The 2023 iteration of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimated prevalence, incidence, and health burden for 375 diseases and injuries, including 12 mental disorders. We assess past, current, and emerging trends in the prevalence and burden of mental disorders across sexes and age groups, for 21 regions, 204 countries and territories, and by Socio-demographic Index (SDI) quintile, from 1990 to 2023. Mental disorders included in GBD 2023 were anxiety disorders, major depressive disorder, dysthymia, bipolar disorder, schizophrenia, autism spectrum disorders, conduct disorder, attention-deficit hyperactivity disorder, anorexia nervosa, bulimia nervosa, idiopathic developmental intellectual disability, and a residual category of other mental disorders. A literature review identified epidemiological data for each disorder. These were analysed via a Bayesian meta-regression to estimate prevalence by disorder, sex, age, location, and year. Disorder-specific prevalence was multiplied by disability weights representing the severity of health loss associated with each disorder to estimate years lived with disability (YLDs). Deaths due to anorexia nervosa were assessed with a Cause of Death Ensemble modelling strategy to estimate deaths by sex, age, location, and year, and then multiplied by the standard life expectancy at age of death to estimate years of life lost (YLLs). YLDs equalled disability-adjusted life-years (DALYs) for all mental disorders except anorexia nervosa (the only mental disorder considered as an underlying cause of death in GBD), for which DALYs represented the sum of YLDs and YLLs. We presented prevalence, deaths, YLDs, YLLs, and DALYs as counts, age-specific rates per 100 000 population, and age-standardised rates per 100 000 population. We estimated 1·17 billion (95% uncertainty interval 1·06-1·31) prevalent cases of mental disorders globally in 2023, equivalent to an age-standardised prevalence rate of 14 210·7 cases (12 849·5-15 940·1) per 100 000 population. These estimates represented a 95·5% (75·0-121·2) increase in prevalent cases and 24·2% (11·4-41·4) increase in age-standardised prevalence rate between 1990 and 2023. All mental disorders showed increases in prevalent cases between 1990 and 2023, while notable increases were seen in age-standardised prevalence rates for anxiety disorders, major depressive disorder, dysthymia, anorexia nervosa, bulimia nervosa, schizophrenia, and conduct disorder. There were an estimated 171 million (127-228) DALYs due to mental disorders globally across sex and age in 2023, equivalent to an age-standardised DALY rate of 2070·5 DALYs (1519·1-2750·5) per 100 000 population. Mental disorders contributed to 6·1% (4·8-7·6) of all-cause DALYs in 2023, making them the fifth leading cause of global DALYs (up from 12th in 1990). DALYs were almost entirely composed of YLDs. Mental disorders were the leading cause of YLDs in 2023 (up from second in 1990), explaining 17·3% (14·8-20·6) of all-cause global YLDs. Leading causes of mental disorder DALYs were anxiety disorders (ranked 11th among the 304 diseases and injuries at Level 4 of the GBD cause hierarchy), major depressive disorder (15th), and schizophrenia (41st). Globally in 2023, mental disorder age-standardised DALY rates were higher among females (2239·6 [1643·7-3014·1] per 100 000) than among males (1900·2 [1399·8-2510·8] per 100 000), and peaked in the 15-19 years age group (2617·3 [1850·6-3696·8] per 100 000). All locations showed increased mental disorder DALY rates in 2023 compared with 1990, ranging across countries and territories from 1302·4 (952·7-1683·7) per 100 000 in Viet Nam to 3555·8 (2661·9-4715·0) per 100 000 in the Netherlands. Across SDI quintiles, DALY rates ranged from 1853·0 (1352·1-2469·3) per 100 000 for middle SDI to 2184·1 (1606·1-2890·3) per 100 000 for high SDI. A significant health burden was imposed by mental disorders in all countries and territories in 2023, irrespective of the health resources available. In some instances, this burden has increased over time and is unevenly distributed across populations. Stronger surveillance systems, particularly in low-income and middle-income countries, are required. Additionally, we need more coordinated and inclusive policies to reduce the burden through early treatment and prevention, tailored to sex and age differences across locations. Responding to the mental health needs of our global population, especially those most vulnerable, is an obligation, not a choice. Gates Foundation, Queensland Health, and University of Queensland.
