Science Translational Medicine

Medication-overuse headache (MOH) is one of the leading causes of chronic daily headache worldwide and arises from the repeated use of acute anti-migraine medications, including triptans. However, the cellular substrates and intracellular pathways driving this paradoxical chronification remain unknown. Here, using Schwann cell-selective silencing of the 5-HT1B/D receptor, we observed that acute triptan administration counteracts CGRP-induced, endosome-confined cAMP accumulation, preventing the development of periorbital mechanical allodynia in mice. In contrast, prolonged 5-HT1B/D activation in Schwann cells induces epigenetic and transcriptomic dysregulation associated with MOH in mice. Specifically, intronic hypermethylation-driven overexpression of BETAGLYCAN promotes activation of a non-canonical TGF-{beta}-dependent signaling cascade. The resulting TGF-{beta}3 upregulation establishes a feed-forward loop that sustains proalgesic paracrine communication between Schwann cells and primary sensory neurons. Analysis of plasma levels from patients with MOH confirmed elevated TGF-{beta}3 levels specifically associated with triptan-dependent MOH, supporting the translational relevance of these findings. Together, our data identify Schwann cell 5-HT1B/D signaling as a dual mediator of both the acute anti-migraine efficacy and the maladaptive mechanisms underlying MOH. These results provide a conceptual framework for strategies aimed at preserving the therapeutic benefits of triptans while limiting the adverse consequences of chronic administration. One Sentence SummarySchwann cell 5-HT1B/D receptor signaling mediates the dual effects of triptans by acutely inhibiting CGRP-driven nociceptive pathways while chronically promoting epigenetically driven TGF-{beta}3-dependent proalgesic signaling that causes medication-overuse headache.

Juvenile dermatomyositis (JDM) is a chronic multisystem vasculopathy and inflammatory myopathy characterized by proximal muscle weakness, distinct rash, and risk of complications such as calcinosis cutis, skin ulceration, and mortality. Molecular insight from diagnostic muscle biopsy histology is limited, and the mechanistic pathoetiology of JDM remains poorly defined. We used single nuclei transcriptomics to assess muscle samples from patients with newly diagnosed treatment-naive JDM. As a control, we assessed muscle samples from patients with congenital (nemaline) myopathy (CM), a non-inflammatory disorder. A total of 25,794 high quality nuclei were analyzed and clustered into various muscle-resident or infiltrating cellular populations. JDM tissue was characterized by an enriched interferon (IFN) response signature across endothelial, stromal, and immune cell compartments. Endothelial and perivascular populations showed increased inflammatory and angiogenic programs. Intercellular communication inference analysis identified dysregulated vascular endothelial growth factor (VEGF)-related signaling involving endothelial, stromal, and myonuclear populations as a possible mechanism for myonuclear-driven modulation of the muscle microvasculature. Spatial RNA in situ hybridization supported increased expression of selected IFN responsive and angiogenesis signaling genes in JDM tissue. Collectively, these data provide a cell type-resolved view of treatment-naive JDM muscle and highlight vascular and IFN pathways for follow-up in larger cohorts.

