bluuebunny/crossref_metadata_2025 huggingface dataset:
Impacts on oral health attitude and knowledge after completing a digital training module among Swedish healthcare professionals working with older adults
Authors: Snogren Maria , Ek Kristina , Browall Maria , Eriksson Irene , Lindmark Ulrika
Published: February 2024

Oral health care is essential, and digital training may influence healthcare professionals’ attitudes to and knowledge of oral health. The aim, therefore, was to evaluate the impact on attitudes to and knowledge of oral health after using a digital training module among Swedish healthcare professionals working within a municipality-run healthcare service for older adults. A secondary aim was to explore the healthcare professionals’ experiences of using the digital module. The study comprised a survey of healthcare professionals (registered nurses (RNs), assistant nurses, and care assistants) caring for older adults in a municipality in Sweden. Pre-post-tests were conducted to evaluate the outcomes for attitudes to and knowledge of oral health and of their experiences of completing the digital training module in oral health. These were statistically explored by comparing differences between the pre-post-tests, while the open-ended questions were analysed with qualitative content analysis. The findings of this study indicate that healthcare professionals had similar perceptions of their attitudes to and knowledge of oral health both before and after the digital training module in oral health. The study also indicates that healthcare professionals experienced that it is easier to perform practical oral health care after completing the digital training. The results also show that healthcare professionals value oral health knowledge and that the digital training module was easy to use and to disseminate knowledge throughout the municipality. The findings have implications for developing, implementing, and promoting healthcare professionals’ attitudes to and knowledge of oral health and in using a digital training module in combination with practical exercises in oral health in municipality health care.
Genome-wide transcriptional profiling and functional analysis of long noncoding RNAs and mRNAs in chicken macrophages associated with the infection of avian pathogenic E. coli
Authors: Sun Hongyan , Cao Xinqi , Sumayya  , Ma Yuyi , Li Huan , Han Wei , Qu Lujiang
Published: February 2024

Background

Avian pathogenic E. coli (APEC) can cause localized or systemic infections, collectively known as avian colibacillosis, resulting in huge economic losses to poultry industry globally per year. In addition, increasing evidence indicates that long non-coding RNAs (lncRNAs) play a critical role in regulating host inflammation in response to bacterial infection. However, the role of lncRNAs in the host response to APEC infection remains unclear.

Results

Here, we found 816 differentially expressed (DE) lncRNAs and 1,798 DE mRNAs in APEC infected chicken macrophages by RNAseq. The identified DE lncRNA-mRNAs were involved in Toll like receptor signaling pathway, VEGF signaling pathway, fatty acid metabolism, phosphatidylinositol signaling system, and other types of O-glycan biosynthesis. Furthermore, we found the novel lncRNA TCONS_00007391 as an important immune regulator in APEC infection was able to regulate the inflammatory response by directly targeting CD86.

Conclusion

These findings provided a better understanding of host response to APEC infection and also offered the potential drug targets for therapy development against APEC infection.
Discovery of a high-performance phage-derived promoter/repressor system for probiotic lactobacillus engineering
Authors: Blanch-Asensio Marc , Tadimarri Varun Sai , Wilk Alina , Sankaran Shrikrishnan
Published: February 2024

Background

The Lactobacillaceae family comprises many species of great importance for the food and healthcare industries, with numerous strains identified as beneficial for humans and used as probiotics. Hence, there is a growing interest in engineering these probiotic bacteria as live biotherapeutics for animals and humans. However, the genetic parts needed to regulate gene expression in these bacteria remain limited compared to model bacteria like E. coli or B. subtilis. To address this deficit, in this study, we selected and tested several bacteriophage-derived genetic parts with the potential to regulate transcription in lactobacilli.

Results

We screened genetic parts from 6 different lactobacilli-infecting phages and identified one promoter/repressor system with unprecedented functionality in Lactiplantibacillus plantarum WCFS1. The phage-derived promoter was found to achieve expression levels nearly 9-fold higher than the previously reported strongest promoter in this strain and the repressor was able to almost completely repress this expression by reducing it nearly 500-fold.

