Donor - Recipient Epstein - Barr Virus Mismatch and Post - Heart Transplant Outcomes in Recipients with Prior Malignancy

Cross‐strand chimeric RNAs (cscRNAs) represent an emerging class of noncanonical fusion transcripts arising from bidirectional transcription, yet their landscape and functional significance in gastric cancer remain unexplored. Here, we systematically investigated cscRNA expression patterns, prognostic relevance, and tumor immune microenvironment associations in gastric cancer through integrated computational and experimental approaches. Analysis of 372 TCGA‐STAD samples revealed tumor‐specific cscRNA enrichment that was independent of clinicopathological variables including tumor stage, histological grade, and lymph node metastasis status. Through a three‐layer machine learning pipeline integrating univariate screening, multivariate feature selection, and bootstrap stability validation, we identified six cscRNA‐enriched genomic regions that collectively formed a reproducible prognostic signature. Patients stratified by the risk score model showed significantly divergent survival outcomes (median survival: 18.9 vs. 69.0 months; univariate HR = 2.54, p < 0.001), and the risk score retained independent prognostic value after adjusting for clinical covariates (multivariable HR = 2.86, p < 0.001). In an exploratory analysis of an independent validation cohort (GSE122401, n = 26), high‐risk tumors showed features consistent with an immunosuppressive microenvironment, including reduced CD8+ T‐cell infiltration (p = 0.042), elevated regulatory T‐cell proportions (p = 0.028), and lower immune scores (p = 0.006). Subgroup analyses by microsatellite instability and Epstein–Barr virus status (n = 4 and n = 6, respectively) suggested differential immune patterns warranting confirmation in larger cohorts. Experimental validation confirmed cscR‐819 as a bona fide posttranscriptional cscRNA product, whose knockdown significantly inhibited gastric cancer cell proliferation, migration, and colony formation while promoting apoptosis. Mechanistically, cscR‐819 was predominantly localized in the cytoplasm and functioned as a translational regulator, selectively enhancing the translation efficiency of genes involved in cell cycle progression, DNA replication, and antiapoptotic pathways, as demonstrated by polyribosome profiling. In conclusion, our study establishes cscRNAs as functionally relevant contributors to gastric cancer pathogenesis and identifies exploratory associations with tumor immune microenvironment features, positioning cscRNA‐based signatures as promising candidate biomarkers for risk stratification and motivating further investigation of cscRNA–immune interactions.

Epstein–Barr virus (EBV) has been consistently detected in head and neck cancer (HNC) tissues, suggesting its potential involvement in disease pathogenesis. These observations underscore the need to further investigate the plausible causal relationship between genetically predicted EBV antibody levels and the risk of developing HNC. We performed a 2-sample Mendelian randomization (MR) analysis. Genetic instruments for 5 EBV antibody levels including immunoglobin G, EBV nuclear antigen 1 (EBNA-1), EBV early antigen diffuse (EA-D), viral capsid antigen, and BamHI Z EBV replication activator were derived from a publicly available genome-wide association study dataset. Summary-level genome-wide association study data for HNC and oral and oropharyngeal cancer were obtained independently. Causal inference was performed using inverse-variance weighted (IVW), weighted median, and MR-Egger regression. Benjamini-Hochberg false discovery rate (FDR) correction was applied for multiple testing. Reverse MR analysis, Cochran Q test, MR-Egger intercept test, leave-one-out analysis, and funnel plot were subsequently conducted to assess the robustness of the results. The results of MR analysis revealed that higher genetically predicted EA-D antibody levels were significantly associated with oral and oropharyngeal cancer (IVW odds ratio [OR] = 1.00146, 95% confidence interval [CI] = 1.00066–1.00227, P = .00035, FDR-adjusted P = .004). The association between EBV EA-D antibody levels and overall HNC was of borderline significance (OR = 1.00132, 95% CI = 1.00012–1.00253, P = .032, FDR-adjusted P = .079). Conversely, elevated levels of EBV EBNA-1 antibody were inversely associated with the risk of HNC (IVW OR = 0.99886, 95% CI = 0.99809–0.99963, P = .00373, FDR-adjusted P = .012,) and oral and oropharyngeal cancer (IVW OR = 0.99897, 95% CI = 0.99836–0.99958, P = .00099, FDR-adjusted P = .005). No significant causal associations were observed for other EBV antibody levels. Reverse MR analysis did not provide evidence for a causal effect of HNC on genetically predicted EBV antibody levels. Sensitivity analyses indicated no major outliers. This study provides suggestive evidence of associations between genetically predicted EBV antibody levels and HNC risk. The inverse associations of EBNA-1 with both HNC subtypes and the positive association of EA-D with oral/oropharyngeal cancer remained significant after FDR correction. The observed effect sizes were modest, and the biological significance of these associations remains uncertain. Further validations in independent populations and mechanistic studies are warranted.