ObjectiveTo determine whether quantitative ultrasound (QUS), which characterizes tissue microstructure using radiofrequency data, can identify regional heterogeneity within seminiferous tubules that corresponds to localized spermatogenesis in men with non-obstructive azoospermia (NOA). DesignTwo-cohort study using a biological extremes cohort to establish plausibility of a QUS biomarker, followed by an independent NOA-biopsy cohort with site-matched imaging and tissue sampling. SettingAcademic male fertility referral center. PatientsThe biological extremes cohort included fertile men with presumed intact spermatogenesis (n=15) and men with NOA and subsequent negative microdissection testicular sperm extraction (mTESE; n=10). The NOA-biopsy cohort consisted of 27 men with NOA undergoing site-matched testicular biopsy via testicular sperm aspiration (TESA) or testicular sperm extraction (TESE), yielding 12 sperm-positive and 36 sperm-negative biopsy sites. InterventionsHigh-frequency testicular ultrasound (36 MHz) with acquisition of raw radiofrequency data, allowing objective, quantitative analysis of tissue scattering patterns beyond conventional grayscale imaging. Regions of interest were manually annotated and, in the NOA-biopsy cohort, spatially matched to biopsy locations. Main Outcome MeasuresAssociation between sperm presence at biopsy sites and a pre-specified QUS measure of local tissue heterogeneity: the 75th percentile of a sliding window coefficient of variation map of the Nakagami k-factor within the superficial testicular parenchyma (K_Zone1_CV). This metric reflects the upper range of local variability in ultrasound backscatter, which is influenced by the underlying organization of seminiferous tubules. ResultsIn the biological extremes cohort, K_Zone1_CV distinguished fertile controls (median 1.79, IQR 1.64-1.85) from NOA men with globally negative mTESE (median 1.51, IQR 1.42-1.58; P < 0.001), with an area under the receiver operating characteristic curve (AUC) of 0.91 (95% CI 0.79-1.00). In the independent NOA-biopsy cohort, K_Zone1_CV discriminated sperm-positive from sperm-negative biopsy sites with an AUC of 0.93 (95% CI 0.85-0.99). At a threshold of 1.60, sensitivity was 100%, specificity was 86.1%, positive predictive value was 70.6%, and negative predictive value was 100%. Serum hormone levels, testicular volumes, and biopsy technique did not differ significantly between groups. ConclusionsRegional testicular tissue heterogeneity measured by quantitative ultrasound is associated with localized spermatogenesis in men with NOA. At the selected threshold, no sperm-positive biopsy site was misclassified as negative. These findings support the hypothesis that QUS can noninvasively detect the focal seminiferous tubule heterogeneity that predicts sperm retrieval success. This imaging approach could inform future image-guided sperm retrieval strategies. Further validation in larger cohorts and assessment of intra-patient variability are needed.

Histopathological evaluation of skeletal muscle biopsies relies on subjective, semi-quantitative assessment with no standardized grading system. We developed a four-tissue deep learning segmentation pipeline using Cellpose-SAM for myofiber instance segmentation, a pixel classifier for fat infiltration, and watershed detection for nuclei. We applied this pipeline to 478 H&E whole-slide images from two independent cohorts: HuashanMuscle (n = 79; China; myotonic dystrophy type 1 [DM1], n = 28; limb-girdle muscular dystrophy type R1 [LGMDR1, calpainopathy], n = 12; type R2 [LGMDR2, dysferlinopathy], n = 22; controls, n = 17) and GTEx (n = 399; United States; three-level myopathy spectrum). Thirty-seven unique morphometric features were extracted per sample. Nuclear centralization index (NCI) and fiber size variability coefficient (fiber CV) discriminated myopathy from controls (p = 1.3E-05, rank-biserial r = 0.69; and p = 2.9E-04, r = 0.58, respectively). DM1 showed the highest NCI (median 0.121), consistent with its centronuclear pathology, and NCI correlated with CTG repeat count (Spearman rho = 0.46, p = 0.042, n = 20). In the GTEx cohort, both biomarkers exhibited significant dose-response trends across the myopathy spectrum (Jonckheere-Terpstra p < E-04). The MyoPath Score, a logistic regression composite of seven pathology indicators trained on GTEx, achieved AUC = 0.788 (LOO-CV 0.735) and transferred to the independent HuashanMuscle cohort with AUC = 0.873 without retraining. Segmentation achieved Dice coefficients of 0.92 (myofiber), 0.95 (fat), 0.87 (nucleus), and 0.88 (connective tissue), with intraclass correlation coefficients exceeding 0.88. NCI and fiber CV provide objective, reproducible quantitative biomarkers for skeletal muscle pathology severity assessment with potential as standardized grading criteria and clinical trial endpoints.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no definitive disease-modifying therapies available, underscoring the urgent need to identify novel druggable targets. The G protein-coupled receptor GPR17 is a critical regulator of oligodendrocyte maturation and has emerged as a candidate target in ALS, yet its relevance to human disease and therapeutic potential remain unclear. Here, we demonstrate that pathological GPR17 upregulation defines a conserved, pathologically immature oligodendroglial state in human ALS that can be pharmacologically leveraged to restore myelin integrity and improve functional outcome in vivo. Publicly available transcriptomics datasets and histological analysis revealed an increased abundance of GPR17-expressing immature oligodendrocytes in post-mortem human spinal cord tissue from ALS cases compared with non-neurological controls. Moreover, sustained activation of GPR17 with a selective agonist was able to induce GPR17 internalization in heterologous expression systems. In line with this mechanism, treatment with the same agonist promoted the differentiation of primary oligodendrocyte precursor cells derived from SOD1G93A mice. Translating these findings in vivo, chronic treatment with a brain-penetrant GPR17 agonist derived from the same pharmacological class significantly extended survival, delayed body weight loss, and improved motor performance in female SOD1G93A mice, whereas male mice showed no therapeutic benefit. These effects were associated with restored oligodendrocyte maturation, preserved myelin integrity, motor neuron survival, and attenuated reactive gliosis in the spinal cord of female SOD1G93A mice, while milder effects were observed in males. Together, these findings establish oligodendroglial GPR17 as a conserved and pharmacologically actionable target in ALS and show that sustained in vivo GPR17 agonism can reprogram altered oligodendroglial states and slow disease progression in a sex-dependent manner.

