Biomedicines

14 pages, 695 KB

Open AccessArticle

Improving Endothelium-Dependent Vasodilation with Dietary Intake of n-3 Polyunsaturated Fatty Acids-Enriched Chicken Meat: A Randomized Controlled Trial

by Tihana Nađ, Martina Kos, Ana Stupin, Ines Drenjančević, Nikolina Kolobarić, Zrinka Mihaljević, Petar Šušnjara, Mia Damašek, Darjan Kardum and Ivana Jukić

Biomedicines 2026, 14(4), 852; https://doi.org/10.3390/biomedicines14040852 (registering DOI) - 8 Apr 2026

Abstract

Objective: Vascular function serves as an early indicator of cardiovascular (CV) risk. The intake of n-3 polyunsaturated fatty acids (PUFAs) has been reported to improve arterial properties and reduce CV risk, but evidence in healthy individuals remains limited. This study investigated the effects [...] Read more.

Objective: Vascular function serves as an early indicator of cardiovascular (CV) risk. The intake of n-3 polyunsaturated fatty acids (PUFAs) has been reported to improve arterial properties and reduce CV risk, but evidence in healthy individuals remains limited. This study investigated the effects of consuming n-3 PUFAs-enriched chicken meat on vascular reactivity at both microvascular and macrovascular levels in healthy young adults. Materials and Methods: In this placebo-controlled, double-blind, randomized interventional trial (ClinicalTrials.gov: NCT05725486), 39 participants (aged 20–26 years) were assigned to either the Control group (n = 20; approximately 118 mg n-3 PUFAs/day) or the n-3 PUFA group (n = 19; approximately 1500 mg n-3 PUFAs/day) for three weeks. Microvascular reactivity was assessed via post-occlusive reactive hyperemia (PORH), acetylcholine-induced dilation (AChID), local thermal hyperemia (LTH), and sodium nitroprusside-induced (SNPID) responses. Macrovascular reactivity was measured by brachial artery flow-mediated dilation (FMD) and nitroglycerine-mediated dilation (NTG-MD). Body composition and blood pressure (BP) were recorded before and after the intervention. Results: Both microvascular (PORH, AChID, and LTH) and macrovascular (FMD) endothelium-dependent vasodilation increased in the n-3 PUFAs group following the dietary protocol compared to the Control group. Conversely, the three-week dietary intervention did not influence endothelium-independent dilation in either the microvasculature (SNPID) or macrovasculature (NTG-MD) within the groups compared to baseline, nor were any differences observed between the groups. No significant changes were noted in BP or body composition after either diet. Conclusions: In healthy young adults, consuming the n-3 PUFAs-enriched chicken meat for three weeks improved endothelium-dependent vasodilation in both micro- and macrocirculation, without affecting endothelium-independent responses. These findings suggest that dietary n-3 PUFA intake may provide vascular benefits even in healthy, disease-free individuals at rest. Full article

(This article belongs to the Special Issue Advances in Cardiovascular Disease: Mechanisms and Treatments)

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20 pages, 811 KB

Open AccessReview

Cell-Based and Cell-Free Non-Invasive Prenatal Analysis of Preeclampsia: An Updated Review of Liquid Biopsy

by Yafeng Ma, Ya-Wen Chiang, Therese M. Becker and Jon Hyett

Biomedicines 2026, 14(4), 851; https://doi.org/10.3390/biomedicines14040851 (registering DOI) - 8 Apr 2026

Abstract

Preeclampsia (PE), pregnancy-associated high blood pressure linked to organ damage, affects 3–8% of all pregnancies and results worldwide in 70,000 maternal and 500,000 perinatal deaths each year. Untreated PE may progress to eclampsia with long-term health implications for both mother and child. Non-invasive [...] Read more.

Preeclampsia (PE), pregnancy-associated high blood pressure linked to organ damage, affects 3–8% of all pregnancies and results worldwide in 70,000 maternal and 500,000 perinatal deaths each year. Untreated PE may progress to eclampsia with long-term health implications for both mother and child. Non-invasive prenatal diagnosis or screening applies cell-free DNA approaches and offers a less invasive and more economical method for early diagnosis and prediction of various pregnancy complications. Recently, cell-free assays, particularly blood-based cell-free DNA and RNA analysis, have shown great potential in early PE prediction and diagnosis. Here, we provide an updated review of the current understanding and discoveries of PE, focusing on recent publications (1 January 2019–30 December 2025) of liquid biopsy-derived circulating fetal cells (circulating trophoblasts and fetal nucleated red blood cells), cell-free DNA, cell-free RNA and small extracellular vesicles (i.e., exosomes). We aim to discuss the conceptual framework and technical evolution of liquid biopsy applications in preeclampsia pathogenesis, prediction and diagnosis. Progressing novel screening and diagnostic molecular biomarkers have high potential to facilitate early detection for patients at risk of PE. Liquid biopsy-based screening strategies may aid in providing timely intervention and treatment. Full article

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

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40 pages, 2982 KB

Open AccessReview

Beyond PAD Inhibition: Emerging Avenues and Natural Products for Targeting Citrullination in Immune Diseases

by Qilei Chen, Yuhang Ma, Yingyi Liu, Xiaojie Wang, Guanhua Huang, Yizhao Yang, Joshua Ka-Shun Ko and Hubiao Chen

Biomedicines 2026, 14(4), 850; https://doi.org/10.3390/biomedicines14040850 - 8 Apr 2026

Abstract

Immune-mediated inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus, impose a severe and growing global health burden, where current therapies are limited by poor specificity and significant side effects. The peptidylarginine deiminase (PAD)/citrullination axis, in which protein citrullination catalyzed [...] Read more.