Epstein–Barr virus (EBV) lytic reactivation contributes to the pathogenesis of EBV-associated epithelial malignancies, including nasopharyngeal carcinoma and gastric carcinoma, highlighting the need for therapeutic strategies targeting viral reactivation. Capsaicin exhibits anticancer and antiviral activities; however, its effects on EBV lytic reactivation remain unclear. This study investigated the effects of capsaicin on EBV lytic reactivation in EBV-positive epithelial cancer models. Capsaicin significantly suppressed the expression of lytic genes, including BZLF1, BRLF1, BMRF1, and BLLF1, and reduced EBV virion production. Proteomic analysis revealed alterations in host cellular pathways associated with metabolism, chromatin organization, and cytoskeletal regulation, whereas metabolomic profiling demonstrated perturbations in nucleotide, amino acid, and polyamine metabolism processes involved in viral DNA replication and protein synthesis. Protein–protein interaction network analysis identified key host proteins, including HSP90AB1, MYH9, and ANXA2, implicated in metabolic reprogramming, cytoskeletal organization, and stress responses. Moreover, upstream regulators associated with EBV lytic activation, including p65, AP-1, HIF-1α, and SP1, were down-regulated following capsaicin treatment. Collectively, these findings demonstrate a multitarget inhibitory effect of capsaicin on EBV lytic reactivation and support its therapeutic potential against EBV-associated epithelial malignancies.

BackgroundInteractions between human papillomavirus (HPV) and co-infecting herpesviruses remain incompletely understood. This study assessed the prevalence of HSV-1, HSV-2, Epstein–Barr virus (EBV), and HHV-8 among HPV-positive women in Iran, and evaluated associations with HPV genotypic risk groups and genotype multiplicity.MethodsThis cross-sectional study analyzed 303 residual cervical cytology samples from HPV-positive women. Herpesviruses were detected using multiplex real-time PCR. Associations between herpesvirus positivity and HPV variables were examined using Logistic regression, Fisher’s Exact Test and nonparametric statistics.ResultsCo-infection of HPV with herpesviruses were detected in 20 of 303 samples (6.6%; 95% CI: 4.1–10.0), including HSV-1 in 2 samples (0.7%), HSV-2 in 10 samples (3.3%), EBV in 8 samples (2.6%), and HHV-8 in none of the samples. No significant associations were found between herpesvirus positivity and HPV risk group or HPV genotype multiplicity (p>0.05). Multivariable models did not identify independent predictors; analyses were limited by the low number of herpesvirus-positive cases and wide confidence intervals.ConclusionCo-infection of HPV with herpesviruses were uncommon among HPV-positive women and were not measurably associated with HPV genotype patterns. The low event frequency and cytology-based sampling likely contributed to nondetection of associations. Studies using tissue-based sampling, HPV–herpesvirus viral load, and high-grade lesions are needed to clarify potential viral synergism.

ABSTRACTAccurate diagnosis of fibromyalgia requires careful consideration of overlapping conditions. This case underscores the role of Epstein–Barr virus (EBV) serology in patients with persistent fatigue and pain, while illustrating the challenges of diagnosing fibromyalgia amid concurrent health problems.

