bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predicting the risk of a clinical event using longitudinal data: the generalized landmark analysis
Authors: Yao Yi , Li Liang , Astor Brad , Yang Wei , Greene Tom 
Published: January 2023

Abstract
Background
In the development of prediction models for a clinical event, it is common to use the static prediction modeling (SPM), a regression model that relates baseline predictors to the time to event. In many situations, the data used in training and validation are from longitudinal studies, where predictor variables are time-varying and measured at clinical visits. But these data are not used in SPM. The landmark analysis (LA), previously proposed for dynamic prediction with longitudinal data, has interpretational difficulty when the baseline is not a risk-changing clinical milestone, as is often the case in observational studies of chronic disease without intervention.

Methods
This paper studies the generalized landmark analysis (GLA), a statistical framework to develop prediction models for longitudinal data. The GLA includes the LA as a special case, and generalizes it to situations where the baseline is not a risk-changing clinical milestone with a more useful interpretation. Unlike the LA, the landmark variable does not have to be time since baseline in the GLA, but can be any time-varying prognostic variable. The GLA can also be viewed as a longitudinal generalization of localized prediction, which has been studied in the context of low-dimensional cross-sectional data. We studied the GLA using data from the Chronic Renal Insufficiency Cohort (CRIC) Study and the Wisconsin Allograft Replacement Database (WisARD) and compared the prediction performance of SPM and GLA.

Results
In various validation populations from longitudinal data, the GLA generally had similarly or better predictive performance than SPM, with notable improvement being seen when the validation population deviated from the baseline population. The GLA also demonstrated similar or better predictive performance than LA, due to its more general model specification.

Conclusions
GLA is a generalization of the LA such that the landmark variable does not have to be the time since baseline. It has better interpretation when the baseline is not a risk-changing clinical milestone. The GLA is more adaptive to the validation population than SPM and is more flexible than LA, which may help produce more accurate prediction.
Estimation of marginal structural models under irregular visits and unmeasured confounder: calibrated inverse probability weights
Authors: Kalia Sumeet , Saarela Olli , Escobar Michael , Moineddin Rahim , Greiver Michelle 
Published: January 2023

AbstractClinical information collected in electronic health records (EHRs) is becoming an essential source to emulate randomized experiments. Since patients do not interact with the healthcare system at random, the longitudinal information in large observational databases must account for irregular visits. Moreover, we need to also account for subject-specific unmeasured confounders which may act as a common cause for treatment assignment mechanism (e.g. glucose-lowering medications) while also influencing the outcome (e.g. Hemoglobin A1c). We used the calibration of longitudinal weights to improve the finite sample properties and to account for subject-specific unmeasured confounders. A Monte Carlo simulation study is conducted to evaluate the performance of calibrated inverse probability estimators using time-dependent treatment assignment and irregular visits with subject-specific unmeasured confounders. The simulation study showed that the longitudinal weights with calibrated restrictions improved the finite sample bias when compared to the stabilized weights. The application of the calibrated weights is demonstrated using the exposure of glucose lowering medications and the longitudinal outcome of Hemoglobin A1c. Our results support the effectiveness of glucose lowering medications in reducing Hemoglobin A1c among type II diabetes patients with elevated glycemic index ($$\ge 8.5 \%$$≥8.5%) using stabilized and calibrated weights.
SPOCK1 and POSTN are valuable prognostic biomarkers and correlate with tumor immune infiltrates in colorectal cancer
Authors: Gan Caiqin , Li Mengting , Lu Yuanyuan , Peng Ganjing , Li Wenjie , Wang Haizhou , Peng Yanan , Hu Qian , Wei Wanhui , Wang Fan , Liu Lan , Zhao Qiu 
Published: January 2023

Abstract
Background
Immune cells and stromal cells in the tumor microenvironment play a vital role in the progression of colorectal cancer (CRC). The study aimed to screen valuable prognostic biomarkers in CRC based on stromal and immune scores.

