Journal of Allergy and Clinical Immunology

BackgroundClinical and genetic evidence on the association between atopic dermatitis (AD) and subsequent psoriasis remains conflicting, and it is unclear whether this risk is modified by systemic treatments. Recent reports suggest type 2-targeted biologics may unmask psoriasis in AD patients, but data are limited. We thus aimed to assess whether AD is associated with incident psoriasis and whether this risk differs by systemic treatment, particularly biologics versus conventional systemic immunosuppressants (cvIS). MethodsScoping analyses informed a locked analytic design, preregistration at OSF, and confirmatory execution. Propensity score-matched analyses compared AD with non-AD controls and biologics with cvIS. Sensitivity analyses, Cox model triangulation, and control outcomes assessed robustness. FindingsAmong [~]300,000 matched pairs, AD was associated with increased psoriasis risk (primary HR 3.81, 95% CI 3.35-4.34), consistent across all 8 sensitivity analyses and model triangulation. Biologic treatment was associated with reduced psoriasis risk versus cvIS (primary HR 0.20, 95% CI 0.11-0.35), consistent across 6 of 7 evaluable sensitivity analyses and Cox triangulation. Positive and negative control outcomes showed expected directional patterns. InterpretationAcknowledging limitations including residual confounding and coding misclassification, AD was associated with increased psoriasis risk and biologics with lower psoriasis risk than cvIS. FundingDFG (EXC2167, SFB1526, LU877/25-1), Schleswig-Holstein Excellence-Chair Program, Swedish Society for Dermatology and Venereology, and the Tore Nilson Foundation. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSAtopic dermatitis (eczema) and psoriasis are the two most common chronic inflammatory skin diseases worldwide. For a long time, doctors and researchers assumed these two conditions could not occur in the same person, as they were thought to involve opposing immune responses. However, this view has been challenged over the past decade. Some large studies, including population-based cohorts from Taiwan and the United Kingdom, have found that people with eczema may be at higher risk of developing psoriasis over time, while other studies, including genetic analyses, have suggested the opposite: that the two diseases may actually protect against each other. This conflicting picture has left clinicians uncertain about the true relationship between the two diseases in everyday clinical practice. A separate but related concern has emerged with the introduction of a new class of highly effective treatments for eczema, biologics, particularly dupilumab. Case reports and observational studies, including a large study published in JAMA Dermatology in 2025, have raised the possibility that these medications might trigger psoriasis in some patients, potentially by shifting the immune system from one inflammatory pattern to another. However, prior studies on this question had important methodological limitations: they were not pre-planned and registered before data collection, they did not always tightly link treatment use to an eczema diagnosis, and critically, none compared biologic treatment directly against conventional immunosuppressant medications, the most relevant clinical comparator. Added value of this studyThis study is a large and methodologically rigorous investigation of both questions: whether eczema itself increases the risk of developing psoriasis, and whether the type of systemic treatment used for eczema influences that risk. Using a database of over 110 million electronic health records from across the United States, we matched approximately 300,000 patients with eczema to 300,000 patients without eczema and followed them for up to seven years. We also compared nearly 5,500 patients treated with biologics to an equal number treated with conventional immunosuppressants. Crucially, our study was pre-registered before any data were analyzed, meaning the research questions, methods, and analyses were locked in advance and could not be adjusted based on what the data showed. We also used a range of additional analyses to test whether our findings were robust, including checks using outcomes that should not be affected by eczema or its treatment (such as appendectomy and hearing loss), which confirmed that our results were not likely explained by bias alone. We found that eczema was associated with an increased risk of developing psoriasis, but that this risk was substantially influenced by the choice of comparison group, ranging from approximately 1.4-fold to nearly 4-fold depending on the analytical approach. More strikingly, we found that patients treated with biologics had a markedly lower risk of developing psoriasis compared with those treated with conventional immunosuppressants, the opposite of what prior reports had suggested. This finding was consistent across nearly all additional analyses performed. Implications of all the available evidenceTaken together with existing evidence, these findings suggest two important conclusions. First, clinicians should be aware that eczema, particularly moderate-to-severe eczema requiring systemic treatment, may carry an elevated risk of developing psoriasis over time. This does not mean that all patients with eczema need to be screened for psoriasis routinely, but it does support clinical awareness and monitoring in higher-risk patients. Second, and perhaps most importantly for treatment decisions, biologics do not appear to increase the risk of psoriasis compared with conventional immunosuppressants and may in fact be associated with a lower risk. This provides reassurance for patients and clinicians considering biologic therapy and challenges the narrative that these medications trigger psoriasis. Future research should aim to confirm these findings in other populations, investigate the biological mechanisms underlying the relationship between eczema and psoriasis, and examine whether specific biologic agents differ from one another in their effects on psoriasis risk.

