bluuebunny/crossref_metadata_2025_split huggingface dataset:
An interactive simulator to deepen the understanding of Guyton’s venous return curve﻿
Authors: Mamorita Noritaka , Takeuchi Akihiro , Kamata Hirotoshi 
Published: March 2024

AbstractMean circulatory filling pressure, venous return curve, and Guyton’s graphical analysis are basic concepts in cardiovascular physiology. However, some medical students may not know how to view and interpret or understand them adequately. To deepen students’ understanding of the graphical analysis, in place of having to perform live animal experiments, we developed an interactive cardiovascular simulator, as a self-learning tool, as a web application. The minimum closed-loop model consisted of a ventricle, an artery, resistance, and a vein, excluding venous resistance. The simulator consists of three modules: setting (parameters and simulation modes), calculation, and presentation. In the setting module, the user can interactively customize model parameters, compliances, resistance, Emax of the ventricular contractility, total blood volume, and unstressed volume. The hemodynamics are calculated in three phases: filling (late diastole), ejection (systole), and flow (early diastole). In response to the user’s settings, the simulator graphically presents the hemodynamics: the pressure–volume relations of the artery, vein, and ventricle, the venous return curves, and the stroke volume curves. The mean filling pressure is calculated at approximately 7 mmHg at the initial setting. The venous return curves, linear and concave, are dependent on the venous compliance. The hemodynamic equilibrium point is marked on the crossing point of venous return curve and the stroke volume curve. Users can interactively do discovery learning, and try and confirm their interests and get their questions answered about hemodynamic concepts by using the simulator.
Socioeconomic inequalities in type 2 diabetes mellitus: a study based on a population-based survey in Iran
Authors: Darvishi Ali , Nikkhah Adeleh , Mahmudimanesh Marzieh , Balajam Narges Zargar , Shafiee Gita , Heshmat Ramin 
Published: March 2024

Abstract
Background
Type 2 diabetes mellitus (T2DM) is the most prevalent form of Diabetes Mellitus (DM), with social and economic determinants significantly influencing its prevalence. This study aimed to analyze the socioeconomic inequalities associated with T2DM in Iran.

Methods
Data from an observational survey in Iran, titled “Diabetes Care (DiaCare),” were utilized for this study. Socioeconomic inequalities were assessed through variables including Hemoglobin A1C (HbA1c), Fasting Blood Glucose (FBG), and Triple target (HbA1c, blood pressure, LDL-C), using concentration indices (CIs) and a multivariate logistic regression analysis. Individual socioeconomic status (SES) was determined by calculating an asset index using principle component analysis (PCA) based on their properties. Data analysis was conducted using STATA software version 14.

Results
A total of 13,321 participants were included in the study. The CIs were significantly positive for controlled HbA1c (0.0324) and triple target (0.1067), while for controlled FBG, it was 0.0125, although not significant. Among females, the CIs were significantly positive for controlled HbA1c (0.0745), FBG (0.0367), and triple target (0.209). Additionally, in the 45–55 and 65–75 age groups, the CIs were significantly positive for controlled HbA1c (0.0607) and FBG (0.0708), respectively. This index was significant for controlled Triple target in the 35–45 (0.376) and 65–75 (0.124) age groups. The CI for controlled FBG was significant in rural dwellers (-0.044) while the concentration of controlled triple target was significant in urban dwellers (0.0967). Controlled HbA1c showed significant concentration in both urban (0.0306) and rural (-0.0576) dwellers. Furthermore, the CIs were significant for controlled HbA1c in regions with medium prevalence (0.0534) and FBG in regions with low prevalence (-0.0277). This index was significantly positive for controlled triple target in regions with high prevalence (0.124).

Conclusions
Diabetes care is more concentrated among individuals with higher SES. Policymakers should consider this to mitigate the inequality and alleviate the burden of T2DM.
Patients’ recommendations to improve help-seeking for vaginismus: a qualitative study
Authors: Pithavadian Rashmi , Dune Tinashe , Chalmers Jane 
Published: March 2024

Abstract
Background
Research to improve healthcare experiences for women with vaginismus tends to be produced from the perspective of healthcare professionals or health-based researchers. There is lacking research on women’s experiences and recommendations to improve help-seeking for vaginismus from their perspective. To address this research gap, this qualitative study aimed to identify the issues that women face when help-seeking for vaginismus and their recommendations to address it. This sought to support the wellbeing of patients to advocate for their healthcare needs which is often overlooked.