People with HIV exhibit elevated inflammation and cardiovascular risk despite antiretroviral therapy. To define the genetic architecture of inflammasome-associated inflammation, we performed whole-genome sequencing and quantified plasma IL-6, IL-1{beta}, and IL-18 in 1,000 ART-suppressed PWH from the U.S. Military HIV Natural History Study. Genome-wide analyses identified 14 loci implicating antiviral defense (DDX17, DDX41, EEA1, BCL11A), lipid metabolism (ABCA1, ABCA12, ABCC1, AGMO), and vascular remodeling (KLHL29, RNF213, ETV1). Transcriptome-wide analyses across cardiovascular and immune tissues identified regulatory programs linking interferon signaling, immune activation, and vascular biology to circulating cytokine levels. Mendelian randomization analyses supported causal relationships between inflammasome-associated cytokines and vascular events. Functional integration with genome-wide CRISPR perturbation datasets in primary CD4 T cells linked cytokine-associated loci to HIV antiviral pathways and cytokine regulatory networks. External validation in cohorts without HIV demonstrated pathway-level convergence despite limited variant-level overlap. These findings define genetic mechanisms linking inflammasome signaling, antiviral defense, and cardiovascular risk.

Sepsis is a dysregulated host response to infection and a leading cause of global mortality, yet effective targeted therapies remain lacking. Here, we applied a proteogenomic framework integrating large-scale human genetics with circulating proteomics to identify therapeutic targets. In a meta-analysis of genome-wide association studies of 60,314 sepsis cases and 1,464,733 controls, we identified four genome-wide significant loci, including a missense variant in SERPINA1, encoding alpha-1 antitrypsin (AAT), that was also associated with 30-day sepsis mortality in the UK Biobank. Mendelian randomization (MR) and colocalization analyses supported a causal and protective effect of higher genetically predicted circulating AAT levels on sepsis risk. The protective association was highly specific to acute infectious phenotypes, including pneumonia, and was not observed for non-infectious traits. In two independent cohorts (UK Genomic Advances in Sepsis and the Biobanque Quebecois sur la COVID-19), circulating AAT increased markedly during acute illness but was significantly attenuated among missense variant carriers in a dose-dependent manner, consistent with impaired protease-antiprotease balance. MR of the AAT-regulated proteome recapitulated findings from prior sepsis trials, both negative and positive, providing orthogonal genetic support for therapeutic modulation of this pathway. Together, these findings provide the first human genetic evidence for AAT's causal role in sepsis, positioning SERPINA1 as a high-priority candidate for drug repurposing and targeted therapeutic interventions.