ImportanceEmerging data show that B-cell depleting chemotherapies, which are increasingly used to treat autoimmune disorders and multiple sclerosis, can be associated with mucosal side effects such as inflammatory vaginitis. ObjectiveEvaluate the impact of rituximab treatment on vaginal mucosal immune markers, endocervical immune cell populations and vaginal microbiome. DesignCross-sectional observational study conducted between 2022 - 2024. SettingAcademic medical center, Boston Massachusetts. ParticipantsWe enrolled women aged >18 years who were either 1) receiving rituximab for autoimmune renal disease or were 2) healthy controls ExposureTreatment with rituximab, an anti CD20 monoclonal antibody. Main outcome and measureWe compared endocervical immune cell populations, vaginal fluid immune markers, vaginal fluid immunoglobulins and vaginal microbiome composition between individuals being treated with rituximab and healthy controls. ResultsWe enrolled 26 women treated with rituximab for autoimmune renal disease and 26 healthy controls. Median circulating and endocervical B-cell and plasma cell proportions were significantly lower in treated participants compared to controls. Median vaginal fluid IgA concentrations were significantly lower in participants treated with rituximab, while ILE, IgM, IgG1, IgG2, IgG3 and IgG4 were not different between groups. Total T cell frequencies were similar between groups, but the proportion of activated T cells (CD4+CD38+HLADR+) was significantly lower in people treated with rituximab. Concentrations of IL10, IL13, IL17, IL21, IL23, IL4, ITAC and TNFa were elevated in vaginal fluid from the rituximab group, while IL-8 was lower. A CST-IV-C, low-Lactobacillus pattern of vaginal microbiota was more common in the rituximab group. Conclusions and RelevanceSystemic B-cell depletion is associated with reduced vaginal fluid IgA, a more diverse microbiome composition, and increases in many vaginal fluid immune markers compared to healthy controls. The reduction in vaginal fluid IgA may provide opportunities for vaginal bacteria to induce inflammation. Key pointsO_ST_ABSQuestionC_ST_ABSHow does circulating B-cell depletion impact the vaginal microenvironment? FindingsIn this cross-sectional study of 52 women, B cell and plasma cell proportions were significantly lower in both blood and vaginal mucosa among rituximab-treated participants compared to healthy controls. Vaginal IgA concentrations, but not other immunoglobulins, were significantly lower in rituximab treated participants. In treated participants, vaginal cytokine concentrations were elevated, and microbiome composition shifted toward non-Lactobacillus-dominant communities. In six people with inflammatory vaginitis, both circulating and endocervical B cells were lowest in people with the most severe symptoms. MeaningSystemic B cell depletion is associated with alterations in vaginal mucosal immune markers and microbiome composition which increase local inflammation.

BackgroundDespite advances in therapy, optimal management of juvenile idiopathic arthritis (JIA) remains challenging. The ability to predict disease progression in JIA can improve personalized treatment decisions, but few reliable clinical predictors have been identified. We developed machine learning approaches to predict disease trajectories in children with JIA. MethodsUsing data from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry (years 2015-2024), we developed machine learning models to predict attainment of inactive disease in children with non-systemic JIA. We applied Dynamic Bayesian Networks (DBN) to model temporal dependencies and causal relationships, and Convolutional Neural Networks (CNN) to capture complex non-linear patterns. Model input included demographic factors, longitudinal clinical factors, and medication use in the preceding 12 months. FindingsA total of 8,093 participants were included. When tested on an independent test cohort, both DBN (AUC:0.76; precision:0.73; recall:0.83; F1-score:0.78; accuracy:0.71) and CNN (AUC:0.76; precision:0.71; recall:0.63; F1-score:0.67; accuracy:0.70) models achieved comparable performance in predicting inactive disease. Disease activity levels in the preceding 12 months, presence of enthesitis and uveitis were the strongest predictors. Causal relationships captured in the DBN model revealed suboptimal care patterns, likely shaped by insurance constraints and a predominantly reactive approach to JIA management. InterpretationOur study demonstrates that machine learning approaches can predict disease trajectories in JIA with good discriminative performance. Unlike prior studies that predict outcomes at single timepoints, our models are the first to predict inactive disease longitudinally. However, suboptimal care patterns in retrospective data limit models capacity to learn treatment-outcome relationships, underscoring critical opportunities to improve JIA care and the need for prospective comparative studies to better inform prediction models. FundingPatient-Centered Outcomes Research Institute (PCORI) Award (ME-2022C2-25573-IC). RESEARCH IN CONTEXT Evidence before this studyNumerous studies have sought to identify clinical predictors of JIA progression and outcomes. However, few reliable predictors have emerged and existing prediction models demonstrate limited performance. As a result, our ability to personalize treatment decisions based on individual risk of severe disease course remains limited. Added value of this studyWe developed novel machine learning models that predict individualized disease trajectories in children with polyarticular and oligoarticular JIA using data from their preceding 12-month clinical course. These models demonstrated strong discriminative performance and outperformed previously published machine learning approaches in JIA. Unlike prior studies limited to single time-point predictions, our models are the first to predict inactive disease longitudinally, enabling a patient-specific projection of disease progression over time. Importantly, our findings also bright to light patterns of suboptimal care, likely driven by insurance constraints and a reactive treatment paradigm, underscoring critical opportunities to improve JIA management. Implications of all the available evidenceOur models have the potential to support clinical decision-making by enabling early identification of children with JIA at risk for unfavorable disease trajectories. In addition, the suboptimal care patterns and systems-level barriers identified through our analyses highlight priority areas for quality improvement initiatives and policy interventions to reduce gaps in JIA care delivery.

