Biomedicines

10 pages, 250 KiB

Open AccessArticle

The Importance of Timing in Performing a Holter ECG in Patients Diagnosed with an Embolic Stroke of Undetermined Source

by Dia Alwilly, Saher Srour, Irina Nordkin, Asaf Honig, Karine Beiruti Wiegler, Ronen R. Leker and Naaem Simaan

Biomedicines 2025, 13(4), 771; https://doi.org/10.3390/biomedicines13040771 (registering DOI) - 21 Mar 2025

Abstract

Background/Objectives: Previously undiagnosed atrial fibrillation (PUAF) is a significant cause of embolic stroke of undetermined source (ESUS). This study aimed to determine whether early heart rhythm monitoring with a Holter ECG after acute stroke enhances the detection of PUAF compared to standard [...] Read more.

Background/Objectives: Previously undiagnosed atrial fibrillation (PUAF) is a significant cause of embolic stroke of undetermined source (ESUS). This study aimed to determine whether early heart rhythm monitoring with a Holter ECG after acute stroke enhances the detection of PUAF compared to standard ambulatory monitoring in ESUS patients, assuming that early cardiac monitoring would lead to a higher detection rate of PUAF. Methods: This cohort study included 100 patients aged 50 and older diagnosed with ESUS and exhibiting sinus rhythm for at least 24 h. All participants were hospitalized in a stroke unit and underwent 48 h of Holter ECG monitoring. A group of 100 ESUS patients who underwent outpatient delayed Holter ECG monitoring served as controls. Results: This study revealed a significantly higher detection rate of AF in the hospitalized group compared to the outpatient group (20% vs. 5%; p = 0.001). The mean age and distribution of risk factors, including hypertension, diabetes, hyperlipidemia, ischemic heart disease, heart failure, chronic kidney disease, smoking, previous stroke, and malignancy, did not differ between the groups. There were no significant differences in initial stroke severity or in outcomes between the groups. Conclusions: Early Holter ECG monitoring in the hospitalized ESUS patients significantly increased the detection rate of PUAF compared to ambulatory monitoring, highlighting the importance of timely cardiac assessment in stroke management. Full article

(This article belongs to the Special Issue Advanced Research in Atrial Fibrillation)

14 pages, 770 KiB

Open AccessArticle

Development and Validation of a Predictive Nomogram for Venous Thromboembolism Risk in Multiple Myeloma Patients: A Single-Center Cohort Study in China

by Haolin Zhang, Xi Zhang, Xiaosheng Li, Qianjie Xu, Yuliang Yuan, Zuhai Hu, Yulan Zhao, Yao Liu, Yunyun Zhang and Haike Lei

Biomedicines 2025, 13(4), 770; https://doi.org/10.3390/biomedicines13040770 - 21 Mar 2025

Abstract

Objectives: Venous thromboembolism (VTE) is a significant complication in patients with multiple myeloma (MM) that adversely affects morbidity, mortality, and treatment outcomes. This study aimed to develop and validate a predictive nomogram for assessing VTE risk in MM patients using clinicopathological factors. Methods: [...] Read more.

Objectives: Venous thromboembolism (VTE) is a significant complication in patients with multiple myeloma (MM) that adversely affects morbidity, mortality, and treatment outcomes. This study aimed to develop and validate a predictive nomogram for assessing VTE risk in MM patients using clinicopathological factors. Methods: Clinical data, including 25 candidate risk factors, were collected. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors for VTE. The nomogram was constructed using these variables, and its performance was evaluated by plotting receiver operating characteristic (ROC) curves, calculating the area under the curve (AUC), and conducting calibration and decision curve analysis (DCA). Additionally, an online calculator was developed for clinical use. Results: In total, 148 patients (17.5%) developed VTE in this study. The independent risk factors included age, Karnofsky performance status (KPS), anticoagulation therapy, erythropoietin use, and hemoglobin (Hb), platelet (PLT), calcium (Ca), activated partial thromboplastin time (APTT), and D-dimer levels. The nomogram demonstrated robust discriminative ability, with a C-index of 0.811 in the training cohort and 0.714 in the validation cohort. The calibration curves exhibited a high level of agreement between the predicted and observed probabilities. DCA confirmed the nomogram’s clinical utility across various threshold ranges, outperforming the “treat all” and “treat none” strategies. Conclusions: This study successfully developed and validated a nomogram for predicting VTE risk in MM patients, demonstrating substantial predictive accuracy and clinical applicability. The nomogram and accompanying online calculator provide valuable tools for individualized VTE risk assessment and informed clinical decision-making. Full article

(This article belongs to the Special Issue Pathogenesis, Diagnosis and Treatment of Hematologic Malignancies)

14 pages, 1982 KiB

Open AccessReview

Iron Deficiency as a Factor of Worse Prognosis in Patients with Acute Myocardial Infarction

by Aleksander Misiewicz, Krzysztof Badura, Oliwia Matuszewska-Brycht, Jan Krekora and Jarosław Drożdż

Biomedicines 2025, 13(4), 769; https://doi.org/10.3390/biomedicines13040769 - 21 Mar 2025

Abstract

Acute coronary syndromes (ACS) are a leading cause of death and impairment in the adult population. Precise identification and modification of risk factors is crucial for a favorable clinical outcome. In this review, we aim to provide a comprehensive overview of the significance [...] Read more.