ABSTRACTObjectivesBoth psychosocial stress and current infection can increase the likelihood of reactivation of latent Epstein–Barr virus (EBV). Pregnancy and infection with SARS‐CoV‐2 can be stressful and modulate immune function. However, it is unknown how SARS‐CoV‐2 infection and stress further interact among postpartum women to affect EBV antigen and antibody expression.MethodsWe examined associations among COVID‐19 diagnosis, self‐reported stress, and EBV immunoglobulin G (IgG) in previously collected data from 45 breastfeeding US women (1–18 months postpartum) during the height of the COVID‐19 pandemic. Between June 2020 and March 2021, stress survey data and capillary dried blood HemaSpot samples were collected from 25 SARS‐CoV‐2 infected and 20 non‐infected participants at multiple time points over the course of 60 days. Samples (N = 104) were later assayed for EBV IgG. Statistical methods were pre‐registered, and relationships among SARS‐CoV‐2 infection, stress, and EBV IgG were analyzed via mixed‐effects regression models, adjusting for time postpartum and time elapsed since enrollment.ResultsThere was a statistically significant association between self‐reported stress and EBV IgG levels, with higher average stress associated with higher average EBV IgG. EBV IgG relative concentration did not vary independently with COVID‐19 positivity status or the number of COVID‐19 symptoms.ConclusionsResults suggest that EBV IgG relative concentrations were elevated across sample participants by stress, but not by the relatively mild cases of COVID‐19 the mothers experienced.

EBV is associated with human B cell lymphomas, including Burkitt lymphomas (BLs), diffuse large B cell lymphomas (DLBCLs), Hodgkin lymphomas (HLs), and Plasmablastic lymphomas (PLs). EBV+ lymphomas in immunocompetent humans are usually derived from germinal center (GC)-experienced B cells and have stringent latency forms that do not express the viral transforming protein, EBNA2. Human EBV+ lymphomas that lack EBNA2 expression are largely driven by the viral LMP1 and LMP2A proteins, which activate NF-κB and B cell receptor-like signaling, respectively, or by Myc translocations. However, EBNA2 is required for EBV-mediated transformation of B cells in vitro and there is currently no model system for studying how EBV transforms human GC-derived B cells into lymphomas in vivo in the absence of EBNA2 expression or Myc translocation. Here, we show that human tonsil GC B cells (GCBs) infected with an EBNA2-deleted EBV mutant proliferate on a CD40L/IL21-expressing feeder layer and form lymphomas in NSG mice that resemble human DLBCLs (both ABC and GCB subtypes) and PLs. These EBV-induced lymphomas occur in the absence of Myc overexpression, often have normal karyotypes, and do not contain mutations in cellular genes (including p53) commonly mutated in uninfected human DLBCLs. Using this model system, we show that LMP2A induces plasmablast differentiation, increases expression of genes involved in lymphocyte mobility and trafficking and enhances tumor invasiveness in vivo. This new model system can thus be used to define roles of viral and cellular proteins in EBV-induced human GCB-derived lymphomas that lack EBNA2 expression.

In Ausimmune, an Australian multicenter incident case–control study, Epstein–Barr virus (EBV)-related measures, including anti-EBNA antibodies and infectious mononucleosis, show multiple sclerosis (MS) associations mediated by DNA methylation (DNAm). Human herpesvirus-6 (HHV-6) DNA has also been linked to increased MS onset risk, though its mechanisms remain unknown. Therefore, we examined an expanded set of human herpesvirus indices including HHV-6 indices. We first tested associations with MS-associated DNAm modules, then assessed whether HHV-6 DNA contributes to MS onset through DNAm pathways. Serological (serum) and viral load (whole blood) measures of EBV (DNA, viral capsid antigen, early antigen diffuse and restricted), HHV-6 (DNA, IgM, IgG), cytomegalovirus (CMV) (IgG), and varicella zoster virus (DNA, IgG) were collected. DNAm was measured from whole blood (Illumina Infinium Human Methylation EPIC v1). DNAm-module (A1–A5) scores were derived using an epigenome-wide association study for MS onset risk and dimension-reduction methods. A total of 206 cases and 348 matched controls were analyzed. Multivariable linear regression demonstrated associations between HHV-6 DNA positivity and the A2-module, and between higher CMV IgG and the A4 module. Counterfactual mediation analysis indicated that 45% of the positive association of HHV-6 DNA positivity with MS onset risk was mediated through the A2 module (Pindirect = .008). The A2 module showed enrichment for lymphatic and immune pathways. These results provide evidence for a distinct DNAm module as a plausible mechanism underlying the associations of HHV-6 with MS onset. Importantly, these epigenetic pathways appear to mediate associations with human herpesviruses beyond EBV. These findings provide further insights into how environmental factors relate to MS onset through epigenetic programming.

