Biologics

Background/Objectives: The therapeutic arsenal for axial spondyloarthritis (axSpA) now includes multiple biologic and targeted synthetic DMARDs (b/tsDMARDs). Following the failure of an advanced therapy, clinicians may either cycle (switch to another drug with the same mechanism of action) or swap (switch to a drug with a different mechanism). The optimal strategy remains unclear. This study aimed to compare the real-world effectiveness of cycling versus swapping in axSpA patients. Methods: This mono-centric, retrospective observational study included axSpA patients who failed ≥1 line of b/tsDMARD therapy. Subsequent treatment courses were classified as cycling (CG) or swapping (SG). Drug retention rates were compared using Kaplan–Meier analysis. A Cox proportional hazards model identified factors associated with treatment persistence. Results: We analyzed 156 patients (59 radiographic, 97 non-radiographic), corresponding to 343 treatment courses (CG: 213; SG: 130). Retention rates at 1, 2, and 3 years were 62.7%, 49.3%, and 39.2% (CG) versus 69.8%, 47.8%, and 31.8% (SG) (HR: 1.13, 95% CI: 0.83–1.53; p = 0.442). In the multivariable model, only a more recent prescription year was associated with higher discontinuation risk (HR: 1.08 per year, 95% CI: 1.03–1.12; p < 0.001). Conclusions: In this real-world cohort, cycling and swapping strategies demonstrated comparable treatment persistence over three years following advanced therapy failure in axSpA. The choice of subsequent therapy should be individualized, as no strategy proved superior. Full article

Objectives: This study aimed to elucidate the multi-target therapeutic mechanisms of Camellia sinensis phytochemicals in periodontitis using an integrative multi-scale molecular modeling strategy. Methods: An integrated in silico strategy was employed, incorporating network-based pharmacological analysis, protein interaction network evaluation, molecular docking assessment, density functional theory (DFT) computations, molecular dynamics (MD) trajectory analysis, MM/PBSA-derived binding energy estimation, and residue-level energetic contribution profiling. Overlapping targets between C. sinensis and periodontitis-associated genes were identified, followed by topological screening to determine crucial hub proteins. The most promising target was subjected to detailed structural and energetic evaluation. Results: Intersection analysis identified 23 common targets, with AKT1, myeloperoxidase (MPO), MMP2, MMP3, MMP9, STAT1, IL2, BCL2, ESR1, and SERPINE1 emerging as central hubs. Functional enrichment highlighted AGE–RAGE and JAK–STAT signaling pathways and extracellular matrix remodeling processes. Docking revealed MPO as the most favorable core target. Gallate-containing catechins, particularly (−)-gallocatechin gallate (−9.63 kcal/mol) and gallocatechin 3-O-gallate (−9.52 kcal/mol), exhibited more favorable binding affinities than the standard inhibitor 4-ABAH (−6.02 kcal/mol). DFT analysis demonstrated moderate HOMO–LUMO gaps (4.31–4.78 eV) and favorable dipole moments supporting electronic stability and reactivity. MD simulations confirmed stable complex formation over 100 ns, with persistent hydrogen bonding and consistent ligand retention. MM/PBSA calculations further validated a favorable binding of (−)-gallocatechin gallate (−27.66 ± 7.53 kcal/mol) and gallocatechin 3-O-gallate (−26.09 ± 8.96 kcal/mol), comparable to or exceeding 4-ABAH (−25.88 ± 4.44 kcal/mol). Conclusions: C. sinensis phytochemicals, particularly gallate-containing catechins, exhibit stable, energetically favorable interactions with MPO, supporting their potential as competitive inhibitors that modulate oxidative stress and inflammatory pathways in periodontitis. Full article