Conclusions

The new parts and insights gained from their engineering will enhance the genetic programmability of lactobacilli for healthcare and industrial applications.
METTL14 enhances the m6A modification level of lncRNA MSTRG.292666.16 to promote the progression of non-small cell lung cancer
Authors: Ji Xianxiu , Wan Xiaoying , Sun Hui , Deng Qinfang , Meng Shuyan , Xie Boxiong , Zhou Songwen
Published: February 2024

Background

m6A modification has close connection with the occurrence, development, and prognosis of tumors. This study aimed to explore the roles of m6A modification and its related mechanisms in non-small cell lung cancer (NSCLC).

Methods

NSCLC tissues and their corresponding para-cancerous tissues were collected to determine the m6A levels of total RNA/lncRNAs and the expression of m6A modification-related genes/lncRNAs. Then, A549 cells were transfected with si-METTL14 or oe-METTL14, and the cell transfection efficiency was assessed. Subsequently, the viability, apoptosis, cell colony formation, migration and invasion of the different cells were determined. Finally, the nude mouse tumorigenicity experiments were performed to observe the effects of METTL14 in vivo.

Results

Compared to the para-NSCLC tissues, the m6A level and METTL14 expression were both significantly increased in the NSCLC tissues (P < 0.05). Based on the expression of METTL14 in the different cell lines, A549 cells were chosen for further experiments. Then, the A549 cells with METTL14 knockdown and overexpression were successfully established, as well as it was found that METTL14 knockdown could inhibit the viability, colony formation, migration, and invasion of A549 cells, while facilitate their apoptosis. In vivo experiments also showed that METTL14 knockdown could inhibit tumor formation and growth. Additionally, the m6A level of MSTRG.292666.16 was higher in the NSCLC tissues; and after METTL14 knockdown, the expression and m6A level of MSTRG.292666.16 were both significantly reduced in A549 cells, and vice versa.

Conclusion

METTL14 may promote the progression of NSCLC through up-regulating MSTRG.292666.16 and enhance its m6A modification level.
Ensemble methods of rank-based trees for single sample classification with gene expression profiles
Authors: Lu Min , Yin Ruijie , Chen X. Steven
Published: February 2024

Building Single Sample Predictors (SSPs) from gene expression profiles presents challenges, notably due to the lack of calibration across diverse gene expression measurement technologies. However, recent research indicates the viability of classifying phenotypes based on the order of expression of multiple genes. Existing SSP methods often rely on Top Scoring Pairs (TSP), which are platform-independent and easy to interpret through the concept of “relative expression reversals”. Nevertheless, TSP methods face limitations in classifying complex patterns involving comparisons of more than two gene expressions. To overcome these constraints, we introduce a novel approach that extends TSP rules by constructing rank-based trees capable of encompassing extensive gene-gene comparisons. This method is bolstered by incorporating two ensemble strategies, boosting and random forest, to mitigate the risk of overfitting. Our implementation of ensemble rank-based trees employs boosting with LogitBoost cost and random forests, addressing both binary and multi-class classification problems. In a comparative analysis across 12 cancer gene expression datasets, our proposed methods demonstrate superior performance over both the k-TSP classifier and nearest template prediction methods. We have further refined our approach to facilitate variable selection and the generation of clear, precise decision rules from rank-based trees, enhancing interpretability. The cumulative evidence from our research underscores the significant potential of ensemble rank-based trees in advancing disease classification via gene expression data, offering a robust, interpretable, and scalable solution. Our software is available at https://CRAN.R-project.org/package=ranktreeEnsemble.
Diagnostic journey for individuals with fibrous dysplasia / McCune albright syndrome (FD/MAS)
Authors: Song Kaiyang , Shrestha Roshi , Delaney Heather , Vijjhalwar Rohit , Turner Alison , Sanchez Maria , Javaid Muhammad Kassim
Published: February 2024

Background

Reducing delayed diagnosis is a significant healthcare priority for individuals with rare diseases. Fibrous Dysplasia/ McCune Albright Syndrome (FD/MAS) is a rare bone disease caused by somatic activation mutations of NASA. FD/MAS has a broad clinical phenotype reflecting variable involvement of bone, endocrine and other tissues, distribution and severity. The variable phenotype is likely to prolong the diagnostic journey for patients further.

Aim

To describe the time from symptom onset to final diagnosis in individuals living with FDMAS.

Methods

We used the UK-based RUDY research database (www.rudystudy.org), where patients self-report their diagnosis of FD/MAS. Participants are invited to complete the diagnostic journey based on the EPIRARE criteria.

