Biomedicines

16 pages, 1283 KiB

Open AccessArticle

Diabetes Prediction Through Linkage of Causal Discovery and Inference Model with Machine Learning Models

by Mi Jin Noh and Yang Sok Kim

Biomedicines 2025, 13(1), 124; https://doi.org/10.3390/biomedicines13010124 - 7 Jan 2025

Background/Objectives: Diabetes is a dangerous disease that is accompanied by various complications, including cardiovascular disease. As the global diabetes population continues to increase, it is crucial to identify its causes. Therefore, we predicted diabetes using an AI model and quantitatively examined causal [...] Read more.

Background/Objectives: Diabetes is a dangerous disease that is accompanied by various complications, including cardiovascular disease. As the global diabetes population continues to increase, it is crucial to identify its causes. Therefore, we predicted diabetes using an AI model and quantitatively examined causal relationships using a causal discovery and inference model. Methods: Kaggle’s dataset from the National Institute of Diabetes and Digestive and Kidney Diseases was analyzed using logistic regression, deep learning, gradient boosting, and decision trees. Causal discovery techniques, such as LiNGAM, were employed to infer relationships between variables. Results: The study achieved high accuracy across models using logistic regression (84.84%) and deep learning (84.83%). The causal model highlighted factors such as physical activity, difficulty in walking, and heavy drinking as direct contributors to diabetes. Conclusions: By combining AI with causal inference, this study provides both predictive performance and insight into the factors affecting diabetes, paving the way for tailored interventions. Full article

(This article belongs to the Special Issue Diabetes: Pathogenesis, Therapeutics and Outcomes)

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13 pages, 241 KiB

Open AccessReview

PET-Assessed Metabolic Tumor Volume Across the Spectrum of Solid-Organ Malignancies: A Review of the Literature

by Anusha Agarwal, Chase J. Wehrle, Sangeeta Satish, Paresh Mahajan, Suneel Kamath, Shlomo Koyfman, Wen Wee Ma, Maureen Linganna, Jamak Modaresi Esfeh, Charles Miller, David C. H. Kwon, Andrea Schlegel and Federico Aucejo

Biomedicines 2025, 13(1), 123; https://doi.org/10.3390/biomedicines13010123 - 7 Jan 2025

Abstract

Solid-organ malignancies represent a significant disease burden and remain one of the leading causes of death globally. In the past few decades, the rapid evolution of imaging modalities has shifted the paradigm towards image-based precision medicine, especially in the care of patients with [...] Read more.

Solid-organ malignancies represent a significant disease burden and remain one of the leading causes of death globally. In the past few decades, the rapid evolution of imaging modalities has shifted the paradigm towards image-based precision medicine, especially in the care of patients with solid-organ malignancies. Metabolic tumor volume (MTV) is one such semi-quantitative parameter obtained from positron emission tomography (PET) imaging with ¹⁸F-fluorodeoxyglucose (FDG) that has been shown to have significant implications in the clinical oncology setting. Across various solid tumor malignancies, including lung cancer, head and neck cancer, breast cancer, esophageal cancer, and colorectal cancer, the current literature has demonstrated an association between MTV and various clinical outcomes. MTV may be used in conjunction with several existing and established clinical parameters to help inform risk stratification and treatment strategies and predict outcomes in cancer. Optimizing such volumetric parameters is paramount for advancing efforts to advance cancer care for our patients. While such advancements are made, it is important to investigate and address the limitations of MTV, including variability in terms of measurement methods, a lack of standardized cut-off values, and the impact of inherent tumor heterogeneity. Despite these limitations, which can precipitate challenges in standardization, MTV as a prognostic factor has great potential and opens an avenue for the future integration of technology into an image-based precision medicine model of care for cancer patients. This article serves as a narrative review and explores the utility and limitations of PET-MTV in various settings of solid-organ malignancy. Full article

(This article belongs to the Special Issue Applications of Imaging Technology in Human Diseases)

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Graphical abstract

23 pages, 3892 KiB

Open AccessArticle

Novel Poly-Arginine Peptide R18D Reduces α-Synuclein Aggregation and Uptake of α-Synuclein Seeds in Cortical Neurons

by Emma C. Robinson, Anastazja M. Gorecki, Samuel R. Pesce, Vaishali Bagda, Ryan S. Anderton and Bruno P. Meloni

Biomedicines 2025, 13(1), 122; https://doi.org/10.3390/biomedicines13010122 - 7 Jan 2025

Abstract

Background/Objectives: The role of α-synuclein (α-syn) pathology in Parkinson’s disease (PD) is well established; however, effective therapies remain elusive. Two mechanisms central to PD neurodegeneration are the intracellular aggregation of misfolded α-syn and the uptake of α-syn aggregates into neurons. Cationic arginine-rich peptides [...] Read more.

Background/Objectives: The role of α-synuclein (α-syn) pathology in Parkinson’s disease (PD) is well established; however, effective therapies remain elusive. Two mechanisms central to PD neurodegeneration are the intracellular aggregation of misfolded α-syn and the uptake of α-syn aggregates into neurons. Cationic arginine-rich peptides (CARPs) are an emerging class of molecule with multiple neuroprotective mechanisms of action, including protein stabilisation. This study characterised both intracellular α-syn aggregation and α-syn uptake in cortical neurons in vitro. Thereafter, this study examined the therapeutic potential of the neuroprotective CARP, R18D (18-mer of D-arginine), to prevent the aforementioned PD pathogenic processes through a cell-free thioflavin-T (ThT) assay and in cortical neurons. Methods: To induce intracellular α-syn aggregation, rat primary cortical neurons were exposed to α-syn seed (0.14 μM) for 2 h to allow uptake of the protein, followed by R18D treatment (0.0625, 0.125, 0.25, 0.5 μM), and a subsequent measurement of α-syn aggregates 48 h later using a homogenous time-resolved fluorescence (HTRF) assay. To assess neuronal uptake, α-syn seeds were covalently labelled with an Alexa-Fluor 488 fluorescent tag, pre-incubated with R18D (0.125, 0.25, 0.5 μM), and then exposed to cortical neurons for 24 h and assessed via confocal microscopy. Results: It was demonstrated that R18D significantly reduced both intracellular α-syn aggregation and α-syn seed uptake in neurons by 37.8% and 77.7%, respectively. Also, R18D reduced the aggregation of α-syn monomers in the cell-free assay. Conclusions: These findings highlight the therapeutic potential of R18D to inhibit key α-syn pathological processes and PD progression. Full article