Acute coronary syndromes (ACS) are a leading cause of death and impairment in the adult population. Precise identification and modification of risk factors is crucial for a favorable clinical outcome. In this review, we aim to provide a comprehensive overview of the significance of iron deficiency (ID) in patients with ACS, particularly myocardial infarction (MI). The paper evaluates the impact of ID on the prognosis of ACS patients, highlighting its potential influence on myocardial healing, regeneration and cardiovascular events during the follow-up period. The findings suggest that iron deficiency may have a negative impact on the prognosis of patients with MI, resulting in worse quality of life, physical capacity and higher rehospitalization rates in comparison to patients with normal iron status. Iron supplementation in patients with MI could be beneficial and may have an effect on myocardial healing and left ventricular remodeling. Full article

(This article belongs to the Special Issue Connections Between Diabetes Mellitus, Other Metabolic and Endocrine Dysfunctions and Cardiovascular Pathologies)

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30 pages, 1691 KiB

Open AccessReview

The Role of Notch Signaling and Gut Microbiota in Autoinflammatory Diseases: Mechanisms and Future Views

by Vincenzo Giambra, Mario Caldarelli, Laura Franza, Pierluigi Rio, Gaja Bruno, Serena di Iasio, Andrea Mastrogiovanni, Antonio Gasbarrini, Giovanni Gambassi and Rossella Cianci

Biomedicines 2025, 13(4), 768; https://doi.org/10.3390/biomedicines13040768 - 21 Mar 2025

Abstract

Notch signaling is an evolutionarily conserved, multifunctional pathway involved in cell fate determination and immune modulation and contributes to the pathogenesis of autoinflammatory diseases. Emerging evidence reveals a bidirectional interaction between Notch and the gut microbiota (GM), whereby GM composition is capable of [...] Read more.

Notch signaling is an evolutionarily conserved, multifunctional pathway involved in cell fate determination and immune modulation and contributes to the pathogenesis of autoinflammatory diseases. Emerging evidence reveals a bidirectional interaction between Notch and the gut microbiota (GM), whereby GM composition is capable of modulating Notch signaling through the binding of microbial elements to Notch receptors, leading to immune modulation. Furthermore, Notch regulates the GM by promoting SCFA-producing bacteria while suppressing proinflammatory strains. Beneficial microbes, such as Lactobacillus and Akkermansia muciniphila, modulate Notch and reduce proinflammatory cytokine production (such as IL-6 and TNF-α). The interaction between GM and Notch can either amplify or attenuate inflammatory pathways in inflammatory bowel diseases (IBDs), Behçet’s disease, and PAPA syndrome. Together, these findings provide novel therapeutic perspectives for autoinflammatory diseases by targeting the GM via probiotics or inhibiting Notch signaling. This review focuses on Notch–GM crosstalk and how GM-based and/or Notch-targeted approaches may modulate immune responses and promote better clinical outcomes. Full article

(This article belongs to the Special Issue The Interplay between Immunity and Microbiota in Human Health and Diseases (2nd Edition))

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14 pages, 6760 KiB

Open AccessReview

The Role of Kidney Biopsy in Fabry Disease

by Irene Capelli, Laura Martano, Gian Marco Berti, Gisella Vischini, Sarah Lerario, Vincenzo Donadio, Alex Incensi, Valeria Aiello, Francesca Ciurli, Benedetta Fabbrizio, Stefano Chilotti, Renzo Mignani, Gianandrea Pasquinelli and Gaetano La Manna

Biomedicines 2025, 13(4), 767; https://doi.org/10.3390/biomedicines13040767 - 21 Mar 2025

Abstract

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to α-galactosidase A deficiency and subsequent accumulation of glycosphingolipids, including globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3), in multiple organs. This accumulation can result in multisystemic disease [...] Read more.

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to α-galactosidase A deficiency and subsequent accumulation of glycosphingolipids, including globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3), in multiple organs. This accumulation can result in multisystemic disease and life-threatening complications. FD presents with a broad phenotypic spectrum, ranging from the classic form, with early and severe symptoms, to a later-onset form with variable manifestations. The severity of the disease in females is more variable due to X-chromosome inactivation (XCI). Renal involvement is a key feature, and kidney biopsy remains a valuable tool for diagnosing FD and assessing the extent of nephropathy. Although molecular genetic testing is the gold standard for diagnosis, kidney biopsy aids in confirming renal involvement, detecting coexisting conditions, and determining the pathogenicity of variants of uncertain significance (VUSs). Moreover, kidney biopsy can serve as a prognostic tool by identifying early markers of nephropathy, such as foot process effacement and glomerular sclerosis, which predict disease progression. Emerging technologies, including machine learning, offer the potential to enhance the analysis of renal histology, improving diagnostic accuracy and patient stratification. Despite the challenges posed by overlapping diseases and potential misdiagnoses, kidney biopsy remains an essential component of FD diagnosis and management, facilitating early detection, the monitoring of disease progression, and the evaluation of therapeutic responses. Full article

(This article belongs to the Special Issue Advances in Fabry Disease: From Molecular Insights to Innovative Therapeutics)

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13 pages, 1462 KiB

Open AccessArticle

Snapping of the Subacromial Bursa: A New Cause of Shoulder Pain Demonstrated with Dynamic Ultrasound

by Arnaud Delafontaine, Raphaël Guillin, Mickael Ropars and Philippe Collin

Biomedicines 2025, 13(4), 766; https://doi.org/10.3390/biomedicines13040766 - 21 Mar 2025

Abstract

Introduction. Compared to pain, weakness, and stiffness, snapping phenomena are less frequently reported. The anatomical implication of subacromial bursa on snapping syndrome has not yet been studied despite of the fact that subacromial volume is implicated in this syndrome. The aim of this [...] Read more.