Immune-mediated inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus, impose a severe and growing global health burden, where current therapies are limited by poor specificity and significant side effects. The peptidylarginine deiminase (PAD)/citrullination axis, in which protein citrullination catalyzed by PADs drives autoantigen generation and sustains inflammation, has emerged as a critical therapeutic target. This review outlines a comprehensive strategy for targeting this axis using natural products. We first detail the established role of natural compounds as direct PAD inhibitors, covering their chemical diversity, inhibitory mechanisms, and therapeutic applications in disease models. Subsequently, the discussion extends to their broader, indirect modulatory functions, highlighting how these compounds can suppress pathogenic citrullination by regulating upstream processes like NETosis and inflammatory signaling. Furthermore, the review introduces the innovative substrate-centric intervention strategy, which represents a paradigm shift toward shielding key arginine residues on autoantigens, thereby preventing the formation of immunogenic neoepitopes. The translational challenges and future directions for each of these avenues are outlined, addressing persistent obstacles including achieving isoform selectivity and biomarker validation. By integrating these multifaceted strategies, from direct inhibition and indirect modulation to substrate protection, this work provides a strategic roadmap for advancing the next generation of more precise, effective, and safe anti-citrullination therapies, ultimately moving beyond conventional enzyme inhibition toward targeted immunomodulation in immune-mediated inflammatory diseases. Full article

(This article belongs to the Special Issue Natural Product for the Interventions of Chronic Diseases: From Source to Therapy)

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33 pages, 4504 KB

Open AccessArticle

A Longitudinal Exploratory Study of SARS-CoV-2 Antibody Dynamics in Young Adults in Bogotá: Lessons from Natural Infection and Post-Vaccination Memory

by María F. Naranjo-Ortíz, Luz Parada-Rubio, José Fuentes-Montoya, Jean Carlos Villamil Poveda, Francy Elaine Torres-Suarez, Heidy-C. Martínez-Díaz, Laura Daniela Ardila Ortiz, Juliana Velosa-Porras, Lorenza Jaramillo, Jorge Andrés Castillo, Jairo Jaime, Nelly S. Roa and Adriana P. Corredor-Figueroa

Biomedicines 2026, 14(4), 849; https://doi.org/10.3390/biomedicines14040849 - 8 Apr 2026

Abstract

Background: Infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have generated major public health concerns worldwide. Young adults represent a critical group for viral transmission due to their high proportion of asymptomatic infections. Objective: To characterize the dynamics of [...] Read more.

Background: Infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have generated major public health concerns worldwide. Young adults represent a critical group for viral transmission due to their high proportion of asymptomatic infections. Objective: To characterize the dynamics of SARS-CoV-2-specific antibodies in individuals aged 20–29 years from Bogotá, Colombia, across two longitudinal phases. Methods: Phase I assessed seroprevalence, seroconversion, spatial clustering, symptoms associated with seropositivity and antibody kinetics following natural infection. Phase II evaluated vaccine-induced antibodies, immune memory, and neutralizing capacity. Analyses included Functional Principal Component Analysis, survival analysis, clustering, and predictive modeling. Results: In Phase I, a seroprevalence of 15.59% (17/109 participants enrolled) was observed, while seroconversion among those who completed all six sampling points was 30.18% (16/53), with clusters of positive cases in different areas of Bogotá. The symptoms most associated with seropositivity included mucus hypersecretion, fever, and respiratory difficulty. Antibody responses were heterogeneous: naturally infected individuals generally showed high titers during the first 1–2 months, remaining detectable up to 4 months. The reduction in dimensionality suggested dominant humoral patterns, and clustering revealed two immune profiles differing in the risk of seroconversion. Predictive modeling indicated diverse antibody trajectories over 12 months. In Phase II (2024), three long-term immune memory clusters (low, medium, high) were observed; post-vaccination IgG titers were observed, although in most cases they lacked neutralizing activity. Conclusions: This longitudinal exploratory observational study provides an initial characterization of antibody dynamics in young adults, suggesting their potential epidemiological relevance and offering preliminary insights into post-infection and post-vaccination immunity. Full article

(This article belongs to the Special Issue The End of the COVID-19 Pandemic—What Is Currently Known and What Could Have Been Useful Four Years Ago? (2nd Edition))

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18 pages, 1237 KB

Open AccessArticle

Development and Validation of an SPE–LC–MS Method for the Determination of Epirubicin, Olaparib and Ribociclib in Human Serum

by Monica Denisa Elena Popescu, Costel-Valentin Manda, Octavian Croitoru, Daniela-Maria Calucică, Johny Neamțu, Andrei Biță, Amelia Maria Găman and Simona-Daniela Neamțu

Biomedicines 2026, 14(4), 848; https://doi.org/10.3390/biomedicines14040848 - 8 Apr 2026

Abstract

Background/Objectives: Epirubicin, Olaparib, and Ribociclib are widely used anticancer agents whose serum concentrations exhibit significant inter-individual variability, supporting the need for reliable and robust analytical methods suitable for pharmacokinetic evaluation and therapeutic exposure assessment. Variations in metabolism, drug–drug interactions, organ function, and [...] Read more.

Background/Objectives: Epirubicin, Olaparib, and Ribociclib are widely used anticancer agents whose serum concentrations exhibit significant inter-individual variability, supporting the need for reliable and robust analytical methods suitable for pharmacokinetic evaluation and therapeutic exposure assessment. Variations in metabolism, drug–drug interactions, organ function, and treatment regimens may substantially influence systemic exposure, highlighting the importance of accurate quantification in clinical practice. This study describes the development and validation of a solid-phase extraction–liquid chromatography–mass spectrometry (SPE–LC–MS) method for the simultaneous quantification of these drugs in human serum. Methods: Sample preparation was performed using Oasis PRiME HLB^® cartridges to ensure efficient clean-up, optimal recovery, and reduced matrix effects. Chromatographic separation was achieved using gradient elution with 0.1% formic acid and acetonitrile on a reversed-phase column, followed by single-quadrupole mass spectrometric (QDa) detection in the selected ion recording mode. The total run time was 13 min, enabling high-throughput analysis. Results: The method demonstrated good linearity (r > 0.997) over the tested concentration ranges, along with adequate selectivity, precision, accuracy, recovery, and stability, fulfilling the ICH M10 guideline validation criteria. No significant carry-over or interference from endogenous compounds was observed. Conclusions: Application to patient samples confirmed reliable performance in real clinical matrices and consistent quantification across different concentration levels. The proposed approach provides a potentially more accessible alternative in laboratories already equipped with LC-MS systems compared to LC-MS/MS platforms and can be applied in pharmacokinetic studies, representing a proof-of-concept for exposure assessment in oncology. Full article

