bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic impact of HER2 biomarker levels in trastuzumab-treated early HER2-positive breast cancer
Authors: Rönnlund Caroline , Sifakis Emmanouil G. , Schagerholm Caroline , Yang Qiao , Karlsson Emelie , Chen Xinsong , Foukakis Theodoros , Weidler Jodi , Bates Michael , Fredriksson Irma , Robertson Stephanie , Hartman Johan 
Published: February 2024

Abstract
Background
Overexpression of human epidermal growth factor receptor 2 (HER2) caused by HER2 gene amplification is a driver in breast cancer tumorigenesis. We aimed to investigate the prognostic significance of manual scoring and digital image analysis (DIA) algorithm assessment of HER2 copy numbers and HER2/CEP17 ratios, along with ERBB2 mRNA levels among early-stage HER2-positive breast cancer patients treated with trastuzumab.

Methods
This retrospective study comprised 371 early HER2-positive breast cancer patients treated with adjuvant trastuzumab, with HER2 re-testing performed on whole tumor sections. Digitized tumor tissue slides were manually scored and assessed with uPath HER2 Dual ISH image analysis, breast algorithm. Targeted ERBB2 mRNA levels were assessed by the Xpert® Breast Cancer STRAT4 Assay. HER2 copy number and HER2/CEP17 ratio from in situ hybridization assessment, along with ERBB2 mRNA levels, were explored in relation to recurrence-free survival (RFS).

Results
The analysis showed that patients with tumors with the highest and lowest manually counted HER2 copy number levels had worse RFS than those with intermediate levels (HR = 2.7, CI 1.4–5.3, p = 0.003 and HR = 2.1, CI 1.1–3.9, p = 0.03, respectively). A similar trend was observed for HER2/CEP17 ratio, and the DIA algorithm confirmed the results. Moreover, patients with tumors with the highest and the lowest values of ERBB2 mRNA had a significantly worse prognosis (HR = 2.7, CI 1.4–5.1, p = 0.003 and HR = 2.8, CI 1.4–5.5, p = 0.004, respectively) compared to those with intermediate levels.

Conclusions
Our findings suggest that the association between any of the three HER2 biomarkers and RFS was nonlinear. Patients with tumors with the highest levels of HER2 gene amplification or ERBB2 mRNA were associated with a worse prognosis than those with intermediate levels, which is of importance to investigate in future clinical trials studying HER2-targeted therapy.
IDHwt glioblastomas can be stratified by their transcriptional response to standard treatment, with implications for targeted therapy
Authors: Tanner Georgette , Barrow Rhiannon , Ajaib Shoaib , Al-Jabri Muna , Ahmed Nazia , Pollock Steven , Finetti Martina , Rippaus Nora , Bruns Alexander F. , Syed Khaja , Poulter James A. , Matthews Laura , Hughes Thomas , Wilson Erica , Johnson Colin , Varn Frederick S. , Brüning-Richardson Anke , Hogg Catherine , Droop Alastair , Gusnanto Arief , Care Matthew A. , Cutillo Luisa , Westhead David R. , Short Susan C. , Jenkinson Michael D. , Brodbelt Andrew , Chakrabarty Aruna , Ismail Azzam , Verhaak Roel G. W. , Stead Lucy F. 
Published: February 2024

AbstractBackgroundGlioblastoma (GBM) brain tumors lackingIDH1mutations (IDHwt) have the worst prognosis of all brain neoplasms. Patients receive surgery and chemoradiotherapy but tumors almost always fatally recur.ResultsUsing RNA sequencing data from 107 pairs of pre- and post-standard treatment locally recurrent IDHwt GBM tumors, we identify two responder subtypes based on longitudinal changes in gene expression. In two thirds of patients, a specific subset of genes is upregulated from primary to recurrence (Up responders), and in one third, the same genes are downregulated (Down responders), specifically in neoplastic cells. Characterization of the responder subtypes indicates subtype-specific adaptive treatment resistance mechanisms that are associated with distinct changes in the tumor microenvironment. In Up responders, recurrent tumors are enriched in quiescent proneural GBM stem cells and differentiated neoplastic cells, with increased interaction with the surrounding normal brain and neurotransmitter signaling, whereas Down responders commonly undergo mesenchymal transition. ChIP-sequencing data from longitudinal GBM tumors suggests that the observed transcriptional reprogramming could be driven by Polycomb-based chromatin remodeling rather than DNA methylation.ConclusionsWe show that the responder subtype is cancer-cell intrinsic, recapitulated in in vitro GBM cell models, and influenced by the presence of the tumor microenvironment. Stratifying GBM tumors by responder subtype may lead to more effective treatment.
Deep learning for differentiation of osteolytic osteosarcoma and giant cell tumor around the knee joint on radiographs: a multicenter study
Authors: Shao Jingjing , Lin Hongxin , Ding Lei , Li Bing , Xu Danyang , Sun Yang , Guan Tianming , Dai Haiyang , Liu Ruihao , Deng Demao , Huang Bingsheng , Feng Shiting , Diao Xianfen , Gao Zhenhua 
Published: February 2024