Interleukin-10 (IL-10) is a potent immunoregulatory cytokine that suppresses pro-inflammatory cytokine production, reduces antigen presentation by myeloid cells, promotes M2 macrophage polarization, and inhibits T cell activation. Despite these well-established immunoregulatory functions, efforts to harness recombinant IL-10 therapeutically have been limited by its short plasma half-life and poor retention in the secondary lymphoid organs (SLOs), key sites of autoreactive T cell priming in autoimmune disease. Previously, we engineered a fusion of serum albumin and IL-10 (SA-IL-10) with extended half-life and enhanced exposure in the SLOs following intravenous administration. Here, we integrate human transcriptomic analyses and a murine model of neuroinflammation, experimental autoimmune encephalomyelitis (EAE), to investigate how sustained IL-10 exposure in the SLOs modulates immune responses under inflammatory conditions. Human single-cell RNA sequencing analyses revealed reduced IL-10 expression alongside increased IL-10 receptor expression across multiple immune cell populations in treatment-naive patients with multiple sclerosis (MS), motivating the investigation of IL-10-based immunomodulatory strategies. Prophylactic SA-IL-10 administration prevented the development and progression of EAE with superior efficacy to wild type IL-10 and comparable protection to fingolimod, an FDA-approved MS therapy. Immunophenotyping of the SLOs revealed that SA-IL-10 suppressed pathogenic, antigen-specific ROR{gamma}t+ Foxp3- TH17 T cells, CD86+ M1-like macrophages, CD86+ dendritic cells, and pro-inflammatory cytokine production, while expanding immunoregulatory CD206+ M2-like macrophages and increasing the frequency of multiple checkpoint markers (CTLA-4, PD-1, TIGIT, ICOS) on GATA3+ Foxp3- TH2 cells. Despite the absence of direct central nervous system targeting, SA-IL-10 treatment also reduced the infiltration of macrophages, dendritic cells, and CD4+ T cells into the spinal cord. Repeated SA-IL-10 administration was well tolerated, as treated EAE mice gained significantly more body weight over the course of treatment compared to PBS- and WT IL-10-treated controls, and exhibited plasma biochemistry parameters comparable to control animals at study endpoint. Together, these findings demonstrate that increasing IL-10 exposure in the SLOs suppresses neuroinflammation by promoting immunoregulation. One Sentence SummarySubcutaneously administered serum albumin-fused interleukin-10 prevents experimental autoimmune encephalomyelitis by suppressing pathogenic TH17 cells and pro-inflammatory myeloid cells in the secondary lymphoid organs and spinal cord, while expanding immunoregulatory cells in the secondary lymphoid organs.

Management of peripheral nervous system (PNS) neuropathies, such as traumatic peripheral nerve injury (PNI), relies on accurate assessment of muscle denervation and recovery. Yet, the current gold-standard clinical test, needle electromyography (EMG), has multiple shortcomings that can complicate surgical treatment. Here, we introduce a noninvasive method for holistic evaluation of muscle denervation by utilizing positron emission tomography (PET) to quantify expression of prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II (GCPII), within muscles. We identified that GCPII is persistently over-expressed in denervated muscles and that expression normalizes with muscle reinnervation. Leveraging this phenomenon, we used two PSMA/GCPII-PET agents that are FDA-approved for prostate cancer imaging, [18F]DCFPyL and [68Ga]PSMA-11, to detect muscle denervation and subsequent reinnervation in experimental models of PNI. We found that denervated muscle had approximately twice the uptake as innervated muscle on GCPII-PET/magnetic resonance (MR) imaging and GCPII-PET/computed tomography (CT), which persisted for at least 16 weeks after nerve injury without repair in rats and swine. GCPII-targeted uptake also declined to near baseline levels with muscle reinnervation after nerve repair. To assess clinical feasibility, we performed [18F]DCFPyL PET/CT in a patient who had sustained a unilateral radial nerve injury 15 weeks prior, and we observed elevations in denervated muscle uptake that mirrored our preclinical findings. Our consistent findings across species of increased GCPII-PET uptake in chronically denervated muscle and its decline with muscle reinnervation, along with the established safety profile of available GCPII-PET agents, support the promise of GCPII-PET as a rapidly translatable strategy for characterization and longitudinal monitoring of PNIs and non-traumatic PNS neuropathies.

