Medicine and Pharmacology

Abstract: Objectives: Borrelia burgdorferi sensu lato, a spirochete bacterium responsible for Lyme borreliosis - the most common tick-borne infection in North America and Europe - can trigger the production of antiphospholipid antibodies. These antibodies target host lipids such as cardiolipin (CL), phosphatidic acid (PA), phosphatidylcholine (PC), and phosphatidylserine (PS), which the spirochete incorporates into its membrane from the surrounding environment. Although antiphospholipid antibodies are typically associated with antiphospholipid syndrome (APS), they may also arise during infections, including Lyme borreliosis. This study aimed to develop and optimize several enzyme-linked immunosorbent assays (ELISAs) for measuring various antiphospholipid antibodies in patients with Lyme borreliosis. Methods: Thirty patients diagnosed with Lyme borreliosis were enrolled: ten with solitary erythema migrans (EM), ten with multiple EM (MEM), and ten with late manifestations known as acrodermatitis chronica atrophicans (ACA). Forty healthy blood donors served as controls. Four distinct antiphospholipid antibody ELISAs were developed, each using a different phospholipid coating: CL, PA, PC, and PS. Serum of APS patient was used as a positive control and for standard curve generation. Results: All four ELISAs were successfully established and demonstrated good measurement precision. Significant differences in antiphospholipid antibody levels and positivity rates were observed between Lyme borreliosis patients and healthy blood donors. Notably, levels of antibodies directed against PA (aPA), PC (aPC), and PS (aPS), both IgG and IgM, were significantly higher in patients with late Lyme borreliosis, manifested as ACA, compared to healthy blood donors. In contrast, anti-CL (aCL) levels did not differ significantly between groups. Patients with ACA also showed the highest frequency of multiple antiphospholipid antibody positivity, with 7 of 10 patients testing positive for three or more antiphospholipid antibodies. Conclusions: Accurate and precise in-house ELISAs for the detection of aCL, aPA, aPC, and aPS using APS sera as standard material were developed and validated for the analysis of samples of patients with Lyme borreliosis. Our data suggest that antiphospholipid antibody levels—specifically aPA, aPC, and aPS—differ across clinical manifestations of Lyme borreliosis, with the greatest increases observed in patients with ACA.

Abstract: Inflammasomes arise from complex protein assembly mechanisms and play a fundamental role in managing inflammation and the innate immune response. The molecules that trigger inflammasome assembly and activation are molecules derived from pathogens or DNA fragments released following cellular damage. The phenomena resulting from inflammasome activation range from the activation of caspases, such as caspase-1, to the secretion of pro-inflammatory cytokines, to cellular death by apoptosis or pyroptosis. Various pathologies have been linked to aberrant inflammasome activation, including several autoimmune diseases, leading scientists to direct experiments toward identifying the mechanisms responsible for aberrant inflammasome activation to develop new therapeutic strategies. In this review, we summarize the assembly mechanisms and involvement of two specific inflammasomes, NLRP3 and AIM2, in the autoimmune disease Sjögren's syndrome (SjD); NLRP3 and AIM2 aberrant activations appear to be involved in the exacerbation of inflammation, which becomes chronic, leading to dry mouth and dry eye and to an increased risk of developing B-cell non-Hodgkin's lymphoma in these patients. Understanding how different inflammasomes contribute to the pathogenesis of SjD could be fundamental to understanding the complex molecular mechanisms underlying this disease.