Results

51 individuals diagnosed with FD/MAS were included in this analysis. Among them, 70% were female, and the median age was 51.0 years (IQR 34.5–57.5]. 12 (35%) individuals reported McCune Albright Syndrome, 11 (21.6%) craniofacial and 11(21.6%) for each of poly- and mono-ostotic FD and 6 (11.8%) did not know their type of FD/MAS. Pain was the commonest first symptom (58.8%), and 47.1% received another diagnosis before the diagnosis of FD/MAS. The median time to final diagnosis from the first symptom was two years with a wide IQR (1,18) and range (0–59 years). Only 12 (23.5%) of individuals were diagnosed within 12 months of their first symptoms. The type of FD/MAS was not associated with the reported time to diagnosis. Significant independent predictors of longer time to final diagnosis included older current age, younger age at first symptom and diagnosis after 2010.

Conclusion

Individuals with FDMAS have a variable time to diagnosis that can span decades. This study highlights the need for further research on how to improve diagnostic pathways within Orthopaedic and Ear, Nose and Throat (ENT)/Maxillofacial services. Our data provides a baseline to assess the impact of novel NHS diagnostic networks on reducing the diagnostic odyssey.
The effects of etidronate on brain calcifications in Fahr’s disease or syndrome: rationale and design of the randomised, placebo-controlled, double-blind CALCIFADE trial
Authors: Snijders Birgitta MG , Mathijssen Gini , Peters Mike JL , Emmelot-Vonk Marielle H , de Jong Pim A , Bakker Susan , Crommelin Heleen A , Ruigrok Ynte M , Brilstra Eva H , Schepers Vera PM , Spiering Wilko , van Valen Evelien , Koek Huiberdina L
Published: February 2024

Background

Fahr’s disease and syndrome are rare disorders leading to calcification of the small arteries in the basal ganglia of the brain, resulting in a wide range of symptoms comprising cognitive decline, movement disorders and neuropsychiatric symptoms. No disease-modifying therapies are available. Studies have shown the potential of treatment of ectopic vascular calcifications with bisphosphonates. This paper describes the rationale and design of the CALCIFADE trial which evaluates the effects of etidronate in patients with Fahr’s disease or syndrome.

Methods

The CALCIFADE trial is a randomised, placebo-controlled, double-blind trial which evaluates the effects of etidronate 20 mg/kg during 12 months follow-up in patients aged ≥ 18 years with Fahr’s disease or syndrome. Etidronate and placebo will be administered in capsules daily for two weeks on followed by ten weeks off. The study will be conducted at the outpatient clinic of the University Medical Center Utrecht, the Netherlands. The primary endpoint is the change in cognitive functioning after 12 months of treatment. Secondary endpoints are the change in mobility, neuropsychiatric symptoms, volume of brain calcifications, dependence in activities of daily living, and quality of life.

Results

Patient recruitment started in April 2023. Results are expected in 2026 and will be disseminated through peer-reviewed journals as well as presentations at national and international conferences.

Conclusions

Fahr’s disease and syndrome are slowly progressive disorders with a negative impact on a variety of health outcomes. Etidronate might be a new promising treatment for patients with Fahr’s disease or syndrome.

Trial registration

ClinicalTrials.gov, NCT05662111. Registered 22 December 2022, https://clinicaltrials.gov/ct2/show/NCT01585402.
Inventory of current practices regarding hematopoietic stem cell transplantation in metachromatic leukodystrophy in Europe and neighboring countries
Authors: Schoenmakers Daphne H. , Mochel Fanny , Adang Laura A. , Boelens Jaap-Jan , Calbi Valeria , Eklund Erik A. , Grønborg Sabine W. , Fumagalli Francesca , Groeschel Samuel , Lindemans Caroline , Sevin Caroline , Schöls Ludger , Ram Dipak , Zerem Ayelet , Graessner Holm , Wolf Nicole I.
Published: February 2024

Background

For decades, early allogeneic stem cell transplantation (HSCT) has been used to slow neurological decline in metachromatic leukodystrophy (MLD). There is lack of consensus regarding who may benefit, and guidelines are lacking. Clinical practice relies on limited literature and expert opinions. The European Reference Network for Rare Neurological Diseases (ERN-RND) and the MLD initiative facilitate expert panels for treatment advice, but some countries are underrepresented. This study explores organizational and clinical HSCT practices for MLD in Europe and neighboring countries to enhance optimization and harmonization of cross-border MLD care.