Subcutaneous immunotherapy (SCIT) is a clinically effective and disease-modifying treatment for house dust mite (HDM)-induced allergic rhinitis (AR). Although SCIT provides long-term symptom improvement for most patients, a subset of patients shows inadequate clinical response. The underlying factors contributing to the heterogeneity in treatment efficacy remain unclear, and robust biomarkers capable of predicting SCIT outcomes are still lacking. This study aimed to evaluate the clinical efficacy of one-year HDM-SCIT and to identify serum biomarkers associated with therapeutic response, with the goal of improving prediction of SCIT outcomes in patients with AR. Eligible patients with HDM-induced allergic rhinitis were prospectively enrolled from two medical centers (Peking Union Medical College Hospital and the Affiliated Hospital of Qingdao University) and subsequently completed one year of HDM-SCIT. Symptom severity was evaluated using the visual analog scale (VAS) and total nasal symptom score (TNSS), and quality of life by the rhinoconjunctivitis quality of life questionnaire (RQLQ) at baseline and one year after treatment. Clinical remission was defined as ≥ 30% improvement of VAS and RQLQ scores. In addition, medication scores and TNSS were also included as secondary endpoints to support the response definition. Paired serum samples collected before and after treatment were analyzed using untargeted metabolomics and targeted bile acid profiling based on liquid chromatography-mass spectrometry. To validate metabolomic findings, an HDM-induced AR mouse model was established, followed by SCIT alone or SCIT combined with taurolithocholic acid (TLCA, a bile acid). Nasal histopathology, T cell subsets in the spleen, and cytokine levels in serum and nasal lavage fluid were assessed. Of the 32 patients who received one-year HDM-SCIT, 22 were responders and 10 were non-responders. No baseline differences in age, AR duration, comorbidities, total IgE, VAS, TNSS, or RQLQ were found between the two groups. However, responders had significantly greater reductions in VAS, TNSS, and RQLQ post-one-year treatment (p < 0.05). Untargeted metabolomics identified 956 differential metabolites (614 upregulated, 342 downregulated) between the pre-treatment group and post-treatment group, 1,389 (582 up, 807 down) and 1574 (342 up, 1232 down) between responders and non-responders at baseline and post-treatment, respectively. KEGG analysis highlighted bile secretion as a key differential pathway. Bile acid targeted metabolomics revealed TLCA as a potential biomarker associated with HDM-SCIT efficacy. Mouse models confirmed that HDM-SCIT combined with TLCA, particularly at high dose, alleviated nasal mucosal inflammation (reduced epithelial damage, eosinophils), increased splenic CD4+Foxp3+ regulatory T cells, reduced CD4+IL-4+ helper T 2 cells and serum IgG1, and dose-dependently decreased serum/nasal lavage interleukin (IL)-5, while increasing serum IL-10/interferon-γ. Serum TLCA levels were associated with clinical response to HDM-SCIT. Animal model validation demonstrated that TLCA may enhance SCIT-induced immune tolerance. These findings support TLCA may serve as a potential metabolite-based biomarker and adjunct target for improving the efficacy of allergen immunotherapy.
Obesity has become a major determinant of outcomes across solid organ transplantation. Beyond its well-recognized metabolic and cardiovascular burden, obesity profoundly affects both immune regulation and the pharmacology of immunosuppressive therapy. Experimental evidence has established adipose tissue as an active immune organ that promotes low-grade inflammation through leptin, TNF-α, and IL-6, thereby altering alloimmune responses and impairing graft tolerance. Clinically, obesity is associated with increased surgical complications, delayed graft function, and reduced survival after kidney, liver, and thoracic organ transplantation. In parallel, obesity modifies drug disposition at every pharmacokinetic step, expanding the distribution volume for lipophilic agents such as calcineurin and mTOR inhibitors, altering CYP3A metabolism, and increasing interindividual variability in exposure. Consequently, both underexposure and toxicity remain frequent, underscoring the need for individualized therapeutic strategies. Current evidence supports the integration of therapeutic drug monitoring, pharmacogenomics, and biomarker-based approaches to refine immunosuppression intensity. This review summarizes experimental and clinical data linking obesity-induced inflammation with altered immunosuppressive pharmacology and proposes a framework for precision immunosuppression that balances efficacy, nephroprotection, and metabolic safety. Tailoring therapy to the specific immunometabolic profile of obese recipients may thus transform a major clinical challenge into an opportunity for precision transplant medicine.