The PRESERVE trial (NCT04972097) is a prospective, single-arm pivotal IDE study evaluating focal irreversible electroporation (IRE) using the NanoKnife System for intermediate-risk prostate cancer. Men with Gleason Grade Group 2-3 disease underwent focal IRE and were followed for durability of oncologic control and safety. At 24 months, 68 patients completed follow-up with no new treatment failures identified. PSA levels were below baseline in 97% of patients, and one clinically triggered biopsy was negative for cancer. No new device- or procedure-related adverse events occurred beyond 12 months. These findings demonstrate durable efficacy and sustained safety of focal IRE.

ABSTRACT Background: The UroLume endoprosthesis (AMS/Endo-care), commercially available 1988-2007 and FDA-approved in 1996, was positioned as a permanent minimally invasive solution for recurrent bulbar urethral stricture and benign prostatic hyperplasia (BPH). Despite early procedural success, long-term data revealed a catastrophic complication profile - including irreversible urethral destruction, spongiofibrosis, MDR infections, chronic kidney disease, and severe psychological morbidity - culminating in the clinical entity termed UroLume Cripple Syndrome. No systematic epidemiological analysis of surviving patients in 2026 currently exists. Objectives: To synthesise four decades of evidence on UroLume pathophysiology, complications, surgical management hierarchy, psychological burden, and cumulative multimorbidity; to perform a pooled meta-analysis of primary complication endpoints; and to present an original epidemiological model estimating surviving patients globally and in Greece in 2026. Methods: PRISMA 2020-compliant systematic review and meta-analysis of PubMed, Embase, and Cochrane Library (all dates to March 2026). Inclusion: peer-reviewed studies of UroLume implantation, explantation, or post-UroLume reconstruction; minimum 12-month follow-up; series n >= 10. Random-effects meta-analysis (DerSimonian-Laird estimator) was performed for three primary complication endpoints across all 43 included studies. An original bottom-up sequential filter epidemiological model was constructed integrating WHO 2021 actuarial tables, published explantation rates, multimorbidity excess mortality, age distributions, complete epithelialisation prevalence, and reconstruction failure rates. Results: Forty-three studies met inclusion criteria (n=3,847 patients). Pooled meta-analysis yielded: restenosis/tissue ingrowth 37.9% (95% CI 36.1%-39.8%, I2=0%); stent explantation 8.7% (95% CI 7.7%-9.8%, I2=0%); urinary incontinence 9.7% (95% CI 8.7%-10.9%, I2=0%). Complete epithelialisation, irreversible after 12 months, affects approximately 8-13% of long-term survivors and defines the UroLume Cripple endpoint. Post-UroLume buccal mucosa graft urethroplasty achieves 76.7% success at 5 years when explantation is feasible. Our epidemiological model estimates 2,500-5,000 surviving patients globally with UroLume in situ in 2026, reducing to fewer than 100 clinically active patients aged <60 years following full multimorbidity adjustment. A six-filter sequential model for Greece converges to a final estimate of 1 surviving patient aged <60 years with complete epithelialisation following failed reconstruction. Conclusions: UroLume Cripple Syndrome is a chronic iatrogenic disease with distinct pathophysiological, reconstructive, psychological, and social dimensions that has received insufficient recognition as a defined clinical entity. The surviving patient population is small but institutionally invisible: no registry exists, no dedicated follow-up protocol has been established, and specialist reconstructive capacity is confined to approximately eight centres worldwide. Registry creation, EAU guideline extension, and specialist referral pathways are the minimum adequate institutional responses. This preprint has been deposited on medRxiv simultaneously with journal submission.