Introduction. Compared to pain, weakness, and stiffness, snapping phenomena are less frequently reported. The anatomical implication of subacromial bursa on snapping syndrome has not yet been studied despite of the fact that subacromial volume is implicated in this syndrome. The aim of this study is to analyze the anatomical and dynamic implication of the subacromial bursa in snapping syndrome. Methods. We conducted a retrospective of symptomatic case series (n = 9) study including dynamic sonography, video recordings resulting from standardized clinical dynamic examinations, and the results of shoulder magnetic resonance imaging. Nine patients complaining of snapping phenomena of the anterior shoulder (seven males and two females, mean age: 37.1 ± 10.2 years old), in whom dynamic sonography could confirm the diagnosis of snapping subacromial bursa, were included in this study. Results. All the patients included in this study presented non-traumatic painful snapping syndrome without plication before the snap on the dynamic sonography. All complained of a disabling snap of the shoulder associated with pain and without folding before the snapping phenomenon. Four of them had a bursitis of the subacromial bursa diagnosed on their shoulder’s magnetic resonance imagery. No significant statistical correlation (rS = −0.372; p = 0.595) was found between the triggering mechanisms, such as the snap shoulder release position, and the position of the anterior recess of the subacromial bursa relative to the biceps’ tendon. Conclusions. This study highlights the anterior recess of the subacromial bursa as a previously underexplored anatomical contributor to snapping syndrome, particularly in young, physically active individuals, emphasizing the need for dynamic sonography in diagnosing this condition. The anterior recess of the subacromial bursa represents an additional cause of snapping, which especially takes place in young and physically active patients. More than sport practice, professional activities that require repetitive tasks of the shoulder seem to represent a risk factor. Full article

(This article belongs to the Topic Human Anatomy and Pathophysiology, 3rd Edition)

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5 pages, 170 KiB

Open AccessEditorial

Pluripotent Stem Cells: Recent Advances and Emerging Trends

by Aline Yen Ling Wang, Ana Elena Aviña, Yen-Yu Liu and Huang-Kai Kao

Biomedicines 2025, 13(4), 765; https://doi.org/10.3390/biomedicines13040765 - 21 Mar 2025

Abstract

The field of induced pluripotent stem cells (iPSCs) continues to evolve, offering unprecedented potential for regenerative medicine, disease modeling, and therapeutic applications [...] Full article

(This article belongs to the Special Issue Pluripotent Stem Cell: Current Understanding and Future Directions)

14 pages, 1895 KiB

Open AccessArticle

Associations of Skin Autofluorescence with Diabetic Kidney Disease in Type 2 Diabetes

by Ziwei Liu, Jingjie Wang, Yuedong Zhao, Zhu Yuan, Xinjuan Zhuang and Jun Yin

Biomedicines 2025, 13(4), 764; https://doi.org/10.3390/biomedicines13040764 - 21 Mar 2025

Abstract

Background: Diabetic kidney disease (DKD), a severe chronic complication of diabetes, significantly impacts the quality of life and life expectancy of affected individuals. Meanwhile, advanced glycation end products (AGEs) are believed to play a central role in the pathogenesis of DKD. Skin [...] Read more.

Background: Diabetic kidney disease (DKD), a severe chronic complication of diabetes, significantly impacts the quality of life and life expectancy of affected individuals. Meanwhile, advanced glycation end products (AGEs) are believed to play a central role in the pathogenesis of DKD. Skin autofluorescence (SAF) is a well-validated, noninvasive technique for the estimation of AGE levels in the dermis. Aims: This study aims to evaluate the correlation between SAF and DKD prevalence, as well as the association between SAF and renal function parameters, in patients with Type 2 Diabetes Mellitus (T2DM). Methods: This cross-sectional analysis included 1259 hospitalized T2DM patients. SAF was measured using a spectroscopy device. Logistic regression analysis, p-trend analysis, and restricted cubic spline were performed with the prevalence of DKD as the dependent variable. Multiple linear regression analyses were conducted to investigate the associations of SAF with renal function parameters, specifically the estimated glomerular filtration rate (eGFR) and the log-transformed albumin-to-creatinine ratio (ln(ACR)). Results: The prevalence of DKD was strongly associated with SAF rather than with glycosylated hemoglobin (HbA1c). For each arbitrary unit (AU) increase in SAF, DKD incidence rose by 1.6%. A significant stepwise increase in the odds ratio (OR) of DKD was observed across SAF quartiles. A dose-response relationship existed between SAF and the OR value of DKD. Additionally, SAF showed a linear correlation with eGFR and ln(UACR). For each AU increase in SAF, eGFR decreased by 0.14 mL/min/1.73 m², while UACR increased by 1.2%. Conclusions: Elevated SAF, rather than HbA1c, is independently associated with increased DKD prevalence and impaired renal function. Full article

(This article belongs to the Section Endocrinology and Metabolism Research)

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10 pages, 1301 KiB

Open AccessArticle

Effect of a Nano-Sized Lipid-Based Eye Drop on Diabetic Dry Eye

by Rosario Gulias-Cañizo, Pablo Alexis Limón-Zurita, Jimena Ceja-Martínez and Oscar Guerrero-Berger

Biomedicines 2025, 13(4), 763; https://doi.org/10.3390/biomedicines13040763 - 21 Mar 2025

Abstract

Background: Dry eye disease (DED) is currently recognized as a global health concern, with a prevalence that ranges from 5% to 75%. Given the severity of dry eye in diabetic patients and the global prevalence of diabetes, it is crucial to evaluate [...] Read more.