Abstract
Objectives
To develop a deep learning (DL) model for differentiating between osteolytic osteosarcoma (OS) and giant cell tumor (GCT) on radiographs.

Methods
Patients with osteolytic OS and GCT proven by postoperative pathology were retrospectively recruited from four centers (center A, training and internal testing; centers B, C, and D, external testing). Sixteen radiologists with different experiences in musculoskeletal imaging diagnosis were divided into three groups and participated with or without the DL model’s assistance. DL model was generated using EfficientNet-B6 architecture, and the clinical model was trained using clinical variables. The performance of various models was compared using McNemar’s test.

Results
Three hundred thirty-three patients were included (mean age, 27 years ± 12 [SD]; 186 men). Compared to the clinical model, the DL model achieved a higher area under the curve (AUC) in both the internal (0.97 vs. 0.77, p = 0.008) and external test set (0.97 vs. 0.64, p < 0.001). In the total test set (including the internal and external test sets), the DL model achieved higher accuracy than the junior expert committee (93.1% vs. 72.4%; p < 0.001) and was comparable to the intermediate and senior expert committee (93.1% vs. 88.8%, p = 0.25; 87.1%, p = 0.35). With DL model assistance, the accuracy of the junior expert committee was improved from 72.4% to 91.4% (p = 0.051).

Conclusion
The DL model accurately distinguished osteolytic OS and GCT with better performance than the junior radiologists, whose own diagnostic performances were significantly improved with the aid of the model, indicating the potential for the differential diagnosis of the two bone tumors on radiographs.

Critical relevance statement
The deep learning model can accurately distinguish osteolytic osteosarcoma and giant cell tumor on radiographs, which may help radiologists improve the diagnostic accuracy of two types of tumors.

Key points
• The DL model shows robust performance in distinguishing osteolytic osteosarcoma and giant cell tumor.
• The diagnosis performance of the DL model is better than junior radiologists’.
• The DL model shows potential for differentiating osteolytic osteosarcoma and giant cell tumor.

Graphical Abstract
Osteogenic human MSC-derived extracellular vesicles regulate MSC activity and osteogenic differentiation and promote bone regeneration in a rat calvarial defect model
Authors: Al-Sharabi Niyaz , Mohamed-Ahmed Samih , Shanbhag Siddharth , Kampleitner Carina , Elnour Rammah , Yamada Shuntaro , Rana Neha , Birkeland Even , Tangl Stefan , Gruber Reinhard , Mustafa Kamal 
Published: February 2024

Abstract
Background
There is growing evidence that extracellular vesicles (EVs) play a crucial role in the paracrine mechanisms of transplanted human mesenchymal stem cells (hMSCs). Little is known, however, about the influence of microenvironmental stimuli on the osteogenic effects of EVs. This study aimed to investigate the properties and functions of EVs derived from undifferentiated hMSC (Naïve-EVs) and hMSC during the early stage of osteogenesis (Osteo-EVs). A further aim was to assess the osteoinductive potential of Osteo-EVs for bone regeneration in rat calvarial defects.

Methods
EVs from both groups were isolated using size-exclusion chromatography and characterized by size distribution, morphology, flow cytometry analysis and proteome profiling. The effects of EVs (10 µg/ml) on the proliferation, migration, and osteogenic differentiation of cultured hMSC were evaluated. Osteo-EVs (50 µg) or serum-free medium (SFM, control) were combined with collagen membrane scaffold (MEM) to repair critical-sized calvarial bone defects in male Lewis rats and the efficacy was assessed using µCT, histology and histomorphometry.

Results
Although Osteo- and Naïve-EVs have similar characteristics, proteomic analysis revealed an enrichment of bone-related proteins in Osteo-EVs. Both groups enhance cultured hMSC proliferation and migration, but Osteo-EVs demonstrate greater efficacy in promoting in vitro osteogenic differentiation, as evidenced by increased expression of osteogenesis-related genes, and higher calcium deposition. In rat calvarial defects, MEM with Osteo-EVs led to greater and more consistent bone regeneration than MEM loaded with SFM.