Lupus nephritis (LN), a severe manifestation of systemic lupus erythematosus (SLE), features heterogeneous renal pathology and reliance on invasive biopsies for diagnosis, prognosis, and treatment selection. Current peripheral clinical markers inadequately capture disease activity and progression. Here, we performed comprehensive serum proteomic profiling of over 5,000 proteins in the large, longitudinal Accelerating Medicines Partnership Rheumatoid Arthritis/SLE cohort of 270 LN patients and 63 healthy controls. Machine learning identified distinct molecular signatures that classified LN versus controls, differentiated histological classes, and delineated activity- and chronicity-associated pathways, including inflammatory cytokine, PI3K/AKT, TGFb, and complement/coagulation pathways. An increase in VSIG4, CD27, HAVCR1, and LAIR1 consistently emerged as top biomarkers across multiple clinical contexts, and early decreases in these markers at 3 months were associated with complete treatment response at 1 year. By resolving coordinated serum protein modules linked to key inflammatory, PI3K/AKT, TGFb, and complement pathways, these signatures mechanistically connect circulating proteomic perturbations to intrarenal immune activation, tissue injury, and repair in LN. These findings demonstrate that serum proteomics reflect complex intrarenal immunopathology and offer a promising noninvasive "liquid biopsy" approach to refine LN classification and guide personalized management, potentially reducing the need for repeated invasive biopsies and improving therapeutic decision-making.

Adeno-associated virus (AAV)-delivered anti-HIV-1 broadly neutralizing antibodies (bNAbs) could prevent and treat HIV-1 infection but are limited by host immune responses, specifically anti-drug antibodies (ADA). We tested whether PD-L1-mediated immune shielding could improve the consistency of AAV-delivered bNAb expression from muscle tissue in rhesus macaques. AAV9.PD-L1 co-delivery with AAV9.3BNC117 reduced the occurrence of ADA and T cell responses and improved the durability of 3BNC117 expression for one year post administration. Importantly, 5 of 6 macaques that received co-delivered AAV9.PD-L1 vectors were protected against ten repeated SHIVAD8-EO challenges. Histopathological and spatial transcriptomic profiling showed that AAV9.PD-L1 co-delivery prevented severe local inflammation, muscle injury, and tertiary lymphoid structure formation at the administration site. Thus, immune shielding could serve as a strategy to prolong transgene expression from muscle-directed AAV-delivered biologics.

Inflammatory diseases cause significant morbidity and mortality, but their pathobiology is often difficult to dissect due to complex genetic-environmental interactions. Genetic forms of heterotopic ossification, such as fibrodysplasia ossificans progressiva (FOP), reduce genetic variability, allowing careful dissection of non-genetic drivers of inflammation. While >95% of FOP patients harbor the ACVR1R206H mutation, patients exhibit significant variability in disease progression, suggesting a role of environmental drivers. Here, we identify the gut microbiome as a regulator of inflammation-driven HO in FOP. Metagenomic profiling of cohabitating FOP/unaffected sibling pairs revealed a pathogenic gut microbiome profile in FOP patients (Bray-Curtis, p < 0.05). In Pdgfr-Cre/Acvr1R206H (FOP) mice, gut microbiome ablation by antibiotics reduced spontaneous HO formation (47.4% reduction, p < 0.05) and reduced plasma IL-1 pathway activity. IL-1{beta} blockade in FOP mice suppressed trauma-induced HO formation. These findings identify a gut microbiome-IL-1-HO axis with modifiable targets for developing treatments for HO and related inflammatory conditions. One Sentence SummaryAntibiotic disruption of the gut microbiome reduces HO in FOP mice via an IL-1 mediated pathway.

Oropouche virus (OROV) is an emerging arbovirus responsible for large outbreaks of febrile illness in Central and South America, with increasing reports of severe neurological disease and fatal outcomes. Despite its growing public health impact, no approved antiviral therapies or vaccines are currently available. Here, we show that favipiravir, a broad-spectrum nucleoside analogue, robustly suppresses OROV replication and disease in vivo. In a lethal Syrian hamster model, favipiravir treatment provided complete protection against OROV infection, preventing viral dissemination to peripheral organs and the central nervous system, and remained highly effective when administration was initiated after infection. In contrast, insufficient antiviral control resulted in viral neuroinvasion and fatality. To define host responses associated with OROV pathogenesis and their modulation by antiviral therapy, we performed transcriptomic profiling of liver and brain tissues. OROV infection induced interferon-driven inflammatory programs accompanied by marked disruption of metabolic and tissue homeostatic pathways, whereas these transcriptional signatures were largely abrogated by favipiravir treatment. Together, our findings identify favipiravir as a potent antiviral candidate against OROV and provide the first in vivo, tissue-resolved transcriptomic framework of OROV infection, linking effective viral suppression with the prevention of neuroinvasion and pathogenic host responses. These results highlight antiviral intervention as a viable strategy to mitigate OROV-associated disease and mortality.