(This article belongs to the Section Neurobiology and Clinical Neuroscience)

27 pages, 1771 KiB

Open AccessReview

Impact of Early-Life Microbiota on Immune System Development and Allergic Disorders

by Norbert Dera, Katarzyna Kosińska-Kaczyńska, Natalia Żeber-Lubecka, Robert Brawura-Biskupski-Samaha, Diana Massalska, Iwona Szymusik, Kacper Dera and Michał Ciebiera

Biomedicines 2025, 13(1), 121; https://doi.org/10.3390/biomedicines13010121 - 7 Jan 2025

Abstract

Introduction: The shaping of the human intestinal microbiota starts during the intrauterine period and continues through the subsequent stages of extrauterine life. The microbiota plays a significant role in the predisposition and development of immune diseases, as well as various inflammatory processes. Importantly, [...] Read more.

Introduction: The shaping of the human intestinal microbiota starts during the intrauterine period and continues through the subsequent stages of extrauterine life. The microbiota plays a significant role in the predisposition and development of immune diseases, as well as various inflammatory processes. Importantly, the proper colonization of the fetal digestive system is influenced by maternal microbiota, the method of pregnancy completion and the further formation of the microbiota. In the subsequent stages of a child’s life, breastfeeding, diet and the use of antibiotics influence the state of eubiosis, which determines proper growth and development from the neonatal period to adulthood. The literature data suggest that there is evidence to confirm that the intestinal microbiota of the infant plays an important role in regulating the immune response associated with the development of allergic diseases. However, the identification of specific bacterial species in relation to specific types of reactions in allergic diseases is the basic problem. Background: The main aim of the review was to demonstrate the influence of the microbiota of the mother, fetus and newborn on the functioning of the immune system in the context of allergies and asthma. Methods: We reviewed and thoroughly analyzed the content of over 1000 articles and abstracts between the beginning of June and the end of August 2024. Over 150 articles were selected for the detailed study. Results: The selection was based on the PubMed National Library of Medicine search engine, using selected keywords: “the impact of intestinal microbiota on the development of immune diseases and asthma”, “intestinal microbiota and allergic diseases”, “the impact of intrauterine microbiota on the development of asthma”, “intrauterine microbiota and immune diseases”, “intrauterine microbiota and atopic dermatitis”, “intrauterine microbiota and food allergies”, “maternal microbiota”, “fetal microbiota” and “neonatal microbiota”. The above relationships constituted the main criteria for including articles in the analysis. Conclusions: In the present review, we showed a relationship between the proper maternal microbiota and the normal functioning of the fetal and neonatal immune system. The state of eubiosis with an adequate amount and diversity of microbiota is essential in preventing the development of immune and allergic diseases. The way the microbiota is shaped, resulting from the health-promoting behavior of pregnant women, the rational conduct of the medical staff and the proper performance of the diagnostic and therapeutic process, is necessary to maintain the health of the mother and the child. Therefore, an appropriate lifestyle, rational antibiotic therapy as well as the way of completing the pregnancy are indispensable in the prevention of the above conditions. At the same time, considering the intestinal microbiota of the newborn in relation to the genera and phyla of bacteria that have a potentially protective effect, it is worth noting that the use of suitable probiotics and prebiotics seems to contribute to the protective effect. Full article

(This article belongs to the Special Issue Advances in Fetal Medicine and Neonatology)

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18 pages, 7538 KiB

Open AccessArticle

Genetic Nurture Effects on Type 2 Diabetes Among Chinese Han Adults: A Family-Based Design

by Xiaoyi Li, Zechen Zhou, Yujia Ma, Kexin Ding, Han Xiao, Tao Wu, Dafang Chen and Yiqun Wu

Biomedicines 2025, 13(1), 120; https://doi.org/10.3390/biomedicines13010120 - 7 Jan 2025

Abstract

Background/Objectives: Genes and environments were transmitted across generations. Parents’ genetics influence the environments of their offspring; these two modes of inheritance can produce a genetic nurture effect, also known as indirect genetic effects. Such indirect effects may partly account for estimated genetic [...] Read more.

Background/Objectives: Genes and environments were transmitted across generations. Parents’ genetics influence the environments of their offspring; these two modes of inheritance can produce a genetic nurture effect, also known as indirect genetic effects. Such indirect effects may partly account for estimated genetic variance in T2D. However, the well-established specific genetic risk factors about genetic nurture effect for T2D are not fully understood. This study aimed to investigate the genetic nurture effect on type 2 diabetes and reveal the potential underlying mechanism using publicly available data. Methods: Whole-genome genotyping data of 881 offspring and/or their parents were collected. We assessed SNP-level, gene-based, and pathway-based associations for different types of genetic effects. Results: Rs3805116 (β: 0.54, p = 4.39 × 10⁻⁸) was significant for paternal genetic nurture effects. MRPS33 (p = 1.58 × 10⁻⁶), PIH1D2 (p = 6.76 × 10⁻⁷), and SD1HD (p = 2.67 × 10⁻⁶) revealed significantly positive paternal genetic nurture effects. Five ontologies were identified as enrichment in both direct and indirect genetic effects, including flavonoid metabolic process and antigen processing and presentation via the MHC class Ib pathway. Two pathways were only enriched in paternal genetic nurture effects, including the transforming growth factor beta pathway. Tissue enrichment of type 2 diabetes-associated genes on different genetic effect types was performed using publicly available gene expression data from the Human Protein Atlas database. We observed significant gene enrichment in paternal genetic nurture effects in the gallbladder, smooth muscle, and adrenal gland tissues. Conclusions: MRPS33, PIH1D2, and SD1HD are associated with increased T2D risk through the environment influenced by paternal genotype, suggesting a novel perspective on paternal contributions to the T2D predisposition. Full article

