LNM in ovarian cancer is still not well understood, posing a significant obstacle to overcome.

Results
Through data mining from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, we have identified MEOX1 as a specific gene associated with LNM in ovarian cancer. The expression of MEOX1 was found to be relatively high in serous ovarian adenocarcinoma, and its higher expression were associated with increased tumor grade and poorer clinical prognosis for ovarian cancer patients. Bioinformatics analysis revealed that MEOX1 exhibited the highest mRNA levels among all cancer types in ovarian cancer tissues and cell lines. Furthermore, gene set enrichment analysis (GSEA) and pathway analysis demonstrated that MEOX1 was involved in various LNM-related biological activities, such as lymphangiogenesis, lymphatic vessel formation during metastasis, epithelial-mesenchymal transition (EMT), G2/M checkpoint, degradation of extracellular matrix, and collagen formation. Additionally, the expression of MEOX1 was positively correlated with the expression of numerous prolymphangiogenic factors in ovarian cancer. To validate our findings, we conducted experiments using clinical tissue specimens and cell lines, which confirmed that MEOX1 was highly expressed in high-grade serous ovarian cancer (HGSOC) tissues and various ovarian cancer cell lines (A2780, SKOV3, HO8910, and OVCAR5) compared to normal ovarian tissues and normal ovarian epithelial cell line IOSE-80, respectively. Notably, we observed a higher protein level of MEOX1 in tumor tissues of LNM-positive HGSOC compared to LNM-negative HGSOC. Moreover, our fundamental experiments demonstrated that suppression of MEOX1 led to inhibitory effects on ovarian cancer cell proliferation and EMT, while overexpression of MEOX1 enhanced the proliferation and EMT capacities of ovarian cancer cells.

Conclusions
The results of our study indicate that MEOX1 plays a role in the lymph node metastasis of ovarian cancer by regulating multiple biological activities, including the proliferation and EMT of ovarian cancer, lymphangiogenesis, and ECM remodeling. Our findings suggest that MEOX1 could serve as a potential biomarker for the diagnosis and treatment of ovarian cancer with LNM.
Real-time machine learning model to predict short-term mortality in critically ill patients: development and international validation
Authors: Lim Leerang , Gim Ukdong , Cho Kyungjae , Yoo Dongjoon , Ryu Ho Geol , Lee Hyung-Chul 
Published: March 2024

Abstract
Background
A real-time model for predicting short-term mortality in critically ill patients is needed to identify patients at imminent risk. However, the performance of the model needs to be validated in various clinical settings and ethnicities before its clinical application. In this study, we aim to develop an ensemble machine learning model using routinely measured clinical variables at a single academic institution in South Korea.

Methods
We developed an ensemble model using deep learning and light gradient boosting machine models. Internal validation was performed using the last two years of the internal cohort dataset, collected from a single academic hospital in South Korea between 2007 and 2021. External validation was performed using the full Medical Information Mart for Intensive Care (MIMIC), eICU-Collaborative Research Database (eICU-CRD), and Amsterdam University Medical Center database (AmsterdamUMCdb) data. The area under the receiver operating characteristic curve (AUROC) was calculated and compared to that for the National Early Warning Score (NEWS).

Results
The developed model (iMORS) demonstrated high predictive performance with an internal AUROC of 0.964 (95% confidence interval [CI] 0.963–0.965) and external AUROCs of 0.890 (95% CI 0.889–0.891) for MIMIC, 0.886 (95% CI 0.885–0.887) for eICU-CRD, and 0.870 (95% CI 0.868–0.873) for AmsterdamUMCdb. The model outperformed the NEWS with higher AUROCs in the internal and external validation (0.866 for the internal, 0.746 for MIMIC, 0.798 for eICU-CRD, and 0.819 for AmsterdamUMCdb; p < 0.001).

Conclusions
Our real-time machine learning model to predict short-term mortality in critically ill patients showed excellent performance in both internal and external validations. This model could be a useful decision-support tool in the intensive care units to assist clinicians.
A phenotypic screen of the Global Health Priority Box identifies an insecticide with anthelmintic activity
Authors: Shanley Harrison T. , Taki Aya C. , Byrne Joseph J. , Nguyen Nghi , Wells Tim N. C. , Jabbar Abdul , Sleebs Brad E. , Gasser Robin B. 
Published: March 2024

Abstract
Background
Infection with parasitic nematodes (helminths), particularly those of the order Strongylida (such as Haemonchus contortus), can cause significant and burdensome diseases in humans and animals. Widespread drug (anthelmintic) resistance in livestock parasites, the absence of vaccines against most of these nematodes, and a lack of new and effective chemical entities on the commercial market demands the discovery of new anthelmintics. In the present study, we searched the Global Health Priority Box (Medicines for Malaria Venture) for new candidates for anthelmintic development.