Methods
Using a feminist theoretical approach, semi-structured interviews were conducted with 21 participants who sought help for their vaginismus. Thematic analysis was employed to analyse participants’ recommendations.

Results
Four main themes emerged: Increase awareness of vaginismus, Dismantle myths about sex, Destigmatise vaginismus, and Empower people with vaginismus during medical consultations. Subthemes were identified as actionable strategies that participants recommended to improve help-seeking and healthcare for vaginismus.

Conclusions
The findings from this study can inform healthcare practice and policy to foster better synchronicity between health professionals and their patients’ perceptions and expectations of treating vaginismus. This can promote more acceptance of patients’ advocacy of their needs and goals to improve the therapeutic alliance and treatment outcomes for vaginismus in healthcare practice. The strategies recommended to increase awareness of vaginismus and challenge its stigma should be considered in policy to incite a culture of change in healthcare practice and broader society.
Astaxanthin attenuates cigarette smoke-induced small airway remodeling via the AKT1 signaling pathway
Authors: Ding Haidong , Yan Liming , Wang Yu , Lu Ye , Deng Mingming , Wang Yingxi , Wang Qiuyue , Zhou Xiaoming 
Published: March 2024

Abstract
Background
Astaxanthin (AXT) is a keto-carotenoid with a variety of biological functions, including antioxidant and antifibrotic effects. Small airway remodeling is the main pathology of chronic obstructive pulmonary disease (COPD) and is caused by epithelial-to-mesenchymal transition (EMT) and fibroblast differentiation and proliferation. Effective therapies are still lacking. This study aimed to investigate the role of AXT in small airway remodeling in COPD and its underlying mechanisms.

Methods
First, the model of COPD mice was established by cigarette smoke (CS) exposure combined with intraperitoneal injection of cigarette smoke extract (CSE). The effects of AXT on the morphology of CS combined with CSE -induced emphysema, EMT, and small airway remodeling by using Hematoxylin-eosin (H&E) staining, immunohistochemical staining, and western blot. In addition, in vitro experiments, the effects of AXT on CSE induced-EMT and fibroblast function were further explored. Next, to explore the specific mechanisms underlying the protective effects of AXT in COPD, potential targets of AXT in COPD were analyzed using network pharmacology. Finally, the possible mechanism was verified through molecular docking and in vitro experiments.

Results
AXT alleviated pulmonary emphysema, EMT, and small airway remodeling in a CS combined with CSE -induced mouse model. In addition, AXT inhibited the EMT process in airway cells and the differentiation and proliferation of fibroblasts. Mechanistically, AXT inhibited myofibroblast activation by directly binding to and suppressing the phosphorylation of AKT1. Therefore, our results show that AXT protects against small airway remodeling by inhibiting AKT1.

Conclusions
The present study identified and illustrated a new food function of AXT, indicating that AXT could be used in the therapy of COPD-induced small airway remodeling.
Sex-specific trends in incidence of first myocardial infarction among people with and without diabetes between 1985 and 2016 in a German region
Authors: Claessen Heiner , Narres Maria , Heier Margit , Kvitkina Tatjana , Linkohr Birgit , Wolff Georg , Roden Michael , Icks Andrea , Peters Annette 
Published: March 2024

Abstract
Background
The reduction of myocardial infarction (MI) and narrowing the gap between the populations with and without diabetes are important goals of diabetes care. We analyzed time trends for sex-specific incidence rates (IR) of first MI (both non-fatal MI and fatal MI) as well as separately for first non-fatal MI and fatal MI in the population with and without diabetes.

Methods
Using data from the KORA myocardial infarction registry (Augsburg, Germany), we estimated age-adjusted IR in people with and without diabetes, corresponding relative risks (RR), and time trends from 1985 to 2016 using Poisson regression.