(This article belongs to the Special Issue Genetic and Molecular Mechanisms of Cardiometabolic Diseases and Cancers—2nd Edition)

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17 pages, 630 KiB

Open AccessArticle

Evidence Gaps and Lessons in the Early Detection of Atrial Fibrillation: A Prospective Study in a Primary Care Setting (PREFATE Study)

by Josep L. Clua-Espuny, Alba Hernández-Pinilla, Delicia Gentille-Lorente, Eulàlia Muria-Subirats, Teresa Forcadell-Arenas, Cinta de Diego-Cabanes, Domingo Ribas-Seguí, Anna Diaz-Vilarasau, Cristina Molins-Rojas, Meritxell Palleja-Millan, Eva M. Satué-Gracia and Francisco Martín-Luján

Biomedicines 2025, 13(1), 119; https://doi.org/10.3390/biomedicines13010119 - 7 Jan 2025

Abstract

Background/Objectives: In Europe, the prevalence of AF is expected to increase 2.5-fold over the next 50 years with a lifetime risk of 1 in 3–5 individuals after the age of 55 years and a 34% rise in AF-related strokes. The PREFATE project investigates [...] Read more.

Background/Objectives: In Europe, the prevalence of AF is expected to increase 2.5-fold over the next 50 years with a lifetime risk of 1 in 3–5 individuals after the age of 55 years and a 34% rise in AF-related strokes. The PREFATE project investigates evidence gaps in the early detection of atrial fibrillation in high-risk populations within primary care. This study aims to estimate the prevalence of device-detected atrial fibrillation (DDAF) and assess the feasibility and impact of systematic screening in routine primary care. Methods: The prospective cohort study (NCT 05772806) included 149 patients aged 65–85 years, identified as high-risk for AF. Participants underwent 14 days of cardiac rhythm monitoring using the Fibricheck^® app (CE certificate number BE16/819942412), alongside evaluations with standard ECG and transthoracic echocardiography. The primary endpoint was a new AF diagnosis confirmed by ECG or Holter monitoring. Statistical analyses examined relationships between AF and clinical, echocardiographic, and biomarker variables. Results: A total of 18 cases (12.08%) were identified as positive for possible DDAF using FibriCheck^® and 13 new cases of AF were diagnosed during follow-up, with a 71.4-fold higher probability of confirming AF in FibriCheck^®-positive individuals than in FibriCheck^®-negative individuals, resulting in a post-test odds of 87.7%. Significant echocardiographic markers of AF included reduced left atrial strain (<26%) and left atrial ejection fraction (<50%). MVP ECG risk scores ≥ 4 strongly predicted new AF diagnoses. However, inconsistencies in monitoring outcomes and limitations in current guidelines, particularly regarding AF burden, were observed. Conclusions: The study underscores the feasibility and utility of AF screening in primary care but identifies critical gaps in diagnostic criteria, anticoagulation thresholds, and guideline recommendations. Full article

(This article belongs to the Special Issue Feature Reviews in Cardiovascular Diseases)

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10 pages, 453 KiB

Open AccessReview

The Impact of Amniotic Fluid Interleukin-6, Interleukin-8, and Metalloproteinase-9 on Preterm Labor: A Narrative Review

by Theodoros Karampitsakos, Despoina Mavrogianni, Nikolaos Machairiotis, Anastasios Potiris, Periklis Panagopoulos, Sofoklis Stavros, Panos Antsaklis and Peter Drakakis

Biomedicines 2025, 13(1), 118; https://doi.org/10.3390/biomedicines13010118 - 7 Jan 2025

Abstract

Background/objectives: Preterm labor is a leading cause of neonatal morbidity and mortality worldwide. Previous research has indicated that an inflammatory response or microbial invasion of the amniotic cavity is a pathological condition linked to preterm birth; hence, inflammatory markers such as metalloproteinase-9 (MMP-9), [...] Read more.

Background/objectives: Preterm labor is a leading cause of neonatal morbidity and mortality worldwide. Previous research has indicated that an inflammatory response or microbial invasion of the amniotic cavity is a pathological condition linked to preterm birth; hence, inflammatory markers such as metalloproteinase-9 (MMP-9), interleukin-6 (IL-6), and interleukin-8 (IL-8) have been utilized to predict preterm delivery. The identification of reliable biomarkers for early prediction is critical for improving maternal, fetal, and neonatal outcomes. Methods: To address this issue, a literature review has been conducted on PubMed/Medline and Scopus databases for articles investigating the possible correlation between IL6, IL8, and MMP9 and preterm labor. Results: Using a comprehensive search of the PubMed and Scopus databases, 12 studies were analyzed to identify the correlation between these biomarkers and preterm labor. Seven studies point the impact of increased IL-6 levels or polymorphisms of the gene and higher incidence of preterm labor. Two of the included studies identified the increased risk for preterm birth in elevated levels of IL-8 in amniotic fluid. Six studies highlight the increased incidence of preterm birth in women with polymorphisms of the MMP-9 gene. Conclusions: Elevated IL-6 levels and specific gene polymorphisms are strongly associated with preterm delivery risk, with IL-8 concentrations correlating with systemic inflammation and histologic chorioamnionitis. MMP-9 gene variations and protein levels showed significant predictive value for membrane rupture and labor onset. The findings emphasize integrating these biomarkers into diagnostic tools for routine prenatal care, enhancing early detection, risk stratification, and timely interventions to improve maternal and neonatal outcomes. Full article

(This article belongs to the Special Issue Advanced Research in Early Pregnancy Loss and Other Pregnancy Complications)

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20 pages, 1932 KiB

Open AccessReview

Application Strategies of Super-Enhancer RNA in Cardiovascular Diseases

by Yi He, Yuwei Cai, Yanyan Cao, Yan Wang, Jing Wang and Hu Ding

Biomedicines 2025, 13(1), 117; https://doi.org/10.3390/biomedicines13010117 - 7 Jan 2025

Abstract

Cardiovascular diseases (CVDs) are a leading cause of death worldwide, and new therapeutic strategies are urgently needed. In recent years, enhancer RNAs (eRNAs) have gradually attracted attention because they offer new directions for the treatment of CVDs. Super-enhancer RNAs (seRNAs) are a subset [...] Read more.