Posttransplant lymphoproliferative disorder (PTLD) is a rare yet potentially fatal complication following liver transplantation. This condition is usually associated with Epstein–Barr virus (EBV) infection and profound immunosuppression. In this report, a young woman is introduced who had undergone liver transplantation due to autoimmune hepatitis and developed persistent diarrhea 3 months after the transplantation. Simultaneously, Cryptosporidium infection was diagnosed as the cause of the diarrhea. However, due to the persistence of symptoms and lack of full recovery with initial treatment, further diagnostic evaluations were conducted. Tissue biopsy confirmed the presence of diffuse large B‐cell lymphoma (DLBCL) as an early‐onset PTLD. Following the diagnosis of PTLD, a reduction in the intensity of immunosuppression and initiation of specific treatment, including the administration of rituximab, were undertaken. Nevertheless, despite the therapeutic interventions, the patient died due to disease progression. This case underscores the necessity of considering PTLD as a differential diagnosis in liver transplant patients presenting with unusual symptoms such as persistent diarrhea—even in the presence of a concurrent opportunistic infection like Cryptosporidium. Timely diagnosis and treatment of PTLD are crucial to improving the prognosis of these patients.

Primary Epstein–Barr virus (EBV) infection in children exhibits substantial clinical heterogeneity, often complicating early diagnosis and leading to unnecessary antibiotic use. This retrospective study evaluated 695 children (0–18 years) diagnosed with primary EBV infection at a tertiary pediatric center between 2010 and 2015, defined by positive viral capsid antigen (VCA) IgM and negative Epstein–Barr nuclear antigen (EBNA) IgG. Clinical, laboratory, and ultrasonographic findings were compared according to age group (≤4 vs. >4 years) and clinical setting (inpatient vs. outpatient). The median age was 3.75 years (IQR: 2–6.25), and more than half of the patients were ≤4 years. Younger children more frequently presented with nonspecific respiratory and gastrointestinal symptoms, whereas older children more commonly exhibited the classic infectious mononucleosis (IM) phenotype, including sore throat, dysphagia, lymphadenopathy, and hepatosplenomegaly (p < 0.001). Antibiotics were prescribed in 64.2% of patients, while 21.7% required hospitalization. Multivariable logistic regression analyses demonstrated that age was not an independent predictor of hospitalization, classic IM phenotype, or antibiotic use. Instead, specific clinical and laboratory findings—such as lymphopenia, lymphadenopathy, vomiting, thrombocytosis, and tonsillar hypertrophy—emerged as the key determinants of clinical outcomes. To enhance diagnostic discrimination, receiver operating characteristic (ROC) analysis of ANC/ALC and AST/ALT ratios was performed, and a composite risk score (0–2) was derived. Although both markers showed modest discriminative ability (AUC 0.607 and 0.575), their high negative predictive values (>90%) suggest potential utility as rule-out tools. The composite score demonstrated a stepwise increase in the probability of classic IM presentation across age groups. In conclusion, primary EBV infection demonstrates a clear age-related clinical spectrum; however, clinical and laboratory features rather than age alone drive key outcomes. These findings highlight the need for age-specific diagnostic strategies and improved antimicrobial stewardship, while the proposed risk score provides a foundation for future validation studies.