Background: Dry eye disease (DED) is currently recognized as a global health concern, with a prevalence that ranges from 5% to 75%. Given the severity of dry eye in diabetic patients and the global prevalence of diabetes, it is crucial to evaluate new treatments that potentially improve tear film stability in this patient population. Methods: Single-center, open-label, single-arm, and interventional study in adult patients with type-2 diabetes mellitus and all DED subtypes evaluating a propylene glycol-hydroxypropyl guar nanoemulsion that has shown in previous studies to improve tear film stability in nondiabetic patients. Results: After 28 days of treatment, the Ocular Surface Disease Index (OSDI) scores showed significant improvement, decreasing from a baseline mean of 42.72 ± 17.69 to 25.53 ± 17.14 on Day 28 (p < 0.001); Non-Invasive Keratograph Break-Up Time (NIKBUT) also improved significantly, increasing from 3.45 ± 1.17 s at baseline to 5.94 ± 1.48 s on Day 28 (p < 0.001). No significant changes were observed in the infrared meibography score (baseline: 1.48 ± 0.93 vs. Day 28: 1.47 ± 0.92, p = 0.279), tear meniscus height (TMH) (baseline: 0.25 ± 0.10 mm vs. Day 28: 0.25 ± 0.08 mm, p = 0.086), or meibomian gland expressibility score (MGES). The redness score significantly decreased from 1.88 ± 0.68 at baseline to 1.40 ± 0.59 on Day 28 (p < 0.001). Conclusions: These findings suggest notable improvements in both signs and symptoms of dry eye disease in diabetic patients with all DED subtypes and severity categories. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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14 pages, 1848 KiB

Open AccessArticle

The Influence of Pituitary Morphology on the Occurrence of Hormonal Disorders in Patients with Empty Sella or Partial Empty Sella

by Bernadetta Kałuża, Mariusz Furmanek, Jan Domański, Aleksandra Żuk-Łapan, Emilia Babula, Iga Poprawa, Małgorzata Landowska, Karolina Jarząbek, Justyna Popczyńska, Paulina Filipowicz, Małgorzata Wielgolewska, Jerzy Walecki and Edward Franek

Biomedicines 2025, 13(4), 762; https://doi.org/10.3390/biomedicines13040762 - 21 Mar 2025

Abstract

Background/Objectives: The aim of the study was to prospectively assess the impact of certain parameters of pituitary morphology assessed with the use of magnetic resonance imaging on the occurrence of hormonal disorders in patients with primary partial empty sella (PES) or primary empty [...] Read more.

Background/Objectives: The aim of the study was to prospectively assess the impact of certain parameters of pituitary morphology assessed with the use of magnetic resonance imaging on the occurrence of hormonal disorders in patients with primary partial empty sella (PES) or primary empty sella (ES). Methods: Forty-three patients were divided into two groups: group 1—patients with PES (n = 20); group 2—patients with ES (n = 23). Results: Patients with ES were characterized by larger both the transverse (14.8 ± 2.9 mm vs. 17.2 ± 2.9 mm, p = 0.016) and anteroposterior (AP) diameters of the pituitary (11.4 ± 1.4 mm vs. 13.2 ± 1.9 mm, p = 0.003), a smaller craniocaudal (CC) diameter (3.9 ± 0.62 mm vs. 2.2 ± 0.6 mm, p = 0.001), and a lower pituitary volume (332.8 ± 107.6 mm³ vs. 243.5 ± 70.9 mm³, p = 0.001). Moreover, an AP infundibular displacement was more common in patients with ES (7 [35%] vs. 16 [69.6%]., p = 0.023). Despite the fact that secondary adrenocortical insufficiency was shown to be significantly more common and ACTH levels to be significantly lower (27.5 ± 13.2 pg/mL vs. 21.8 ± 17.6 pg/mL, p = 0.039) in patients with ES (0 [0%] vs. 3 [13.4%], p = 0.046), univariate logistic regression did not reveal any significant associations of pituitary diameters, pituitary volume, or pituitary stalk displacement with endocrine disorders, such as secondary adrenocortical insufficiency or hyperprolactinemia, which was confirmed with multivariate logistic regression adjusted for age, sex, BMI, and arterial hypertension. Conclusions: Radiologically assessed CC, AP, and transverse pituitary diameters, pituitary volume, or pituitary stalk displacement in patients with PES or ES have no bearing on the rates of hormonal disorders. Nonetheless, certain hormonal disorders may be more common in patients with ES, which suggests a need for hormone-level assessments in this population. Full article

(This article belongs to the Special Issue State-of-the-Art Endocrinology and Metabolism Research in Poland (Volume II))

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13 pages, 1649 KiB

Open AccessArticle

Comparison of Inflammatory Biomarkers in Females with and Without Patellofemoral Pain and Associations with Patella Position, Hip and Knee Kinematics, and Pain

by Lori A. Bolgla, Sharad Purohit, Daniel C. Hannah and David Monte Hunter

Biomedicines 2025, 13(3), 761; https://doi.org/10.3390/biomedicines13030761 - 20 Mar 2025

Abstract

Background/Objectives: Patellofemoral pain (PFP) is believed to be a precursor to knee osteoarthritis (OA). The primary purpose of this study was to compare matrix metalloproteinase-9 (MMP-9) levels in young adult females with and without PFP. The secondary purpose was to determine the [...] Read more.