Cardiovascular diseases (CVDs) are a leading cause of death worldwide, and new therapeutic strategies are urgently needed. In recent years, enhancer RNAs (eRNAs) have gradually attracted attention because they offer new directions for the treatment of CVDs. Super-enhancer RNAs (seRNAs) are a subset of non-coding RNAs that are transcribed from regions of the genome known as super enhancers, which are large clusters of enhancers with a high density of transcription factors and cofactors. These regions play a pivotal role in regulating genes involved in cell identity and disease progression. This article reviews the characteristics of seRNAs, their expression patterns, and regulatory mechanisms in the cardiovascular system. We also explore their role in the occurrence and development of CVDs, as well as their potential as diagnostic biomarkers and therapeutic targets. Currently, therapies targeting seRNAs are a research hotspot. The development of specific inhibitors or activators is expected to facilitate precise interventions for CVDs. In addition, the use of gene editing techniques to modify relevant eRNA introduces new possibilities for disease treatment. This review aims to provide a comprehensive overview of seRNAs in CVDs and discusses their potential as a novel class of therapeutic targets. Full article

(This article belongs to the Special Issue Feature Reviews in Cardiovascular Diseases)

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25 pages, 14655 KiB

Open AccessSystematic Review

Blinded by the Mind: Exploring the Hidden Psychiatric Burden in Glaucoma Patients

by Jeniffer Jesus, João Ambrósio, Dália Meira, Ignácio Rodriguez-Uña and João Melo Beirão

Biomedicines 2025, 13(1), 116; https://doi.org/10.3390/biomedicines13010116 - 7 Jan 2025

Abstract

Glaucoma is one of the leading causes of permanent vision loss worldwide and has a profound impact on patients’ quality of life. Vision impairment is strongly associated with several psychiatric disorders, like depression, anxiety, and sleep problems. These psychiatric issues are often exacerbated [...] Read more.

Glaucoma is one of the leading causes of permanent vision loss worldwide and has a profound impact on patients’ quality of life. Vision impairment is strongly associated with several psychiatric disorders, like depression, anxiety, and sleep problems. These psychiatric issues are often exacerbated by the gradual, irreversible, and typically silent progression of the disease, contributing to increased mental health challenges for affected individuals. A systematic review was conducted following PRISMA guidelines across six different databases (CINAHL, MEDLINE, PsycINFO, Web of Science, Scopus, and the Cochrane Library) and one gray literature source (Google Scholar), covering the period from 2013 to 2024. Twenty-nine studies involving a total of 13,326,845 subjects were included in the synthesis, highlighting a considerable prevalence of psychiatric disorders among glaucoma patients. Depression and anxiety were the most common conditions identified, with depression rates ranging from 6.6% to 57% and anxiety from 12.11% to 49%. Other less frequent but still significant conditions like sleep disorders, psychosis, dementia, and post-traumatic stress disorder were also observed. The findings also indicated that psychiatric severity was influenced by socio-demographic factors, glaucoma severity, and treatment duration. Given the high occurrence of psychiatric pathologies among individuals with glaucoma, it is essential to develop comprehensive care strategies that address both eye and mental health needs. Multidisciplinary collaboration among ophthalmologists, psychiatrists, psychologists, and primary care physicians is crucial for developing personalized treatment plans that effectively manage both the ocular and psychological aspects of the disease. Full article

(This article belongs to the Collection Neurodegeneration No More: Cutting-Edge Technologies and Therapies in the Evolution of Neurodegenerative Disease Management)

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22 pages, 640 KiB

Open AccessReview

Recent Advances in the Mechanisms of Postoperative Neurocognitive Dysfunction: A Narrative Review

by Tingting Wang, Xin Huang, Shujun Sun, Yafeng Wang, Linlin Han, Tao Zhang, Tianhao Zhang and Xiangdong Chen

Biomedicines 2025, 13(1), 115; https://doi.org/10.3390/biomedicines13010115 - 7 Jan 2025

Abstract

Postoperative neurocognitive dysfunction (PND) is a prevalent and debilitating complication in elderly surgical patients, characterized by persistent cognitive decline that negatively affects recovery and quality of life. As the aging population grows, the rising number of elderly surgical patients has made PND an [...] Read more.

Postoperative neurocognitive dysfunction (PND) is a prevalent and debilitating complication in elderly surgical patients, characterized by persistent cognitive decline that negatively affects recovery and quality of life. As the aging population grows, the rising number of elderly surgical patients has made PND an urgent clinical challenge. Despite increasing research efforts, the pathophysiological mechanisms underlying PND remain inadequately characterized, underscoring the need for a more integrated framework to guide targeted interventions. To better understand the molecular mechanisms and therapeutic targets of PND, this narrative review synthesized evidence from peer-reviewed studies, identified through comprehensive searches of PubMed, Embase, Cochrane Library, and Web of Science. Key findings highlight neuroinflammation, oxidative stress, mitochondrial dysfunction, neurotransmitter imbalances, microvascular changes, and white matter lesions as central to PND pathophysiology, with particular parallels to encephalocele- and sepsis-associated cognitive impairments. Among these, neuroinflammation, mediated by pathways such as the NLRP3 inflammasome and blood–brain barrier disruption, emerges as a pivotal driver, triggering cascades that exacerbate neuronal injury. Oxidative stress and mitochondrial dysfunction synergistically amplify these effects, while neurotransmitter imbalances and microvascular alterations, including white matter lesions, contribute to synaptic dysfunction and cognitive decline. Anesthetic agents modulate these interconnected pathways, exhibiting both protective and detrimental effects. Propofol and dexmedetomidine demonstrate neuroprotective properties by suppressing neuroinflammation and microglial activation, whereas inhalational anesthetics like sevoflurane intensify oxidative stress and inflammatory responses. Ketamine, with its anti-inflammatory potential, offers promise but requires further evaluation to determine its long-term safety and efficacy. By bridging molecular insights with clinical practice, this review highlights the critical role of personalized anesthetic strategies in mitigating PND and improving cognitive recovery in elderly surgical patients. It aims to inform future research and clinical decision-making to address this multifaceted challenge. Full article