Atopic dermatitis (AD) is a common inflammatory skin disorder which presents with recurrent eczematous lesions and itching. Its pathophysiology is complex and multifactorial. Alterations in cell-mediated immune responses, barrier dysfunction, environmental aspects and IgE-mediated hypersensitivity are all involved. This review aims to provide the clinician with an update on the impact that Th2 inflammation can have on growth and osteoimmunology. The potential adverse or protective effects brought on by the many therapies administered in this condition are also considered. Moreover, through this analysis, we aim to show how, by inhibiting the IL-4 and IL-13 signaling pathways—fundamental in the T helper 2 (Th2) immune axis and in AD pathogenesis—dupilumab may exert a protective role on growth and osteoimmunology in moderate-to-severe AD, particularly in young patients. This focus is essential for the correct, safe management of patients with Th2 inflammation. Full article

Background: Intracavernosal platelet-rich plasma (PRP) is increasingly used for erectile dysfunction (ED), despite the absence of standardized biological characterization and clear dose definitions. This systematic review evaluates the clinical efficacy of PRP in ED while integrating emerging immune-centric mechanistic evidence. Methods: Following PRISMA 2020 guidelines, randomized controlled trials (RCTs) and prospective studies (2020–2025) investigating intracavernosal PRP in adult men with ED were identified across major databases. Validated outcomes included International Index of Erectile Function (IIEF-EF or IIEF-5), Erection Hardness Score (EHS), Sexual Encounter Profile (SEP), and penile Doppler parameters. Preclinical data were narratively integrated to contextualize biological plausibility. Results: Fourteen clinical studies met the inclusion criteria (six RCTs, eight prospective cohorts). Across most studies, PRP produced clinically relevant within-patient improvements, and three RCTs demonstrated minimal clinically important difference (MCID) responder rates compared with placebo. However, other trials showed comparable improvements in placebo arms, underscoring substantial contextual effects. Safety was consistently favourable. Marked heterogeneity in blood volume processed (10–120 mL), injected PRP volume (3–12 mL), preparation systems, and session protocols precluded cross-study comparability. Critically, no study reported platelet dose, leukocyte subsets, peripheral blood mononuclear cell (PBMNC) content, or red blood cell contamination. Preclinical models consistently demonstrate that PRP restores erectile function through angiogenic, neuroprotective, and immunomodulatory mechanisms, including CXCL5-mediated monocyte recruitment and M1-to-M2 macrophage polarization. Conclusions: Intracavernosal PRP shows promising short-term efficacy signals and a favourable short-term safety profile in mild-to-moderate vasculogenic ED, but current evidence is limited by profound biological and methodological heterogeneity. PRP should be reconsidered as an immune-regenerative intervention requiring dose-defined, composition-defined, and mechanistically informed randomized trials. Interpretation of these findings is constrained by the absence of formal risk-of-bias assessment for non-randomized studies, substantial clinical and biological heterogeneity across trials, and the lack of standardized PRP characterization. Full article

Fetal therapy has evolved into a rapidly advancing field with the potential to alter the natural history of many severe congenital and genetic disorders before irreversible injury occurs. Progress in prenatal imaging, molecular diagnostics, and fetal intervention techniques now enables the earlier identification of disease and, in select settings, targeted prenatal treatment. This review synthesizes the current landscape of fetal therapies, spanning established surgical interventions for structural anomalies and emerging biologic and molecular approaches, including enzyme replacement therapy, stem cell-based strategies, gene therapy, and gene editing. The intrauterine environment provides a distinct therapeutic context, with developmental plasticity, immune immaturity, enhanced tissue accessibility, and relatively permissive central nervous system exposure that together define a time-sensitive window for intervention. Preclinical studies and early clinical experience across both structural anomalies and genetic disorders, including lysosomal storage disorders, osteogenesis imperfecta, and spinal muscular atrophy, support the premise that prenatal treatment can preserve organ development and improve pediatric outcomes. However, translation remains constrained by procedural risks, uncertainty regarding long-term safety and durability, ethical and regulatory complexities, and challenges with equitable access, alongside the need for robust comparative evidence versus early postnatal therapy. As the field advances, multidisciplinary collaboration, rigorous trial design with meaningful developmental endpoints, and ethically grounded implementation frameworks will be essential to guide responsible clinical adoption and maximize benefit for children and families. Full article

