Citations

Abstract Myelodysplastic syndromes (MDS) are clinically and biologically diverse disorders, emphasizing the need for personalized treatment approaches. The International Working Group for Prognostication of MDS (IWG_PM) recently introduced a molecular classification, referred to as the MDS taxonomy, that categorizes patients into 16 subgroups based on 21 gene mutations, 6 cytogenetic abnormalities, and loss of heterozygosity (LOH) at TP53 and TET2 loci. This study sought to validate and enhance the clinical relevance of the MDS taxonomy by analyzing a large retrospective cohort ( n = 5136) and transcriptomic data from a prospective cohort ( n = 477). The taxonomy successfully identified subgroups with distinct clinical characteristics and disease progression patterns. However, incorporating gene interactions from taxonomy subgroups did not improve the prognostic performance of the Molecular International Prognostic Scoring System (IPSS‐M). We further assessed whether the taxonomy could guide management in patients receiving disease‐modifying therapies. Except for the “ TP53 ‐complex” subgroup, taxonomy classifications were not predictive of hypomethylating agent response or transplant outcomes. Nonetheless, they correlated with overall survival, suggesting that while both IPSS‐M and the taxonomy capture disease biology, other non‐genetic factors may influence treatment response. RNA sequencing confirmed the biological distinctiveness of the taxonomy groups. Transcriptomic profiling of CD34+ bone marrow cells revealed unique, homogeneous gene expression patterns, particularly within the AML‐like, bi TET2 , SF3B1 , and TP53 ‐complex subgroups. Further integration of multi‐omics data may refine MDS classification, improving clinical decision‐making and guiding the development of targeted therapies.

Key Points Alanyl-transfer RNA synthetase 1 (AARS1) was upregulated and promoted cyst growth in autosomal dominant polycystic kidney disease. AARS1 promoted lysine lactylation of signal transducer and activator of transcription 3 (K140) and NF-κB p65 (K310), enhancing their phosphorylation, interaction, and transcriptional activity. AARS1 transcriptionally repressed its novel targets, Atg5 and Dusp4, to impair autophagy but activate polycystic kidney disease signaling pathways. Background Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder, characterized by metabolic reprogramming with enhanced glycolysis and lactate accumulation. However, the enzyme that senses lactate and uses it as a substrate for protein lactylation in ADPKD remains unknown. Alanyl-transfer RNA synthetase 1 (AARS1) is a lactate-responsive enzyme with lactyltransferase activity, while its role and mechanisms in ADPKD have not been defined. Methods To investigate the role of AARS1, we generated Pkd1 and Aars1 double conditional knockout Pkd1 fl/fl :Aars1 fl/fl :Ksp-Cre mice and evaluated the effect of AARS1 inhibitor β -alanine in two ADPKD mouse models. Coimmunoprecipitation and Cleavage Under Targets and Tagmentation analyses were performed to identify novel AARS1 substrates and downstream target genes involved in cystogenesis. Results AARS1 was elevated in Pkd1 mutant renal epithelial cells and kidneys, and genetic deletion of Aars1 significantly delayed cyst growth, preserved kidney function, and reduced renal lactylation in Pkd1 mutant mice. Mechanistically, AARS1 promoted lactylation-dependent activation of signal transducer and activator of transcription 3 (STAT3) and NF-κB (p65), specifically at STAT3 K140 and p65 K310, thereby amplifying pro-proliferative and proinflammatory transcriptional programs. AARS1 also associated with promoter regions and mediated histone H3 lysine 14 lactylation, thereby repressing the transcription of Atg5 to impair autophagy and suppressing the transcription of Dusp4 to sustain phosphorylation of cAMP response element–binding protein and retinoblastoma protein. Cytokine signaling through IL-6 and TNF- α further reinforced AARS1 expression through STAT3- and NF-κB–dependent feed-forward loops. Importantly, inhibition of AARS1 with β -alanine markedly slowed cyst progression in Pkd1 mutant mouse models. Conclusions Our study identified AARS1 as a central metabolic sensor linking lactate-driven lysine lactylation to transcriptional, epigenetic, and signaling pathways that drive ADPKD progression.