(This article belongs to the Special Issue Advanced Research in Anticancer Inhibitors and Targeted Therapy)

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16 pages, 944 KB

Open AccessArticle

Early Functional Impairment in Smokers with CT-Detected Emphysema: Spirometry Provides Complementary Physiological Information in Lung Cancer Screening

by Sanja Dimic-Janjic, Ivana Buha, Jelena Cvejic, Nikola Kostadinovic, Slavko Stamenic, Anka Postic, Ana Ratkovic, Kristina Stosic-Markovic, Ivana Sekulovic-Radovanovic, Marija Vukoja, Nikola Trboljevac, Lidija Isovic, Ruza Stevic, Nikola Colic, Katarina Lukic, Spasoje Popevic, Natasa Djurdjevic, Milan Savic, Nikola Subotic and Mihailo Stjepanovic

Biomedicines 2026, 14(4), 847; https://doi.org/10.3390/biomedicines14040847 - 8 Apr 2026

Abstract

Background: Low-dose computed tomography (LDCT) lung cancer screening (LCS) frequently identifies emphysema in high-risk smokers. However, the extent to which CT-detected emphysema reflects underlying physiological impairment remains uncertain. We evaluated whether spirometry can detect functional abnormalities in this population beyond structural imaging [...] Read more.

Background: Low-dose computed tomography (LDCT) lung cancer screening (LCS) frequently identifies emphysema in high-risk smokers. However, the extent to which CT-detected emphysema reflects underlying physiological impairment remains uncertain. We evaluated whether spirometry can detect functional abnormalities in this population beyond structural imaging findings. Methods: This cross-sectional study included 323 individuals with LDCT- detected emphysema and no lung cancer or prior chronic respiratory diseases within a screening cohort (n = 3076). Participants underwent pre-bronchodilator spirometry and symptom assessments (COPD Assessment test (CAT) and Modified Medical Research Council (mMRC) Dyspnea Scale). Pre-bronchodilator airflow limitation was defined as forced expiratory volume in one second to forced vital capacity ratio (FEV₁/FVC) < 0.70. Small airways dysfunction was defined by ≥2 reduced mid-expiratory flow parameters (<60% predicted). Flow–volume curve morphology was assessed qualitatively. Results: Pre-bronchodilator airflow limitation was observed in 45.2% of participants, predominantly mild. Small-airway dysfunction was present in 52%, and an abnormal flow–volume curve morphology in 67.5%. Notably, functional abnormalities were frequently observed despite preserved FEV₁. Symptom burden was low, with only 7.7% of participants reporting clinically significant symptoms. Functional impairments often overlapped and were common in minimally symptomatic individuals. Conclusions: In a lung cancer screening (LCS) cohort with CT-detected emphysema, functional abnormalities are frequently observed, including in individuals with preserved FEV₁ and minimal symptoms. Spirometry provides additional physiological insight beyond structural imaging; however, these findings are descriptive and should not be interpreted as diagnostic of COPD. Further studies are needed to determine their clinical relevance. Full article

(This article belongs to the Special Issue Integrative Insights into Biology, Diagnosis and Treatment of Pulmonary Diseases)

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13 pages, 1642 KB

Open AccessArticle

Ultrasound-Assisted Wound Debridement for Diabetic Foot Ulcers: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

by Shasha Mei, Hua Chen and Jiezhi Dai

Biomedicines 2026, 14(4), 846; https://doi.org/10.3390/biomedicines14040846 - 8 Apr 2026

Abstract

Background: Diabetic foot ulcers (DFUs) represent a severe and costly complication of diabetes mellitus. This meta-analysis aims to compare the efficacy of ultrasound-assisted wound debridement (UAWD) and conventional debridement in promoting wound healing in patients with DFUs. Methods: A systematic literature search was [...] Read more.

Background: Diabetic foot ulcers (DFUs) represent a severe and costly complication of diabetes mellitus. This meta-analysis aims to compare the efficacy of ultrasound-assisted wound debridement (UAWD) and conventional debridement in promoting wound healing in patients with DFUs. Methods: A systematic literature search was conducted using PubMed, EMBASE, BIOSIS, Web of Science, and the Cochrane Library from inception to 31 October 2025. Randomized controlled trials (RCTs) that compared UAWD with a placebo or standard wound care in patients with DFUs were included. Primary outcomes were the healing rate, time to complete healing, and reduction in wound area. Results were expressed as odds ratios (ORs) or mean differences (MDs) with 95% confidence intervals (CIs). This study was registered on the PROSPERO platform (CRD420251229633). Results: Ten RCTs that involved 386 patients were included. The meta-analysis showed that the treatment group had a significantly higher complete wound healing rate compared with the control group (OR: 2.92; 95% CI: 1.82 to 4.70; p = 0.75; I² = 0%). The rate of wound area reduction was also significantly greater in the treatment group (MD: 21.29%; 95% CI: 3.03 to 39.56; p = 0.003; I² = 75%). Furthermore, the time to complete healing was significantly shorter in the treatment group (MD: −4.84 weeks; 95% CI: −8.65 to −1.03; I² = 61%, p = 0.05). Conclusions: UAWD appears to be more effective than conventional debridement alone in improving healing rates and accelerating wound closure in diabetic foot ulcers. However, safety data were inadequately reported across most included studies, with adverse events poorly characterized. Future large-scale RCTs should prioritize rigorous adverse event reporting to establish both the efficacy and safety profile of this intervention. Full article

(This article belongs to the Special Issue Diabetes: Comorbidities, Therapeutics and Insights (3rd Edition))

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12 pages, 571 KB

Open AccessArticle

Effect of Roxadustat and Erythropoietin on Glycated Hemoglobin of Non-Dialysis Type 2 Diabetic Nephropathy Anemia Patients

by Zhouxia Xiang, Wenqian Wei, Shunian Guo, Hanyu Meng and Shu Rong

Biomedicines 2026, 14(4), 845; https://doi.org/10.3390/biomedicines14040845 - 8 Apr 2026

Abstract

Objectives: To investigate the effects of Roxadustat and recombinant human erythropoietin (rHuEPO) on glycemic control and glycated hemoglobin (HbA1c) in non-dialysis type 2 diabetic kidney disease (DKD) patients with anemia. Methods: This retrospective study enrolled 449 patients, who were divided into [...] Read more.