Background/Objectives: The continuous emergence of immune-evasive SARS-CoV-2 variants underscores the need for adaptable and accessible therapeutics that complement vaccination. Single-domain antibodies (sdAbs) offer advantages in size, stability, and production costs compared to conventional monoclonal antibodies, but their clinical utility is limited by rapid clearance. This study aimed to develop a rabbit-derived sdAb with broad SARS-CoV-2 neutralization capacity and improved pharmacokinetic properties. Methods: A rabbit-derived variable light-chain (VL) sdAb library was constructed and subjected to phage display selection to identify high-affinity binders. Candidate sdAbs were characterized for cross-variant binding and neutralization. The lead sdAb, B3, was fused to the albumin-binding domain (ABD) of the Streptococcus zooepidemicus Zag protein to enhance in vivo half-life. Expression, albumin-binding capacity, and in vitro neutralization were assessed, followed by biodistribution studies in mice. Results: The selected sdAb, B3, showed strong binding and cross-variant neutralization against multiple SARS-CoV-2 lineages, including Delta and Omicron. Fusion to ABD(Zag) preserved neutralization potency, increased expression yields ~5-fold, and enabled cross-species albumin binding. In vivo, B3-ABD(Zag) exhibited markedly extended blood retention, showing a 21.2-fold increase at 24 h post-injection (5.30 vs. 0.25% I.A./g), and reduced renal uptake by 40% compared with unmodified B3. Conclusions: Rabbit-derived VL sdAbs fused to ABD(Zag) provide a promising platform for next-generation SARS-CoV-2 biologics. The enhanced pharmacokinetic profile of B3-ABD(Zag) supports its potential as a scalable therapeutic modality and highlights the broader utility of this approach for future emerging infectious threats. Full article

Background/Objectives: Protein–protein interactions (PPIs) involving oncogenic drivers remain among the most intractable targets in cancer biology due to their dynamic conformations and limited accessibility to conventional small molecules. Although antibodies and inhibitors have achieved clinical success against targets such as PD-1/PD-L1 and MYC, challenges persist related to tissue penetration, intracellular delivery, resistance, and incomplete blockade of key interface hotspots. The objective of this study is to develop an integrated computational framework for systematically designing hotspot-conditioned de novo miniprotein binders to target these interfaces. Methods: We present DesignForge, a computational protein design pipeline that integrates energetic hotspot identification, generative backbone design, sequence optimization, and structural confidence evaluation. The framework combines hotspot mapping using an open force-field-based energetic analysis module with generative backbone sampling using BindCraft, sequence optimization using ProteinMPNN, and structural validation using AlphaFold2. This in silico pipeline was applied to three representative oncogenic interfaces: PD-1/PD-L1, MYC/MAX, and KRAS/RAF. Results: Computationally generated designs exhibited high predicted structural confidence, favorable interface energetics, and consistent engagement of identified hotspot residues across targets. AlphaFold2-Multimer structural modeling indicated that the candidate PD-1 mimetic scaffolds, MYC/MAX interface binders, and KRAS interaction candidates can adopt conformations compatible with the target interfaces. Energetic contact analysis further supported predicted engagement of key hotspot residues. These findings support the computational feasibility of hotspot-conditioned binder generation using a unified design workflow. Conclusions: DesignForge provides a reproducible computational framework for hotspot-guided de novo protein binder design targeting oncogenic protein–protein interfaces. The designs reported here represent computational predictions derived from structural modeling and energetic analysis. Experimental biochemical and cellular validation will be required to determine the functional activity of the proposed binders. Full article