Background/Objectives: Patellofemoral pain (PFP) is believed to be a precursor to knee osteoarthritis (OA). The primary purpose of this study was to compare matrix metalloproteinase-9 (MMP-9) levels in young adult females with and without PFP. The secondary purpose was to determine the associations between MMP-9, patella position, hip and knee kinematics, and pain in females with PFP. Methods: Plasma was analyzed for MMP-9. Patellar position was measured using diagnostic ultrasound as the degree of offset (RAB angle) from the deepest aspect of the femoral trochlear groove to the inferior pole of the patella. A positive RAB angle suggested patella lateralization. Hip and knee kinematics during a single-leg squat were measured using 2-dimensional motion analysis and quantified as the dynamic valgus index (DVI), a combined measure of hip and knee motion. A higher DVI suggests increased valgus loading at the patellofemoral joint. Pain was measured using a 10 cm visual analog scale. Results: Females with PFP had significantly higher levels of MMP-9 than controls (72.7 vs. 58.0 ng/mL, p = 0.03). Females with PFP had a significant positive association between MMP-9 and patella lateralization (r = 0.38, p = 0.04), suggesting that greater patellar lateralization may contribute to increased joint inflammation. A significant inverse association was observed between MMP-9 and the DVI (r = −0.50, p = 0.007), indicating that individuals with higher inflammatory marker levels may adopt movement patterns that reduce valgus loading. Conclusions: The significant association between MMP-9 and patella lateralization suggested a potential link between patella alignment and joint inflammation, which may contribute to early joint degeneration. The inverse association between MMP-9 levels and the DVI suggested that subjects with higher MMP-9 levels adjusted their movement pattern as a compensatory mechanism to reduce knee valgus stress to reduce joint degeneration. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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12 pages, 765 KiB

Open AccessArticle

The Hospital Frailty Risk Score as a Predictor of Mortality, Complications, and Resource Utilization in Heart Failure: Implications for Managing Critically Ill Patients

by Nahush Bansal, Eun Seo Kwak, Abdel-Rhman Mohamed, Vaishnavi Aradhyula, Mohanad Qwaider, Alborz Sherafati, Ragheb Assaly and Ehab Eltahawy

Biomedicines 2025, 13(3), 760; https://doi.org/10.3390/biomedicines13030760 - 20 Mar 2025

Abstract

Background: Frailty, with a high prevalence of 40–80% in heart failure, may have a significant bearing on outcomes in patients. This study utilizes the Hospital Frailty Risk Score (HFRS), a validated tool derived from the administrative International Classification of Diseases, 10th Revision, Clinical [...] Read more.

Background: Frailty, with a high prevalence of 40–80% in heart failure, may have a significant bearing on outcomes in patients. This study utilizes the Hospital Frailty Risk Score (HFRS), a validated tool derived from the administrative International Classification of Diseases, 10th Revision, Clinical Modifications (ICD-10-CM) codes, in investigating the mortality, morbidity, and healthcare resource utilization among heart failure hospitalizations using the Nationwide Inpatient Sample (NIS). Methods: A retrospective analysis of the 2021 NIS database was assessed to identify adult patients hospitalized with heart failure. These patients were stratified by the HFRS into three groups: low frailty (LF: <5), intermediate frailty (IF: 5–15), and high frailty (HF: >15). The outcomes analyzed included inpatient mortality, length of stay (LOS), hospitalization charges, and complications including cardiogenic shock, cardiac arrest, acute kidney injury, and acute respiratory failure. These outcomes were adjusted for age, race, gender, the Charlson comorbidity score, hospital location, region, and teaching status. Multivariate logistic and linear regression analyses were used to assess the association between frailty and clinical outcomes. STATA/MP 18.0 was used for statistical analysis. Results: Among 1,198,988 heart failure admissions, 47.5% patients were in the LF group, whereas the IF and HF groups had 51.1% and 1.4% patients, respectively. Compared to the LF group, the IF group showed a 4-fold higher (adjusted OR = 4.60, p < 0.01), and the HF group had an 11-fold higher (adjusted OR 10.90, p < 0.01) mortality. Frail patients were more likely to have a longer length of stay (4.24 days, 7.18 days, and 12.1 days in the LF, IF, and HF groups) and higher hospitalization charges (USD 49,081, USD 84,472, and USD 129,516 in the LF, IF, and HF groups). Complications were also noticed to be significantly (p < 0.01) higher with increasing frailty from the LF to HF groups. These included cardiogenic shock (1.65% vs. 4.78% vs. 6.82%), cardiac arrest (0.37% vs. 1.61% vs. 3.16%), acute kidney injury (19.2% vs. 54.9% vs. 74.6%), and acute respiratory failure (29.6% vs. 51.2% vs. 60.3%). Conclusions: This study demonstrates the application of HFRS in a national dataset as a predictor of outcome and resource utilization measures in heart failure admissions. Stratifying patients based on HFRS can help in holistic assessment, aid prognostication, and guide targeted interventions in heart failure. Full article

(This article belongs to the Special Issue The Treatment of Cardiovascular Diseases in the Critically Ill)

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20 pages, 769 KiB

Open AccessReview

Navigating Glioma Complexity: The Role of Abnormal Signaling Pathways in Shaping Future Therapies

by Qiang Chen, Jin Jin, Pian Li, Xiuping Wang and Qianyan Wang

Biomedicines 2025, 13(3), 759; https://doi.org/10.3390/biomedicines13030759 - 20 Mar 2025

Abstract

Gliomas are a type of highly heterogeneous and invasive central nervous system tumor. Traditional treatment methods have limited efficacy, and the prognosis for patients remains poor. Recent studies have revealed the crucial roles of several abnormal signaling pathways in the pathogenesis of gliomas, [...] Read more.