Objectives: To investigate the effects of Roxadustat and recombinant human erythropoietin (rHuEPO) on glycemic control and glycated hemoglobin (HbA1c) in non-dialysis type 2 diabetic kidney disease (DKD) patients with anemia. Methods: This retrospective study enrolled 449 patients, who were divided into three groups—the rHuEPO group (n = 252), the Roxadustat group (n = 102), and the switch group (n = 95)—in which patients were converted from rHuEPO to Roxadustat. All treatments lasted for more than three months. Changes in HbA1c and other indicators within groups as well as differences among groups were evaluated. Results: In the rHuEPO group, HbA1c levels decreased from 7.08 ± 1.19 to 6.41 ± 0.60 (p < 0.001), and they returned to baseline levels by 6–12 months (p > 0.05). In the Roxadustat group, HbA1c fluctuated but none of the differences reached statistical significance (p > 0.05). In the switch group, HbA1c decreased during rHuEPO treatment (p < 0.05) and returned to baseline after switching to Roxadustat (p > 0.05). No significant changes in blood glucose levels were observed in any group after treatment (p > 0.05). Multivariate linear regression analysis showed that changes in iron metabolism parameters, erythrocyte parameters, inflammatory markers, and glucose-lowering or lipid-lowering regimens had no significant effect on the change in HbA1c in the Roxadustat group (F = 0.834, p = 0.620), while the multivariate model of rHuEPO group also lacked statistical significance (F = 1.142, p = 0.170). After treatment, all three groups showed improvements in anemia, iron metabolism, renal function, inflammatory markers, and lipid profiles compared with baseline (p < 0.05). Additionally, further improvements in these parameters were observed after the transition from rHuEPO to Roxadustat (p < 0.05). Compared with rHuEPO group, the Roxadustat group exhibited significantly greater increases in hemoglobin, red blood cell count, total iron-binding capacity, transferrin, and serum iron (p < 0.05). Conclusions: In non-dialysis DKD patients with anemia, rHuEPO can significantly decrease HbA1c values, while Roxadustat does not. Roxadustat offers advantages over rHuEPO in terms of efficacy and assessment of glycemic control. Full article

(This article belongs to the Special Issue Innovations in Kidney Disease: From Pathogenesis to Therapy)

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17 pages, 1073 KB

Open AccessReview

Cannabinoids in Motor Control: From Receptor Distribution to Motor Disorders

by Dan Faganeli and Metoda Lipnik-Stangelj

Biomedicines 2026, 14(4), 844; https://doi.org/10.3390/biomedicines14040844 - 8 Apr 2026

Abstract

Cannabinoid receptors occupy strategic control nodes within motor circuitry, making them potential targets for modulating different motor manifestations. They are positioned both within basal ganglia circuits that regulate movement and within spinal circuits that control skeletal muscle tone. Consequently, cannabinoids have been studied [...] Read more.

Cannabinoid receptors occupy strategic control nodes within motor circuitry, making them potential targets for modulating different motor manifestations. They are positioned both within basal ganglia circuits that regulate movement and within spinal circuits that control skeletal muscle tone. Consequently, cannabinoids have been studied across diverse motor disorders, most notably in movement disorders and tone disorders, particularly those resulting in spasticity. Because motor control spans multiple anatomically and functionally distinct levels, relating cannabinoid signaling to effects on motor function is not straightforward. Limited understanding of cannabinoid receptor distribution has led to cannabinoids being tested even in disorders where receptor localization would predict little or no benefit. Mapping receptor distribution within individual motor circuits and integrating them with their pharmacological effects can help anticipate how cannabinoid signaling shapes motor output. Combined with characteristic motor manifestations, one can identify motor disorders in which cannabinoids may have therapeutic value. In this review, we integrate existing evidence to place cannabinoid receptors within key motor pathways, ranging from basal ganglia circuits controlling movement to peripheral mechanisms governing muscle tone. We consider both cannabinoid 1 receptor (CB₁R) and cannabinoid 2 receptor (CB₂R), with CB₂R gaining attention only recently for its potential relevance within the central nervous system. Building on this framework, we infer how cannabinoids acting at these sites may modulate motor control, and consequently, influence motor manifestations across major motor disorders. Finally, we examine how these distribution-based expectations align with available clinical observations. Full article

(This article belongs to the Special Issue Cannabinoids in Therapeutics: Mechanisms, Signaling Pathways and Personalized Treatment Strategies)

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39 pages, 1660 KB

Open AccessReview

Natural Polymers in Tissue Engineering and Regeneration: Material–Cell Mechanotransduction, Biofabrication Strategies, and Clinical Translation

by Gabriela Calin, Mihnea Costescu, Marcela Nour, Camer Salim, Nicu Ovidiu Lungu, Alina Stefanache, Roman Rusnac, Elena Costescu, Mihai Cozmin, Petruta Iuliana Moraru, Alina Mitocaru, Tatiana Iov and Letiția Doina Duceac

Biomedicines 2026, 14(4), 843; https://doi.org/10.3390/biomedicines14040843 - 8 Apr 2026

Abstract

Fractures are becoming a bigger and bigger global health problem, with an estimated 178 million new cases each year and 455 million people living with disabilities caused by fractures. Donor site morbidity, the risk of immune rejection, and limited functional integration all make [...] Read more.