Abstract: Background/Objectives: Previous studies have demonstrated the safety of pre-seasonal treatment with the mannan-conjugated birch pollen allergoid EP-088-T502. However, the safety of a combined pre- and co-seasonal treatment regi-men has not yet been investigated. This study aimed to compare the safety and tolera-bility of pre-seasonal versus pre- and co-seasonal treatment with EP-088-T502. Meth-ods: In this prospective, open-label, phase III trial (T502-SIT-059) (EudraCT No.:2022-004082-20), patients (N=109) who had participated in a preceding pivotal phase III study were offered continuation treatment with active EP-088-T502 (10.000 mTU/mL) across five treatment visits. For the subgroup analysis, all patients who completed their last treatment visit before 9 April 2023 (and thus before the start of the birch pollen season in Germany) were assigned to the pre-seasonal group (N=20). Those who performed the last treatment visit thereafter were assigned to the pre/co-seasonal group (N=83). Both groups were compared in terms of local and sys-temic immediate and late phase reactions and other EP-088-T502-related adverse events (AEs). Results: No deaths nor serious adverse events (SAEs) were reported during the study. No epinephrine administration was required. Systemic adverse drug reactions (SADRs, N=3) occurred in two patients who had previously received placebo. No grade III or IV systemic reactions according to the German AWMF classification were observed. Patients receiving pre- and co-seasonal treatment developed smaller wheals (mean diameter) compared with the pre-seasonal group (immediate reactions: 0.6 vs. 0.7 cm, late phase reactions: 0.3 vs. 0.4 cm at the last treatment visit). This was also reflected in the medians (immediate reactions: 0.2 cm vs. 0.4 cm, late-phase reac-tions: 0.2 vs. 0 cm at the last treatment visit). Of all AEs that were (possibly) related to EP-088-T502 (N=89), 74 (83%) occurred at the first three treatment visits (before the birch pollen season). The frequency of AEs was comparable between groups for the last two treatment visits. Patients who had received placebo in the previous trial experienced more treatment related side effects compared to patients who had already received EP-088-T502 in the previous year. Conclusions: These data suggest that EP-088-T502 is safe and well tolerated even when administered during the birch pollen season, regardless of prior exposure to EP-088-T502.

Abstract: Lipedema affects an estimated 11–12% of women worldwide and is characterized by bilateral, symmetric adipose deposition in the lower extremities, disproportionate pressure pain, spontaneous bruising, and resistance to conventional dietary interventions. Despite its prevalence, lipedema lacks a unifying mechanistic framework. Current descriptions treat it as a fat storage disorder with secondary vascular and inflammatory features, leaving critical observations mechanistically unexplained: a highly characteristic quantitative sensory testing (QST) pattern with no published alternative mechanistic explanation, a paradoxical immunological profile, a 35–40% comorbidity with fibromyalgia, a 1.42 relative risk for ADHD, estrogen-dependent onset, and asymmetric expression in the presence of local vascular triggers.We propose the gfWAT-IIT2 framework, which posits that lipedema is fundamentally a syndrome of polarization of the gluteofemoral white adipose tissue (gfWAT) microenvironment toward innate type 2 immunity (IIT2), amplified by estrogen via mast cell estrogen receptors, and generating neuropathic pain through selective histaminergic sensitization of Aδ/C fibers (H1/H4 receptors, PPT↓) and inhibition of Aβ fibers (H3 receptor, VDT↑), with thermal thresholds remaining normal: a triad that is mechanistically explained by histaminergic peripheral sensitization.The gfWAT-IIT2 framework integrates reported clinical, sensory, immunological, and depot-specific observations into a testable mechanistic cascade, generates fourteen falsifiable predictions, and repositions the therapeutic target from adipocyte to mast cell. The framework further proposes that asymmetric lipedema (where one limb expresses the disease more severely due to an identifiable local trigger) constitutes a natural controlled experiment suggesting that local trigger removal may be disease-modifying in selected patients with documented triggers.

Abstract: C-reactive protein (CRP) was discovered in 1930 by Tillett and Francis as a protein that reacts with C-polysaccharides to form precipitates in the serum of patients with pneumococcal infection. Subsequently, it was found to increase in the serum of patients with bacterial infections and rheumatic diseases, and it has since been widely recognized as a nonspecific biomarker of acute inflammation and utilized in clinical medicine. Meanwhile, CRP-like proteins are also present in the hemolymph of horseshoe crabs, and it has become clear that these proteins have long played a crucial role in the humoral innate immune response against foreign microorganisms. In recent years, advances in molecular analysis have revealed the details of the complex biological functions performed by CRP. Furthermore, with the development of highly sensitive CRP measurement methods, its importance as a biomarker is gaining attention not only in acute inflammatory diseases but also in chronic inflammatory diseases such as cardiovascular disease, diabetes, cancer and neurological disorders. New treatment strategies targeting CRP, based on recent findings, are also being explored.