Results
There were 19,683 people with first MI (34% fatal MI, 71% men, 30% with diabetes) between 1985 and 2016. In the entire study population, the IR of first MI decreased from 359 (95% CI: 345–374) to 236 (226–245) per 100,000 person years. In men with diabetes, IR decreased only in 2013–2016. This was due to first non-fatal MI, where IR in men with diabetes increased until 2009–2012, and slightly decreased in 2013–2016. Overall, fatal MI declined stronger than first non-fatal MI corresponding to IRs. The RR of first MI substantially increased among men from 1.40 (1.22–1.61) in 1985–1988 to 2.60 (2.26–2.99) in 1997–2000 and moderately decreased in 2013–2016: RR: 1.75 (1.47–2.09). Among women no consistent time trend for RR was observed. Time trends for RR were similar regarding first non-fatal MI and fatal MI.

Conclusions
Over the study period, we found a decreased incidence of first MI and fatal MI in the entire study population. The initial increase of first non-fatal MI in men with diabetes needs further research. The gap between populations with and without diabetes remained.
The molecular subtyping and precision medicine in triple-negative breast cancer---based on Fudan TNBC classification
Authors: Weng Lijuan , Zhou Jianliang , Guo Shenchao , Xu Nong , Ma Ruishuang 
Published: March 2024

AbstractTriple-negative breast cancer (TNBC) is widely recognized as the most aggressive form of breast cancer, occurring more frequently in younger patients and characterized by high heterogeneity, early distant metastases and poor prognosis. Multiple treatment options have failed to achieve the expected therapeutic effects due to the lack of clear molecular targets. Based on genomics, transcriptomics and metabolomics, the multi-omics analysis further clarifies TNBC subtyping, which provides a greater understanding of tumour heterogeneity and targeted therapy sensitivity. For instance, the luminal androgen receptor subtype (LAR) exhibits responsiveness to anti-AR therapy, and the basal-like immune-suppressed subtype (BLIS) tends to benefit from poly (ADP-ribose) polymerase inhibitors (PARPis) and anti-angiogenic therapy. The efficacy of multi-dimensional combination therapy holds immense importance in guiding personalized and precision medicine for TNBC. This review offers a systematic overview of recent FuDan TNBC molecular subtyping and its role in the instruction of clinical precision therapy.
Biological roles of SLC16A1-AS1 lncRNA and its clinical impacts in tumors
Authors: Liao Bing , Wang Jialing , Yuan Yalin , Luo Hongliang , Ouyang Xi 
Published: March 2024

AbstractRecent studies have increasingly highlighted the aberrant expression of SLC16A1-AS1 in a variety of tumor types, where it functions as either an oncogene or a tumor suppressor in the pathogenesis of different cancers. The expression levels of SLC16A1-AS1 have been found to significantly correlate with clinical features and the prognosis of cancer patients. Furthermore, SLC16A1-AS1 modulates a range of cellular functions, including proliferation, migration, and invasion, through its interactions with diverse molecules and signaling pathways. This review examines the latest evidence regarding the role of SLC16A1-AS1 in the progression of various tumors and explores its potential clinical applications as a novel prognostic and diagnostic biomarker. Our comprehensive review aims to deepen the understanding of SLC16A1-AS1’s multifaceted role in oncology, underscoring its potential as a significant biomarker and therapeutic target.
Neuromodulation by nanozymes and ultrasound during Alzheimer’s disease management
Authors: Karthika Viswanathan , Badrinathan Sridharan  , Nam Ji Won , Kim Daehun , Gyun Lim Hae 
Published: March 2024