Fractures are becoming a bigger and bigger global health problem, with an estimated 178 million new cases each year and 455 million people living with disabilities caused by fractures. Donor site morbidity, the risk of immune rejection, and limited functional integration all make current grafting techniques less effective. Biomaterials that come from nature, like collagen, gelatin, chitosan, alginate, hyaluronic acid (HA), and silk fibroin, have become promising scaffolds because they are bioactive, mimic the extracellular matrix (ECM), and can be broken down by enzymes. Crosslinking and composite reinforcement can greatly change how well they work. For example, collagen scaffolds that are highly crosslinked with glutaraldehyde keep up to 51.9% of their tensile strength after being exposed to enzymes, while non-crosslinked scaffolds only keep 12% of their strength. Chitosan–hydroxyapatite matrices, on the other hand, can reach compressive strengths of 2–12 MPa, which is close to the strength of cancellous bone. Additive manufacturing and 4D printing allow for precise control of structures and the ability to change their shape over time, which helps with vascularization and mechanical adaptation. Injectable and in situ-forming hydrogels show clinically important results, such as filling 85% of osteochondral defects in rabbits, improving left ventricular ejection fraction by up to 9% in large-animal cardiac models, and speeding up healing by 25–40% in chronic wounds. Even with these improvements, it is still hard to get batch consistency, a standardized way to test mechanical properties, and production that meets GMP (Good Manufacturing Practices) standards and can be scaled up. Full article

(This article belongs to the Special Issue Bioengineering and Translational Research for Bone and Joint Disorders)

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21 pages, 1284 KB

Open AccessArticle

Disentangling Uric Acid and Renal Pathways in SGLT2 Inhibitor Effects After Acute Myocardial Infarction: A Retrospective Mediation Analysis

by Ioana Maria Suciu, Călin Muntean, Laura Gaiță, Teodora Mateoc-Sîrb, Daliborca Cristina Vlad, Bogdan Timar and Dan Gaiță

Biomedicines 2026, 14(4), 842; https://doi.org/10.3390/biomedicines14040842 - 7 Apr 2026

Abstract

Background/Objectives: Sodium–glucose cotransporter-2 (SGLT2) inhibitors have demonstrated cardiovascular benefits beyond glycemic control, yet the specific biological pathways potentially linking SGLT2 inhibitor exposure to cardiovascular outcomes after acute myocardial infarction (AMI) remain incompletely characterized. Two biologically plausible pathways, serum uric acid (SUA) reduction and [...] Read more.

Background/Objectives: Sodium–glucose cotransporter-2 (SGLT2) inhibitors have demonstrated cardiovascular benefits beyond glycemic control, yet the specific biological pathways potentially linking SGLT2 inhibitor exposure to cardiovascular outcomes after acute myocardial infarction (AMI) remain incompletely characterized. Two biologically plausible pathways, serum uric acid (SUA) reduction and renal functional preservation, have been proposed, but not directly compared in a unified analytical framework. This study aimed to explore whether associations between SGLT2 inhibitor exposure and recurrent post-AMI outcomes may be more strongly linked to SUA reduction and to renal functional changes, using a hypothesis-generating causal mediation analysis. Methods: This retrospective observational cohort study included 142 consecutive patients hospitalized for AMI who underwent percutaneous coronary intervention (PCI) during the index hospitalization, reflecting standard-of-care management for AMI in this tertiary center. Patients were categorized by SGLT2 inhibitor exposure (n = 57) vs. controls (n = 85). Both diabetic (47.2%) and non-diabetic (52.8%) patients were included. The primary endpoint was change in SUA (ΔUA); the secondary endpoint was myocardial infarction (MI) recurrence. Causal mediation analysis with nonparametric bootstrap simulation tested both mechanistic pathways. Results: SGLT2 inhibitor therapy was associated with significant SUA reduction (ΔUA = −0.99 mg/dL vs. +0.56 mg/dL in controls; p < 0.001), consistent across diabetic and non-diabetic subgroups and independent of AMI recurrence. Each 1 mg/dL decrease in SUA was associated with lower odds of recurrent MI in the initial model (β = −0.25; p = 0.041). However, after incorporation of renal functional change, the uric acid-mediated pathway lost significance (ACME p = 0.462), whereas the renal-mediated pathway remained significant (ACME p = 0.038). Serum creatinine change emerged as the strongest independent predictor of MI recurrence (β = 2.22; p = 0.015). Conclusions: The findings are more consistent with a renal-mediated pathway than with an independent uric acid-mediated pathway in explaining the observed associations between SGLT2 inhibitor exposure and recurrent post-AMI outcomes. These hypothesis-generating results from a retrospective design warrant prospective validation. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: From Pathophysiology to Novel Therapeutic Approaches, 2nd Edition)

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26 pages, 1047 KB

Open AccessReview

Management Strategies for Congestive Heart Failure in Chronic Kidney Disease: Narrative Review

by Pamela Soto-Santillan, Andres Jacobo-Ruvalcaba, Michael Eduard Wasung-de Lay and Oscar Orihuela-Rodriguez

Biomedicines 2026, 14(4), 841; https://doi.org/10.3390/biomedicines14040841 - 7 Apr 2026

Abstract

Heart failure (HF) affects approximately 64 million people globally. HF often coexists with chronic kidney disease. HF may affect the heart during diastolic filling, systolic ejection, or both. Conventionally, HF is categorized by left ventricular ejection fraction (LVEF). One of the leading causes [...] Read more.

Heart failure (HF) affects approximately 64 million people globally. HF often coexists with chronic kidney disease. HF may affect the heart during diastolic filling, systolic ejection, or both. Conventionally, HF is categorized by left ventricular ejection fraction (LVEF). One of the leading causes of death in chronic kidney disease (CKD) patients of cardiovascular origin increase hospitalizations and worsen quality of life by causing fluid and electrolyte overload. As kidney function declines, increases risk of development of HF in CKD, with a negative impact and worse prognosis in these patients. This narrative review provides healthcare professionals—including nephrologists, car-diologists, internists, and general practitioners—with evidence-based strategies to iden-tify and manage this complex comorbidity, aiming to reduce hospitalization and mor-tality in CKD patients. By synthesizing recent findings on risk stratification, diagnostic modalities, and individualized treatment—particularly for patients undergoing renal replacement therapy—clinicians can enhance volume management and optimize patient outcomes. Considering the increasing prevalence of chronic kidney disease and associated cardiovascular comorbidities, this review addresses pathogenic mechanisms, diagnostic approaches, pharmacological treatments, and dialytic therapy modifications. Full article

(This article belongs to the Special Issue Advances in the Pathogenesis and Treatment of Heart Failure and Cardiomyopathy)

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24 pages, 648 KB

Open AccessArticle

Intuitive Risk Equation for Post-Transplant Bloodstream Infection Prediction: A Symbolic Regression Approach

by Sungsu Oh, Jeogin Jang, Yunseong Ko, Hyunsu Lee and Seungjin Lim

Biomedicines 2026, 14(4), 840; https://doi.org/10.3390/biomedicines14040840 - 7 Apr 2026

Abstract

Background: Liver transplant recipients are highly susceptible to infectious complications due to surgical invasiveness and immunosuppressive therapy, and post-transplant bloodstream infection is associated with substantial morbidity and mortality. Although several prediction models for bloodstream infection have been proposed, most focus on emergency department [...] Read more.