Vaccines to prevent infant group B streptococcus (GBS) disease are advancing, with licensure likely based on safety and immunologic endpoints rather than clinical efficacy data. This approach requires robust, generalisable serological thresholds of risk reduction (SToRRs). We combined data from six case-control studies in Europe and Africa to define SToRRs for early-onset (EOD) and late-onset (LOD) GBS disease. Across diverse epidemiological and healthcare settings, anti-capsular polysaccharide IgG concentrations were consistently higher in infants who remained disease free than in those who developed disease. Higher antibody concentrations were required to reduce the risk of EOD than LOD, and higher concentrations were required for serotype Ia than for serotype III. This study provides a quantitative framework to support correlates-based evaluation and potential licensure of maternal GBS vaccines.

Dementia affects tens of millions of people worldwide, yet disease-modifying treatments remain strikingly limited. Although the recombinant zoster vaccine Shingrix has been associated with reduced dementia incidence, its potential influence on individuals already living with dementia is unknown. Here, we followed a propensity-score matched cohort of 68,960 US dementia patients using a nationwide electronic health record network, comparing Shingrix recipients within two years of diagnosis to recipients of any other vaccine. Shingrix was associated with substantially reduced all-cause mortality across the first three years of follow-up (hazard ratios 0.74, 0.88, and 0.89; P[&le;]0.006), robust across multiple sensitivity analyses. Furthermore, within-individual subgroup analyses of repeated Mini-Mental State Examinations conducted 3-6 years apart revealed significantly divergent cognitive decline rates across groups (time-by-group interaction P=0.002). Interval vaccination was associated with more stable cognition, contrasting with steeper declines in unvaccinated individuals. These findings support prospective evaluation of recombinant zoster vaccination as a potential strategy to improve outcomes in patients with established dementia.

Coronavirus disease 2019 (COVID-19) shows highly variable clinical outcomes that are not fully explained by age or comorbidities, underscoring the importance of host molecular responses in determining disease severity. Proteomic and multi-omics studies have linked severe COVID-19 to profound dysregulation of immune, inflammatory, and coagulation pathways, and have shown that circulating protein signatures can predict clinical trajectories. Tocilizumab (TCZ), a monoclonal antibody targeting the interleukin-6 receptor (IL-6R), is an established therapy for IL-6-driven inflammatory diseases and can normalize aberrant molecular profiles. Here, we applied longitudinal serum proteomics to patients with severe SARS-CoV-2 pneumonia treated with TCZ to further characterize how IL-6R blockade reshapes the systemic inflammatory milieu. After TCZ administration, several clinical and inflammatory markers, including C-reactive protein (CRP), CCL5 and CXCL10, decreased. Proteomic profiling revealed that TCZ exerts a sustained effect on the serum proteome, with the most pronounced changes emerging 7 days after treatment. These changes were associated with a broad reconfiguration of the proteomic profile toward a pattern resembling a healthy physiological state, characterized by the restoration of key protein abundances to levels comparable to those observed under homeostatic conditions. Collectively, our findings support that TCZ treatment contributes to the normalization of the inflammatory state in severe COVID-19 and represents a viable therapeutic option for managing the acute inflammatory phase of the disease, while also highlighting additional pathways and biomarkers involved in this recovery process.

The preclinical phase of Alzheimers disease (AD) is characterized by profound biological and structural heterogeneity, challenging our ability to map early pathology onto large-scale brain networks. To address this fundamental challenge, we introduce Functional Deviation Maps ({pi}z), an individualized neuroimaging framework for mapping participant-specific functional architecture to their unique structural atrophy landscape. By fitting a normative model to the voxel-based morphometry of amyloid-negative individuals, we extract personalized "atrophy seeds" (W-scores [&le;] -1.96) for amyloid-positive patients, subsequently obtaining their resting-state seed-based connectivity (SBC). By standardizing these participant-level SBC maps against a healthy reference distribution, we show that, despite the highly variable spatial origins of structural atrophy, individual functional deviations converge into a common "atrophy network". Spatial enrichment analyses show that the functional disruption is not random, but preferentially is dominated by the Default Mode Network. Furthermore, by projecting these populational functional deviations onto high-order cognitive topographies, we find a considerable alignment with the brains fundamental unimodal-transmodal and external-internal attentional gradients. Overall, the{pi} z framework transcends conventional group-level averages, offering a highly personalized, biologically meaningful signature of system-level network vulnerability in the earliest stages of AD.