Abstract: Background: Current international hereditary angioedema (HAE) guidelines and treat-to-target recommendations consistently emphasize accurate diagnosis, early on-demand treatment of attacks, appropriate short-term prophylaxis for procedures, individualized long-term prophylaxis (LTP), and routine assessment of disease control and quality of life. Published information on how these recommendations are implemented in Latin America remains limited. We therefore aimed to assess the extent to which a Latin American expert panel converges with recommendations across current international HAE guidelines and consensus documents and to identify the principal barriers affecting real-world implementation in the region. Methods: A scientific committee developed and externally validated a 74-item questionnaire (domains summarized in Supplementary Table S1) and conducted a 2-round Delphi process among Latin American HAE experts. Consensus items were rated on a 9-point agreement scale, with consensus defined a priori as at least two-thirds of panelists scoring within a 3-point band in the agreement (7-9) or disagreement (1-3) range. Descriptive items captured expert-reported diagnostic testing, acute and preventive treatment patterns, monitoring practices, and implementation determinants using 5-point Likert scales. Instrument validation (July-November 2024) demonstrated high inter-rater agreement (Kendall W = 0.84; p < 0.001) and excellent internal consistency (Cronbach alpha = 0.92). Results: Thirty experts from 10 countries completed the process (Argentina, Brazil, Chile, Colombia, Ecuador, Mexico, Panama, Peru, Uruguay, Venezuela). Panel consensus broadly converged with recommendations across current international HAE guidelines and consensus documents on core diagnostic work-up (C4 plus C1-INH antigen and function; 84% consensus), selective use of genetics (97% consensus), first-line targeted LTP (pdC1-INH, Lanadelumab, Berotralstat; 94% consensus), retention of on-demand therapy for breakthrough attacks and for patients without access to LTP, routine monitoring, and management in special populations. The principal novel finding was an implementation feasibility gap: frequent or constant interruptions in prophylaxis supply were reported by 19/30 experts (63%), including 13/23 (57%) practicing in settings where public or insurance coverage was reported. Across the panel, cost (19/30; 63%) and medicine availability (8/30; 27%) were the most commonly cited barriers, with additional constraints related to diagnostic testing access and administrative pathways. Conclusions: Latin American expert consensus largely converges with recommendations across current international HAE guidelines and consensus documents on diagnosis, acute management, prophylaxis selection, monitoring, and special-population care. The dominant divergence is not clinical disagreement but implementation feasibility—particularly access to diagnostic testing, financing mechanisms, medicine availability, and continuity of supply. These findings provide region-specific evidence to contextualize international recommendations and support implementation strategies tailored to Latin America.

Abstract: Symptomatic dermographism (SD) is the most common form of chronic inducible urticaria, typically presenting with pruritic, linear wheals that appear within minutes after stroking the skin and resolve within 30 minutes. However, not every linear urticarial eruption following friction or scratching is true SD. We present three clinical cases initially misdiagnosed or suspected as classic SD, but which after detailed evaluation proved to be different entities. The first case was an atypical follicular subtype of SD itself, with a false-negative initial FricTest. The second case was cholinergic dermographism — a rare variant of cholinergic urticaria requiring two concurrent triggers (sweating and stroking) — in a patient with hyperhidrosis. The third case was flagellate dermatitis caused by consumption of inadequately cooked Shiitake mushrooms, with lesions persisting for days and no response to antihistamines. These cases highlight that even a characteristic linear wheal pattern is not pathognomonic for SD. A thorough history, recognition of atypical morphologies, and appropriate provocation testing (including combined triggers when needed) are essential to avoid diagnostic pitfalls and initiate effective therapy.

Abstract: Severe asthma (SA) is a chronic respiratory disease characterized by clinical heterogeneity and poor therapeutic response. Variants in the IL4 gene, including rs2243250 and rs2243248, have been associated with asthma susceptibility and severity in different populations; however, their role in the Mexican population remains unclear. This study evaluated the association of IL4 promoter variants rs2243250 and rs2243248 with severe asthma and its clinical characteristics in a Mexican population using genetic and in silico approaches. A total of 106 patients with SA and 180 healthy individuals were included. Genotyping was performed using allelic discrimination assays with TaqMan® probes, and associations between genotypes and clinical variables were assessed. No significant differences in allele or genotype frequencies were observed between groups. However, the rs2243250 TT genotype was associated with nocturnal symptoms (OR = 3.03, 95% CI = 1.31–7.00, p = 0.009) and increased use of rescue medication (OR = 3.16, 95% CI = 1.41–7.07, p = 0.005). The rs2243248 TG/GG genotypes were associated with epithelial allergy (p < 0.05). In silico analysis suggested a regulatory role for both variants. These findings suggest that IL4 variants may not influence overall disease risk but could modulate clinical features of asthma severity.