Gliomas are a type of highly heterogeneous and invasive central nervous system tumor. Traditional treatment methods have limited efficacy, and the prognosis for patients remains poor. Recent studies have revealed the crucial roles of several abnormal signaling pathways in the pathogenesis of gliomas, including the Receptor Tyrosine Kinase/Rat Sarcoma Virus Oncogene/Phosphatidylinositol-3-Kinase (RTK/RAS/PI3K) pathway, the Wingless-Related Integration Site/β-Catenin (Wnt/β-Catenin) pathway, the Hippo/YAP (Hippo/Yes-associated protein) pathway, and the Slit/Robo (Slit Guidance Ligands/Roundabout) signaling pathway. These pathways play extremely vital roles in tumor proliferation, invasion, and treatment resistance. This article comprehensively and systematically reviews the molecular mechanisms of these signaling pathways, deeply summarizing the research progress of various treatment strategies, including targeted inhibitors, gene therapy, and nanomedicine against them. Moreover, the combination of targeted therapy and personalized treatment regimens is expected to overcome the current treatment bottleneck and provide a more favorable survival prognosis for glioblastoma patients. Full article

(This article belongs to the Special Issue Gliomas: Signaling Pathways, Molecular Mechanisms and Novel Therapies (2nd Edition))

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18 pages, 1667 KiB

Open AccessConference Report

Scientific Advancements in Gene Therapies: Opportunities for Global Regulatory Convergence

by Jimi Olaghere, David A. Williams, Jeremy Farrar, Hildegard Büning, Cecelia Calhoun, Tony Ho, Maneesha S. Inamdar, David Liu, Julie Makani, Kwasi Nyarko, Sol Ruiz, John Tisdale, Joseph M. McCune, Esther Boadi and Reagan-Udall Foundation for the FDA

Biomedicines 2025, 13(3), 758; https://doi.org/10.3390/biomedicines13030758 - 20 Mar 2025

Abstract

On 4 September 2024, the Reagan-Udall Foundation for the FDA (FDA Foundation) in collaboration with the Food and Drug Administration (FDA) and the Gates Foundation hosted a workshop titled “Scientific Advancements in Gene Therapies: Opportunities for Global Regulatory Convergence”. The event brought together [...] Read more.

On 4 September 2024, the Reagan-Udall Foundation for the FDA (FDA Foundation) in collaboration with the Food and Drug Administration (FDA) and the Gates Foundation hosted a workshop titled “Scientific Advancements in Gene Therapies: Opportunities for Global Regulatory Convergence”. The event brought together a diverse group of experts, including international regulatory bodies, regulated industries, healthcare professionals, patients, academic researchers and global health advocates, to discuss the rapid advancements in gene therapy and the pressing need for equitable access in low-and middle-income countries (LMICs), with sickle cell disease (SCD) serving as the model disorder for the discussions. Although there has been significant progress in gene therapy, such as breakthroughs in clustered regularly interspaced short palindromic repeats (CRISPR)-based technologies and FDA-approved therapies, access to these therapies remain limited in underresourced regions. The workshop addressed critical challenges, including the high cost of therapies, regulatory gaps and barriers and ethical concerns regarding informed consent and public engagement in LMICs. This paper highlights the critical discussion points from the workshop with a focus on exploring strategies for global regulatory convergence, the role of international collaborations and the potential pathways to making gene therapies affordable and accessible to all. Full article

(This article belongs to the Section Gene and Cell Therapy)

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27 pages, 3323 KiB

Open AccessArticle

Inhibition of the Renin–Angiotensin System Improves Hemodynamic Function of the Diabetic Rat Heart by Restoring Intracellular Calcium Regulation

by Krisztina Anna Paulik, Tamás Ivanics, Gábor A. Dunay, Ágnes Fülöp, Margit Kerék, Klára Takács, Zoltán Benyó and Zsuzsanna Miklós

Biomedicines 2025, 13(3), 757; https://doi.org/10.3390/biomedicines13030757 - 20 Mar 2025

Abstract

Background/Objectives: Disrupted intracellular calcium (Ca²⁺_i) regulation and renin–angiotensin system (RAS) activation are pathogenetic factors in diabetic cardiomyopathy, a major complication of type 1 (T1D) and type 2 (T2D) diabetes. This study explored their potential link in diabetic rat hearts. Methods: [...] Read more.