Conclusions
This study discloses differences in the protein profile and functional effects of EVs obtained from naïve hMSC and hMSC during the early stage of osteogenesis, using different methods. The significant protein profile and cellular function of EVs derived from hMSC during the early stage of osteogenesis were further verified by a calvarial bone defect model, emphasizing the importance of using differentiated MSC to produce EVs for bone therapeutics.
A systematic review, meta-analysis, and meta-regression of the prevalence of self-reported disordered eating and associated factors among athletes worldwide
Authors: Ghazzawi Hadeel A. , Nimer Lana S. , Haddad Areen Jamal , Alhaj Omar A. , Amawi Adam T. , Pandi-Perumal Seithikurippu R. , Trabelsi Khaled , Seeman Mary V. , Jahrami Haitham 
Published: February 2024

Abstract
Background
The purpose of this meta-analysis was to provide a pooled prevalence estimate of self-reported disordered eating (SRDE) in athletes based on the available literature, and to identify risk factors for their occurrence.

Methods
Across ten academic databases, an electronic search was conducted from inception to 7th January 2024. The proportion of athletes scoring at or above predetermined cutoffs on validated self-reporting screening measures was used to identify disordered eating (DE). Subgroup analysis per country, per culture, and per research measure were also conducted. Age, body mass index (BMI), and sex were considered as associated/correlated factors.

Results
The mean prevalence of SRDE among 70,957 athletes in 177 studies (132 publications) was 19.23% (17.04%; 21.62%), I2 = 97.4%, τ2 = 0.8990, Cochran's Q p value = 0. Australia had the highest percentage of SRDE athletes with a mean of 57.1% (36.0%-75.8%), while Iceland had the lowest, with a mean of 4.9% (1.2%-17.7%). The SRDE prevalence in Eastern countries was higher than in Western countries with 29.1% versus 18.5%. Anaerobic sports had almost double the prevalence of SRDE 37.9% (27.0%-50.2%) compared to aerobic sports 19.6% (15.2%-25%). Gymnastics sports had the highest SRDE prevalence rate, with 41.5% (30.4%-53.6%) while outdoor sports showed the lowest at 15.4% (11.6%-20.2%). Among various tools used to assess SRDE, the three-factor eating questionnaire yielded the highest SRDE rate 73.0% (60.1%-82.8%). Meta-regression analyses showed that female sex, older age, and higher BMI (all p < 0.01) are associated with higher prevalence rates of SRDE.

Conclusion
The outcome of this review suggests that factors specific to the sport affect eating behaviors throughout an athlete's life. As a result, one in five athletes run the risk of developing an eating disorder. Culture-specific and sport-specific diagnostic tools need to be developed and increased attention paid to nutritional deficiencies in athletes.
Applying ONCO-RADS to whole-body MRI cancer screening in a retrospective cohort of asymptomatic individuals
Authors: Hu Yong-Sin , Wu Chia-An , Lin Dao-Chen , Lin Po-Wei , Lee Han-Jui , Lin Lo-Yi , Lin Chung-Jung 
Published: February 2024

Abstract
Background
Whole-body magnetic resonance imaging (WB-MRI) has emerged as a valuable tool for cancer detection. This study evaluated the prevalence rates of cancer in asymptomatic individuals undergoing WB-MRI according to the Oncologically Relevant Findings Reporting and Data System (ONCO-RADS) classifications in order to assess the reliability of the classification method.

Methods
We retrospectively enrolled 2064 asymptomatic individuals who participated in a WB-MRI cancer screening program between 2017 and 2022. WB-MRI was acquired on a 3-T system with a standard protocol, including regional multisequence and gadolinium-based contrast agent-enhanced oncologic MRI. Results of further examinations, including additional imaging and histopathology examinations, performed at our institute were used to validate the WB-MRI findings. Two radiologists blinded to the clinical outcome classified the WB-MRI findings according to the ONCO–RADS categories as follows: 1 (normal), 2 (benign finding highly likely), 3 (benign finding likely), 4 (malignant finding likely), and 5 (malignant finding highly likely). Firth logistic regression analysis was performed to determine the associations between participant characteristics and findings of ONCO-RADS category ≥ 4.

Results
Of the 2064 participants with median age of 55 years, 1120 (54.3%) were men, 43 (2.1%) had findings of ONCO-RADS category ≥ 4, and 24 (1.2%) had confirmed cancer. The cancer prevalence rates were 0.1%, 5.4%, 42.9%, and 75% for ONCO-RADS categories 2, 3, 4, and 5, respectively. In the multivariable model, older age (OR: 1.035, p = 0.029) and history of hypertension (OR: 2.051, p = 0.026), hepatitis B carrier (OR: 2.584, p = 0.013), or prior surgery (OR: 3.787, p < 0.001) were independently associated with the findings for ONCO-RADS category ≥ 4.