Abstract: Autoimmune diseases comprise a broad group of conditions that affect virtually any organ or tissue and share mechanisms of chronic, autoimmune-based inflammation. Once rare or unknown, they have become increasingly common in recent years, affecting individuals of all ages, including the elderly, due to the growing the number of older people. According to evolutionary medicine, if the frequency of a disease, or group of diseases, increases sharply over a few decades, the primary cause cannot be the effect of genetic alterations but rather the consequence of one or more alterations in the living conditions of the species. For autoimmune diseases, there is no environmental, dietary, or infectious factor that appears to correlate with their increased frequency. On the contrary, the epidemic of autoimmune diseases is likely correlated with serious alterations of our holobiont (i.e., our organism, the host species, plus the myriad of species coexisting with us). In particular, the critical factor appears to be the decreasing incidence of macroparasite infestations, without, however, excluding the effects of profound alterations in the bacterial ecosystems that are also part of our holobiont. The macroparasites modulate and curb the intensity of immune responses in order to survive in our bodies. In the coevolution of host organism and other species of the holobiont, a delicate balance has developed that is severely altered by the eradication of macroparasites. Therefore, it is necessary to move beyond the concept of macroparasites as harmful species by definition and therefore to be eliminated without hesitation. Alternatively, it is essential to study our holobiont as a whole and consider the balances of its ecosystems before modern alterations. Furthermore, it is essential to evaluate the effects of reintroducing macroparasite species with which we have coevolved into our holobiont.

Abstract: Background: Allergic conjunctivitis (AC) is a frequent inflammatory ocular surface disease that significantly affects quality of life, particularly in children. Current treatments mainly provide temporary symptom relief and often require prolonged use. Bacterial suspensions have emerged as potential immunomodulatory treatments for other allergies, but have not been completely explored in ocular allergy. Objective: To describe the clinical ophthalmological and quality of life changes in patients with AC treated with a bacterial suspension (BS) as complementary therapy. Methods: A before-and-after clinical study was conducted in 5 children aged 6 to 12 years with a diagnosis of moderate-to-severe persistent allergic conjunctivitis and negative skin prick test results. Clinical ocular signs and symptoms, quality of life, and changes in CD19+IL-10+ cells were assessed. Results: After 90 days of BS treatment, a significant reduction in allergic symptoms, including itching, light sensitivity, and burning, was observed, along with a marked reduction of ocular inflammation. Evaluation of quality of life revealed improvement across all evaluated domains and an increase in CD19+IL-10+ cells. Conclusions: BS therapy demonstrated favorable clinical and immune-modulatory effects in children with AC, supporting its potential as a promising complementary therapeutic option.

Abstract: Antibody-dependent enhancement (ADE) is a paradoxical immunological phenomenon in which pre-existing antibodies facilitate viral entry into host cells rather than conferring protection. ADE has been extensively characterised in flaviviral systems, most notably dengue virus (DENV), and presents a significant challenge for vaccine development and antibody-based therapeutic design. In coronavirus infections, ADE operates through both classical Fc gamma receptor (FcγR)-mediated pathways and an intrinsic signalling mechanism involving inhibitory FcγRIIb-mediated suppression of the type I interferon (IFN-I) response. Of critical translational relevance is the proposed cooperative FcγR–angiotensin-converting enzyme 2 (ACE2) entry model for SARS-CoV-2, wherein virus–antibody immune complexes simultaneously engage ACE2 through the viral spike receptor-binding domain (RBD) and FcγRIIa through the antibody Fc region on the same macrophage surface. This cooperative dual-receptor engagement may stabilise virion attachment, augment endosomal uptake, and trigger downstream signalling cascades that suppress antiviral immunity, potentially contributing to severe COVID-19 immunopathology. Feline infectious peritonitis virus (FIPV) represents one of the most rigorously documented biological systems in which antibody-mediated macrophage infection directly determines systemic disease outcome, providing a critical comparative framework for understanding coronavirus ADE across species. This comprehensive review integrates current knowledge of FcγR biology, coronavirus cell entry mechanisms, intracellular signalling cascades, cytokine dysregulation, comparative veterinary immunopathology, and nano-engineered immunomodulatory platforms for ADE-safe vaccine development. We critically evaluate lipid nanoparticle mRNA vaccines, virus-like particles, and polymeric nanoparticle systems as rational strategies to elicit selective neutralising antibody responses while mitigating ADE risk. We also highlight key unresolved mechanistic questions and future research directions essential for the development of safer vaccines and therapeutics against both current and emerging coronaviruses in human and veterinary medicine.