INTRODUCTION: Recurrent Clostridioides difficile infection (rCDI) is associated with substantial morbidity, healthcare utilization, and costs. US FDA-approved microbiota-based therapies, fecal microbiota spores, live-brpk (VOS) and fecal microbiota, live-jslm (RBL), reduce recurrence risk, but cost-effective placement within the rCDI treatment pathway remains uncertain. METHODS: We performed a US payer-perspective cost-effectiveness analysis using decision-tree modeling according to CHEERS 2022 guidelines. Adults with rCDI entered the model after the first or second recurrence and were followed for <1 year. Effectiveness inputs were derived from ECOSPOR III/IV (VOS), PUNCH CD3/CD3-OLS (RBL) trials, and published literature for standard-of-care (SoC) comparators. Outcomes included costs (2025 USD), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). Probabilistic and deterministic sensitivity analyses were performed using a willingness-to-pay threshold (WTP) of $150,000/QALY. ICERs were interpreted across $50,000, $100,000, $120,000, and $150,000/QALY. RESULTS: After the first recurrence, RBL was cost-effective vs SoC alone ($25,415/QALY). Early initiation remained favorable compared with delayed use for VOS ($27,239/QALY) and RBL ($26,704/QALY). After the second recurrence, VOS remained cost-effective vs SoC (ICER $53,983/QALY), whereas RBL exceeded the WTP threshold (ICER $171,496/QALY). Exploratory cross-trial VOS vs RBL comparisons yielded ICERs of $124,636/QALY after first recurrence and $137,350/QALY after second recurrence, indicating threshold-sensitive product-to-product comparisons. DISCUSSION: Earlier initiation of microbiota-based therapies after the first rCDI provides greater health benefits at acceptable cost-effectiveness thresholds compared with delayed use, supporting earlier integration into rCDI treatment strategies. VOS vs RBL comparisons should be interpreted as exploratory indirect comparisons pending comparative real-world or head-to-head data.

Abstract Background Dalbavancin is increasingly used off-label for chronic Gram-positive bone and joint infections (BJIs) requiring prolonged antimicrobial therapy, but optimal dosing strategies and the role of therapeutic drug monitoring (TDM) remain unclear. We evaluated the real-world implementation of a proactive TDM-guided dalbavancin workflow within an outpatient parenteral antimicrobial therapy (OPAT) programme. Methods Single-centre prospective observational implementation study including adult patients with BJIs consecutively treated with dalbavancin in OPAT service between July 2022 and August 2025. A multidisciplinary team developed a workflow incorporating TDM-guided pharmacokinetic modelling to individualize dosing intervals after fixed initial administrations (Days 1, 8 and 43). Target Cmin concentrations were ≥8 mg/L, later increased to ≥15 mg/L after European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoint revision. Primary outcomes included implementation metrics (feasibility, fidelity and appropriateness). Secondary outcomes were clinical effectiveness, safety and overall workflow success. Results The workflow was applied to 101 patients accounting for 418 TDM-guided dalbavancin administrations (feasibility). Three patient-driven treatment discontinuations were observed (3/101, 3.0%), and scheduled administrations occurred within the predefined time window in 335/418 (83.5%) of cases (fidelity). Pharmacological target attainment was achieved in 285/342 (89.6%) of administrations without dosing delays (appropriateness). Clinical effectiveness was achieved in 55/73 (75.3%) patients completing therapy, with 28/101 (28%) still on treatment. Adverse events–related discontinuation occurred in 3/101 (3%) patients. Overall workflow success was observed in 74/101 (73.2%) patients. Conclusions A multidisciplinary TDM-guided dalbavancin workflow within an OPAT programme was feasible and safe, achieving high target attainment and favourable clinical outcomes. This approach supports individualized long-acting dalbavancin therapy for complex chronic BJIs.