(This article belongs to the Section Neurobiology and Clinical Neuroscience)

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11 pages, 1079 KiB

Open AccessArticle

Between Consecutive Fractures: Time and Sex as Dominant Factors in Type and Severity Concordance of Contralateral Hip Injuries

by Neta Leshem, Ido Stahl, Farouk Khury and Ianiv Trior Simonovich

Biomedicines 2025, 13(1), 114; https://doi.org/10.3390/biomedicines13010114 - 6 Jan 2025

Abstract

Background/Objectives: Hip fractures present a global public health concern, with a forecasted rise in incidence and having associated increased mortality rates. This study aimed to investigate whether the AO Foundation/Orthopaedic Trauma Association (AO/OTA) classification of a first hip fracture can predict the [...] Read more.

Background/Objectives: Hip fractures present a global public health concern, with a forecasted rise in incidence and having associated increased mortality rates. This study aimed to investigate whether the AO Foundation/Orthopaedic Trauma Association (AO/OTA) classification of a first hip fracture can predict the location and severity of a subsequent contralateral fracture. Methods: We retrospectively evaluated patients with non-simultaneous bilateral hip fractures between January 2000 and February 2021 and analyzed the type and severity of each fracture using the AO/OTA classification system, interval between fractures (TI), and patients’ characteristics, including sex, age at time of each fracture, and radiographic measurements of hip morphology. Results: The study included 182 fractures in 91 patients (68% women, mean age: 79.5 and 82.2 years at first and second fractures, respectively; mean TI: 975 days). A strong association (lambda = 0.437, p < 0.001) was demonstrated between the first and second fracture classifications, which was higher in men (lambda = 0.60, p < 0.001) and for TI < 3 years (lambda = 0.625–0.688, p < 0.001). The mean TI was significantly shorter between the first and subsequent identical fractures than between different fracture types. However, mean hip morphological features did not significantly differ between groups. Conclusions: The initial hip fracture classification significantly predicted the type and severity of a subsequent contralateral fracture, particularly within 3 years and in men. Providing appropriate patient guidance and preventive measures is crucial, particularly for those with primary fractures that are associated with higher morbidity and mortality. Specific fracture-focused interventions, such as preventive intramedullary nail fixation, should be considered. Full article

(This article belongs to the Special Issue Diseases and Regeneration for Muscle, Joint and Bone)

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18 pages, 997 KiB

Open AccessArticle

The Impact of Infectious Diseases on Clinical Characteristics and Immunological Correlations in Pediatric Henoch–Schönlein Purpura: A Five-Year Retrospective Study

by Sînziana Oprițescu, Gabriela Viorela Nițescu, Mihaela Golumbeanu, Dora Boghițoiu, Elena Iuliana Ioniță, Diana-Andreea Ușurelu, Cristian Lucaci, Adriana Negoiță and Elena Moroșan

Biomedicines 2025, 13(1), 113; https://doi.org/10.3390/biomedicines13010113 - 6 Jan 2025

Abstract

Background/Objectives: Immunoglobulin A (IgA) vasculitis (IgAV), classically known as Henoch–Schönlein purpura (HSP), is a type of nonthrombocytopenic small-vessel vasculitis. HSP is the most frequent kind of systemic vasculitis in children, characterized by purpura, arthritis or arthralgia, gastrointestinal pain, and kidney dysfunction. The aim [...] Read more.

Background/Objectives: Immunoglobulin A (IgA) vasculitis (IgAV), classically known as Henoch–Schönlein purpura (HSP), is a type of nonthrombocytopenic small-vessel vasculitis. HSP is the most frequent kind of systemic vasculitis in children, characterized by purpura, arthritis or arthralgia, gastrointestinal pain, and kidney dysfunction. The aim of our research was to investigate and observe the clinical characteristics of children diagnosed with HSP and to explore the correlation between infectious diseases and HSP. Furthermore, this retrospective study considered other factors, such as demographic characteristics (sex, area/environment, and age), and their effect on the pediatric population diagnosed with HSP. Methods: To answer this question, we conducted a five-year hospital-based retrospective study that included 144 hospitalized children who were diagnosed with HSP during hospitalization. Measurements of immunological panels (IgA, IgM, IgG, and IgE), C3, C4, C-reactive protein, fibrinogen, and hematite sedimentation rate (VSH) determined using blood samples revealed that there is a strong correlation between the elements of the immunological panel and the HSP manifestations. Results: Additionally, elevated IgG and normal IgA serum levels in pediatric HSP patients are strongly associated with infectious diseases. Conclusions: Notably, patients with infectious diseases exhibited high IgG and normal IgA serum levels post-treatment and a higher risk of relapses. Full article

(This article belongs to the Section Immunology and Immunotherapy)

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21 pages, 7668 KiB

Open AccessArticle

MicroRNAs Expression Profile in MN1-Altered Astroblastoma

by Francesca Gianno, Evelina Miele, Claudia Sabato, Elisabetta Ferretti, Simone Minasi, Francesca Romana Buttarelli, Debora Salerno, Natalia Pediconi, Giuseppe Rubens Pascucci, Francesca Guerrieri, Andrea Ciolfi, Simone Pizzi, Maura Massimino, Veronica Biassoni, Elisabetta Schiavello, Marco Gessi, Sofia Asioli, Angela Mastronuzzi, Antonio d’Amati, Giuseppina Catanzaro, Elisabetta Viscardi, David Capper, Felice Giangaspero and Manila Antonelli Show full author list Hide full author list

Biomedicines 2025, 13(1), 112; https://doi.org/10.3390/biomedicines13010112 - 6 Jan 2025

Abstract

Background/Objectives: Astroblastoma is a rare glial neoplasm more frequent in young female patients, with unclear clinical behaviors and outcomes. The diagnostic molecular alteration is a rearrangement of the Meningioma 1 (MN1) gene. MicroRNAs (miRNAs) are important gene expression regulators with strong [...] Read more.