Abstract / SummarySurvival outcomes for pediatric Burkitt lymphoma (BL) substantially vary depending on geography (50-90%), which also serves as a proxy for the prevalence of Epstein-Barr virus (EBV) within the tumors. Although BL is considered an immunologically "cold" tumor with few tumor-infiltrating lymphocytes (TILs), their functional status has not been fully evaluated, especially for EBV-positive disease. Here, we characterize the exhaustion and activation profiles of T cells in the tumor microenvironment (TME) of EBV-positive BL using orthogonal methods, single-cell gene expression analysis, spectral flow cytometry, and immuno-histochemistry staining (IHC). We found that CD8+ TILs displayed a mosaic of immune inhibitory gene expression encoding, PD1, TIGIT, LAG3 and HAVCR2/TIM3. IHC validated the expression of PD1 and TIGIT on CD8+ TILs, as well as their respective ligands, PDL-1, PVR, and Nectin-2 on malignant B cells. Despite exhaustion-associated signatures, CD8+ TILs retain cytotoxic potential, expressing granules (i.e. Granzyme A, Perforin) and cytokines (i.e. IFN{gamma}) and demonstrate an increased uptake of metabolites such as glucose, arginine, and methionine. In peripheral blood, pediatric BL patients exhibited a significantly higher abundance of PD1+TIGIT+ CD8+ T cells compared to healthy children. Notably, these circulating T cells from BL patients express significantly lower levels of TOX, suggesting they are not irreversibly dysfunctional. Together, our results indicate that CD8+ T cells both in the TME and in circulation of children with BL are not terminally exhausted but remain poised for functional re-invigoration. These findings support the potential integration of immune checkpoint inhibitors into combination chemotherapeutic regimens to improve outcomes for these children. SignificanceEBV-positive BL tumors contain functional, metabolically active CD8+ T cells. Circulating PD1+TIGIT+CD8+ T cells found in BL patients blood are a biomarker for those in the tumor microenvironment.

BackgroundChronic relapsing inflammatory optic neuropathy (CRION) is a steroid-dependent form of optic neuritis with incompletely understood pathophysiology. The identification of myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) in a substantial patient subset has challenged the diagnostic and therapeutic management. The aim of this study was to investigate clinical profiles and treatment outcomes of patients with CRION, comparing MOG-IgG-positive (MOG+) and seronegative (MOG-) subgroups. MethodsPatients from six European tertiary centers fulfilling diagnostic criteria for CRION were included. All underwent cell-based autoantibody testing. Clinical outcomes (visual acuity, annualized relapse rate), laboratory and imaging findings (MRI, OCT), and treatment responses were retrospectively analyzed. ResultsSixty patients were included (median age 33 years; 70% female); 27 (45%) were MOG+. MOG+ CRION was associated with later onset, higher ARR before treatment (median [IQR] 2 [1-3] vs. 1 [1-2], p = 0.023), and a trend toward shorter inter-relapse intervals. Additional distinguishing features included higher frequencies of antinuclear antibody positivity, elevated CSF interleukin-6, and extensive optic neuritis on MRI. Relapse burden correlated with visual acuity decline and retinal thinning. In MOG+ patients, monoclonal antibody therapy reduced the ARR (n = 21; 2 [1-3] vs. 0 [0-2], p = 0.024), primarily driven by tocilizumab (n = 11; 2 [1-3] vs. 0 [0-1], p = 0.023). In MOG-patients, rituximab and azathioprine showed a trend toward ARR reduction. ConclusionCRION represents a heterogeneous syndrome encompassing distinct subgroups. MOG+ patients demonstrate higher disease activity but respond favorably to tocilizumab. Serological testing is critical for treatment stratification and preventing relapses.