Abstract Migraine attacks can be provoked in people with underlying primary headache disorders by multiple peripheral mechanisms suggesting the possible convergence of trigeminal nociceptive inputs onto a common, unknown central circuit. As calcitonin gene-related peptide (CGRP) expressing cells in the parabrachial nucleus (PBN) have been implicated in nociplastic pains, we hypothesized that (a) PBN CGRP-expressing neurons and their projections to the central amygdala (CeA) may be an essential central relay of multiple peripheral inputs promoting injury-free migraine headache and (b) this pathway may prioritize threat from activation of cranial afferents over other nociceptive inputs. Periorbital cutaneous allodynia (CA) was determined following supradural application of a cocktail of inflammatory mediators (IM), CGRP or pituitary adenylate cyclase-activating polypeptide (PACAP), or systemic administration of nitroglycerin (NTG) in CalcaCre or wild-type mice. Decreased rearing and photophobia were respectively evaluated as measures of ongoing headache and light-evoked migraine-like pain. Phosphorylation of extracellular signal-regulated kinases (pERK) was evaluated to assess regional neuronal activation. Compared with vehicle, supradural IM increased pERK in the trigeminal nucleus caudalis and PBN, but not in the paraventricular thalamus. Chemogenetic activation (Gq-DREADD) of PBN CGRP neurons elicited CA and photophobia while decreasing rearing. Lesioning of PBN neurons with ibotenic acid suppressed CA produced by supradural IM. Chemogenetic silencing (Gi-DREADD) or expression of tetanus toxin (TeNT) in PBN Calca neurons to prevent neurotransmitter release also inhibited CA elicited by supradural IM, CGRP, PACAP or systemic NTG. CRISPR/Cas9 editing of CeA receptor-associated membrane protein-1 (Ramp1) prevented IM-induced migraine-like symptoms revealing CGRP/CGRP-receptor activation from PBN→CeA projections. In contrast, PBN lesions, chemogenetic manipulation, and TeNT expression in PBN Calca cells and CeA Ramp1 CRISPR/Cas9 editing did not affect acute pain responses induced by hind paw IM injection, intraperitoneal acetic acid, or acute nociceptive behaviors from IM stimulation of the maxillary (V2) and mandibular (V3) branches of the trigeminal nerve. These data reveal a central pathway composed of PBN Calca neurons and CeA CGRP receptor signaling that is both sufficient to elicit migraine-like pain in naive mice and necessary to promote migraine-like pain following activation of the ophthalmic (V1) branch of the trigeminal nerve. Importantly, this pathway is essential for acute pain arising from V1 trigeminal, but dispensable for acute stimuli from other nociceptive afferents. The prioritization of V1 acute nociception suggests evolutionary importance for detecting threats to the head to promote survival through advantageous behaviors such as defensive coping observed in migraine.