Background: Liver transplant recipients are highly susceptible to infectious complications due to surgical invasiveness and immunosuppressive therapy, and post-transplant bloodstream infection is associated with substantial morbidity and mortality. Although several prediction models for bloodstream infection have been proposed, most focus on emergency department or general ward populations and rely on black-box approaches. This limits their applicability and clinical interpretability in liver transplant settings. Therefore, this study aimed to develop predictive models for post-transplant bloodstream infection using preoperative and perioperative clinical data and to derive an interpretable risk equation through symbolic regression. Methods: We conducted a retrospective observational study including 245 adult liver transplant recipients treated at a single tertiary center. Clinical and laboratory variables were extracted from electronic medical records and analyzed using standard statistical methods. For prediction tasks, multiple conventional machine learning models were developed and compared with a symbolic regression-based model. Predictive performance and model interpretability were evaluated using discrimination metrics and Shapley Additive Explanations. Results: Post-transplant bloodstream infection occurred in 82 patients (33.4%). In the test set, conventional machine learning models showed modest discriminative performance (area under the curve, 0.53–0.64). The symbolic regression model achieved comparable discrimination (area under the curve, 0.63) while providing transparent, threshold-based risk equations. While conventional models primarily relied on laboratory variables, symbolic regression additionally identified perioperative clinical factors and viral serologic markers as important predictors. Discussion: Although overall predictive performance was modest, symbolic regression highlighted viral serologic markers as potential indicators of immunologic vulnerability, extending beyond standard laboratory predictors. Conclusions: This interpretability-focused approach may inform future risk stratification models incorporating richer perioperative data. Full article

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

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17 pages, 977 KB

Open AccessArticle

Prognostic Value of International Normalized Ratio and Thrombocytopenia in Early Risk Stratification of Septic Patients

by Sofía Tejada, Andrés Giglio, Maria Aranda, Antonia Socias, Alberto del Castillo, Joana Mena, Sara Franco, Maria Ortega, Yasmina Nieto and Marcio Borges-Sa

Biomedicines 2026, 14(4), 839; https://doi.org/10.3390/biomedicines14040839 - 7 Apr 2026

Abstract

Background/Objective: Coagulopathy is a hallmark of sepsis, associated with poor outcomes. Although platelet count has commonly been used for risk stratification, its prognostic value has remained limited. This study compared the ability of the International Normalized Ratio (INR) and platelet count to [...] Read more.

Background/Objective: Coagulopathy is a hallmark of sepsis, associated with poor outcomes. Although platelet count has commonly been used for risk stratification, its prognostic value has remained limited. This study compared the ability of the International Normalized Ratio (INR) and platelet count to predict in-hospital mortality in septic patients; Methods: A retrospective study was conducted including adult patients diagnosed with sepsis and admitted to Hospital Universitario Son Llàtzer (Spain) between 2006 and 2022. The INR and platelet count at diagnosis were categorized using clinical thresholds. The primary outcome was in-hospital mortality. Results: Among 6433 patients (60.6% females), mortality was 8.8%. Mortality increased from 6.3% (INR ≤ 1.2) to 20.2% (INR 2.0–3.0), slightly decreasing at INR > 3.0 (10.8%). The platelet count showed a weaker association, with the highest mortality observed at <50 × 10⁹/L (24.6%). The combined markers identified a high-risk subgroup with 50% mortality (INR > 3.0 and platelet count < 50 × 10⁹/L). In the full cohort, multivariable analysis confirmed the INR as an independent predictor of mortality (OR 2.183, p = 0.0002), whereas the platelet count was not significant. The model including the INR achieved an AUC 0.746, while adding the platelet count did not improve performance. Conclusions: the INR at diagnosis was a strong and independent predictor of in-hospital mortality, outperforming the platelet count. These findings could support the consideration of the INR in early risk stratification frameworks and highlight the need for prospective validation before integration into sepsis guidelines. Full article

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

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20 pages, 1249 KB

Open AccessReview

Microbial Shifts After Sleeve Gastrectomy: The Gut–Oral Axis, Periodontal Outcomes, and Competing Oral Risks

by Felicia Gabriela Beresescu, Razvan Marius Ion, Adriana-Stela Crisan and Andrea Bors

Biomedicines 2026, 14(4), 838; https://doi.org/10.3390/biomedicines14040838 - 7 Apr 2026

Abstract

Background: Severe obesity is associated with chronic low-grade inflammation, dysglycemia, and higher periodontitis risk. Sleeve gastrectomy (SG) is now a dominant bariatric procedure and reliably improves weight and metabolic status yet reported oral and periodontal trajectories after surgery remain heterogeneous. Objective: [...] Read more.