BackgroundTBX4 variants are a recognised cause of paediatric pulmonary hypertension (PH), often associated with interstitial lung disease (ILD). Evidence for ILD-directed therapy in this group is lacking. MethodsWe conducted a retrospective study of children ([≤]18 years) with TBX4-associated PH at a national centre (2001-2025). ILD was defined using ChILD-EU criteria. Patients treated with pulsed intravenous methylprednisolone were assessed for response using ChILD-EU categories. Secondary outcomes included respiratory severity score (RSS), functional class (FC), echocardiographic measures, and NT-proBNP. ResultsOf 21 children, 11 (52%) had ILD; 9 received corticosteroids. Median age at treatment was 0.8 years. A clear or best response occurred in 7/9 (78%). RSS improved in 6/9 (p=0.02), with all children on respiratory support showing partial or complete weaning. Functional class improved in all with FC III/IV at baseline (p=0.02). Right ventricular function improved (TAPSE z-score +1.65, p=0.04), and elevated NT-proBNP normalised. Key clinical milestones included ECMO weaning, transplant delisting, and discontinuation of prostacyclin therapy. No significant adverse effects were observed. Untreated children showed no early improvement. ConclusionsCorticosteroids were associated with meaningful improvements in respiratory and PH outcomes in TBX4-associated PH with ILD. Prospective evaluation is warranted.

Orientia tsutsugamushi (Ot) is an obligately intracellular bacterium that causes scrub typhus, a potentially severe infectious disease characterized by systemic inflammation and multiorgan dysfunction. We recently reported a protective role for IFN-{gamma} signaling in host defense against Ot infection; however, the underlying mechanisms remain obscure. Inducible nitric oxide synthase (iNOS, encoded by Nos2) is a key antimicrobial effector induced downstream of IFN-{gamma} signaling. Here, we used transgenic mouse models to further investigate the biological functions of iNOS. We first revealed the requirement of iNOS for the restriction of Ot growth in cultured bone marrow-derived macrophages. Using an intradermal mouse model, we found that while tissues of Nos2-/- and wild-type mice exhibited comparable bacterial burdens during acute infection phases, Nos2-/- mice developed eschar-like lesions similar to those observed in Ifngr1-/- mice, indicating a critical role for the IFN-{gamma}/iNOS axis in regulating skin pathology in scrub typhus. Notably, Nos2-/- mice displayed impaired bacterial clearance during the recovery phase (day 42), with persistent bacterial burdens in multiple organs accompanied by sustained immune activation and elevated inflammatory responses. Histopathological and biochemical analyses further revealed increased tissue damage and dysregulated physiological homeostasis in Nos2-/- mice during recovery. Mechanistically, iNOS deficiency resulted in heightened myeloid cell activation and prolonged expression of proinflammatory mediators, suggesting a dual contribution of iNOS in both antimicrobial defense and inflammation resolution. Collectively, these findings provide new insight into IFN-{gamma}-mediated defense mechanisms and imply the distinct roles of iNOS during different stages of scrub typhus. Author summaryScrub typhus is a potentially severe infectious disease caused by the bacterium Orientia tsutsugamushi (Ot), which is transmitted to humans through the bite of infected mites. Despite its global impact and expanding geographic distribution, the immune mechanisms that protect against this infection remain incompletely understood. In this study, we examined the role of inducible nitric oxide synthase (iNOS), an immune effector molecule that helps the host control infection. Using mouse models, we found that iNOS plays dual and stage-specific roles during Ot infection. Mice lacking iNOS developed dysregulated immune homeostasis during acute infection and exhibited skin lesions resembling the eschars observed in some patients with scrub typhus. In addition, these mice showed delayed bacterial clearance, prolonged inflammation, and increased tissue damage during the recovery phase. Our findings indicate that iNOS contributes not only to host antimicrobial defense but also to the control of excessive inflammation following infection. These results provide new insight into host defense mechanisms in scrub typhus and may help inform future therapeutic or preventive strategies.