Methods

A web-based EUSurvey was distributed through the ERN-RND and the European Society for Blood and Marrow Transplantation Inborn Errors Working Party. Personal invitations were sent to 89 physicians (43 countries) with neurological/metabolic/hematological expertise. The results were analyzed and visualized using Microsoft Excel and IBM SPSS statistics.

Results

Of the 30 countries represented by 42 respondents, 23 countries offer HSCT for MLD. The treatment is usually available in 1–3 centers per country (18/23, 78%). Most countries have no or very few MLD patients transplanted during the past 1–5 years. The eligibility criteria regarding MLD subtype, motor function, IQ, and MRI largely differ across countries.

Conclusion

HSCT for MLD is available in most European countries, but uncertainties exist in Eastern and South-Eastern Europe. Applied eligibility criteria and management vary and may not align with the latest scientific insights, indicating physicians’ struggle in providing evidence-based care. Interaction between local physicians and international experts is crucial for adequate treatment decision-making and cross-border care in the rapidly changing MLD field.
Maternal and perinatal risks for monozygotic twins conceived following frozen-thawed embryo transfer: a retrospective cohort study
Authors: Lin Jing , Zhang Kai , Wu Fenglu , Wang Bian , Chai Weiran , Zhu Qianqian , Huang Jialyu , Lin Jiaying
Published: February 2024

Background

The present study aimed to explore the maternal and perinatal risks in cases of monozygotic twins (MZT) following frozen-thawed embryo transfer (FET).

Methods

All twin births that were conceived following FET from 2007 to 2021 at Shanghai Ninth People’s Hospital in Shanghai, China were retrospectively reviewed. The exposure variable was twin type (monozygotic and dizygotic). The primary outcome was the incidence of neonatal death while secondary outcomes included hypertensive disorders of pregnancy, gestational diabetes, intrahepatic cholestasis of pregnancy, placenta previa, placental abruption, preterm premature rupture of the membranes, Cesarean delivery, gestational age, birth weight, weight discordance, stillbirth, birth defects, pneumonia, respiratory distress syndrome, necrotizing enterocolitis, and neonatal jaundice. Analysis of the outcomes was performed using logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). The causal mediation analysis was conducted. A doubly robust estimation model was used to validate the results. Kaplan-Meier method was used to calculate survival probability. The sensitivity analysis was performed with a propensity score-based patient-matching model.

Results

Of 6101 dizygotic twin (DZT) and 164 MZT births conceived by FET, MZT showed an increased risk of neonatal death based on the multivariate logistic regression models (partially adjusted OR: 4.19; 95% CI, 1.23–10.8; fully adjusted OR: 4.95; 95% CI, 1.41–13.2). Similar results were obtained with the doubly robust estimation. Comparing MZT with DZT, the neonatal survival probability was lower for MZT (P < 0.05). The results were robust in the sensitivity analysis. Females with MZT pregnancies exhibited an elevated risk of preterm premature rupture of the membranes (adjusted OR: 2.42; 95% CI, 1.54–3.70). MZT were also associated with higher odds of preterm birth (prior to 37 weeks) (adjusted OR: 2.31; 95% CI, 1.48–3.67), low birth weight (adjusted OR: 1.92; 95% CI, 1.27–2.93), and small for gestational age (adjusted OR: 2.18; 95% CI, 1.21–3.69) in the fully adjusted analyses. The effect of MZT on neonatal death was partially mediated by preterm birth and low birth weight (P < 0.05).

Conclusions

This study indicates that MZT conceived by FET are related to an increased risk of neonatal death, emphasizing a potential need for comprehensive antenatal surveillance in these at-risk pregnancies.
Procalcitonin for the diagnosis of postoperative bacterial infection after adult cardiac surgery: a systematic review and meta-analysis
Authors: Nicolotti Davide , Grossi Silvia , Palermo Valeria , Pontone Federico , Maglietta Giuseppe , Diodati Francesca , Puntoni Matteo , Rossi Sandra , Caminiti Caterina
Published: February 2024

Background and aims

Patients undergoing cardiac surgery are subject to infectious complications that adversely affect outcomes. Rapid identification is essential for adequate treatment. Procalcitonin (PCT) is a noninvasive blood test that could serve this purpose, however its validity in the cardiac surgery population is still debated. We therefore performed a systematic review and meta-analysis to estimate the accuracy of PCT for the diagnosis of postoperative bacterial infection after cardiac surgery.