Background: Diffuse large B-cell lymphoma (DLBCL) is one of the most frequent lymphomas. To date, it is not possible to identify which DLBCL patients will have an aggressive clinical evolution only by using hematoxylin and eosin (H&E) histological images. Methods: This study predicted the prognosis of DLBCL using H&E images, computer vision and deep learning. The series included 114 DLBCL cases, split into 2 prognostic groups according to overall survival, and 44 cases of reactive lymphoid tissue. Results: The curve fitting and slope analysis showed a point of inflection at 2 years (24 months), which differentiated patients with aggressive clinical evolution (“Dead < 2 years”, b1 = −0.024) from the rest with moderate clinical evolution (“Others”, b1 = −0.003). Twenty different convolutional neural networks (CNNs) were used, and explainable artificial intelligence (XAI) was also applied. The final model based on DarkNet-19 predicted prognosis groups with high performance (test set accuracy = 96.3%). The other performance parameters were precision (94.5%), recall (95.0%), false positive rate (3.1%), specificity (96.9%), and F1 score (94.7%). XAI, including grad-CAM, occlusion sensitivity, and image-LIME, confirmed that the CNN focused on the correct areas. Hybrid partitioning to prevent information leakage with patient-based analysis, image classification between DLBCL and 44 cases of reactive lymphoid tissue, and hyperparameter tuning were also successfully performed. Correlation with the clinicopathological characteristics found that the Dead < 2 years group was correlated with stage III–IV, International Prognostic Index (IPI) High + High/intermediate, progressive disease, non-GCB cell-of-origin, CD10−, BCL2+, and Epstein–Barr virus (EBER)+. Analysis of the microenvironment, immune checkpoint, cell cycle, and germinal center markers showed that Dead < 2 years had higher IL10, PD-L1, and CD163 levels and lower E2F1 protein expression. No differences were found for Ki67, CSF1R, CASP8, TNFAIP8, LMO2, MYC, MDM2, CDK6, and TP53 markers at a quantitative level. Conclusions: The DLBCL overall survival can be predicted using H&E histological images and deep learning using the 2-year (24 months) point (similar to POD24). This trained CNN can be used as a pretrained model for transfer learning in the future.

Background:ARID1A mutations are frequent in gastric cancer (GC) and may indicate an immune-active tumor microenvironment.Objectives:This study aimed to assess the efficacy of the immune checkpoint inhibitor (ICI) plus chemotherapy as first-line therapy in advanced GC and explore its association with key molecular features according to the status of ARID1A-mutation.Design:This was a retrospective, single-center cohort study.Methods:We analyzed 258 patients with advanced HER2-negative GC who received ICI plus chemotherapy between 2022 and 2024. ARID1A mutation status and other molecular features were assessed using next-generation sequencing. Also, the status for Epstein–Barr virus (EBV), programmed death-ligand 1 (PD-L1), and claudin 18.2 was done. Treatment outcomes were evaluated between ARID1A-mutant and wild-type groups.Results:Among 258 patients, 67 (26.0%) harbored at least one ARID1A mutation. ARID1A mutant tumors (MT) showed significantly higher tumor mutational burden (median 18.0 vs 6.7 mut/Mb), EBV positivity (11.8% vs 0.6%), MSI-H status (10.6% vs 6.3%), and PD-L1 CPS ⩾50 (14.9% vs 1.0%) compared to wild-type (WT). The median progression-free survival (PFS) was numerically longer in the ARID1A MT group (9.7 vs 8.5 months; HR 0.75; 95% CI, 0.53–1.10), though not statistically significant. There was no significant difference for the ORR (55.2% vs 64.4%, p = 0.19), and the overall survival (27.4 vs 31.1 months; HR 0.83; 95% CI, 0.58–1.20) between the two groups.Conclusion:ARID1A mutations were associated with immune-active molecular features and a trend toward improved PFS to ICI plus chemotherapy. Further research for ARID1A as a potential biomarker for ICI is warranted in advanced GC.

Clinicopathologic characteristics and genomic profiling of HER2-low advanced gastric or gastroesophageal junction cancer

Mixed autoimmune hemolytic anemia (mAIHA) is a rare clinical condition where both warm and cold antibodies lead to autoimmune red cell destruction and progressive anemia. Herein, we report a rare case of combined warm and cold agglutinin‐mediated autoimmune hemolytic anemia in a 61‐year‐old male who initially presented with incidental macrocytic anemia during a preoperative evaluation for pterygium surgery. Investigations showed the presence of both warm (IgG) and cold (IgM) autoantibodies, evidenced by a positive direct Coombs test (both anti‐IgG and anti‐C3), and elevated serum IgM levels. Type and cross‐isolate revealed two distinct autoantibodies with different thermal amplitudes. Further workup did not reveal a definitive underlying etiology for the hemolysis. Mycoplasma pneumoniae and Epstein–Barr virus antibody panels were not suggestive of active infection. He was treated with corticosteroids and rituximab, resulting in an improvement in his hemoglobin levels, a reduction in splenomegaly, and ultimately remission of his autoimmune hemolytic anemia. This case emphasizes the need for a thorough workup to identify the cause of anemia, even in the context of seemingly unrelated surgical procedures.