In multiple sclerosis (MS), autoreactive B cells play a central role in driving CD4 T cell-mediated inflammatory damage to myelin (1). Here we investigated how disrupting Brutons tyrosine kinase (BTK) signaling exclusively in B cells shapes the course of experimental autoimmune encephalomyelitis (EAE), a model for MS, through alterations in B cell development and activity. B cell-specific BTK deletion significantly ameliorated both human MOG (hMOG) induced EAE (p = 0.0087) as well as spontaneous disease in 2D2+IgHMOG mice (p = 0.0004). Additionally, MOG-specific cells were found to be more sensitive to loss of BTK than tolerant clones (p = 0.0002) and production of anti-MOG immunoglobulins was also found to be diminished (p < 0.004) while overall IgG was unchanged (p = 0.44). B cells isolated from conditional knockout mice did not upregulate expression of co-stimulatory receptors or MHC II to the same extent as controls when cultured alongside MOG-specific CD4 T cells (p < 0.005) and were inferior at driving T cell proliferation (p < 0.0001) in vitro. Lastly, while BTK deletion diminished the proliferative and survival response of B cells following mitogen stimulation, B cell trafficking to the leptomeninges and organization into ectopic lymphoid tissues (ELTs) in 2D2+IgHMOG mice continued unabated. We identified that BTK signaling regulates several features adopted by autoreactive B cells that contribute to EAE pathogenesis. This study provides mechanistic insights into the therapeutic benefits of BTK inhibitors observed in clinical trials exploring BTK as a therapeutic target in the context of MS. Significance statementAutoreactive B cells contribute to the neuroinflammation that drives multiple sclerosis (MS) and related diseases, yet the molecular mechanisms enabling their pathogenicity remain incompletely understood. This study demonstrates that B cell-specific deletion of Brutons tyrosine kinase (BTK) markedly reduces disease severity in two complementary versions of experimental autoimmune encephalomyelitis (EAE), a widely used animal model for MS. Loss of BTK impairs autoreactive B cell survival, antibody production, antigen presentation to encephalitogenic T cells, and T cell activation, while leaving meningeal ectopic lymphoid tissue formation intact. These findings provide direct mechanistic evidence that BTK signaling in B cells promotes neuroinflammatory damage and supports the therapeutic targeting of BTK to limit B cell-driven pathology in MS.

The A(H1N1)pdm09 virus remains a major global health threat. This study examined the burden of ICU admission, mortality, and associated predictors among patients with A(H1N1)pdm09 pneumonia in a leading center for infectious diseases in Vietnam. Information on demographic, clinical, and laboratory characteristics, and outcomes was retrieved from medical records of adults admitted with influenza A(H1N1)pdm09 during 2009-2019. Among 729 cases, 21.7% (158/729) developed pneumonia. Among 158 pneumonia cases, 36.7% (58/158) developed moderate-to-severe acute respiratory distress syndrome (ARDS), and 15.2% (24/158) received invasive ventilation. ICU admission and mortality rates were 48.7% (77/158, 95%CI 41.1-56.5%) and 8.2% (13/158, 95%CI 4.9-13.6%), respectively. Predictors of ICU admission included being >60 years old (adjusted OR [AOR] 13.864, 95%CI 2.185-87.956, P=0.005), comorbidities (AOR 6.527, 95%CI 1.710-24.915, P=0.006), AST (AOR 1.013, 95%CI 1.001-1.025, P=0.029), and moderate-to-severe ARDS (AOR 14.027, 95%CI 4.220-46.627, P<0.001). Predictors of mortality were invasive ventilation (AOR 55.355, 95%CI 1.486-2062.375, P=0.030) and double-dose oseltamivir or combination therapy (AOR 32.625, 95%CI 1.594-667.661, P=0.024). In conclusion, mortality is not rare in A(H1N1)pdm09 infection. Monitoring of older patients and those with comorbidities, liver enzyme elevation, or moderate-to-severe ARDS is essential for the timely detection of complications requiring intensive care.

Genome-wide association studies of idiopathic pulmonary fibrosis (IPF) have identified 35 common genetic risk loci associated with IPF susceptibility. In this study, we evaluated the effects of the reported variants in clinically curated non-European individuals. Despite limited sample sizes, we observed partial replication, limited transferability of some variants and evidence of ancestry-specific effects. The MUC5B promoter variant rs35705950 emerged as the dominant and most consistent signal across ancestries. Our findings highlight the need for larger, well-characterised studies in understudied populations to support robust discovery and translation.