Background/Objectives: Disrupted intracellular calcium (Ca²⁺_i) regulation and renin–angiotensin system (RAS) activation are pathogenetic factors in diabetic cardiomyopathy, a major complication of type 1 (T1D) and type 2 (T2D) diabetes. This study explored their potential link in diabetic rat hearts. Methods: Experiments were conducted on T1D and T2D Sprague-Dawley rats induced by streptozotocin and fructose-rich diet, respectively. In T1D, rats were treated with Enalapril (Ena) or Losartan (Los) for six weeks, whereas T2D animals received high-dose (HD) or low-dose (LD) Ena for 8 weeks. Heart function was assessed via echocardiography, Ca²⁺_i transients by Indo-1 fluorometry in Langendorff-perfused hearts, and key Ca²⁺_i cycling proteins by Western blot. Data: mean ± SD. Results: Diabetic hearts exhibited reduced contractile performance that was improved by RAS inhibition both in vivo (ejection fraction (%): T1D model: Control: 79 ± 7, T1D: 54 ± 11, T1D + Ena: 65 ± 10, T1D + Los: 69 ± 10, n = 18, 18, 15, 10; T2D model: Control: 73 ± 8, T2D: 52 ± 6, T2D + LDEna: 62 ± 8, T2D + HDEna: 76 ± 8, n = 9, 8, 6, 7) and ex vivo (+dPressure/dt_max (mmHg/s): T1D model: Control: 2532 ± 341, T1D: 2192 ± 208, T1D + Ena: 2523 ± 485, T1D + Los: 2643 ± 455; T2D model: Control: 2514 ± 197, T2D: 1930 ± 291, T2D + LDEna: 2311 ± 289, T2D + HDEna: 2614 ± 268). Analysis of Ca²⁺_i transients showed impaired Ca²⁺_i release and removal dynamics and increased diastolic Ca²⁺_i levels in both models that were restored by Ena and Los treatments. We observed a decrease in sarcoendoplasmic reticulum Ca²⁺-ATPase2a (SERCA2a) expression, accompanied by a compensatory increase in 16Ser-phosphorylated phospholamban (P-PLB) in T2D that was prevented by both LD and HD Ena (expression level (% of Control): SERCA2a: T2D: 36 ± 32, T2D + LDEna: 112 ± 32, T2D + HDEna: 106 ± 30; P-PLB: T2D: 557 ± 156, T2D + LDEna: 129 ± 38, T2D + HDEna: 108 ± 42; n = 4, 4, 4). Conclusions: The study highlights the critical role of RAS activation, most likely occurring at the tissue level, in disrupting Ca²⁺_i homeostasis in diabetic cardiomyopathy. RAS inhibition with Ena or Los mitigates these disturbances independent of blood pressure effects, underlining their importance in managing diabetic heart failure. Full article

(This article belongs to the Special Issue Renin-Angiotensin System in Cardiovascular Biology, 2nd Edition)

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18 pages, 5609 KiB

Open AccessArticle

Molecular Genetic Architecture of Morbid Obesity in Russian Children

by Ildar R. Minniakhmetov, Rita I. Khusainova, Olga V. Vasyukova, Daria A. Kopytina, Bulat I. Yalaev, Ramil R. Salakhov, Raisat M. Guseynova, Valentina A. Peterkova and Natalia G. Mokrysheva

Biomedicines 2025, 13(3), 756; https://doi.org/10.3390/biomedicines13030756 - 20 Mar 2025

Abstract

Background: Over the past few decades, the prevalence of obesity has significantly increased worldwide, particularly among children. This trend represents a global health challenge. Considering the pivotal role of obesity in the development of metabolic disorders, the identification and characterization of pathogenic [...] Read more.

Background: Over the past few decades, the prevalence of obesity has significantly increased worldwide, particularly among children. This trend represents a global health challenge. Considering the pivotal role of obesity in the development of metabolic disorders, the identification and characterization of pathogenic gene variants in children with severe forms of obesity are key priorities in fundamental endocrinology. Methods: We performed whole-exome sequencing (WES) in 163 Russian children with morbid obesity and identified 96 pathogenic or likely pathogenic variants in 61 genes. These variants were clinically significant in 64 children (38.79% of the cohort). Results: Notably, 42 of the identified variants have not been previously described in the literature or reported in existing databases. Conclusions: The findings of this study will enable a more personalized approach to the diagnosis and treatment of patients with syndromic and polygenic forms of obesity. Moreover, these results advance our understanding of the genetic architecture of obesity in the Russian population. Full article

(This article belongs to the Special Issue Molecular Research in Obesity, 2nd Edition)

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17 pages, 3412 KiB

Open AccessHypothesis

Ethanol Induces Craniofacial Defects in Bmp Mutants Independent of nkx2.3 by Elevating Cranial Neural Crest Cell Apoptosis

by Hieu D. L. Vo and C. Ben Lovely

Biomedicines 2025, 13(3), 755; https://doi.org/10.3390/biomedicines13030755 - 20 Mar 2025

Abstract

Background: Craniofacial malformations lie at the heart of fetal alcohol spectrum disorders (FASDs). While there is growing evidence for a genetic component in FASDs, little is known of the cellular mechanisms underlying these ethanol-sensitive loci in facial development. The bone morphogenetic protein (Bmp) [...] Read more.