Background: Dextran sodium sulfate (DSS)-induced colitis serves as a preclinical model for studying gut dysbiosis and inflammation relevant to inflammatory bowel disease (IBD) and its long-term complication of colorectal cancer (CRC). Beetroot (Beta vulgaris L.) extract, rich in betalains, polyphenols, and nitrates, exhibits antioxidant and anti-inflammatory properties. This study investigated beetroot extract’s effects on gut microbiota composition and predicted functional pathways in DSS-induced colitis. Methods: Male BALB/c mice were divided into four groups: control (water), DSS-only, beetroot 250 mg/kg + DSS, and beetroot 500 mg/kg + DSS. Beetroot extract was administered orally for 14 days prior to and during DSS exposure. Gut microbial profiles were analyzed using 16S rRNA sequencing, while microbial diversity, community structure, and predicted metabolic functions were evaluated using Shannon, Chao1, PCoA, PERMANOVA, and PICRUSt2 analyses. Results: DSS administration significantly reduced body weight, microbial diversity, and Bacteroidota abundance, while increasing Proteobacteria and Desulfobacterota—a classic colitis-associated dysbiosis signature. Beetroot supplementation restored body weight and microbial balance in a dose-dependent manner, with the 500 mg/kg group showing near-complete normalization of the microbiota. Functional predictions revealed the upregulation of short-chain fatty acid (SCFA) biosynthesis, glutathione metabolism, and amino acid pathways, and suppression of lipopolysaccharide biosynthesis. Identified phytochemicals, including betanin, ferulic acid, and rutin, were associated with antioxidant and prebiotic activities that support microbial restoration. Conclusions: Beetroot extract mitigates DSS-induced gut dysbiosis and inflammation by enhancing microbial diversity, restoring SCFA-associated taxa, and promoting anti-inflammatory and antioxidant pathways. These findings highlight beetroot as a promising natural dietary intervention for colitis and microbiome-associated intestinal disorders. Full article

Background: Cerliponase alfa is an intracerebroventricular (ICV) enzyme replacement therapy (ERT) and the only approved treatment for neuronal ceroid lipofuscinosis type 2 (CLN2) disease. While generally well tolerated, infusion-associated reactions (IARs), including hypersensitivity events and anaphylaxis, remain a recognized safety consideration. Methods: This single-center, retrospective study describes the incidence and management of IARs in pediatric patients with CLN2 receiving long-term ICV cerliponase alfa at Great Ormond Street Hospital, London, United Kingdom. Results: Over a 10-year period (2014–2024), 31 patients received approximately 2705 ICV infusions. Eleven patients experienced at least one IAR. Most reactions were mild and transient, typically consisting of pyrexia, vomiting, or rash, and were managed conservatively with antipyretics and antihistamines. Four patients required steroid intervention following recurrent or more pronounced symptoms, which led to improved infusion tolerance. One patient experienced a single episode of anaphylaxis that required treatment with intramuscular adrenaline and intravenous hydrocortisone. Therapy was continued with a revised pre-medication regime, with no further severe reactions. Conclusions: These findings demonstrate that IARs to ICV cerliponase alfa are typically mild and readily manageable within a multidisciplinary framework. They highlight the importance of structured infusion protocols, vigilant monitoring strategies, and a coordinated management approach to ensure the long-term safety of ERT for children with CLN2 disease. Full article

Background/Objectives: Brucella is a major global One Health threat, causing an estimated 2.1 million human infections and substantial livestock losses annually, with no vaccine currently available for humans, underscoring the urgent need for a safe and effective vaccine. Methods: Employing a reverse vaccinology approach, a novel 175-mer multiepitope vaccine (Mvax) targeting Brucella FrpB was computationally designed in this study, incorporating two B-cell, two MHC class I (MHC-I), and three MHC class II (MHC-II) epitopes selected for their high predicted antigenicity, safety, and IFN-γ-inducing potential. Human β-defensin-3 (hBD3) was fused to the N-terminus as an adjuvant, followed by comprehensive in silico evaluation of the construct. Results: Population coverage analysis predicted 99.59% global MHC class I/II coverage for selected epitopes. In silico analyses predicted that Mvax has high solubility (Protein-SOL score: 0.808), a high antigenicity score (VaxiJen: 1.06), and a negative GRAVY index (−0.881), indicating favorable predicted physicochemical characteristics. iMODS, CABS-Flex 3, and molecular dynamics simulations suggested theoretical stability trends for the modeled vaccine complexes. C-ImmSim immune simulations further predicted elevated Th1 cell populations and associated cytokines (IL-12, IFN-γ, IL-2) following both single and multiple simulated Mvax exposures. Conclusions: The computational analyses described here provide a theoretical modeling basis for an antivirulence multi-epitope vaccine design against human brucellosis, with predicted metrics and simulated immune responses requiring empirical validation. Full article