AbstractAlzheimer’s disease (AD) is a neurodegenerative disorder with complex pathogenesis and effective clinical treatment strategies for this disease remain elusive. Interestingly, nanomedicines are under extensive investigation for AD management. Currently, existing redox molecules show highly bioactive property but suffer from instability and high production costs, limiting clinical application for neurological diseases. Compared with natural enzymes, artificial enzymes show high stability, long-lasting catalytic activity, and versatile enzyme-like properties. Further, the selectivity and performance of artificial enzymes can be modulated for neuroinflammation treatments through external stimuli. In this review, we focus on the latest developments of metal, metal oxide, carbon-based and polymer based nanozymes and their catalytic mechanisms. Recent developments in nanozymes for diagnosing and treating AD are emphasized, especially focusing on their potential to regulate pathogenic factors and target sites. Various applications of nanozymes with different stimuli-responsive features were discussed, particularly focusing on nanozymes for treating oxidative stress-related neurological diseases. Noninvasiveness and focused application to deep body regions makes ultrasound (US) an attractive trigger mechanism for nanomedicine. Since a complete cure for AD remains distant, this review outlines the potential of US responsive nanozymes to develop future therapeutic approaches for this chronic neurodegenerative disease and its emergence in AD management.
Graphical Abstract
Focused ultrasound-mediated blood–brain barrier opening is safe and feasible with moderately hypofractionated radiotherapy for brainstem diffuse midline glioma
Authors: Tazhibi Masih , McQuillan Nicholas , Wei Hong-Jian , Gallitto Matthew , Bendau Ethan , Webster Carrion Andrea , Berg Xander , Kokossis Danae , Zhang Xu , Zhang Zhiguo , Jan Chia-Ing , Mintz Akiva , Gartrell Robyn D. , Syed Hasan R. , Fonseca Adriana , Pavisic Jovana , Szalontay Luca , Konofagou Elisa E. , Zacharoulis Stergios , Wu Cheng-Chia 
Published: March 2024

Abstract
Background
Diffuse midline glioma (DMG) is a pediatric tumor with dismal prognosis. Systemic strategies have been unsuccessful and radiotherapy (RT) remains the standard-of-care. A central impediment to treatment is the blood–brain barrier (BBB), which precludes drug delivery to the central nervous system (CNS). Focused ultrasound (FUS) with microbubbles can transiently and non-invasively disrupt the BBB to enhance drug delivery. This study aimed to determine the feasibility of brainstem FUS in combination with clinical doses of RT. We hypothesized that FUS-mediated BBB-opening (BBBO) is safe and feasible with 39 Gy RT.

Methods
To establish a safety timeline, we administered FUS to the brainstem of non-tumor bearing mice concurrent with or adjuvant to RT; our findings were validated in a syngeneic brainstem murine model of DMG receiving repeated sonication concurrent with RT. The brainstems of male B6 (Cg)-Tyrc-2J/J albino mice were intracranially injected with mouse DMG cells (PDGFB+, H3.3K27M, p53−/−). A clinical RT dose of 39 Gy in 13 fractions (39 Gy/13fx) was delivered using the Small Animal Radiation Research Platform (SARRP) or XRAD-320 irradiator. FUS was administered via a 0.5 MHz transducer, with BBBO and tumor volume monitored by magnetic resonance imaging (MRI).

Results
FUS-mediated BBBO did not affect cardiorespiratory rate, motor function, or tissue integrity in non-tumor bearing mice receiving RT. Tumor-bearing mice tolerated repeated brainstem BBBO concurrent with RT. 39 Gy/13fx offered local control, though disease progression occurred 3–4 weeks post-RT.

Conclusion
Repeated FUS-mediated BBBO is safe and feasible concurrent with RT. In our syngeneic DMG murine model, progression occurs, serving as an ideal model for future combination testing with RT and FUS-mediated drug delivery.
Real world clinical experience using daily intelligence-assisted online adaptive radiotherapy for head and neck cancer
Authors: Blumenfeld Philip , Arbit Eduard , Den Robert , Salhab Ayman , Falick Michaeli Tal , Wygoda Marc , Hillman Yair , Pfeffer Raphael M. , Fang Marcel , Misrati Yael , Weizman Noam , Feldman Jon , Popovtzer Aron 
Published: March 2024

Abstract
Background
Adaptive radiation therapy (ART) offers a dynamic approach to address structural and spatial changes that occur during radiotherapy (RT) for locally advanced head and neck cancers. The integration of daily ART with Cone-Beam CT (CBCT) imaging presents a solution to enhance the therapeutic ratio by addressing inter-fractional changes.