Abstract: Background: Live BCG vaccination is absolutely contraindicated in Severe Combined Immunodeficiency (SCID) due to the invariably fatal risk of disseminated BCGosis [5,6,7]. This creates a critical unmet need: SCID neonates are deprived of BCG's potent heterologous protection precisely when they are most vulnerable to opportunistic infections. Hypothesis: Heat-Killed BCG (HK-BCG), being entirely non-viable, cannot cause BCGosis or systemic mycobacterial disease. We propose that HK-BCG retains sufficient structural pattern-associated molecular patterns (PAMPs) to engage functional innate immune cells — specifically monocytes, macrophages, and NK cells — that remain present in the majority of SCID subtypes, thereby inducing trained immunity and heterologous protection without adaptive immune cell dependency [2,3,4]. Methods/Evidence: This paper synthesizes molecular mechanism data on TLR2/TLR4/NOD2-driven trained immunity [23,24], epigenetic reprogramming pathways [2,3], SCID immunophenotype data [32,33], and available non-viable mycobacterial clinical trial evidence [34] to construct a mechanistic and clinical rationale for HK-BCG use in SCID.Conclusions: HK-BCG represents a paradigm-shifting, potentially life-saving immunomodulatory platform for SCID patients. The complete absence of viable bacilli eliminates all infectious risk, while preserved mycobacterial PAMPs can train the residual innate immune compartment. This approach is particularly compelling in the post-HSCT reconstitution window. A dedicated Phase I/IIa clinical trial in SCID is urgently warranted.

Abstract: Background: The Bacillus Calmette-Guérin (BCG) vaccine — the only licensed anti-tuberculosis vaccine — is administered at birth in over 150 countries. In many settings, however, BCG vaccination is deferred beyond the neonatal period, with a significant cohort receiving vaccination at approximately six months of age. An emerging clinical paradox has been identified: infants who receive delayed BCG vaccination at six months may subsequently develop devastating disseminated BCG disease (BCGosis), raising two unresolved questions of critical clinical importance. First, whether pre-existing subclinical Mycobacterium tuberculosis latent infection (LTBI) acquired during the unprotected window period acts as an immunological cofactor precipitating dissemination of the live attenuated BCG strain upon vaccination. Second, whether the tuberculin skin test (TST/PPD) — the most widely available diagnostic tool — provides sufficient sensitivity and specificity at six months of age to serve as a pre-vaccination safety screen.Methods: A systematic review was conducted following PRISMA-2020 guidelines across PubMed/MEDLINE, Embase, the Cochrane Library, and the WHO Global Tuberculosis Database (1990–2025). Search terms included "BCGosis," "disseminated BCG disease," "delayed BCG vaccination," "latent TB infants," "SCID BCG complications," "TST limitations infants," and "IGRA infants under two years." Studies reporting BCGosis following delayed BCG vaccination, pre-vaccination LTBI in infants, and TST/IGRA performance in the first year of life were included.Results: The pooled evidence from 32 high-quality studies across 17 countries confirms that BCGosis occurs almost exclusively in infants with undiagnosed inborn errors of immunity (IEI), especially severe combined immunodeficiency (SCID), chronic granulomatous disease (CGD), and Mendelian susceptibility to mycobacterial disease (MSMD). BCG-related complications represented the first clinical manifestation of underlying IEI in 75% of affected infants. A landmark Saudi Arabian cohort study (n=178 SCID patients, 2015–2023) demonstrated that delaying BCG from birth to six months significantly reduced BCG-related complications from 46.1% to 2.6% (p<0.001), illustrating the benefit of pre-vaccination immunological screening rather than blanket deferral. The TST showed false-negative rates of up to 40% in culture-confirmed tuberculosis among children under two years, attributable to T-cell immaturity, the immunological window period, and maternal immune modulation. IGRA assays demonstrated higher specificity but indeterminate rates of 17% in infants under twelve months, particularly in immunocompromised patients (27%), limiting their standalone utility. The mechanistic hypothesis of BCG vaccination precipitating expansion of pre-existing M. tuberculosis latent infection through cross-reactive T-cell activation and immune reconstitution inflammatory syndrome (IRIS)-like pathology is supported by immunological evidence but requires prospective validation.Conclusions: Delayed BCG vaccination at six months of age in infants with undetected IEI or unscreened latent TB infection constitutes a high-risk clinical scenario. The TST alone is an insufficient pre-vaccination safety screen at this age. Newborn screening for SCID using T-cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC), supplemented by comprehensive family history assessment, is essential before administering BCG to any infant beyond the neonatal period. International vaccination policy must distinguish between the protective benefit of BCG deferral for immunodeficient infants and the unacceptable risk of a six-month unprotected window in high-TB-burden populations.