Background: Severe obesity is associated with chronic low-grade inflammation, dysglycemia, and higher periodontitis risk. Sleeve gastrectomy (SG) is now a dominant bariatric procedure and reliably improves weight and metabolic status yet reported oral and periodontal trajectories after surgery remain heterogeneous. Objective: To synthesize SG-centered evidence on periodontal outcomes, oral and gut microbiome remodeling, and mechanistic pathways that may link postoperative physiology to the gut–oral axis. Methods: We conducted a structured narrative review guided by SANRA principles using targeted searches of PubMed/MEDLINE, Web of Science, Scopus, and Embase, complemented by citation chaining of key reviews and mechanistic anchor papers; evidence was organized into clinical, oral microbiome, gut microbiome, and mechanistic gut–oral axis streams and interpreted with a pragmatic evidence hierarchy. Results: Small prospective SG cohorts suggest bleeding on probing (BOP), gingival indices, and sometimes probing depth (PD) may improve in some patients, particularly alongside weight loss, improved glycemic control, and lower systemic inflammatory burden, whereas clinical attachment level (CAL) and longer-term structural trajectories remain mixed; mixed-procedure syntheses also report early deterioration in some settings. Oral microbiome findings after bariatric surgery are site- and time-dependent, and salivary signals do not necessarily mirror subgingival plaque, whereas gut microbiome remodeling and bile acid signaling changes are more consistently reported and provide plausible but indirect mediator candidates. At the same time, reflux, vomiting, salivary changes, diet patterning, medications, and periodontal care can modify or counteract potential periodontal benefits and may increase competing risks such as caries or erosive tooth wear. Conclusions: The SG–gut–oral axis-periodontal pathway is a biologically plausible working hypothesis rather than a proven causal pathway in humans. The present evidence for any periodontal benefit relies mainly on small observational cohorts and is most credibly demonstrated for inflammatory, not structural, endpoints. Full article

(This article belongs to the Special Issue Advances in Periodontal Disease and Systemic Disease)

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16 pages, 742 KB

Open AccessReview

The Role of Cytokines in Vascular Endothelial Glycocalyx Integrity and Impairment Following Open-Heart Surgery

by Lara Batičić, Božena Ćurko-Cofek, Gordana Taleska Štupica, Matej Jenko, Marko Zdravković, Lea Cofek, Antea Krsek, Tanja Batinac, Danijel Knežević, Marino Damić, Mia Šestan, Aleksandra Ljubačev, Maja Šoštarič and Vlatka Sotošek

Biomedicines 2026, 14(4), 837; https://doi.org/10.3390/biomedicines14040837 - 7 Apr 2026

Abstract

Open-heart surgery with cardiopulmonary bypass (CPB) is a high-risk procedure with significant morbidity and mortality. CPB, tissue injury, blood loss, endotoxemia and ischemia–reperfusion injury induce a pronounced systemic inflammatory response, leading to endothelial glycocalyx (EG) damage and vascular endothelial dysfunction. Consequently, immune cells, [...] Read more.

Open-heart surgery with cardiopulmonary bypass (CPB) is a high-risk procedure with significant morbidity and mortality. CPB, tissue injury, blood loss, endotoxemia and ischemia–reperfusion injury induce a pronounced systemic inflammatory response, leading to endothelial glycocalyx (EG) damage and vascular endothelial dysfunction. Consequently, immune cells, reactive oxygen species, and enzymes gain free access to vascular endothelial cells, resulting in their dysfunction and enhancing inflammation, vascular permeability, and microvascular impairment. EG degradation is most commonly assessed by measuring the circulating levels of its degradation products. Additionally, CPB triggers an early inflammatory response that is characterized by the secretion of interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor alpha, and IL-18, which play roles in initiating the process of EG injury. EG damage is further propagated by the sustained release of cytokines, inhibiting the regeneration of the glycocalyx layer. Heparanase and matrix metalloproteinases are enzymatic pathways involved in cytokine-mediated EG degradation after cardiac surgery, and the balance between the pro- and anti-inflammatory cytokines determines the magnitude and duration of the inflammatory response and EG impairment, which correlates with adverse clinical outcomes, including myocardial dysfunction, acute lung and kidney injury, neurological complications, and prolonged need for intensive care. Thus, identifying patients with an exaggerated cytokine response could potentially provide more personalized therapy based on the circulating biomarkers of EG shedding, and cytokine-directed preservation of EG represents a promising therapeutic strategy in vascular dysfunction prevention during and after open-heart surgery. In this review, we summarize the current knowledge on cytokine-mediated EG impairment following open-heart surgery with CPB. Full article

(This article belongs to the Special Issue The Role of Cytokines in Health and Disease: 3rd Edition)

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15 pages, 940 KB

Open AccessReview

Alpha-Ketoglutarate: A Metabolic Regulator of Cellular Homeostasis and Pathophysiology

by Vinay Devulapalli, Akash Sathiyamurthi, Surabhi Gautam and Pallavi Bhattaram

Biomedicines 2026, 14(4), 836; https://doi.org/10.3390/biomedicines14040836 - 7 Apr 2026

Abstract

Alpha-Ketoglutarate (AKG), a central intermediate of the tricarboxylic acid cycle, is a crucial metabolic and signaling molecule that connects mitochondrial function with cellular homeostasis, immunological modulation, epigenetic remodeling, and lifespan. While mitochondrial AKG maintains energy metabolism, the nuclear AKG pool influences chromatin remodeling [...] Read more.

Alpha-Ketoglutarate (AKG), a central intermediate of the tricarboxylic acid cycle, is a crucial metabolic and signaling molecule that connects mitochondrial function with cellular homeostasis, immunological modulation, epigenetic remodeling, and lifespan. While mitochondrial AKG maintains energy metabolism, the nuclear AKG pool influences chromatin remodeling through DNA and histone modifications, which together control hypoxia responses and shape gene expression patterns. This dual role demonstrates AKG’s significance in mediating metabolic state, gene expression, and long-term cellular adaptability. AKG modulates immunological responses, reduces reactive oxygen species (ROS), promotes the polarization of anti-inflammatory macrophages, and suppresses nuclear factor kappa B (NF-κB) activation, thereby reducing chronic inflammatory processes. AKG restricts pro-inflammatory cytokine production, increases extracellular matrix synthesis, and reduces cartilage degradation in arthritic models, suggesting potential therapeutic benefits in autoimmune diseases and joint degeneration. Additionally, AKG affects lifespan in several model organisms, where supplementation enhances metabolic resilience, lowers age-related inflammation, modifies mTOR signaling, and preserves youthful epigenetic profiles. Additionally, because endogenous AKG levels decrease with age, oral supplementation of AKG, especially with calcium and arginine, has drawn attention to its potential benefits in longevity and metabolic health. Thus, AKG is versatile and has encouraging therapeutic promise for cancer, aging, and inflammatory illnesses. However, a lack of human clinical evidence prompts further research to determine ideal dosage, tissue selectivity, and long-term safety. The goal of this review is to critically examine the current mechanistic knowledge related to AKG biosynthesis and breakdown and its future implications in maintaining cellular homeostasis and controlling chronic inflammation. Full article