Background: Craniofacial malformations lie at the heart of fetal alcohol spectrum disorders (FASDs). While there is growing evidence for a genetic component in FASDs, little is known of the cellular mechanisms underlying these ethanol-sensitive loci in facial development. The bone morphogenetic protein (Bmp) signaling pathway-dependent endoderm pouch formation is a key mechanism in facial development. We have previously shown that multiple Bmp mutants are sensitized to ethanol-induced facial defects. However, ethanol does not directly impact Bmp signaling. This suggests that downstream effectors, like nkx2.3, may mediate the impact of ethanol on Bmp mutants. Methods: We use an ethanol exposure paradigm with nkx2.3 knockdown approaches to test if nkx2.3 loss sensitizes Bmp mutants to ethanol-induced facial defects. We combine morphometric approaches with immunofluorescence and a hybridization chain reaction to examine the cellular mechanisms underlying Bmp–ethanol interactions. Results: We show that Bmp–ethanol interactions alter the morphology of the endodermal pouches, independent of nkx2.3 gene expression. Knockdown of nkx2.3 does not sensitize wild-type or Bmp mutants to ethanol-induced facial defects. However, we did observe a significant increase in CNCC apoptosis in ethanol-treated Bmp mutants, suggesting an ethanol sensitive, Bmp-dependent signaling pathway driving tissue interactions at the heart of FASDs. Conclusions: Collectively, our work builds on the mechanistic understanding of ethanol-sensitive genes and lays the groundwork for complex multi-tissue signaling events that have yet to be explored. Ultimately, our work provides a mechanistic paradigm of ethanol-induced facial defects and connects ethanol exposure with complex tissue signaling events that drive development. Full article

(This article belongs to the Special Issue Zebrafish Models for Development and Disease 4.0)

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12 pages, 1794 KiB

Open AccessArticle

Systemic Inflammatory Markers as Prognostic Factors in Oral Squamous Cell Carcinoma of the Tongue

by Maria Giulia Cristofaro, Francesco Ferragina, Federico Tolino and Ida Barca

Biomedicines 2025, 13(3), 754; https://doi.org/10.3390/biomedicines13030754 - 20 Mar 2025

Abstract

Background: Oral tongue squamous cell carcinoma (OTSCC) is a common disease that can cause occult metastasis (OM). Methods: This study aims to investigate the role of the pre-treatment neutrophil-to-lymphocyte ratio (NLR) in predicting the presence of neck OM in early-stage OTSCC. [...] Read more.

Background: Oral tongue squamous cell carcinoma (OTSCC) is a common disease that can cause occult metastasis (OM). Methods: This study aims to investigate the role of the pre-treatment neutrophil-to-lymphocyte ratio (NLR) in predicting the presence of neck OM in early-stage OTSCC. We reprocessed the pre-treatment blood data to calculate the NLR and the PLR on patients treated for OTSCC. We used a logistic regression model and the ROC curve to estimate the probability of metastases in cervical lymph nodes using data from pre-surgery blood tests. Results: During the period under review, 113 patients were treated for OTSCC; however, only 74 met the inclusion criteria and were, therefore, enrolled in the study. Twenty-five patients (35.3%) had lymph node metastases, and 46 (64.7%) did not. Without the NLR influence, the probability of metastasis is less than 50% (β0 = −1.058). A higher NLR value means a higher chance of metastasis. This is shown by the positive value of the NLR level coefficient (β1 = 0.135) and the ROC curve (AUC = 0.83). Conclusions: Our study showed a statistical correlation between high pre-treatment NLR values and neck OM in patients with OTSCC. These results may help to identify which patients are at risk of developing OM and then choose the right treatment. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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14 pages, 3792 KiB

Open AccessArticle

The Causal Relationship Between Gut Microbiomes, Inflammatory Mediators, and Traumatic Brain Injury in Europeans: Evidence from Genetic Correlation and Functional Mapping Annotation Analyses

by Bingyi Song, Youjia Qiu, Zilan Wang, Yuchen Tao, Menghan Wang, Aojie Duan, Minjia Xie, Ziqian Yin, Zhouqing Chen, Chao Ma and Zhong Wang

Biomedicines 2025, 13(3), 753; https://doi.org/10.3390/biomedicines13030753 - 20 Mar 2025

Abstract

Background: The gut microbiome (GM) has been reported to play a role in traumatic brain injury (TBI). To investigate the causal relationship between GMs, inflammatory mediators, and TBI, a comprehensive Mendelian randomization (MR) analysis was conducted. Methods: We utilized Genome-Wide Association Study (GWAS) [...] Read more.

Background: The gut microbiome (GM) has been reported to play a role in traumatic brain injury (TBI). To investigate the causal relationship between GMs, inflammatory mediators, and TBI, a comprehensive Mendelian randomization (MR) analysis was conducted. Methods: We utilized Genome-Wide Association Study (GWAS) summary statistics to examine the causal relationships between GM and TBI. To assess the potential causal associations between GM and TBI, we employed the inverse-variance-weighted, MR-Egger, and weighted median methods. Mediation analysis was used to assess the possible mediating factors. Several sensitivity analyses methods were implemented to verify the stability of the results. Additionally, we utilized FUMA GWAS to map single-nucleotide polymorphisms to genes and conduct transcriptomic MR analysis. Results: We identified potential causal relationships between nine bacterial taxa and TBI. Notably, class Methanobacteria, family Methanobacteriaceae, and order Methanobacteriales (p = 0.0003) maintained a robust positive correlation with TBI. This causal association passed false discovery rate (FDR) correction (FDR < 0.05). Genetically determined 1 inflammatory protein, 30 immune cells and 3 inflammatory factors were significantly causally related to TBI. None of them mediated the relationship between GMs and TBI. The outcome of the sensitivity analysis corroborated the findings. Regarding the mapped genes of significant GMs, genes such as CLK4, MTRF1, NAA16, SH3BP5, and ZNF354A in class Methanobacteria showed a significant causal correlation with TBI. Conclusions: Our study reveals the potential causal effects of nine GMs, especially Methanogens on TBI, and there was no link between TBI and GM through inflammatory protein, immune cells, and inflammatory factors, which may offer fresh insights into TBI biomarkers and therapeutic targets through specific GMs. Full article

(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development: 2nd Edition)

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