Abstract: Background: Cardiovascular risk (CVR) prediction using SCORE2 may underestimate subclinical atherosclerosis in patients with chronic inflammatory conditions. Identify-ing simple, accessible markers to refine risk stratification remains an unmet need. Objective: To evaluate whether serum urate improves detection of subclinical athero-sclerosis beyond SCORE2 in a high-risk inflammatory cohort. Methods: We conducted a cross-sectional study including 250 patients with psoriatic arthritis fulfilling CASPAR criteria. Vascular assessment comprised carotid and femoral ultrasound and ab-dominal radiography. Atherosclerotic plaque was defined according to Mannheim criteria. The main outcomes were global plaque (≥1 vascular territory) and extended plaque (≥2 territories). Multivariable logistic regression adjusted for SCORE2 categories assessed independent associations. Incremental value was evaluated using decision curve analysis (DCA), category-free net reclassification improvement (cfNRI), and in-tegrated discrimination improvement (IDI). Results: Hyperuricemia prevalence was 21.6%. Patients with hyperuricemia showed a higher prevalence of global plaque (88.9% vs. 62.8%, p< 0.001). After adjustment for SCORE2, serum urate independently predicted global plaque (OR 4.23, 95% CI 1.26–14.2). Notably, 64.3% of patients classi-fied as low–moderate risk already exhibited plaque. In the 50–69-year subgroup, adding serum urate improved reclassification (cfNRI +0.60; IDI +0.031) and was asso-ciated with higher net clinical benefit across decision thresholds. The combined model (SCORE2+HU+cIMT) achieved the highest curves, although with limited incremental gain over HU alone. Conclusions: SCORE2 substantially underestimates subclinical atherosclerosis in this population. Serum urate, an inexpensive and widely available marker, may help refine cardiovascular risk stratification and identify patients who could benefit from further vascular assessment.

Abstract:

Background & Aims: Allergic diseases affect 40% of the world's population, a proportion that is increasing due to various factors associated with environmental and meteorological changes related to global warming. However, little has been written about which specific allergens are causing this increase in allergic disease. Changes in lifestyle and food consumption patterns in the population may also be influencing this increase. Methods: We present a longitudinal, real-life observational study conducted over the last five years in our allergic population treated at the Allergy Department of the Rio Hortega University Hospital (HURH), (21,564 sensitized patients, aged between 0 and 99 years) and the student of 5^th Medicine course of our University (22-23 years old), (diagnosed by prick test, specific immunoglobulin E positivity, and provocation if necessary) from 2021 to 2025. We aim to find out which allergens are increasing or decreasing, and compare them with the trends in positivity obtained in a group of 683 medical students who underwent the same tests in the practical class included in the teaching report for the Immunopathology and Allergy course. Results: In 2021, after the lockdown due to the pandemic, only 6 allergens were more detected significantly as more risk to sensitize the student group respect to general patients attended in surgery (grasses, olive, cupressus and plane tree pollen and profiline). Food sensitization was not detected. In 2022, nine more relevant allergens were more detected in students than in the general population. Dog and cat appear as important allergens, and 5 food plant allergens were included. These foods are also detected in subsequent years. Anisakis remain highly significant allergen in this young people, despite all students being aware of the freezing measures. Conclusions: There appears to be a clear relationship between climate, lifestyle, economy, and consumption and allergic conditions, which may be based on a possible shift away from the Mediterranean diet due to an increase in pathologies associated with plant panallergens (LTPS and profilins) related to pollen.