Abstract Purpose: To explore the potential of the metaverse, a three-dimensional platform merging physical and virtual realities (VRs), in advancing the field of ophthalmology. This study examines its applications in areas such as VR-based surgical training, augmented reality (AR)-assisted surgeries, artificial intelligence (AI)-driven diagnostics, and teleophthalmology. This review builds upon previous literature by integrating recent evidence and technological advancements, offering a more comprehensive analysis of particular applications and barriers in ophthalmology. Methods: Academic literature published between 2019 and 2024 was identified through searches in the PubMed database and Google Scholar search engine using relevant keywords. This review focused on studies discussing the application of the metaverse in health care and ophthalmology, with particular attention to key trends, emerging uses, technological features, and associated challenges. Results: A total of 60 studies were deemed relevant for inclusion in this review. The infrastructure supporting the Metaverse comprises technologies such as the Internet of Things, digital twins, mirror worlds, nonfungible tokens, blockchain technology, and lifelogging. Together, these technologies create immersive environments that users can access through VR headsets, AR glasses, and handheld controllers. The metaverse presents promising opportunities in ophthalmology, particularly in enhancing clinical training through simulators such as the EyeSi™ surgical simulator, VRmagic EyeSi Slit Lamp, and the HelpMeSee™ VR simulator. In addition, it facilitates remote consultations and improves diagnostic and treatment options, exemplified by tools such as the Vivid Vision™ system for amblyopia, the Microsoft HoloLens™ for navigating complex anatomical structures, and AI-based platforms for the early detection of diseases such as glaucoma and diabetic retinopathy. Furthermore, the metaverse may enhance patient education by simulating the visual effects of ophthalmic conditions and visualizing postoperative outcomes. However, challenges, including financial limitations, data security concerns, and cultural acceptance, must be addressed. Conclusions: A gradual and context-specific integration of the metaverse is essential, particularly in underdeveloped regions. As the metaverse evolves, it holds significant potential to transform the field of ophthalmology by promoting global collaboration and innovation, complementing traditional practices, and ensuring equitable access to advanced healthcare solutions.

Multiple sclerosis is an immune-driven neurological disease that affects myelinated axons in the central nervous system. However, the trigger of the (dysregulated) immune reactions is not known. According to Wilkin’s primary lesion theory, myelin-reactive T cells present in the immune repertoire hyper-react to myelin antigens that are released from idiopathic lesions within the central nervous system. However, neither the cause of the primary lesion nor the cause of the immune hyper-reactivity is known. We investigated whether these unknown activation signals may be relayed by common herpesviruses. In this concept paper, we propose the novel paradigm that the trigger of autoimmunity in MS comprises a conspiracy of three common herpesviruses: human herpesvirus-6A as a potential trigger of primary lesions due to its proven capacity to cause oligodendrogliopathy, cytomegalovirus as a trigger for the formation of effector memory cytotoxic T cells with proven capacity to induce multiple sclerosis pathology in a non-human primate MS model and Epstein-Barr Virus due to its capacity to render B cells capable to effectively present a critical myelin antigen to these effector memory cytotoxic T cells.

Abstract Introduction Pulmonary fibrosis is characterized by excessive fibroblast activation and alveolar remodeling, leading to progressive lung dysfunction. Osteoglycin (OGN), a small leucine-rich proteoglycan, and its functional fragment MC002 have been identified as regulators of alveolar epithelial regeneration, a process that is impaired in fibrotic lung disease. This study investigates the effects of OGN and MC002 on TGF-β-induced fibrotic responses in lung fibroblasts, organoids, and an in vivo fibrosis model. Methods Human lung fibroblasts (MRC5) were treated with OGN or MC002 for 48 hours, with or without transforming growth factor-beta (TGF-β; 2 ng/mL). Expression of the myofibroblast marker α-smooth muscle actin (ACTA2) and matrix markers collagen 1a1 (COL1A1) and fibronectin (FN1) was assessed by RT-PCR and Western blotting. Global transcriptomic changes were analyzed by RNA sequencing. Myofibroblast differentiation was evaluated by phalloidin staining and quantified using the phalloidin/DAPI ratio. Murine lung organoids were generated by co-culturing epithelial progenitor cells with fibroblasts and treated with TGF-β (2 ng/mL) in the presence or absence of OGN or MC002. Organoid number, size, and alveolar differentiation were quantified after 14 days. In vivo, pulmonary fibrosis was induced in mice using intratracheal bleomycin. MC002 was administered at different doses (6.75 µg or 20.25 µg) every other day starting from day 7 post-bleomycin, and lung weight and pressure-volume (PV) loops were assessed to evaluate fibrotic burden and lung mechanics. Osteoglycin expression in human lung tissue from 13 non-smokers, 11 ex-smokers, and 12 IPF patients was analyzed by immunostaining. Results TGF-β induced pro-fibrotic gene expression in fibroblasts, while OGN and MC002 alone had no pro-fibrotic effects. MC002 fully reversed TGF-β-induced ACTA2, COL1A1, and FN1 expression, whereas OGN selectively attenuated COL1A1. RNA-sequencing revealed broad suppression of fibrosis- and ECM-associated gene programs by MC002. At the protein level, TGF-β-induced ACTA2 expression was reversed by MC002 but not by OGN. Both compounds reduced TGF-β-induced stress fiber formation. In lung organoids, TGF-β impaired organoid formation and alveolar differentiation, effects that were restored by OGN and MC002 in a concentration-dependent manner. In the bleomycin model, MC002 significantly reduced lung weight and improved PV loop profiles, indicating attenuation of fibrotic stiffening and improved lung compliance. Osteoglycin protein expression was significantly diminished in IPF whole lung tissue and parenchyma compared to controls. Conclusion OGN, and particularly MC002, counteract TGF-β-driven fibroblast activation and myofibroblast differentiation while promoting alveolar preservation. The superior efficacy of MC002 supports its potential as a therapeutic candidate for pulmonary fibrosis. This abstract is funded by: Lung Foundation Netherlands 10.1.23.021PPS