Interleukin-6 (IL-6) is a multifunctional cytokine with an essential role in immunity, inflammation, and cancer. Produced by immune, stromal and epithelial cells in response to infection or tissue stress, IL-6 regulates immune responses, acute-phase proteins (including serum amyloid A and C-reactive protein), hematopoiesis, and tissue remodeling. These effects are mediated via classical and trans-signaling pathways, which activate key intracellular cascades such as JAK/STAT3, MAPK, and PI3K/AKT. Accumulating evidence implicates dysregulated IL-6 signaling in both oncologic and infectious diseases, where it contributes to disease progression, immune evasion, and therapeutic resistance. This review aims to critically examine the role of IL-6 as a biomarker and therapeutic target in these two major clinical contexts: in cancer, IL-6 levels reflect tumor burden, prognosis, and therapy resistance in both adult and pediatric patients; in infectious diseases, circulating IL-6 may support early diagnosis and risk stratification, particularly in vulnerable pediatric populations. By integrating molecular mechanisms with clinical evidence, this review highlights IL-6 as a unifying biomarker linking inflammation, infection, and malignancy. It also addresses current limitations, including assay variability, lack of standardized reference ranges, especially in children, and challenges in clinical implementation. Full article

Background/Objectives: The rates and predictors of clinical remission, a novel and practical therapeutic goal in severe asthma, have been inconsistently reported across studies. Data on clinical remission in Japanese patients remain limited. The aim of this study was to assess the rate of four-component clinical remission and its predictors in Japanese adult patients with severe asthma. Methods: This retrospective study enrolled adult patients with severe asthma who had initiated biologic therapy at least 12 months prior to inclusion at Nagoya City University Hospital. The primary endpoint was the achievement rate of four-component clinical remission, defined as (1) no maintenance oral corticosteroids (OCS); (2) no exacerbations for 12 months; (3) Asthma Control Test (ACT) score ≥ 20; and (4) forced expiratory volume in one second (FEV₁) ≥ 80% of predicted. The secondary endpoint was to identify factors, including airway structural indices measured using chest computed tomography (CT), associated with clinical remission at 12 months. Results: Among 87 patients with severe asthma, 26 (30%) achieved four-component clinical remission after 12 months of biologic therapy. In univariate analysis, clinical remission was more frequently achieved in patients with chronic rhinosinusitis, higher FEV₁ (% predicted), higher blood eosinophil counts, higher ACT scores, fewer exacerbations in the previous year, higher Lund–Mackay scores, and smaller airway wall thickness and luminal areas on CT (all p < 0.05). Multivariate analysis revealed that higher blood eosinophil counts and fewer exacerbations in the previous year were independently associated with clinical remission (both p < 0.05). Conclusions: After 12 months of biologic therapy, 30% of patients with severe asthma achieved four-component clinical remission. Higher blood eosinophil counts and fewer prior exacerbations were associated with higher remission rates. Full article