Background/Objectives: Astroblastoma is a rare glial neoplasm more frequent in young female patients, with unclear clinical behaviors and outcomes. The diagnostic molecular alteration is a rearrangement of the Meningioma 1 (MN1) gene. MicroRNAs (miRNAs) are important gene expression regulators with strong implications in biological processes. Here, we investigated microRNA expression, regulation, and biological processes correlated to target genes of deregulated miRNAs in MN1-altered astroblastoma. Methods: A cohort of 14 tumor samples, histologically classified as astroblastoma, was retrospectively collected and analyzed through their DNA methylation profiles. MiRNA expression profiles were then detected on MN1-altered astroblastomas (n = 8) and normal brain controls (n = 2) by Nanostring technology and validated by RT-qPCR; then, the expression of deregulated miRNAs was correlated with clinical-pathological characteristics. Subsequently, the methylation status of promoters of deregulated miRNAs was investigated through a methylation profiling microarray. Finally, bioinformatics analysis was conducted to explore the biological processes (BPs) and target genes of differentially expressed miRNAs. Results: Eight MN-altered astroblastoma were identified. Thirty-nine miRNAs were deregulated in tumor samples compared to normal brain tissue. Downregulated microRNAs exhibited an association with an increased risk of recurrence. The promoter methylation status was investigated in 32/39 miRNAs: 14/32 were epigenetically deregulated. None of them were genetically regulated. Conclusions: MN1-altered astroblastomas have an miRNA expression signature that identifies specific BPs and pathways. Our findings suggested that the involved pathways could be associated with clinical and pathological characteristics of MN1-altered astroblastomas. Also, the biology of this rare tumor could have potential implications on prognostic markers and therapy. Full article

(This article belongs to the Section Cancer Biology and Oncology)

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11 pages, 767 KiB

Open AccessArticle

Evaluation of Inflammatory Markers and Clinical Outcomes in COVID-19 Patients with Concurrent Clostridioides difficile Infection: A Comparative Cohort Analysis

by Flavia Ignuta, Adrian Vlad, Teodor Cerbulescu, Stana Loredana, Felix Bratosin, Ovidiu Rosca, Lavinia Stelea and Daciana Nistor

Biomedicines 2025, 13(1), 111; https://doi.org/10.3390/biomedicines13010111 - 6 Jan 2025

Abstract

Background and Objectives: Co-infection with Clostridioides difficile (C. difficile) in COVID-19 patients has emerged as a clinical challenge associated with increased morbidity and mortality. While both infections elicit systemic inflammation, the interplay between inflammatory markers, disease severity, and outcomes in patients [...] Read more.

Background and Objectives: Co-infection with Clostridioides difficile (C. difficile) in COVID-19 patients has emerged as a clinical challenge associated with increased morbidity and mortality. While both infections elicit systemic inflammation, the interplay between inflammatory markers, disease severity, and outcomes in patients with COVID-19 and concurrent C. difficile infection remains poorly characterized. This study aimed to evaluate the inflammatory status and clinical outcomes of patients hospitalized with COVID-19, with and without C. difficile co-infection, and to identify the inflammatory markers most predictive of severe disease. Methods: We conducted a retrospective cohort study of 200 hospitalized adults with confirmed COVID-19, of whom 92 had laboratory-confirmed C. difficile infection. Baseline demographic data, comorbidities, inflammatory markers (C-reactive protein [CRP], interleukin-6 [IL-6], ferritin, neutrophil-to-lymphocyte ratio [NLR], platelet count, albumin, and derived indices such as the CRP-to-Albumin Ratio [CAR] and Prognostic Nutritional Index [PNI]) were recorded. Clinical outcomes included ICU admission, need for mechanical ventilation, length of stay, and in-hospital mortality. Results: Patients with COVID-19 and C. difficile co-infection had significantly elevated inflammatory markers (CRP, IL-6, NLR) and higher CAR, alongside lower PNI, compared to those with COVID-19 alone (p < 0.001). Inflammatory indices correlated strongly with disease severity: elevated CAR and low PNI were associated with higher odds of ICU admission and mortality (p < 0.001). Multivariate analysis identified co-infection status, increased IL-6, and elevated CAR as independent predictors of severe outcomes. Conclusions: C. difficile co-infection in COVID-19 patients is associated with an intensified inflammatory response and worse clinical outcomes. Among the evaluated markers, CAR and PNI emerged as robust predictors of severe disease. Timely recognition of C. difficile co-infection and use of targeted anti-inflammatory and supportive therapies may improve patient management. Future studies should expand on these findings to optimize care and guide therapeutic strategies. Full article

(This article belongs to the Section Microbiology in Human Health and Disease)

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16 pages, 849 KiB

Open AccessArticle

Fetal Hemoglobin as a Predictive Biomarker for Retinopathy of Prematurity: A Prospective Multicenter Cohort Study in Portugal

by Mariza Fevereiro-Martins, Laura Aguiar, Ângela Inácio, Carlos Cardoso, Ana Carolina Santos, Carlos Marques-Neves, Hercília Guimarães, Rui Pinto and Manuel Bicho

Biomedicines 2025, 13(1), 110; https://doi.org/10.3390/biomedicines13010110 - 6 Jan 2025

Abstract

Background/Objectives: Retinopathy of prematurity (ROP) is a leading cause of vision impairment in preterm infants, with its pathogenesis linked to oxygen exposure. Red blood cell (RBC) transfusions, commonly performed in neonatal intensive care units (NICUs), reduce fetal hemoglobin (HbF) fraction, altering oxygen dynamics [...] Read more.