Method
The ESTIMATE algorithm was used to calculate the immune and stromal scores of CRC samples in TCGA. Then samples were divided into high and low score groups based on the median value of the scores. Differentially expressed genes (DEGs) associated with immune and stromal scores were screened. WGCNA and univariate COX regression analysis were performed to further identify key prognostic genes. Analysis of scRNA-seq for CRC was used for verifying the main source of the key genes. The prognostic value of they was validated based on The Gene Expression Profiling Interactive Analysis and GSE17536 dataset. TIMER and CIBERSORT algorithms were applied to analyze the correlations among key genes and tumor-infiltrating immune cells. Several pairs of colon cancer tissue were used to be proven.

Result
1314 upregulated and 4 downregulated genes were identified, which were significantly enriched in immune-related biological processes and pathways. Among these DEGs, SPOCK1 and POSTN were identified as key prognostic genes and mainly expressed in cancer-associated fibroblasts for CRC. High expression of SPCOK1 and POSTN was associated with advanced clinical stage, T stage, N stage, and poor prognosis of CRC. The results from CIBERSORT and TIMER revealed that SPOCK1 and POSTN were associated with tumor-infiltrating immune cells, especially macrophages and neutrophils. Meanwhile, in several pairs of human colorectal tissue samples, SPOK1 and POSTN were found to be significantly overexpressed in colorectal tissue compared with para-cancer tissue, and macrophage surface markers CD68 (co-expressed by M1 and M2 macrophages) and CD206 (M2-specific macrophage expression) were also overexpressed in cancer tissue. Besides, SPOCK1 and POSTN expression were positively correlated with the expression of immune checkpoints.

Conclusion
Collectively, our results indicate that SPOCK1 and POSTN associated with CAF may be novel prognostic biomarkers in CRC and correlate with immune infiltrates.
Time course of serum cytokine level changes within 72 h after onset in children with acute encephalopathy and febrile seizures
Authors: Tomioka Kazumi , Nishiyama Masahiro , Tokumoto Shoichi , Yamaguchi Hiroshi , Aoki Kazunori , Seino Yusuke , Toyoshima Daisaku , Kurosawa Hiroshi , Tada Hiroko , Sakuma Hiroshi , Nozu Kandai , Maruyama Azusa , Tanaka Ryojiro , Iijima Kazumoto , Nagase Hiroaki 
Published: January 2023

Abstract
Background
Cytokine levels have been measured in acute encephalopathy (AE) to determine its pathology or as a diagnostic biomarker to distinguish it from febrile seizures (FS); however, the dynamics of cytokine level changes have not yet been fully captured in these two neurological manifestations. Thus, we aimed to explore the time course of serum cytokine level changes within 72 h after onset in AE and FS.

Methods
We retrospectively measured cytokine level in residual serum samples at multiple timepoints in seven children whose final diagnoses were AE or FS.

Results
The levels of 13 cytokines appeared to increase immediately after onset and peaked within 12–24 h after onset: interleukin (IL)-1β, IL-4 IL-5, IL-6, IL-8, IL-10, IL-17, eotaxin, fibroblast growth factor, granulocyte colony-stimulating factor, interferon gamma, interferon-inducible protein-10, and macrophage chemoattractant protein-1. There were no dynamic changes in the levels of three cytokines (IL-1 receptor agonist, macrophage inflammatory protein-1α, and platelet-derived growth factor-bb) 72 h after onset. Levels of some cytokines decreased to around control levels within 48 h after onset: IL-1β, IL-4, IL-5, IL-17, fibroblast growth factor, and interferon gamma. The levels of most cytokines appeared to be higher in AE, especially in hemorrhagic shock encephalopathy syndrome, than in FS.

Conclusions
Cytokine levels in both AE and FS change dynamically, such as the levels of several cytokines increased within a few hours after onset and decreased at 12–24 h after onset. Therefore, it will be desirable to make clinical decisions regarding the administration of anti-inflammatory therapy in 24 h after onset in AE.
Ritodrine-induced rhabdomyolysis and psychiatric symptoms: a case report and literature review
Authors: Sun Li , Tang Mimi , Peng Mei , Xu Ping , Wang Ying 
Published: January 2023

Abstract
Background
Ritodrine hydrochloride, a β2-adrenergic agonist, has been widely used in Asia and Europe to treat preterm labor in pregnant women. It has some typical side effects, such as palpitations, pulmonary edema, and hypokalemia. Here, we report a case of rhabdomyolysis and psychiatric symptoms might be associated with intravenous ritodrine.