Methods
We evaluated the initial clinical experience of daily ART for patients with head and neck cancer using an online adaptive platform with intelligence-assisted workflows on daily CBCT. Treatment included auto-contour and structure deformation of Organs at Risk (OARs) and target structures, with adjustments by the treating physician. Two plans were generated: one based on the initial CT simulation with the edited structures (scheduled) and a re-optimized plan (adaptive). Both plans were evaluated and the superior one approved and delivered. Clinical and dosimetric outcomes were reviewed.

Results
Twenty two patients with head and neck cancers (7 Nasopharynx, 6 Oropharynx, 1 oral cavity, 8 larynx) stages I-IVA were treated with daily ART. 770 adaptive and scheduled radiotherapy plans were generated. 703 (91.3%) adaptive plans were chosen. Median time to deliver ART was 20 minutes (range: 18-23). Adaptive compared to scheduled plans demonstrated improved mean V95 values for the PTV70, PTV59.5, and PTV56 by 1.2%, 7.2%, and 6.0% respectively and a mean 1.4% lower maximum dose in PTV70. Fourteen of 17 OARs demonstrated improved dosimetry with adaptation, with select OARs reaching statistical significance. At a median follow up of 14.1 months, local control was 95.5%, two patients developed metastatic disease and four patients died. 9.1% of patients had acute grade 3 dysphagia and 13.6% had grade 2 chronic xerostomia.

Discussion
These findings provide real world evidence of the feasibility and dosimetric benefit of incorporating daily ART on CBCT in the treatment of head and neck cancer. Prospective study is needed to determine if these dosimetric improvements translate into improved outcomes.
FNDC5/irisin ameliorates bone loss of type 1 diabetes by suppressing endoplasmic reticulum stress‑mediated ferroptosis
Authors: Dong Qianqian , Han Ziqi , Gao Mingdong , Tian Limin 
Published: March 2024

Abstract
Background
Ferroptosis is known to play a crucial role in diabetic osteopathy. However, key genes and molecular mechanisms remain largely unclear. This study aimed to identify a crucial ferroptosis-related differentially expressed gene (FR-DEG) in diabetic osteopathy and investigate its potential mechanism.

Methods
We identified fibronectin type III domain-containing protein 5 (FNDC5)/irisin as an essential FR-DEG in diabetic osteopathy using the Ferroptosis Database (FerrDb) and GSE189112 dataset. Initially, a diabetic mouse model was induced by intraperitoneal injection of streptozotocin (STZ), followed by intraperitoneal injection of irisin. MC3T3-E1 cells treated with high glucose (HG) were used as an in vitro model. FNDC5 overexpression plasmid was used to explore underlying mechanisms in vitro experiments. Femurs were collected for micro-CT scan, histomorphometry, and immunohistochemical analysis. Peripheral serum was collected for ELISA analysis. Cell viability was assessed using a CCK-8 kit. The levels of glutathione (GSH), malondialdehyde (MDA), iron, reactive oxygen species (ROS), and lipid ROS were detected by the corresponding kits. Mitochondria ultrastructure was observed through transmission electron microscopy (TEM). Finally, mRNA and protein expressions were examined by quantitative real‐time PCR (qRT‐PCR) and western blot analysis.

Results
The expression of FNDC5 was found to be significantly decreased in both in vivo and in vitro models. Treatment with irisin significantly suppressed ferroptosis and improved bone loss. This was demonstrated by reduced lipid peroxidation and iron overload, increased antioxidant capability, as well as the inhibition of the ferroptosis pathway in bone tissues. Furthermore, in vitro studies demonstrated that FNDC5 overexpression significantly improved HG-induced ferroptosis and promoted osteogenesis. Mechanistic investigations revealed that FNDC5 overexpression mitigated ferroptosis in osteoblasts by inhibiting the eukaryotic initiation factor 2 alpha (eIF2α)/activated transcription factor 4 (ATF4)/C/EBP-homologous protein (CHOP) pathway.

Conclusions
Collectively, our study uncovered the important role of FNDC5/irisin in regulating ferroptosis of diabetic osteopathy, which might be a potential therapeutic target.