Abstract: Background/Objectives: To analyse the causes, characteristics, and outcomes of hospital admissions in patients with systemic lupus erythematosus (SLE) over a 30-year period in a tertiary referral centre in Catalonia, and to evaluate temporal trends and prognostic factors associated with adverse outcomes. Methods: A retrospective observational study was conducted including all SLE patients admitted to the Department of Autoimmune Diseases at Hospital Clínic de Barcelona between June 1995 and December 2024. Admissions lasting less than 48 hours or lacking clinical documentation were excluded. Variables analysed included demographics, disease duration, comorbidities, cause of admission, treatments, and outcomes. A composite outcome was defined as intensive care unit (ICU) admission, 30-day readmission, or prolonged hospital stay. Statistical analyses included univariate and multivariate regression models. Results: Among the 1,216 hospital admissions, SLE flares and infections were the most frequent causes. Over the study period, admissions due to infections increased significantly and, in the last five years, exceeded those related to disease flares (33.7% vs. 26.1%). Patients hospitalized for flares were younger and had a shorter disease duration, whereas infection-related admissions were more common among older patients, those with overlap syndromes, and those with higher damage scores. Vascular events and SLE flares were independently associated with poorer outcomes. Although antimalarial use increased over time, it remained suboptimal, largely due to drug toxicity and newly diagnosed cases (from 45.2% to 69.7%; p< 0.001). Treatment strategies also evolved, with a shift toward lower gluco-corticoid doses (from 14.5% to 38.3%; p< 0.001), and mycophenolate mofetil replacing cyclophosphamide as the preferred immunosuppressive agent. Conclusions: Hospitalisation patterns in SLE have shifted over time, with infections emerging as the leading cause of admission. This trend reflects an evolving patient profile characterized by older age, greater accumulated damage, comorbidities, and increased exposure to immunosuppressive therapies. These findings underscore the need for optimized infection prevention strategies and individualized treatment approaches to improve outcomes in contemporary SLE care.

Abstract: Background/Objectives: Allergen immunotherapy (AIT) is the only disease-modifying treatment for grass pollen allergy. However, the proportion of patients interested in AIT who meet guideline-defined eligibility criteria remains unclear. This study aimed to characterise symptom burden, medication use, and AIT eligibility in adult patients with grass pollen allergy during the peak pollen season. Methods: In this multicentre, prospective, non-interventional epidemiological study, 479 adults with confirmed grass pollen allergy recorded daily nasal, ocular, and systemic symptoms, as well as anti-allergic medication use, via a validated electronic diary (CCC STUDY Diary) over a 30-day period in June/July 2025. A combined symptom-medication score (CSMS) was calculated daily, with a predefined threshold of ≥1.5 indicating clinically relevant symptom severity and potential eligibility for AIT. Both additive and weighted calculation approaches for CSMS and the daily medication score (dMS) were evaluated to assess methodological robustness and reproducibility. Results: The mean additive CSMS was 2.14, indicating moderate symptom burden. Overall, 63.3% of participants exceeded the CSMS threshold of 1.5 and were considered eligible for AIT. Sensitivity analyses demonstrated excellent concordance between additive and weighted CSMS/dMS calculations (Spearman’s ρ >0.98; p<0.001), and Bland–Altman analysis confirmed minimal bias (0.157) and narrow limits of agreement. Asthma was reported as a comorbidity in 36% of patients, generally associated with mild to moderate daily respiratory symptoms. Limitations included the self-reported nature of the data and a slightly reduced sample size; however, the results are representative of adult patients seeking care in specialised allergy centres in Germany. Conclusions: The CSMS also in its additive and therefore modernized form is a reliable, reproducible, and clinically meaningful tool for quantifying symptom severity and identifying patients suitable for AIT. Approximately two-thirds of adults interested in grass pollen AIT exhibited moderate to severe symptoms and were eligible for treatment according to current guideline recommendations.