Background: Acute necrotizing encephalopathy (ANE) is a rare and severe neurologic complication of viral infection in children, thought to result from a hyperacute cytokine storm causing blood-brain barrier disruption and central nervous system injury. Despite characteristic clinical and radiologic features, ANE remains poorly understood at the molecular level, with no validated biomarkers or targeted therapies. We aimed to determine whether genetic predisposition to ANE due to RANBP2 variants is associated with a distinct immunologic signature. Methods: We conducted a prospective biological study of familial ANE (ANE1, NCT06731790). We included 23 heterozygous carriers of the RANBP2 c.1754C>T (p.Thr585Met) variant from 10 families, and 28 noncarriers (median age, 40 years [range, 4-72]). Soluble immune mediators, transcriptomic analyses, multiparameter flow cytometry, and cellular imaging were analysed in peripheral blood mononuclear cells (PBMCs) and monocytes. Baseline and resiquimod stimulated immune responses were analysed within the same statistical model, with genetic status as the primary predictor. Findings: The RANBP2 Thr585Met mutation was associated with a dysregulated inflammatory phenotype characterized by reduced basal mediator production and exaggerated TNF- responses following stimulation (estimated difference, +2,098 pg/mL; 95% CI, 1,121 to 3,076; P=0.0001). Transcriptomic and flow cytometry analyses showed broad reprogramming of myeloid cells with enrichment of CXCR3-high CD14-high subsets. Expansion of these populations was associated with increased long-term disease burden. The RANBP2 variant was the only independent factor associated this inflammatory phenotype. Interpretation: RANBP2-associated ANE is characterised by a distinct immunological signature that can inform disease stratification and support the development of targeted immunotherapeutic approaches.

Background: Ageing is a systems level biological process underlying the onset and progression of multiple chronic disorders. Rather than arising from a single pathway, age related decline reflects interacting disturbances in metabolic regulation, inflammation, nutrient sensing, cellular stress responses, and tissue repair. Although GLP1 receptor agonists, sodium glucose cotransporter2 inhibitors, metformin, and rapamycin are usually evaluated against disease-specific endpoints. Objective: To develop an SBML compliant quantitative systems pharmacology model in which ageing is the primary pharmacological endpoint and to evaluate which combination therapy provides the greatest benefit for both metabolic and ageing related outcomes. Methods: We developed model comprising four layers: a metabolic/pharmacodynamic layer describing weight loss, HbA1c reduction, and nausea with tolerance; a drug layer capturing class-specific effects of GLP1 agonists, sodium glucose cotransporter2 inhibitors, metformin, and rapamycin; an ageing layer representing damage accumulation, repair capacity, frailty, and biological age gap; and a biomarker layer generating trajectories and estimated glucose disposal rate. Calibration was staged across semaglutide clinical endpoints. Bayesian hierarchical meta analysis, global sensitivity analysis, and practical identifiability analysis were used to assess robustness and interpretability. Results: The model reproduced semaglutide efficacy and tolerability dynamics and supported distinct drug-class profiles across metabolic and ageing axes. Rapamycin showed minimal glycaemic effect but emerged as a dominant driver of repair related ageing outcomes. Combination simulations predicted two distinct optima: one favouring metabolic improvement and one favouring ageing related benefit. Conclusion: The model supports the view that metabolic and ageing optimization are mechanistically distinct objectives and that weight loss and glycaemic improvement alone may be insufficient surrogates for health span benefit.

Hereditary hearing loss is highly genetically heterogeneous, with emerging overlap between genes implicated in early-onset and age-related hearing loss. We report a consanguineous family with autosomal recessive, non-syndromic hearing loss in which the proband harbors a homozygous splice-site variant in PALM3 (NM_001145028.2:c.314+1G>A) and a homozygous missense variant in OTOA. A minigene assay for the PALM3 variant demonstrated aberrant splicing with exon skipping, resulting in a frameshift and a large inframe deletion, both consistent with loss of function and impacting all known transcripts. While the organ of Corti from 12-month-old heterozygous Palm3 mice showed preserved overall architecture, published Palm3 knockout mice exhibit auditory dysfunction, supporting an auditory phenotype with loss of function. Although a dual molecular diagnosis cannot be excluded, the combined genetic, functional, and comparative data support PALM3 as a strong candidate gene for autosomal recessive hearing loss.