(This article belongs to the Special Issue Drug Discovery of Novel Anti-Inflammatory Compounds, Their Molecular Targets, and Translational Advancements)

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50 pages, 2248 KB

Open AccessReview

Research Progress of PROTACs in Breast Cancer: Subtype-Oriented Target Landscape, Clinical Stratification Evidence, and Engineering Strategies for Translation

by Senyang Guo, Jianhua Liu, Hongmei Zheng and Xinhong Wu

Biomedicines 2026, 14(4), 835; https://doi.org/10.3390/biomedicines14040835 - 6 Apr 2026

Abstract

Molecular subtype–guided therapy for breast cancer (BC) remains limited in a subset of patients by suboptimal efficacy, acquired resistance, and the presence of “undruggable” targets. Proteolysis-targeting chimeras (PROTACs) represent a targeted protein degradation (TPD) strategy that differs fundamentally from conventional occupancy-driven inhibition. By [...] Read more.

Molecular subtype–guided therapy for breast cancer (BC) remains limited in a subset of patients by suboptimal efficacy, acquired resistance, and the presence of “undruggable” targets. Proteolysis-targeting chimeras (PROTACs) represent a targeted protein degradation (TPD) strategy that differs fundamentally from conventional occupancy-driven inhibition. By inducing ubiquitination of a protein of interest and subsequent proteasomal degradation, PROTACs can directly reduce pathogenic protein abundance and potentially abrogate non-catalytic or scaffolding functions, thereby enabling more durable pathway suppression in selected resistance contexts. This review comprehensively summarizes the mechanisms of action, key molecular design elements, and the developmental landscape of PROTACs, and maps target selection and research progress across BC molecular subtypes. In hormone receptor–positive/HER2-negative BC, clinical translation is most advanced for estrogen receptor alpha-directed PROTACs; Phase III evidence indicates biomarker-dependent efficacy, with clearer benefit signals in resistant subgroups such as estrogen receptor 1 mutations, suggesting that the net clinical benefit of TPD is more likely to be realized through precision stratification. In contrast, in solid-tumor settings, including human epidermal growth factor receptor 2 (HER2)-positive BC and triple-negative breast cancer, PROTAC translation is more frequently constrained by an “exposure–selectivity–therapeutic window” trade-off driven by physicochemical liabilities, insufficient tumor penetration, and broad target expression. Accordingly, engineering strategies—such as antibody/aptamer-mediated targeted delivery, stimulus-responsive prodrugs, nanocarriers, and local administration—are emerging as decisive approaches to enable safe and effective clinical implementation. Looking forward, further progress of PROTACs in BC will depend on expanding the spectrum of E3 ubiquitin ligases and recruitment modalities, establishing predictable and dynamically monitorable biomarker systems, optimizing rational combination/sequencing regimens with exposure- and schedule-guided dosing, and advancing scalable manufacturing and quality control capabilities, thereby translating mechanistic advantages of TPD into verifiable precision-therapy applications. Full article

(This article belongs to the Special Issue Innovative Therapeutic Strategies and Molecular Mechanisms in Breast Cancer)

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12 pages, 343 KB

Open AccessArticle

Therapeutic Efficacy of Different Bladder Monotherapies Versus Multimodal Therapy in Patients with Interstitial Cystitis/Bladder Pain Syndrome

by Wan-Ru Yu, Jia-Fong Jhang, Yuan-Hong Jiang and Hann-Chorng Kuo

Biomedicines 2026, 14(4), 834; https://doi.org/10.3390/biomedicines14040834 - 6 Apr 2026

Abstract

Purpose: This study compared the therapeutic efficacy of different bladder monotherapies and multimodal therapy in patients with interstitial cystitis/bladder pain syndrome (IC/BPS). Materials and methods: In total, 190 patients with a confirmed diagnosis of IC/BPS were treated with different bladder therapies. [...] Read more.

Purpose: This study compared the therapeutic efficacy of different bladder monotherapies and multimodal therapy in patients with interstitial cystitis/bladder pain syndrome (IC/BPS). Materials and methods: In total, 190 patients with a confirmed diagnosis of IC/BPS were treated with different bladder therapies. The bladder monotherapies included intravesical platelet-rich plasma (PRP) injection (n = 60), intravesical botulinum toxin A (BoNT-A) injection (n = 33), intravesical hyaluronic acid (HA) instillation (n = 36), and low-energy shock wave (LESW) bladder therapy (n = 61). Multimodal therapy (MMT) was provided to patients who had unsuccessful initial bladder treatment targeting chronic inflammation, urothelial dysfunction, bladder pain, pelvic floor muscle pain, psychological stress, and lower urinary tract dysfunction. The treatment outcome was assessed using self-reported Global Response Assessment scores at 3 months and during the follow-up time points after bladder treatment. Results: Thirty-one patients received MMT. The 3-month success rates of bladder therapy were 55.0% for PRP injection, 57.6% for BoNT-A injection, 50.0% for HA instillation, 46.7% for LESW bladder therapy, and 58.1% for MMT. The success rates of bladder monotherapy decreased after 6 months. However, the success rate of MMT increased at 9 (67.7%) and 12 (73.1%) months. Patients treated with MMT exhibited improvement in glomerulation grade after cystoscopic hydrodistention. Only patients with successful treatment outcomes after MMT had improvement in bladder pain severity and pelvic floor muscle pain parameters. Conclusions: Bladder monotherapy such as PRP injection, BoNT-A injection, HA instillation, and LESW bladder therapy had successful treatment outcomes in patients with IC/BPS. In patients who had unsuccessful initial bladder therapy, the 3-month success rate of MMT was 58.1% and sustained improvement with time, particularly in the improvement of bladder pain and PFM pain severity. Full article

(This article belongs to the Topic Clinical, Translational, and Basic Research and Novel Therapy on Functional Bladder Diseases and Lower Urinary Tract Dysfunctions)

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