The complement system is a key component of innate immunity, responsible for mediating the rapid clearance of pathogens and coordinating adaptive immune responses. Although complement activation is essential for effective infection control and prevention, its excessive or dysregulated function contributes to the pathogenesis of various immune-mediated disorders. Therefore, therapeutic inhibition of the overactive complement cascade, in which specific components are selectively blocked to suppress pathological activation, plays an important role in the treatment of various complement (immune)-mediated diseases. This article provides an overview of complement inhibition as a therapeutic strategy, highlighting the infectious risks associated with its use. Disruption of complement-dependent host defence mechanisms increases the risk of invasive infections (caused by encapsulated pathogens, e.g., Neisseria spp., Streptococcus pneumoniae and Haemophilus influenzae type B), which represent a significant clinical challenge. Therefore, the use of complement inhibition should not only be effective but also safe in combination with the application of all possible tools to prevent infections. Strategies, such as vaccination and antibiotic prophylaxis, are crucial to minimise these complications, despite the persistence of the risk of breakthrough infections. Furthermore, this review examines advancements in patient risk stratification, evaluates alternative preventive measures, and identifies key gaps in current clinical practice. Future directions include improving monitoring protocols, creating more selective or locally acting complement inhibitors, and implementing biomarker-driven personalised therapies that maximise benefits while reducing side effects. Full article

Bone tissue engineering offers a promising alternative to autografts and allografts for treating critical bone defects. Hydrogels, three-dimensional hydrophilic polymer networks, have emerged as leading scaffold materials due to their ability to mimic native extracellular matrix properties while providing tunable biocompatibility, biodegradability, mechanical characteristics, and high water content, enabling nutrient transport and cell viability. These scaffolds can be loaded with bioactive cues, including growth factors, peptides, and nanoparticles, and can deliver stem cells, supporting localised and sustained bone regeneration. Recent advances in hydrogel design have improved osteoinductivity and osteoconductivity through controlled physical, chemical, and mechanical properties, and sophisticated fabrication strategies such as 3D bioprinting and nanostructuring. This review provides a comprehensive overview of hydrogel-based scaffolds for bone tissue engineering, discussing material types, bioactive factor delivery, host tissue interactions, including immune modulation and osteogenic differentiation, and the latest preclinical and clinical applications. Finally, we highlight the remaining challenges and critical design requirements for developing next-generation hydrogels that integrate structural integrity with biological functionality. Full article

The cellular prion protein (PrP^C) displays a functional repertoire that extends well beyond its classical link to transmissible spongiform encephalopathies. Abundant in the nervous system and localized within lipid raft microdomains, PrP^C has emerged as a multifunctional signaling platform that regulates cell differentiation, neurogenesis, neuroprotection, and synaptic plasticity. Recent evidence highlights its dynamic expression in stem cell populations, where it participates in multimolecular complexes that control lineage commitment, particularly during neuronal differentiation. PrP^C expression tightly correlates with stem cell status, making it a promising biomarker of stemness and developmental progression. Through interactions with growth factors, extracellular matrix components, and synaptic proteins, PrP^C functions as a molecular integrator of signals essential for tissue repair and regeneration. Preclinical studies demonstrate that recombinant PrP^C can stimulate neurogenesis and tissue repair, while monoclonal antibodies modulate its physiological and pathological functions. Likewise, cell-based therapies leveraging PrP^C-enriched stem cells or PrP^C-dependent signaling profiles have shown promise in models of neurodegeneration and ischemia. Conversely, dysregulated PrP^C expression has also been observed in solid tumors, where it contributes to cancer cell survival, proliferation, metastasis, and therapy resistance, reinforcing its role as a regulator of cell fate and an oncological target. This review integrates stem cell biology, tissue regeneration, and oncology into a unified framework, offering a novel perspective in which PrP^C emerges as a shared molecular hub governing both physiological repair and pathological tumor behavior, opening previously unrecognized conceptual and translational opportunities. Full article