Case presentation
A 32-year-old Chinese primigravida woman who was pregnant with twins by in vitro fertilization-embryo transfer was diagnosed with placenta previa and threatened abortion at 21 gestational weeks (GW). The patient was then treated with ritodrine hydrochloride. The initial dose of ritodrine was 150 μg/min, gradually increasing to 360 μg/min at 235/7 GW and 400 μg/min at 271/7 GW. Magnesium sulfate was added to the ritodrine regimen at 215/7 GW in dosage of 1-2 g/h. Psychiatric symptoms appeared at 245/7, 265/7, and 273/7 GW, manifesting as depression, anxiety, and suicidal tendencies. Severe muscle pain in her limbs and general weakness appeared after six weeks of ritodrine administration, which might have been a sign of rhabdomyolysis resulting from ritodrine administration. After ceasing the administration of ritodrine, the muscle pain and relevant data from laboratory tests on the patient were significantly improved, and her mood was stable. It is worth noting that this is the first time to report psychiatric symptoms may associated with the administration of ritodrine. In addition, we reviewed and analyzed six reported cases of rhabdomyolysis caused by ritodrine.

Conclusion
Our results suggest that we should pay more attention to the risk of rhabdomyolysis and psychiatric symptoms induced by intravenous ritodrine hydrochloride, especially in patients with a history of neuromuscular disorder, or concomitant use of magnesium sulfate.
High-dose chemotherapy with stem cell rescue to treat stage III homologous deficient breast cancer: factors influencing clinical implementation
Authors: Verbeek Joost G. E. , de Jong Vincent M. T. , Wijnja Hanna M. , Jager Agnes , Linn Sabine C. , Retèl Valesca P. , van Harten Wim H. 
Published: January 2023

Abstract
Background
High-dose chemotherapy with autologous stem cell rescue (HDCT) is a promising treatment for patients with stage III, HER2-negative, homologous recombination deficient (HRD) breast cancer. Clinical effectiveness and cost-effectiveness are currently under investigation in an international multicenter randomized controlled trial. To increase the chance of successful introduction of HDCT into daily clinical practice, we aimed to identify relevant factors for smooth implementation using an early comprehensive assessment framework.

Methods
This is a qualitative, multi-stakeholder, exploratory research using semi-structured interviews guided by the Constructive Technology Assessment model, which evaluates the quality of a novel health technology by clinical, economic, patient-related, and organizational factors. Stakeholders were recruited by purposeful stratified sampling and interviewed until sufficient content saturation was reached. Two researchers independently created themes, categories, and subcategories by following inductive coding steps, these were verified by a third researcher.

Results
We interviewed 28 stakeholders between June 2019 and April 2021. In total, five overarching themes and seventeen categories were identified. Important findings for optimal implementation included the structural identification and referral of all eligible patients, early integration of supportive care, multidisciplinary collaboration between- and within hospitals, (de)centralization of treatment aspects, the provision of information for patients and healthcare professionals, and compliance to new regulation for the BRCA1-like test.

Conclusions
In anticipation of a positive reimbursement decision, we recommend to take the highlighted implementation factors into consideration. This might expedite and guide high-quality equitable access to HDCT for patients with stage III, HER2-negative, HRD breast cancer in the Netherlands.
Cuproptosis regulatory genes greatly contribute to clinical assessments of hepatocellular carcinoma
Authors: Ke Changwei , Dai Shejiao , Xu Fangshi , Yuan Jia , Fan Shuting , Chen Yang , Yang Longbao , Li Yong 
Published: January 2023

Abstract
Background
Hepatocellular carcinoma (HCC) is a common abdominal cancer with dissatisfactory therapeutic effects. The discovery of cuproptosis lights on new approach for cancer treatment and assessment. So far, there is extremely limited research investigating the roles of cuproptosis-related (CR) genes in cancers.