Background/Objectives: Retinopathy of prematurity (ROP) is a leading cause of vision impairment in preterm infants, with its pathogenesis linked to oxygen exposure. Red blood cell (RBC) transfusions, commonly performed in neonatal intensive care units (NICUs), reduce fetal hemoglobin (HbF) fraction, altering oxygen dynamics and potentially contributing to ROP. We aimed to investigate the relationship between RBC transfusions, HbF percentage, and ROP, evaluating HbF as a potential predictive biomarker. Methods: A multicenter, prospective study was conducted across eight Portuguese NICUs, involving infants born at <32 weeks gestational age (GA) or <1500 g. ROP staging followed the International Classification of ROP (ICROP2). Clinical data were collected during hospitalization, and HbF fractions were measured from blood samples in the first four weeks of life using standardized methods. Infants were stratified by ROP presence and treatment requirement. Statistical analysis was performed using SPSS 28.0, with p < 0.05. Results: Eighty-two infants (mean GA: 28.1 ± 2.1 weeks, birth weight: 1055.8 ± 258.3 g) were included. Among them, 29 (35.4%) presented ROP and 4 (4.9%) required treatment. Infants with ROP had more RBC transfusions and lower HbF percentages than those without ROP (p < 0.05). Lower HbF was associated with more RBC transfusions (p < 0.001). Kaplan–Meier survival curves showed a higher ROP risk in infants with reduced HbF (p < 0.05). Conclusions: Low HbF percentage in the first four weeks of life may increase ROP risk in preterm infants. HbF could serve as a biomarker for ROP prediction. Interventions preserving HbF may reduce ROP risk. Further studies are needed to validate HbF as a biomarker and refine prevention strategies. Full article

(This article belongs to the Special Issue Neonatal Disease: From Pathophysiology to Current and Emerging Therapeutic Approaches (2nd Edition))

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15 pages, 291 KiB

Open AccessReview

Non-Invasive Detection of Tumors by Volatile Organic Compounds in Urine

by Tomoaki Hara, Sikun Meng, Yasuko Arao, Yoshiko Saito, Kana Inoue, Aya Hasan Alshammari, Hideyuki Hatakeyama, Eric di Luccio, Andrea Vecchione, Takaaki Hirotsu and Hideshi Ishii

Biomedicines 2025, 13(1), 109; https://doi.org/10.3390/biomedicines13010109 - 6 Jan 2025

Abstract

Cancer is one of the major causes of death, and as it becomes more malignant, it becomes an intractable disease that is difficult to cure completely. Therefore, early detection is important to increase the survival rate. For this reason, testing with blood biomarkers [...] Read more.

Cancer is one of the major causes of death, and as it becomes more malignant, it becomes an intractable disease that is difficult to cure completely. Therefore, early detection is important to increase the survival rate. For this reason, testing with blood biomarkers is currently common. However, in order to accurately diagnose early-stage cancer, new biomarkers and diagnostic methods that enable highly accurate diagnosis are needed. This review summarizes recent studies on cancer biomarker detection. In particular, we focus on the analysis of volatile organic compounds (VOCs) in urine and the development of diagnostic methods using olfactory receptors in living organisms. Urinary samples from cancer patients contain a wide variety of VOCs, and the identification of cancer specific compounds is underway. It has also been found that the olfactory sense of organisms can distinguish cancer-specific odors, which may be applicable to cancer diagnosis. We explore the possibility of novel cancer biomarker candidates and novel diagnostic methods. Full article

(This article belongs to the Special Issue State-of-the-Art and Novel Approaches in Molecular and Translational Medicine in Europe)

38 pages, 4554 KiB

Open AccessReview

Oncolytic Viruses and Immunotherapy for the Treatment of Uveal Melanoma and Retinoblastoma: The Current Landscape and Novel Advances

by Merve Kulbay, Nicolas Tuli, Massimo Mazza, Armaan Jaffer, Sarinee Juntipwong, Emily Marcotte, Stuti Misty Tanya, Anne Xuan-Lan Nguyen, Miguel N. Burnier, Jr. and Hakan Demirci

Biomedicines 2025, 13(1), 108; https://doi.org/10.3390/biomedicines13010108 - 6 Jan 2025

Abstract

Intraocular malignant tumors are rare; however, they can cause serious life-threatening complications. Uveal melanoma (UM) and retinoblastoma (RB) are the most common intraocular tumors in adults and children, respectively, and come with a great disease burden. For many years, several different treatment modalities [...] Read more.

Intraocular malignant tumors are rare; however, they can cause serious life-threatening complications. Uveal melanoma (UM) and retinoblastoma (RB) are the most common intraocular tumors in adults and children, respectively, and come with a great disease burden. For many years, several different treatment modalities for UM and RB have been proposed, with chemotherapy for RB cases and plaque radiation therapy for localized UM as first-line treatment options. Extraocular extension, recurrence, and metastasis constitute the major challenges of conventional treatments. To overcome these obstacles, immunotherapy, which encompasses different treatment options such as oncolytic viruses, antibody-mediated immune modulations, and targeted immunotherapy, has shown great potential as a novel therapeutic tool for cancer therapy. These anti-cancer treatment options provide numerous advantages such as selective cancer cell death and the promotion of an anti-tumor immune response, and they prove useful in preventing vision impairment due to macular and/or optic disc involvement. Numerous factors such as the vector choice, route of administration, dosing, and patient characteristics must be considered when engineering an oncolytic virus or other forms of immunotherapy vectors. This manuscript provides an in-depth review of the molecular design of oncolytic viruses (e.g., virus capsid proteins and encapsulation technologies, vectors for delivery, cell targeting) and immunotherapy. The most recent advances in preclinical- and clinical-phase studies are further summarized. The recent developments in virus-like drug conjugates (i.e., AU011), oncolytic viruses for metastatic UM, and targeted immunotherapies have shown great results in clinical trials for the future clinical application of these novel technologies in the treatment algorithm of certain intraocular tumors. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Target through Emerging In Vitro Approaches)