Abstract Introduction Kleine–Levin syndrome (KLS) is a rare, relapsing–remitting neurologic sleep disorder characterized by recurrent episodes of severe hypersomnia accompanied by cognitive, behavioral, and autonomic disturbances, with complete inter-episode recovery. It predominantly affects adolescent males. Diagnosis is frequently delayed because of its episodic nature, nonspecific symptoms, and lack of definitive biomarkers. Objective documentation of hypersomnia during symptomatic periods is challenging. Actigraphy offers a practical, noninvasive approach to capturing sleep–wake patterns during active episodes. Report of case(s) A 16-year-old male presented with a nearly two-year history of recurrent hypersomnia episodes occurring every 2–3 months and lasting several days to weeks. During episodes, he slept 15–20 hours per day and exhibited hyperphagia and mild irritability as prodromal symptoms. Initial symptom onset followed multiple upper respiratory infections. Between episodes, he returned fully to baseline with normal sleep patterns and daytime functioning. Extensive medical evaluation was unrevealing. Epstein–Barr virus serology showed elevated IgG titers with negative PCR and low IgM levels, not felt to explain his presentation. Evaluation for Marfan syndrome, primary immunodeficiency, autoinflammatory and autoimmune disorders, and immunologic abnormalities was normal. Neurologic workup, including head CT, brain MRI, and EEG, was unremarkable. Wrist actigraphy performed during a symptomatic episode demonstrated markedly prolonged total sleep time, reduced daytime wakefulness, and disrupted circadian organization. Subsequent polysomnography revealed mild obstructive sleep apnea. A multiple sleep latency test was not consistent with narcolepsy (mean sleep latency 9 minutes, two sleep-onset REM periods). These objective findings, in conjunction with the characteristic clinical course and exclusion of secondary causes, supported a diagnosis of Kleine–Levin syndrome. Conclusion This case highlights the clinical utility of actigraphy as an accessible and objective tool for documenting hypersomnia during acute KLS episodes. While polysomnography may be logistically difficult during symptomatic periods, actigraphy allows longitudinal assessment of sleep–wake patterns and can aid in distinguishing KLS from other hypersomnia disorders, mood disorders, and behavioral sleep disturbances. Support (if any)

Multiple sclerosis (MS) susceptibility and severity are mediated by different genetic and environmental risk factors. Familial aggregation in MS is partially explained by susceptibility determinants, yet impact on early disease course after clinically isolated syndrome (CIS) is uncertain. We investigated associations of reported familial MS with genetic and environmental risk factors, and with clinical presentation and disease course after CIS. CIS participants were included in a prospective cohort within six months after symptom onset. Family history was assessed at baseline. We evaluated weighted genetic risk scores (wGRS) for MS susceptibility, 25-hydroxyvitamin D (25(OH)D) and body mass index (BMI), and determined HLA-DRB1*15:01 and MS severity SNP rs10191329 carriership. Anti-Epstein Barr virus Nuclear Antigen-1 (anti-EBNA1) IgG antibodies and 25(OH)D levels were measured. Disease course associations were estimated with Cox regression. Family members with MS were reported by 81/415 (19.5%) CIS participants. Familial MS was associated with higher MS susceptibility wGRS (7.54 (SD1.17) vs. 7.19 (SD1.22), p=0.04) and more frequent HLA-DRB1*15:01 carriership (first-degree 66.7%, other-degree 30.2%, no 38.4%, p=0.02). Anti-EBNA1 IgG and 25(OH)D levels did not differ, yet wGRS for lower 25(OH)D and higher adult BMI characterised MS participants with first-degree MS relatives. Baseline characteristics and disease severity measures were similar between participants with and without familial MS. Our results confirm that familial MS is associated with enrichment of genetic risk for MS susceptibility, low 25(OH)D and high BMI, but not with early disease course after CIS. These data support that MS susceptibility and disease course are driven by different pathophysiological processes.