Abstract Problem Statement Communication failures in critical care contribute to preventable medical errors, impaired team performance, and unsafe care environments. Despite recognition of its importance, communication training for fellows remains inconsistent across hierarchical (ICU) and non-hierarchical (research/QI) environments. This variability limits fellows’ ability to adapt communication strategies, affecting clinical decision making and collaboration. Existing curricula often lack experiential rehearsal and cross-context transfer, leaving trainees underprepared to communicate across settings. Targeted Needs Assessment A pre-course focused assessment of critical care fellows at a single center revealed heterogeneity in formal communication training and confidence in applying communication strategies across team structures. Peer feedback identified gaps in negotiation, nonverbal cue recognition, and role clarity. Primary Goal Equip critical care fellows to communicate with intentional presence and professionalism across hierarchical and non-hierarchical clinical settings. Objectives Implement a one-day curriculum aligned with ACGME Critical Care Medicine milestones and CCF HRO (High Reliability Organization) principles. - Demonstrate effective active listening and closed-loop communication - Identify and respond to verbal and nonverbal cues - Exhibit leadership behaviors promoting psychological safety - Adapt communication strategies across team structures Educational Strategies and Curriculum Design Curriculum planning involved interdisciplinary meetings between critical care faculty, simulation education specialists, curriculum leads, and improvisation specialist. Design aligned with adult learning and simulation best practices. The curriculum integrated three educational approaches 1) Improvisational communication training emphasizing inclusive language and nonverbal cue awareness 2) Narrative reflection and professional identity formation 3) High fidelity simulation using communication-intensive ICU and non-ICU scenarios. Simulation scenarios included a) Dual patient respiratory failure and cardiac arrest requiring role assignment and closed-loop communication b) Plane crash survival lab requiring group consensus without assigned leadership Implementation and Learner Evaluation Eleven of twelve critical care medicine fellows participated. Pre and post-course surveys assessing communication confidence across settings were completed by all participants. Faculty observation rubrics assessed communication behaviors. Key Outcomes/Results (see graphs) Substantial increases in communication confidence were observed across hierarchical ICU and non-hierarchical environments. Fellows agreed that communication competency should be a required component of training. High impact elements included a) Improvisational communication techniques integrated with simulation b) Nonverbal communication awareness c) Adoption of inclusive language d) Psychological safety e) Improved professionalism and interdisciplinary communication consistency Conclusion and Next Steps This improvisation-enhanced simulation curriculum improved fellows’ confidence communicating across hierarchical and non-hierarchical settings. Next steps include incorporating cognitive load management training; the curriculum is adaptable to external audiences and supports organizational HRO principles. This abstract is funded by: N/A