Methods
A novel CR risk signature was constructed using the Lasso regression analysis. Its prognostic value was assessed via a series of survival analyses and validated in three GEO cohorts. The effects of CR risk signature on tumor immune microenvironment (TIM) were explored through CIBERSORT, ESTIMATE, and ssGSEA algorithms. Using GESA, we investigated its impacts on various metabolism process. The somatic mutation features of CR signature genes were also explored via cBioPortal database. Using tumor mutation burden, expressions of immune checkpoints, TIDE score, IMvigor 210 cohort, and GSE109211 dataset, we explored the potential associations of CR risk score with the efficacy of immune checkpoint inhibitors (ICIs) and sorafenib. Finally, the biofunctions of DLAT in HCC cells were ascertained through qPCR, immunohistochemistry, colony formation, and Transwell assays.

Results
FDX1, DLAT, CDKN2A and GLS constituted the CR risk signature. CR risk signature possessed high prognostic value and was also applicable to three validation cohorts. Meanwhile, it could improve the accuracy and clinical making-decision benefit of traditional prognostic model. Moreover, high CR risk was indicative of unfavorable anti-tumor immune response and active metabolisms of glycolysis and nucleotide. As for therapeutic correlation, CR risk score was a potential biomarker for predicting the efficacy of ICIs and sorafenib. Through qPCR and immunohistochemistry detection in clinical samples, we reconfirmed DLAT was significantly upregulated in HCC samples. Overexpression of DLAT could promote the proliferation, migration, and invasion of HepG2 and HuH-7 cells.

Conclusions
The novel CR risk signature greatly contributed to the clinical assessment of HCC. Cuproptosis regulatory gene DLAT possessed cancer-promoting capacities and was expected to be a promising therapeutic target for HCC.
EOAI, a ubiquitin-specific peptidase 5 inhibitor, prevents non-small cell lung cancer progression by inducing DNA damage
Authors: Zheng Yuanyuan , Wang Longhao , Niu Xiaoyu , Guo Yongjun , Zhao Jiuzhou , Li Lifeng , Zhao Jie 
Published: January 2023

Abstract
Objective
Targeting deubiquitinases (DUBs) has emerged as a promising avenue for anticancer drug development. However, the effect and mechanism of pan-DUB inhibitor EOAI on non-small cell lung cancer (NSCLC) remains to be studied.

Materials and methods
The expression of ubiquitin-specific peptidase 5 (USP5) in NSCLC was evaluated by immunohistochemistry. The effect of the USP5 inhibitor, EOAI, on NSCLC cell growth and cell cycle was evaluated by CCK-8 and PI staining. Apoptosis was detected by Annexin V-FITC/PI double staining. Autophagy was examined by LC3 immunofluorescence. Comet assay and γ-H2AX immunofluorescence staining were used to detect DNA damage, and Western blotting was used to detect the expression of apoptosis, cycle, autophagy and DNA damage-related proteins. In vivo experiments demonstrated the effect of EOAI on NSCLC.

Results
We also found that USP5 was significantly upregulated in NSCLC tissues in this study. In addition, we show that EOAI can cause DNA damage in NSCLC cells while modulating the transcriptional activity of P53, thereby inducing cell cycle arrest in NSCLC cells, autophagy and apoptosis. In vivo experiments have shown that EOAI can inhibit tumors and synergistically enhance the anti-tumor effect of cisplatin.

Conclusion
USP5-mediated epigenetic regulation of oncogenes promotes the occurrence of NSCLC, which provides ideas for developing potential targeted therapy.
Barriers, facilitators, and opportunities to promote healthy weight behaviors among preschool-aged children in two rural U.S communities
Authors: Pope Katherine Jochim , Whitcomb Cason , Vu Maihan , Harrison Lisa Macon , Gittelsohn Joel , Ward Dianne , Erinosho Temitope 
Published: January 2023

Abstract
Background
Obesity levels are higher in rural versus urban children. Multi-level community-based interventions can be effective in promoting healthy child weight, but few of such interventions have focused on rural children. This formative study assessed barriers, facilitators, and opportunities to promote healthy child weight in two rural communities.