Type 2 diabetes mellitus (T2DM) is a progressive metabolic disorder characterized by persistent hyperglycemia, insulin resistance, and chronic low-grade inflammation. Despite the widespread use of established therapies such as metformin, long-term glycemic control remains suboptimal, and disease progression is often not adequately prevented. This highlights the need for novel therapeutic strategies that address both metabolic dysfunction and the underlying immunometabolic components of the disease. In this study, GLX10 (GLXM100) was evaluated as a novel immune modulator in a high-fat diet (HFD) and low-dose streptozotocin (STZ)-induced rat model of T2DM over a 91-day period. Glycemic outcomes were assessed using terminal random blood glucose and oral glucose tolerance testing (OGTT), with glucose exposure quantified by area under the curve (AUC 0-120). Complementary in vitro investigations were performed in hepatic and macrophage cell models to assess cytocompatibility, nitric oxide production, and modulation of pro-inflammatory cytokines, including IL-6 and TNF-. GLX10 treatment resulted in a significant reduction in random blood glucose levels and a marked improvement in glucose tolerance compared to diabetic control animals. Importantly, GLX10 demonstrated greater improvement in OGTT AUC compared to metformin under the same experimental conditions, indicating enhanced dynamic glucose regulation. In vitro, GLX10 maintained viability in normal hepatic cells while significantly suppressing nitric oxide production and inflammatory cytokine outputs in macrophages, supporting a favorable safety and immune profile. Collectively, these findings demonstrate that GLX10 exerts robust antidiabetic activity through a dual mechanism involving metabolic regulation and suppression of inflammatory signaling. The integration of in vivo efficacy with supportive in vitro safety and mechanistic data provides a strong preclinical foundation and supports the further development of GLX10 as a promising therapeutic candidate for T2DM.

BackgroundPsoriasis is a chronic immune-mediated inflammatory disease (IMID) with systemic involvement. In mild-to-moderate disease, circulating cytokines may inadequately capture systemic inflammatory burden. Composite haematological indices derived from complete blood counts, such as the systemic immune-inflammation index (SII) and systemic inflammation response index (SIRI), have emerged as sensitive prognostic markers of systemic inflammation, including in psoriasis. This exploratory post hoc analysis investigated the effects of orally administered herring roe oil (HRO), a phospholipid-rich marine oil, on systemic inflammation in patients with mild-to-moderate psoriasis utilizing these biomarkers. MethodsData were analysed from a randomized, double-blind, placebo-controlled 26-week clinical study which investigated HRO supplementation in patients (N = 64) with mild-to-moderate psoriasis (NCT03359577). SII, SIRI, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) were calculated at baseline, week 12, and week 26 for patients where baseline complete blood counts (CBCs) were available (n = 60). Patients missing baseline CBCs were excluded from the analysis. Continuous changes were assessed using ANCOVA with baseline adjustment. Categorical responder analyses were performed with 25% and 30% reduction thresholds and stratification by baseline biomarker medians were performed to evaluate treatment responses and impact of baseline inflammation. ResultsCompared with placebo, HRO treatment resulted in significant mean reductions in SII, SIRI, and PLR at week 26, with supportive trends and responder effects observed as early as week 12 compared to placebo. Patients with elevated baseline inflammatory indices showed the greatest reductions in systemic inflammation. Stratification by baseline SII further revealed enhanced clinical benefit, with statistically significant PASI50 response rates in the HRO arm at week 26 among patients with lower baseline SII. ConclusionHRO supplementation was associated with a time{square}dependent reduction in systemic inflammatory biomarkers in mild{square}to{square}moderate psoriasis patients. These findings support the utility of composite inflammatory indices for monitoring systemic inflammation and suggest that baseline SII may have utility in predicting treatment response and may be a useful tool for stratification in clinical trials in mild to moderate psoriasis patients. These results could also suggest platform-potential of HRO for resolution{square}oriented interventions across several inflammatory conditions.

Rheumatoid arthritis (RA) is a heritable and common autoimmune condition. To date, most genetic associations were derived from individuals with either European or East Asian ancestries. Here, we applied a multimodal automated phenotyping strategy to define RA and performed a genome-wide association study (GWAS) of RA in the Million Veteran Program (MVP), including underrepresented African American (AFR) and Admixed American (AMR) populations. Meta-analyses with previous RA cohorts identified 152 autosomal genome-wide significant loci, of which 31 were novel. Inclusion of multi-ancestry data dramatically improved fine-mapping resolution. Functional characterization of these loci using single-cell transcriptomic and chromatin data suggested new RA genes such as CHD7 and CD247. We identified underappreciated functional roles of fine-grained immune cell states other than T cells, such as B cell and myeloid cell states. We observed that multi-ancestry polygenic risk scores using our data demonstrated better predictive ability, especially for AFR and AMR populations.

Drug targets supported by human genetic evidence have significantly higher approval rates, making genome-wide association studies a valuable resource for drug candidate prioritisation. Transcriptome-wide association study signature-matching is an emerging in silico approach that integrates GWAS data with expression quantitative trait loci to generate a disease gene expression signature, which is then compared against drug perturbation databases such as the Connectivity Map. Despite recent adoption, there is no consensus on optimal methodology. Here, we systematically benchmark key parameters, including TWAS method, eQTL tissue model, similarity metric, gene set size, and CMap cell line, using LDL cholesterol, familial combined hyperlipidemia, and asthma as proof-of-concept traits. We demonstrate that while TWAS signature-matching can successfully prioritise known first-line treatments, performance is highly sensitive to parameter choice; for instance, the selection of the cell line used for drug signatures alone can dramatically alter drug prioritisation. Based on these findings, we propose a best-practice framework for robust, genetically-informed drug prioritisation using TWAS signature-matching.