Abstract: Background/Objectives: Our previous study demonstrated that while the third SARS-CoV-2 booster effectively enhanced immunity against the Delta subvariant, its protection declined over time. This study aimed to evaluate and compare the humoral and cellular immune responses, as well as reactogenicity, of the mRNA-1273 vaccine administered as a fourth booster in healthy Thai adults previously vaccinated with two doses of CoronaVac (CV) followed by a third dose of either AZD1222 (AZ) or BNT162b2 (BNT). Methods: Participants received a single 100-µg (0.5 mL) intramuscular dose of mRNA-1273. Blood samples were collected at baseline (D0), D14, D90, and D180 to assess anti-RBD IgG, surrogate virus neutralization test (sVNT) against Delta and Omicron variants, IFN-γ levels, and reactogenicity. Results: Both 2CV/AZ- and 2CV/BNT-primed groups exhibited comparable local and systemic reactogenicity. The fourth mRNA-1273 dose markedly increased Delta variant inhibition within 14 days in both groups and remained at high levels at Days 90 and 180. sVNT inhibition against Omicron rose similarly in both groups at Day 14, it declined sharply by Days 90 and 180, with the 2CV/AZ-primed group showing significantly lower levels than the 2CV/BNT-primed group. Baseline anti-RBD IgG levels were lower in the 2CV/AZ group (p = 0.003) but surpassed those of the 2CV/BNT group by Day 14, with no significant differences at later time points. IFN-γ responses followed a similar pattern to anti-RBD IgG. Conclusions: A heterologous fourth mRNA-1273 booster in both 2CV/AZ- and 2CV/BNT-primed groups effectively enhances B-cell and T-cell responses against SARS-CoV-2. However, emerging variants such as Omicron may still pose challenges.

Abstract: Background: Personalized mRNA neoantigen vaccines represent a transformative approach to cancer immunotherapy, with recent Phase IIb data demonstrating a 49% reduction in melanoma recurrence when combined with pembrolizumab. However, two fundamental limitations constrain their efficacy: (1) fewer than 2% of mRNA molecules delivered via lipid nanoparticles (LNPs) escape the endosomal compartment to reach the cytoplasm, and (2) immunosuppressive tumor microenvironments (TMEs) in “cold” tumors blunt vaccine-induced T-cell responses. Current approaches address these challenges separately.Hypothesis: We propose that hydroxychloroquine (HCQ), when structurally incorporated as the ionizable lipid component of the LNP delivery system rather than administered as a separate systemic drug, creates a dual-function nanoparticle that simultaneously: (a) enhances mRNA endosomal escape by modulating endosomal pH maturation kinetics; (b) repolarizes tumor-associated macrophages from M2 to M1 phenotype via lysosomal Ca2+/mucolipin-1/p38/NF-κB signaling; (c) inhibits tumor-protective autophagy; and (d) reduces LNP-induced inflammatory side effects, enabling repeated dosing required for neoantigen vaccine protocols.Supporting evidence: Two independent 2025 studies demonstrated that HCQ-derived ionizable lipids achieve spleen-tropic mRNA delivery with simultaneous M2→M1 macrophage repolarization and anti-inflammatory properties permitting repeated dosing. We integrate these findings with our AI-driven Tumor Vaccine Responsiveness Score (TVRS) framework, which analyzed 8,432 TCGA Pan-Cancer Atlas specimens across 20 cancer types and identified that tumors most resistant to standard mRNA vaccines (pancreatic TVRS=11.7, glioblastoma TVRS=15.3) are precisely those where autophagy-dependent immune evasion is most active — making them ideal candidates for HCQ-LNP.

Abstract: Multiple sclerosis (MS) remains a leading cause of neurological disability, primarily due to the limited efficacy of current disease-modifying therapies in arresting progressive neurodegeneration. While peripheral lymphocyte depletion effectively manages relapsing activity, it fails to address the compartmentalized, smoldering inflammation driven by interactions between adaptive and innate immune systems within the central nervous system (CNS). The CD40–CD40L costimulatory pathway has emerged as a central regulator of these immune interactions, positioning it as a unique therapeutic target capable of addressing the full spectrum of MS pathology. This review examines the multimodal effects of CD40L blockade across peripheral and CNS-resident cell populations. Preclinical and genetic models demonstrate that inhibiting this axis suppresses pathogenic T-cell and B-cell responses while modulating innate immune activation, including macrophages, microglia, and astrocytes, and disrupting pro-inflammatory glial crosstalk. Early clinical data from second-generation, non-thromboembolic CD40L inhibitors, such as frexalimab, demonstrate reductions in markers of neuroaxonal injury and inflammatory disease activity. By simultaneously modulating systemic lymphocyte responses and CNS-resident innate immune processes, CD40L blockade represents a promising strategy to address both relapsing disease activity and progressive disability accumulation, thereby overcoming key therapeutic barriers in multiple sclerosis.