Background/Objectives: Overactivation of the HGF/c-MET pathway is implicated in various cancers, making its inhibition a promising therapeutic strategy. While several MET-targeting agents are currently approved or in advanced clinical development, patient selection often relies on invasive tissue-based assays. The development of a specific c-MET radioligand for PET imaging and radioligand therapy represents a non-invasive alternative, enabling real-time monitoring of target expression and offering a pathway to personalized treatment. Methods: Radiosynthesis of [⁶⁸Ga]Ga-DOTA-EMP100 was performed using a GMP-certified ⁶⁸Ge/⁶⁸Ga generator connected to an automated synthesis module. The radiopharmaceutical production was optimized by scaling down the amount of DOTA-EMP-100 from 50 to 20 μg. Synthesis efficiency and release criteria were assessed according to Ph. Eur. for all the final products by evaluating radiochemical yield (RY%), radiochemical purity, presence of free gallium (by Radio-UV-HPLC) and gallium colloids (by Radio-TLC), molar activity (Am), chemical purity, pH, and LAL test results. Results: An optimized formulation of [⁶⁸Ga]Ga-DOTA-EMP-100, using 40 μg of precursor, provided the best outcome in terms of radiochemical performance. Process validation across three independent productions confirmed a consistent radiochemical yield of 64.5% ± 0.5, high radiochemical purity (>99.99%), and a molar activity of 53.41 GBq/µmol ± 0.8. Conclusions: [⁶⁸Ga]Ga-DOTA-EMP-100 was successfully synthesized with high purity and reproducibility, supporting its potential for multi-dose application in clinical PET imaging and targeted radioligand therapy. Full article

Introduction: Patients with inflammatory bowel disease (IBD) have an increased risk of Clostridioides difficile infection (CDI). While antibiotic exposure has been considered the most prominent risk factor for CDI, proton pump inhibitor (PPI) use is another potential risk factor. Methods: From January 2017 to April 2021, we examined the University of Missouri’s IBD patients’ medical records. Laboratory-confirmed CDI diagnosis was the main outcome of interest. The usage of PPIs was the exposure of interest. The odds ratio between CDI risk in PPI users and non-users was estimated using logistic regression models. We investigated CDI risk with PPI use duration using stratified analysis. Results: Overall prevalence of CDI was 9%. 358 patients (42%) reported using PPI, with an average duration of ~30 months, with a range of 0.1 to 255. PPI use was associated with a higher risk of CDI in both the unadjusted (OR = 1.58 [0.98–2.53]; p = 0.06) and adjusted models (9.23 [2.11–40.34]; p = 0.003). Only those who used PPIs for less than 30 months had a greater risk of CDI in the stratified analysis (OR = 2.10 [1.16–3.38], p = 0.014). Long-term use (≥30 months) did not increase the incidence of CDI (OR = 0.74 [0.29, 1.83]; p = 0.510). Discussion: This is the single largest study of the US general IBD population to evaluate the association between PPI use and risk of developing CDI. PPI therapy was linked to a significant elevation in CDI risk, restricted to PPI use for up to 30 months. Histamine-2 receptor antagonists (H2RAs) did not increase the risk of CDI. Full article

Mesenchymal stem cells are multipotent stromal cells with immunomodulatory, anti-inflammatory, and trophic properties that support tissue repair and regeneration. Increasing evidence suggests that their therapeutic effects are primarily mediated by paracrine signaling, especially through extracellular vesicles, which can cross the blood–brain barrier and act as cell-free therapeutic agents. Preclinical and clinical studies in stroke, multiple sclerosis, spinal cord injury, and neurodegenerative diseases report encouraging outcomes but also reveal major challenges, including limited engraftment, donor-related heterogeneity, incomplete understanding of mechanisms, and potential oncogenic risks. Recent advances in biotechnology—such as mesenchymal stem cell-derived extracellular vesicles, genetic engineering using CRISPR/Cas9 or viral vectors, 3D culture systems, and bioengineered delivery platforms—offer new opportunities to overcome these limitations. Early clinical trials demonstrate promising safety and functional improvements, yet results remain inconsistent, highlighting the need for standardized protocols and large-scale controlled studies. This review outlines current knowledge, key challenges, and emerging strategies aimed at optimizing mesenchymal stem cell-based approaches for regenerative neurology. Full article