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14 pages, 2205 KiB

Open AccessArticle

Germline Single-Nucleotide Polymorphism GFI1-36N Causes Alterations in Mitochondrial Metabolism and Leads to Increased ROS-Mediated DNA Damage in a Murine Model of Human Acute Myeloid Leukemia

by Jan Vorwerk, Longlong Liu, Theresa Helene Stadler, Daria Frank, Helal Mohammed Mohammed Ahmed, Pradeep Kumar Patnana, Maxim Kebenko, Eva Dazert, Bertram Opalka, Nikolas von Bubnoff and Cyrus Khandanpour

Biomedicines 2025, 13(1), 107; https://doi.org/10.3390/biomedicines13010107 - 5 Jan 2025

Abstract

Background/Objectives: GFI1-36N represents a single-nucleotide polymorphism (SNP) of the zinc finger protein Growth Factor Independence 1 (GFI1), in which the amino acid serine (S) is replaced by asparagine (N). The presence of the GFI1-36N gene variant is associated with a reduced DNA [...] Read more.

Background/Objectives: GFI1-36N represents a single-nucleotide polymorphism (SNP) of the zinc finger protein Growth Factor Independence 1 (GFI1), in which the amino acid serine (S) is replaced by asparagine (N). The presence of the GFI1-36N gene variant is associated with a reduced DNA repair capacity favoring myeloid leukemogenesis and leads to an inferior prognosis of acute myeloid leukemia (AML) patients. However, the underlying reasons for the reduced DNA repair capacity in GFI1-36N leukemic cells are largely unknown. Since we have demonstrated that GFI1 plays an active role in metabolism, in this study, we investigated whether increased levels of reactive oxygen species (ROS) could contribute to the accumulation of genetic damage in GFI1-36N leukemic cells. Methods: We pursued this question in a murine model of human AML by knocking in human GFI1-36S or GFI1-36N variant constructs into the murine Gfi1 gene locus and retrovirally expressing MLL-AF9 to induce AML. Results: Following the isolation of leukemic bone marrow cells, we were able to show that the GFI1-36N SNP in our model is associated with enhanced oxidative phosphorylation (OXPHOS), increased ROS levels, and results in elevated γ-H2AX levels as a marker of DNA double-strand breaks (DSBs). The use of free radical scavengers such as N-acetylcysteine (NAC) and α-tocopherol (αT) reduced ROS-induced DNA damage, particularly in GFI1-36N leukemic cells. Conclusions: We demonstrated that the GFI1-36N variant is associated with extensive metabolic changes that contribute to the accumulation of genetic damage. Full article

(This article belongs to the Special Issue Molecular Research on Acute Myeloid Leukemia (AML) Volume II)

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13 pages, 2397 KiB

Open AccessArticle

Lidocaine Shows Significant Antimicrobial Effects Against Staphylococcus Species: An In-Vitro Study Comparing Different Combinations of Lidocaine and Clinically Used Injectables, like Steroids and Hyaluronan, in the Context of Arthritis Management

by Stephan Heller, Ricarda Johanna Seemann, Rainer Burgkart, Andreas Obermeier and Hermann Locher

Biomedicines 2025, 13(1), 106; https://doi.org/10.3390/biomedicines13010106 - 5 Jan 2025

Abstract

Introduction: Intra-articular injections, commonly used in osteoarthritis treatment, are debated due to their potential link to septic arthritis, though its incidence remains low. Lidocaine, used as a “carrier” for therapeutic substances like hyaluronan or triamcinolone, has pain-relieving and antimicrobial properties. This study investigates [...] Read more.

Introduction: Intra-articular injections, commonly used in osteoarthritis treatment, are debated due to their potential link to septic arthritis, though its incidence remains low. Lidocaine, used as a “carrier” for therapeutic substances like hyaluronan or triamcinolone, has pain-relieving and antimicrobial properties. This study investigates the concentration-dependent antimicrobial effects of lidocaine in combination with hyaluronan and triamcinolone in both standard and synovial fluid cultures. Methods: The antimicrobial efficacy of lidocaine against Staphylococcus aureus was investigated, with variations in bacterial and lidocaine concentrations. Bacterial growth was monitored using a UV/VIS spectrometer at 600 nm. Lidocaine solutions of 1% and 2% were tested, both alone and in combination with hyaluronic acid or Triam40, in tryptic soy broth (TSB), to reflect knee joint applications. The groups included pure lidocaine (L), Triam (T), hyaluronan (H), and combinations (LT, LH, TH, LTH) with 1% or 2% lidocaine. A bacterial inoculum of 300 CFU/mL was used, and samples were incubated for 12 and 24 h. Additional tests were conducted on Staphylococcus epidermidis and methicillin-resistant Staphylococcus aureus (MRSA), as well as on S. aureus in human synovial fluid. Results: Lidocaine showed a concentration-dependent antimicrobial effect, with greater inhibition at higher concentrations and lower bacterial densities. All lidocaine-containing combinations significantly reduced the bacterial levels of S. aureus in TSB. Similar results were seen for S. epidermidis and MRSA, with notable inhibition in synovial fluid after 12 h, especially with 2% lidocaine. Conclusions: Lidocaine exhibits dose-dependent antimicrobial effects against key pathogens responsible for septic arthritis. Its combination with Triam40 and hyaluronan may reduce the risk of septic arthritis, supporting its clinical relevance. Full article

(This article belongs to the Section Microbiology in Human Health and Disease)

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