Multiple sclerosis (MS) is a debilitating disease affecting more than 1 million Americans, and today is assessed primarily through magnetic resonance imaging (MRI) and observational clinical symptoms. Given the autoimmune nature of MS, we hypothesized that high-dimensional gene expression data from peripheral blood mononuclear cells (PBMCs), when analyzed with the assistance of AI, may collectively serve as valuable biomarkers for the real-time risk and progression of MS. Here, we present PBMC RNA sequencing (RNAseq) results from N=997 samples, including 540 MS, 221 neuromyelitis optica (NMO), and 149 healthy controls. We constructed and optimized ensemble models for three clinical outcomes: (1) discrimination of early MS (EDSS [&le;] 2.0) from healthy individuals with 74% AUC at 100% coverage, (2) differential diagnosis of MS from NMO with 91% AUC at 80% coverage, and (3) subtyping RRMS from progressive MS with 79% AUC at 80% coverage. To our knowledge, no prior molecular test has been reported for any of these three MS clinical tasks, and these results may have immediate impact on clinical management of MS patients. Two innovations that improved the stratification accuracy of our models: selection of gene sets based on expression variance in disease states, and use of non-linear rank sort and conviction weighting in the ensemble score calculation.

Alternative-splicing events (ASE) increase transcriptomic variability and play key roles in biological functions. The contribution of ASE to bipolar disorder (BD) remains largely unexplored. We performed a Transcriptome-Wide Alternative-Splicing Analysis (TWASA) to identify ASEs and genes potentially involved in BD. The study comprised 635 individuals: a discovery sample (DS) of 31 individuals from eight multiplex BD families (16 BD cases; 15 unaffected relatives), and a replication sample (RS) of 604 subjects (372 BD cases; 232 controls). Sequencing was conducted on RNA from lymphoblastoid cell lines (DS) and whole blood (RS). TWASA was performed using VAST-TOOLS (VT), rMATS (RM), and MAJIQ/MOCCASIN (MCC). Gene-set association analyses of genes containing ASEs were performed across six psychiatric disorders. Novel ASE (nASE) were investigated in the DS using FRASER. Limited gene overlap was observed across TWASA tools. MCC identified 2,031 complex ASEs involving 1,508 genes, showing the strongest genetic association with BD across psychiatric phenotypes. Prioritization of MCC-identified ASE genes yielded 441 candidates, including DOCK2 as top candidate from the DS. Replication was obtained for 98 genes, five with an identical ASE, and four (RBM26, QKI, ANKRD36, and TATDN2) showing a concordant percentage-spliced-in direction with the DS. Finally, 578 nASE were identified in the DS, with no evidence of familial segregation or differences in ASE types. This first TWASA in BD reveals tool-specific variability, complex ASE for genes specifically associated with BD, and novel candidate genes for BD. Alternative transcript isoform abundance may represent a mechanism contributing to BD pathophysiology.

In recent years, immunotherapy of patients with higher-risk non-muscle invasive bladder cancer (NMIBC) in North America has relied on the use of the TICE strain of BCG. However, limitations in the supply chain have warranted investigation of the therapeutic benefit of other strains of BCG, such as BCG-Russia. Trained immunity, a form of innate immune memory, is now widely believed to be an important component of the therapeutic benefit of BCG. Therefore, in the present study we compared the effects of BCG-TICE and BCG-Russia on the acquisition of trained immunity and related secondary immune responses. C57BL/6 mice received a single intravenous injection of BCG-Russia or BCG-TICE. Four weeks later, bone marrow was collected for flow cytometric analysis of hematopoietic stem and progenitor cell (HSPC) populations, generation of bone marrow-derived macrophages, functional assessment of trained immunity, and transcriptomic profiling. Compared with BCG-Russia, BCG-TICE elicited stronger levels of trained immunity, characterized by higher production of several proinflammatory cytokines upon secondary activation. BCG promoted the expansion of HSPCs independent of strain. BCG-TICE was linked to upregulation of key inflammation-related genes and enrichment of functionally relevant pathways. The results of this study reveal strain-dependent differences in the ability of BCG to induce innate immune memory and inflammatory pathways that could ultimately determine efficacy of immunotherapy of patients with NMIBC.