Methods
Multiple data collection methods were used concurrently in two rural communities in Indiana and North Carolina. Focus groups and interviews were conducted with participants, including parents of children aged 2–5 years (n = 41), childcare providers (n = 13), and stakeholders from 23 community organizations. Observational audits were conducted at 19 food outlets (grocery stores) and 50 publicly-accessible physical activity resources. Focus groups/interviews were analyzed thematically. Surveys were analyzed using descriptive statistics, Fisher’s exact test, and t-tests.

Results
Family level barriers included limited financial resources and competing priorities, whereas parental role-modeling was perceived as a facilitator of healthy weight behaviors. At the organizational level, childcare providers and community stakeholders cited limited funding and poor parental engagement in health promotion programs as barriers. Childcare providers explained that they were required to comply with strict nutrition and physical activity guidelines, but expressed concerns that similar messages were not reinforced at home. Facilitators at the organizational level included healthy meals provided at no cost at childcare programs, and health promotion programs offered through community organizations. At the community level, lack of public transportation, and limited access to healthy food outlets and physical activity-promoting resources posed barriers, whereas existing physical activity resources (e.g., parks) and some ongoing investment to improve physical activity resources in the community were assets. In designing/implementing a potential child obesity prevention intervention, participants discussed the need to garner community trust, emphasize wellness instead of obesity prevention, establish community partnerships, and leverage existing community resources.

Conclusions
Rural areas experience multiple challenges that make it difficult for children/families to engage in healthy weight behaviors. This study highlights several assets (existing programs/resources, expertise within communities) that can be leveraged as facilitators. Findings will guide the study team in developing a child obesity prevention intervention for the two rural communities.
The effectiveness of pay-it-forward in addressing HPV vaccine delay and increasing uptake among 15–18-year-old adolescent girls compared to user-paid vaccination: a study protocol for a two-arm randomized controlled trial in China
Authors: Li Yifan , Qin Chuanyu , Qiu Shengyue , He Yu , Pang Linchuan , Xu Xiaolan , Yim Vivian Wan-Cheong , Tang Shenglan , Du Heng , Gong Wenfeng , Yang Fan , Tucker Joseph D. , Tang Weiming , Wang Yun , Lin Leesa , Jit Mark , Song Wei , Li Chunrong , Smith Jennifer , Li Jing , Wu Dan 
Published: January 2023

Abstract
Background
Human papillomavirus (HPV) vaccination could prevent cervical and other HPV-associated cancers attributable to vaccine-associated HPV types. However, HPV vaccination coverage among women aged 9–18 years old is low in China. Common barriers include poor financial affordability, minimal public engagement, and low confidence in domestically produced HPV vaccines. Pay-it-forward offers an individual a free or subsidized service then an opportunity to voluntarily donate and/or create a postcard message to support future people. This study aims to assess the effectiveness of pay-it-forward as compared to standard-of-care self-paid vaccination to improve HPV vaccine uptake among adolescent girls aged 15–18 years, who are left out in the current pilot free HPV vaccination task force in some parts of China.

Methods
This is a two-arm randomized controlled trial in Chengdu, China. Eligible adolescent girls (via caregivers) will be randomly selected and recruited through four community health centers (one in the most developed urban areas, one in higher middle-income and one in lower middle-income suburban areas, and one in the least developed rural areas) using the resident registration list. A total of 320 participants will be randomized into two study arms (user-paid versus pay-it-forward vaccination) in a 1:1 ratio. The intervention assignment will be blinded to recruiters and participants using envelop concealment until the research assistants open the envelop to determine which treatment to deliver to each individual. The primary outcome of the study will be HPV vaccine uptake by administrative data. Secondary outcomes include costs, vaccine hesitancy, and the completion rates of the 3-dose HPV vaccination series.

Discussion
This study will investigate an innovative pay-it-forward strategy’s effectiveness and economic costs to improve HPV vaccination among 15–18-year-old adolescent girls. Study findings will have implications for increasing HPV vaccine uptake in places where HPV vaccines are provided for a fee.

Trial registration
Chinese Clinical Trial Registry (ChiCTR), ChiCTR2200055542. Registered on 11 January 2022.

Graphical Abstract