Methods

We included studies on adult cardiac surgery patients, providing estimates of test accuracy. Search was performed on PubMed, EmBase and WebOfScience on April 12th, 2023 and rerun on September 15th, 2023, limited to the last 10 years. Study quality was assessed with the QUADAS-2 tool. The pooled measures of performance and diagnostic accuracy, and corresponding 95% Confidence Intervals (CI), were calculated using a bivariate regression model. Due to the variation in reported thresholds, we used a multiple-thresholds within a study random effects model for meta-analysis (diagmeta R-package).

Results

Eleven studies were included in the systematic review, and 10 (2984 patients) in the meta-analysis. All studies were single-center with observational design, five of which with retrospective data collection. Quality assessment highlighted various issues, mainly concerning lack of prespecified thresholds for the index test in all studies. Results of bivariate model analysis using multiple thresholds within a study identified the optimal threshold at 3 ng/mL, with a mean sensitivity of 0.67 (0.47–0.82), mean specificity of 0.73 (95% CI 0.65–0.79), and AUC of 0.75 (IC95% 0.29–0.95). Given its importance for practice, we also evaluated PCT’s predictive capability. We found that positive predictive value is at most close to 50%, also with a high prevalence (30%), and the negative predictive value was always > 90% when prevalence was < 20%.

Conclusions

These results suggest that PCT may be used to help rule out infection after cardiac surgery. The optimal threshold of 3 ng/mL identified in this work should be confirmed with large, well-designed randomized trials that evaluate the test’s impact on health outcomes and on the use of antibiotic therapy.

PROSPERO Registration number CRD42023415773. Registered 22 April 2023.

Graphical abstract
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

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

Background

Glioblastoma (GBM) brain tumors lackingIDH1mutations (IDHwt) have the worst prognosis of all brain neoplasms. Patients receive surgery and chemoradiotherapy but tumors almost always fatally recur.

Results

Using 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.

Conclusions

We 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

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

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

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

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

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

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

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

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.
Patient Characteristics Associated With Worsening of Neck Pain–Related Disability After Surgery for Degenerative Cervical Myelopathy: A Nationwide Study of 1508 Patients
Authors: Danielsen Elisabet , Ingebrigtsen Tor , Gulati Sasha , Salvesen Øyvind , Johansen Tonje O. , Nygaard Øystein P. , Solberg Tore K.
Published: February 2024

BACKGROUND AND OBJECTIVES:

Functional status, pain, and quality of life usually improve after surgery for degenerative cervical myelopathy (DCM), but a subset of patients report worsening. The objective was to define cutoff values for worsening on the Neck Disability Index (NDI) and identify prognostic factors associated with worsening of pain-related disability 12 months after DCM surgery.

METHODS:

In this prognostic study based on prospectively collected data from the Norwegian Registry for Spine Surgery, the NDI was the primary outcome. Receiver operating characteristics curve analyses were used to obtain cutoff values, using the global perceived effect scale as an external anchor. Univariable and multivariable analyses were performed using mixed logistic regression to evaluate the relationship between potential prognostic factors and the NDI.

RESULTS:

Among the 1508 patients undergoing surgery for myelopathy, 1248 (82.7%) were followed for either 3 or 12 months. Of these, 317 (25.4%) were classified to belong to the worsening group according to the mean NDI percentage change cutoff of 3.3. Multivariable analyses showed that smoking (odds ratio [OR] 3.4: 95% CI 1.2-9.5:P< .001), low educational level (OR 2.5: 95% CI 1.0-6.5:P< .001), and American Society of Anesthesiologists grade >II (OR 2.2: 95% CI 0.7-5.6:P= .004) were associated with worsening. Patients with more severe neck pain (OR 0.8: 95% CI 0.7-1.0:P= .003) and arm pain (OR 0.8: 95% CI 0.7-1.0;P= .007) at baseline were less likely to report worsening.

CONCLUSION:

We defined a cutoff value of 3.3 for worsening after DCM surgery using the mean NDI percentage change. The independent prognostic factors associated with worsening of pain-related disability were smoking, low educational level, and American Society of Anesthesiologists grade >II. Patients with more severe neck and arm pain at baseline were less likely to report worsening at 12 months.