Conclusions
The ONCO-RADS categories for cancer risk stratification were validated and found to be positively correlated with cancer risk. The application of ONCO-RADS facilitates risk-based management after WB-MRI for cancer screening.
Happiness and air quality: microdata analysis in Indonesia
Authors: Limayani Novilya , Tanur Erwin 
Published: February 2024

Abstract
Background
While economics is growing in Indonesia, its Happiness Index remains steady. Regarding the average concentration of dissolved particles, Indonesia is ranked sixth globally. Many factors can affect happiness. Environmental conditions, especially air quality, are considered to influence individual happiness. Therefore, this research investigates the impact of air quality and health on happiness.

Methods
Data used in this study is the microdata of Indonesia’s Happiness Survey (SPTK) in 2021. With more than 70,000 respondents, the study uses Ordered Probit as an analysis method with subjective happiness as the dependent variable. The independent variables used in this study are air quality, age, gender, housing area per capita, marital status, and health status. All independent variables except age are categorical. The variable of interest, air quality, is coded “1” if the IKU achieves the Strategic Plan’s target of 84.2 and “0” otherwise. IKU is a regional air quality index that combines two substances.

Results
At a significance level of 5%, there is a positive relationship between subjective happiness and air quality. In other words, if air quality (IKU) meets the Strategic Plan target (≥ 84.2), then a person is more likely to have a higher level of happiness. It can be explained more with the marginal effect. The marginal effect concludes that if the target is achieved, the probability of having a lower level of happiness decreases by up to 2.8%, and a very high level of happiness rises by 5.1%. Regarding health status, the rarer someone gets sick, the happier she/he is.

Conclusion
The study finds that air pollution could lower happiness, while better health increases happiness. Therefore, it is important to meet the target of IKU and to improve public health. Some good practices can be adopted to achieve this goal.
Fuel types misrepresent forest structure and composition in interior British Columbia: a way forward
Authors: Baron Jennifer N. , Hessburg Paul F. , Parisien Marc-André , Greene Gregory A. , Gergel Sarah. E. , Daniels Lori D. 
Published: February 2024

Abstract
Background
A clear understanding of the connectivity, structure, and composition of wildland fuels is essential for effective wildfire management. However, fuel typing and mapping are challenging owing to a broad diversity of fuel conditions and their spatial and temporal heterogeneity. In Canada, fuel types and potential fire behavior are characterized using the Fire Behavior Prediction (FBP) System, which uses an association approach to categorize vegetation into 16 fuel types based on stand structure and composition. In British Columbia (BC), provincial and national FBP System fuel type maps are derived from remotely sensed forest inventory data and are widely used for wildfire operations, fuel management, and scientific research. Despite their widespread usage, the accuracy and applicability of these fuel type maps have not been formally assessed. To address this knowledge gap, we quantified the agreement between on-site assessments and provincial and national fuel type maps in interior BC.

Results
We consistently found poor correspondence between field assessment data and both provincial and national fuel types. Mismatches were particularly frequent for (i) dry interior ecosystems, (ii) mixedwood and deciduous fuel types, and (iii) post-harvesting conditions. For 58% of field plots, there was no suitable match to the extant fuel structure and composition. Mismatches were driven by the accuracy and availability of forest inventory data and low applicability of the Canadian FBP System to interior BC fuels.

Conclusions
The fuel typing mismatches we identified can limit scientific research, but also challenge wildfire operations and fuel management decisions. Improving fuel typing accuracy will require a significant effort in fuel inventory data and system upgrades to adequately represent the diversity of extant fuels. To more effectively link conditions to expected fire behavior outcomes, we recommend a fuel classification approach and emphasis on observed fuels and measured fire behavior data for the systems we seek to represent.
Crenolanib and Intensive Chemotherapy in Adults With Newly Diagnosed FLT3-Mutated AML
Authors: Wang Eunice S. , Goldberg Aaron D. , Tallman Martin , Walter Roland B. , Karanes Chatchada , Sandhu Karamjeet , Vigil Carlos E. , Collins Robert , Jain Vinay , Stone Richard M. 
Published: February 2024