Background: Epstein–Barr virus (EBV)-associated infectious mononucleosis (IM) elicits a robust cellular immune response; however, systemic chemokine profiles in pediatric IM and their diagnostic relevance remain insufficiently characterized. This study evaluated proinflammatory chemokine expression in children with acute EBV-associated IM and its relationship with disease presence and severity. Methods: In this retrospective study, 64 children with confirmed acute EBV-associated IM and 16 healthy controls were included. Clinical severity was classified using the Severity of Mononucleosis (SOM) scale. Plasma concentrations of 12 chemokines were quantified by bead-based flow cytometry. Groups were compared using nonparametric tests, and logistic regression with cross-validation identified predictors distinguishing IM from controls. Results: CXCL9, CXCL10, and CXCL11 concentrations were significantly elevated in IM patients compared with controls across all severity strata (p ≤ 0.011), with no differences between SOM categories. CXCL5 concentrations were lower in severe (SOM ≥ 2) than moderate disease (p = 0.037). Other chemokines showed no significant differences. CXCL9 and CXCL10 effectively distinguished IM (AUC = 0.86, sensitivity = 0.71, specificity = 0.96). Conclusions: IFN-γ–inducible chemokines CXCL9–11 are markedly elevated in pediatric EBV-associated IM, irrespective of clinical severity, whereas CXCL5 may be associated with disease severity. Prospective validation of these preliminary findings is strongly warranted.

ABSTRACT Epstein–Barr virus (EBV) is a significant global health concern due to its association with malignancies and autoimmune diseases like multiple sclerosis. Rapid, accessible detection methods are essential, especially in resource‐limited settings. Although polymerase chain reaction (PCR) remains the gold standard, its high cost and complexity underscore the need for simpler alternatives. This study presents a visual, user‐friendly biosensor using gold nanoparticles (AuNPs) for point‐of‐care detection of EBV DNA. A specific DNA probe was synthesized and conjugated to ∼30 nm spherical AuNPs via thiol linkages. Target EBV DNA induced nanoparticle aggregation, and subsequent HCl addition caused a distinct color change from red to blue, enabling visual detection. The biosensor achieved a detection limit of 200 pmol and produced results within 5 min. Nanoparticle uniformity and stability were confirmed through characterization. Compared to PCR, the biosensor demonstrated comparable specificity in cross‐validation experiments, while offering superior speed, cost‐effectiveness, and operational simplicity. This AuNP‐based biosensor represents a promising, low‐cost diagnostic tool for rapid EBV screening, particularly in low‐resource environments. Further validation with diverse clinical samples is recommended to enhance reliability and support broader application.

Archaic introgression has shaped the modern human immune system, particularly components involved in RNA virus responses. In contrast, its contribution to DNA virus defense remains poorly understood. Here, we investigate the contribution of Neandertal- and Denisovan-introgressed haplotypes to viral load of five common DNA viruses in UK Biobank samples, using genome-wide association summary statistics. We identified 18 genome-wide significant associations, predominantly involving Epstein–Barr virus (EBV) and loci within the Major Histocompatibility Complex, including a Denisovan-like haplotype tightly linked to HLA-A*11:01. Notably, the archaic alleles of these haplotypes showed a directional bias toward increased viral loads. Focusing on two chromosome 17 haplotypes associated with higher EBV load, we identified phenotypic associations with blood cell traits and disease markers, as well as functional effects on immune-relevant genes, including GSDMB, ARRB2, and ALOX15. Allele frequency analysis of one of the chromosome 17 haplotypes revealed signatures of shifting modes of selection, possibly reflecting changes in pathogen landscapes over time. Our results suggest that archaic DNA systematically contributes to DNA virus immunity in modern humans, with effects distinct from previously described RNA virus associations. These findings provide novel evolutionary and functional insights into host–virus interactions and the role of archaic admixture in antiviral defense.