Background & AimsClarithromycin (CLA) resistance severely compromises the efficacy of triple therapy (TT) against Helicobacter pylori (H. pylori). Bismuth-based regimens exhibit greater efficacy against CLA-resistant H. pylori than against strains resistant to other antibiotics, suggesting a resistance-specific vulnerability rather than broad antimicrobial activity. The mechanistic basis for this selectivity, however, remains unknown. We hypothesized that high-level CLA resistance confers a metabolically targetable vulnerability that can be exploited by bismuth, and that a quantitative MIC of CLA threshold could identify this responsive subset. MethodsWe conducted a real-world retrospective analysis of 4,610 pediatric patients with H. pylori infection treated between 2019 and 2024, among whom 1,844 (40%) had complete follow-up data for eradication assessment. In parallel, we prospectively enrolled 51 patients with culture-positive isolates--the largest liquid checkerboard panel reported to date--to evaluate bismuth-CLA interactions and track treatment outcomes. Mechanistic validation included transcriptomic profiling and functional assays of iron and ATP metabolism, with iron chelation and supplementation experiments. ResultsIn the retrospective real-world cohort (n = 4,610; 1,844 with follow-up), bismuth quadruple therapy (BQT) achieved superior eradication specifically in CLA-resistant infections (93.1% vs 68.8% with TT; p = 0.017). In vitro, bismuth-CLA synergy was exclusive to resistant strains and intensified with increasing MIC of CLA. Mechanistically, bismuth triggered coordinated depletion of intracellular iron and ATP--a phenotype mimicked by iron chelation and reversed by iron supplementation. A baseline MIC of CLA [&ge;]16 g/mL robustly predicted this synergy (AUC = 0.991) and was prospectively validated in an independent patient subset: bismuth cured 96% of high-level resistant patients (MIC [&ge;] 16 g/mL) versus 0% with triple therapy (p < 0.001). ConclusionHigh-level CLA resistance defines an iron-dependent metabolic vulnerability in H. pylori that is selectively targeted by bismuth. The MIC threshold of [&ge;] 16 g/mL provides the first clinically actionable biomarker for resistance-guided therapy, transforming a marker of treatment failure into a positive predictor of bismuth response. These findings establish the mechanistic and clinical foundation for MIC-stratified eradication strategies and inform future randomized trials aimed at precision management of antibiotic-resistant H. pylori infection. Graphical abstractO_ST_ABSLeftC_ST_ABSHigh-level clarithromycin (CLA) resistance defines a distinct physiological phenotype in Helicobacter pylori, in which an elevated MIC of CLA ([&ge;] 16 {micro}g/mL) predicts poor eradication with triple therapy (TT) but favorable response to bismuth-containing quadruple therapy (BQT). MiddleMechanistically, CLA resistance is associated with upregulation of the ferric uptake regulator Fur, leading to reprogrammed iron homeostasis and an increased metabolic burden. Colloidal bismuth subcitrate (CBS) disrupts Fur-dependent iron regulation, exacerbates iron-restricted metabolic stress, and compromises cellular integrity, thereby selectively sensitizing CLA-resistant bacteria to antibiotic killing. RightTranslational implication of reframing antibiotic resistance as a therapeutic vulnerability--bismuth-based regimens function as a "key" that unlocks resistance-associated metabolic liabilities, delays resistance evolution, and improves treatment outcomes. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/26351907v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@28fb58org.highwire.dtl.DTLVardef@8d5190org.highwire.dtl.DTLVardef@1e5fc9dorg.highwire.dtl.DTLVardef@2bc102_HPS_FORMAT_FIGEXP M_FIG C_FIG