PURPOSE Crenolanib is a second-generation tyrosine kinase inhibitor with activity against FLT3-ITD– and TKD-mutant AML. We conducted a trial of crenolanib plus intensive chemotherapy in adults with newly diagnosed FLT3-mutant AML. METHODS Eligible patients were 18 years and older. Induction chemotherapy consisted of cytarabine (100 mg/m2) continuous infusion on days 1-7 and anthracycline (daunorubicin 60-90 mg/m2 or idarubicin 12 mg/m2, once daily) on days 1-3 followed by consolidation with high-dose cytarabine (1-3 g/m2 twice daily on days 1, 3, 5) and/or allogeneic transplant. Crenolanib (100 mg thrice a day) was given from day 9 until 72 hours before the next cycle, after consolidation, and for 12 months after consolidation or transplant. RESULTS Forty-four patients (median age, 57; range, 19-75 years) were enrolled. Thirty-six had FLT3-ITD, and 11 had FLT3-TKD mutations. European LeukemiaNet 2017 disease risk was favorable in 34%, intermediate in 30%, and adverse in 36%. The overall response rate was 86% (complete remission [CR], 77%; CR with incomplete count recovery [CRi], 9%): 90% in patients 60 years and younger and 80% in older patients. Measurable residual disease–negative CR/CRi rates were 89% and 45%, respectively. With a 45-month follow-up, median overall survival has not been reached and the median event-free survival was 44.7 months. Among younger patients, the estimated 3-year survival was 71.4% with 15% cumulative incidence of relapse. Treatment-related serious adverse events included febrile neutropenia, diarrhea, and nausea. The median time to platelets ≥100,000/µL and absolute neutrophil count ≥1,000/µL during induction was 29 and 32 days, respectively. No new FLT3-mutant clones were detected at relapse in patients completing consolidation. CONCLUSION Crenolanib plus intensive chemotherapy in adults with newly diagnosed FLT3-mutant AML results in high rate of deep responses and long-term survival with acceptable toxicity. A randomized trial of crenolanib versus midostaurin plus chemotherapy in younger patients is ongoing.
Rationing by Inconvenience: How Insurance Denials Induce Administrative Burdens
Authors: Yaver Miranda 
Published: February 2024

Abstract
Context: How do health coverage denials keep care out of reach for American patients by imposing unevenly distributed administrative burdens? This article argues that the process of appealing insurers’ denials imposes administrative burdens on patients inequitably, deepening the divide between those with meaningful access to health coverage and those for whom benefits are out of reach.
Methods: The author conducted a nationwide survey of 1,340 US adults on their experiences with coverage denials; this was supplemented with 110 semistructured interviews with patients, physicians, and former health insurance executives.
Findings: Those who were less affluent were significantly less likely than their wealthier counterparts to appeal denials of coverage. Patients who underestimated the rate at which patients prevail in insurance appeals were less likely to appeal their own denials. Black Medicaid patients and those who were in worse health were significantly less likely to prevail in the appeals they pursued. Many unappealed denials were attributable to the significant administrative burdens associated with appeal, including learning and psychological costs.
Conclusions: Administrative burdens associated with appealing denials of coverage can deepen health inequities along class and race lines, suggesting a need for policy interventions to make it easier to navigate the health insurance bureaucracy.
Inside “Operation Change Agent”: Mallinckrodt's Plan for Capturing the Opioid Market
Authors: Eisenkraft Klein Daniel , MacKenzie Ross , Hawkins Ben , Koon Adam D. 
Published: February 2024

Abstract
Context: The United States is deeply entangled in an opioid crisis that began with the overuse of prescription painkillers. At the height of the prescription opioid crisis (2006–2012), Mallinckrodt Pharmaceuticals was the nation's largest opioid manufacturer. This study explores Mallinckrodt's strategies for expanding its market share by promoting a new opioid.
Methods: The authors used the Opioid Industry Document Archive to analyze the incentive structures, sales contests, and rhetorical strategy behind Mallinckrodt's “Operation Change Agent,” a campaign to switch patients from OxyContin to Mallinckrodt-manufactured painkillers. A structured search of the archive in October 2022 retrieved 464 documents dated between 2010 and 2020.
Findings: The authors identified a range of Mallinckrodt's sales force motivational techniques, including hypertargeting high-decile prescribers, providing free trial kits, using emotion-based language to connect with prescribers, and strategies for opposing prescriber resistance. Throughout, managers used specific incentivization metaphors to frame strategies in terms of sport and ultramarathons.
Conclusions: This research on internal corporate strategy joins the growing challenges to industry claims that opioid sales teams simply educated providers and helped fill existing demand for their products. It has important implications for regulatory policy and consumer protections that can better protect health in the face of competitive market forces.