Methods
We employed a whole-organism, motility-based phenotypic screening assay to identify compounds from the Global Health Priority Box with activity against larvae of the model parasite H. contortus, and the free-living comparator nematode Caenorhabditis elegans. Hit compounds were further validated via dose–response assays, with lead candidates then assessed for nematocidal activity against H. contortus adult worms, and additionally, for cytotoxic and mitotoxic effects on human hepatoma (HepG2) cells.

Results
The primary screen against H. contortus and C. elegans revealed or reidentified 16 hit compounds; further validation established MMV1794206, otherwise known as ‘flufenerim’, as a significant inhibitor of H. contortus larval motility (half-maximal inhibitory concentration [IC50] = 18 μM) and development (IC50 = 1.2 μM), H. contortus adult female motility (100% after 12 h of incubation) and C. elegans larval motility (IC50 = 0.22 μM). Further testing on a mammalian cell line (human hepatoma HepG2 cells), however, identified flufenerim to be both cytotoxic (half-maximal cytotoxic concentration [CC50] < 0.7 μM) and mitotoxic (half-maximal mitotoxic concentration [MC50] < 0.7 μM).

Conclusions
The in vitro efficacy of MMV1794206 against the most pathogenic stages of H. contortus, as well as the free-living C. elegans, suggests the potential for development as a broad-spectrum anthelmintic compound; however, the high toxicity towards mammalian cells presents a significant hindrance. Further work should seek to establish the protein–drug interactions of MMV1794206 in a nematode model, to unravel the mechanism of action, in addition to an advanced structure–activity relationship investigation to optimise anthelmintic activity and eliminate mammalian cell toxicity.

Graphical Abstract
Robotic resection for splenic artery aneurysm associated with neurofibromatosis type 1: a case report
Authors: Ueda Akihiko , Saito Kenta , Murase Hiromichi , Kato Tomokatsu , Imafuji Hiroyuki , Morimoto Mamoru , Ogawa Ryo , Takahashi Hiroki , Matsuo Yoichi , Takiguchi Shuji 
Published: March 2024

Abstract
Background
Neurofibromatosis type 1 is an autosomal-dominant disease characterized by café-au-lait spots and neurofibromas, as well as various other symptoms in the bones, eyes, and nervous system. Due to its connection with vascular fragility, neurofibromatosis type 1 has been reported to be associated with vascular lesions, such as aneurysms. However, there have been few reports of abdominal visceral aneurysms associated with neurofibromatosis type 1. Furthermore, there have been no reports of robotic treatment of aneurysms associated with neurofibromatosis type 1. In this report, we describe the case of a patient with neurofibromatosis type 1 with a splenic artery aneurysm who was successfully treated with robotic surgery.

Case presentation
This report describes a 41-year-old Asian woman with a history of neurofibromatosis type 1 who was referred to our hospital for evaluation of a 28 mm splenic artery aneurysm observed on abdominal ultrasound. The aneurysm was in the splenic hilum, and transcatheter arterial embolization was attempted; however, this was difficult due to the tortuosity of the splenic artery. Thus, we suggested minimally invasive robotic surgery for treatment and resection of the splenic artery aneurysm with preservation of the spleen. The postoperative course was uneventful, and the patient was discharged on the eighth day after surgery. At 1 year of follow-up, the patient was doing well, with no evidence of recurrence.

Conclusion
We encountered a rare case of splenic artery aneurysm in a patient with neurofibromatosis type 1 who was successfully treated with robotic surgery. There is no consensus on treatment modalities for neurofibromatosis-related aneurysms, and endovascular treatment is considered safe and effective; however, surgery remains an important treatment modality. Especially in patients with stable hemodynamic status, robotic surgery may be considered as definitive treatment. To our knowledge, this is the first successfully treated case of a splenic artery aneurysm in a patient with neurofibromatosis type 1.