The diphtheria, tetanus, and acellular pertussis combined vaccine (DTaP) is a trivalent formulation containing acellular pertussis antigens, diphtheria toxoid, and tetanus toxoid, and provides simultaneous protection against pertussis, diphtheria, and tetanus. This study aimed to systematically evaluate the effects of repeated intramuscular administration of an adsorbed acellular diphtheria-tetanus-pertussis (reduced-dose) combined vaccine (Tdacp) on gamete maturation, mating performance, fertility, and embryo-fetal development in Sprague-Dawley (SD) rats, thereby providing experimental evidence for its reproductive safety. Sexually mature SD rats were randomly assigned, stratified by sex and body weight into four groups: negative control, adjuvant control, low-dose, and high-dose, with 40 rats per group (20 males and 20 females). Male and female rats were paired for mating according to group assignment and identification number. Animals received two intramuscular injections; the low-dose group received 0.25 mL/rat, whereas all other groups received 0.5 mL/rat. Evaluated parameters included clinical signs, food consumption, body weight, reproductive organ coefficients, estrous cycle characteristics in females, sperm parameters in males, embryo-fetal growth and development, and vaccine-induced antibody responses. Repeated intramuscular administration of Tdacp did not result in significant adverse effects on food consumption, body weight, or reproductive function in either the low-dose or high-dose group compared with the negative control group. Likewise, no treatment-related embryo-fetal developmental toxicity or teratogenic effects were observed. Although several embryo-fetal developmental parameters in the adjuvant control group, including implantation loss, fetal viability, embryo/fetal resorption, and selected skeletal ossification findings, differed from those in the negative control group, similar findings were not observed in the vaccine-treated groups. Immunogenicity analysis demonstrated positive antibody responses against diphtheria, tetanus, and pertussis antigens in both vaccine groups following immunization. These findings indicate that Tdacp has a favorable reproductive safety profile and good immunogenicity in SD rats. The results provide important nonclinical evidence to support its further clinical development. Manufactured using advanced chromatographic purification technology, this combined vaccine may contribute to the establishment and implementation of a life-course pertussis prevention and immunization strategy in China.
Insomnia is closely associated with immune dysregulation, yet the overall pattern of peripheral-central immune disequilibrium and its underlying molecular basis remains incompletely understood. To characterize the peripheral-central immune features associated with insomnia, identify key immune cell populations and core molecular programs, and prioritize candidate therapeutic compounds with preliminary experimental validation. Peripheral blood bulk transcriptomic dataset GSE208668 was analyzed using differential expression analysis, weighted gene co-expression network analysis (WGCNA), and functional enrichment analysis to identify insomnia-associated genes. Protein-protein interaction network analysis and machine learning models were then applied in independent peripheral blood datasets to refine core genes. Immune deconvolution and peripheral blood single-cell transcriptomic dataset GSE213496 were used to determine the immune-cell context, cell-type localization, and intercellular communication features of these genes. The brain single-cell transcriptomic dataset GSE137665 was further analyzed to assess central alterations. Drug prediction, molecular docking, and molecular dynamics simulations were performed to prioritize candidate compounds, followed by in vitro validation of resveratrol in an LPS-induced THP-1 macrophage model. A total of 5,321 differentially expressed genes associated with insomnia were identified, and weighted gene co-expression network analysis highlighted the turquoise and blue modules as key insomnia-related modules. Integrative analysis yielded 390 intersecting genes enriched mainly in immune, inflammatory, and oxidative stress-related pathways. Protein interaction analysis and machine learning further identified six refined core genes: FN1, HMOX1, HSP90AA1, IL10, MYD88, and NFE2L2. Because IL10 was not stably detected in the single-cell datasets, the remaining five genes were used for downstream single-cell analyses. Immune deconvolution suggested selective peripheral immune remodeling in insomnia, characterized by increased resting CD4 memory T cells and M2 macrophages, together with reduced activated NK cells. Peripheral single-cell analysis showed that HMOX1, HSP90AA1, MYD88, and NFE2L2 were mainly enriched in neutrophils, inflammatory macrophages, conventional dendritic cells, and selected lymphocyte populations, whereas FN1 showed a more restricted distribution pattern. CellChat analysis indicated enhanced intercellular communication under the sleep deprivation-related condition. In contrast, brain single-cell analysis revealed comparatively modest but detectable central alterations, including enrichment of ependymal cells, slight increases in excitatory neurons, brain endothelial cells, and choroid plexus stromal fibroblasts, together with heterogeneous expression of the core hub genes and selective rewiring of intracerebral communication networks. Drug prediction consistently prioritized quercetin and resveratrol, and structural analyses supported stable interactions with key targets. In THP-1 macrophages, resveratrol downregulated MYD88 and HSP90AA1 while further upregulating HMOX1. Insomnia appears to be associated predominantly with a peripheral-centered immune disequilibrium pattern, characterized by selective remodeling of innate immune-related populations, enhanced inflammatory and oxidative stress programs, and increased intercellular communication. The MYD88-HMOX1-HSP90AA1-NFE2L2 axis may represent a key molecular program linking inflammatory activation and oxidative stress adaptation. Resveratrol was identified as a potential compound and has been validated through preliminary in vitro experiments.
Cytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC) is a treatment for peritonitis carcinomatosa. These procedures often involve significant blood and fluid loss, leading to hyperdynamic circulation and vasodilation, necessitating intraoperative fluids and vasoconstrictors such as catecholamines. Excessive fluid administration to counteract vasodilation can cause intraoperative fluid overload, which is linked to increased postoperative complications. Vasopressin has emerged as a potential alternative to catecholamines, restoring vascular tone via non-adrenergic pathways and supporting perfusion pressure, potentially reducing the need for compensatory fluids solely administered to compensate for vasodilation. We hypothesise that compared with norepinephrine, vasopressin reduces cumulative intraoperative fluid administration during CRS-HIPEC within a goal-directed fluid therapy (GDFT) protocol, ultimately leading to a lowering of postoperative complications. HiPress is a two-centre, two-arm randomised clinical trial with blinding of both patients and outcome assessors. A total of 70 adult patients undergoing CRS-HIPEC will be included. Patients will be randomised to receive either continuous low-dose argipressin or continuous low-dose norepinephrine. Both groups will receive standardised GDFT during the procedure. The primary endpoint is cumulative intraoperative fluid administration (mL). Secondary endpoints include direct fluid-related outcomes (eg, cumulative intraoperative fluid (ml/kg/hour), postoperative fluid balance until day five and ultrasound-assessed pulmonary oedema and venous congestion) and indirect fluid-associated outcomes (eg, quality of recovery, surgical and abdominal complications, acute kidney injury (AKI), pulmonary complications, length of ICU and hospital stay and 30-day mortality). The study is enrolling patients since February 2025. The trial is approved by the Medical Research Ethics Committee (hereinafter: MREC) NedMec, The Netherlands (Ref: D-25-500202). Results of the trial will be published in an international peer-reviewed journal and announced at national and international scientific meetings. Clinical Trials Information System (CTIS): European Union clinical trials register (EUCT) number: 2024-5 13 598-33-00.
The nuclear factor κB (NF-κB)-related disorders encompassed not only common variable immunodeficiency but also manifestations of autoinflammation, autoimmunity, and malignancies. While most cases have been reported in European populations, reports in the Chinese population are sparse. Clinical data and genetic variants from four Chinese patients with NFKB1 variants, alongside four previously reported cases, were analyzed and compared with an international cohort. Additionally, comprehensive in vitro functional assays-including immunoblotting, transcript analyses, dual-luciferase reporter, and co-immunoprecipitation assays-were conducted to explore the molecular defects of the novel variants. Our cohort included three men and one woman, all presenting with recurrent fever and hypogammaglobulinemia. Three patients experienced recurrent sinopulmonary infections, accompanied by decreased B cells and NK cells, while two patients developed pneumonia, bronchiectasis, and hepatitis. Three novel NFKB1 (NM_003998) variants were identified: c.559C>T (p. Arg187Trp), c.1509del (p. Glu504Argfs*19), and c.1753-11_1760del (p. Thr585Alafs*9). Functional analyses revealed distinct pathomechanisms: the frameshift/splicing variants drive classical haploinsufficiency via nonsense-mediated mRNA decay (NMD), triggering compensatory inflammatory hyperactivation; conversely, the p.Arg187Trp missense variant maintains protein stability and heterodimerization but strictly abolishes DNA-binding capacity. Compared to a previously reported cohort, Chinese patients were predominantly male, had a later median age of onset and diagnosis. Notably, Chinese patients exhibited a higher prevalence of hepatitis (25%) and cirrhosis (12.5%), potentially reflecting the high endemicity of hepatitis B virus in China. They also showed increased rates of viral infections, sepsis, and bronchiectasis, with more pronounced reductions in NK and B cells. In contrast, autoimmune diseases and bronchitis were less frequent than in the foreign cohort. This study represents the first and largest case series of Chinese patients with NF-κB1-related diseases, providing molecular characterization for three novel variants. In this limited case series, the observed delayed onset and frequent hepatic complications in our cohort may reflect regional factors, such as HBV endemicity, or ascertainment bias. Our findings underscore that suspected AOSD accompanied by hypogammaglobulinemia warrants immediate genetic investigation. Early diagnosis is essential to prioritize immunoglobulin replacement and prevent fatal complications from immunosuppressive therapy.
Background/Objectives: Psoriasis and Hashimoto's thyroiditis are chronic immune-mediated disorders affecting distinct target organs but sharing overlapping pathogenic mechanisms, including gut dysbiosis, impaired intestinal barrier function, and systemic immune dysregulation. Growing evidence highlights the gut-skin and gut-thyroid axes as important interfaces linking microbial alterations to immune-mediated inflammation. This review aims to synthesize current knowledge on gut microbiota alterations in psoriasis and Hashimoto's thyroiditis, with particular emphasis on intestinal permeability, immune pathways, and microbiome-derived metabolites. Methods: A narrative review of experimental and human observational studies was conducted to evaluate evidence on gut microbiota composition, intestinal barrier integrity, immune regulation, bile acid metabolism, and dietary influences in psoriasis and Hashimoto's thyroiditis. The relevant literature examining mechanistic pathways and clinical associations was included. Results: Both conditions are associated with altered gut microbial composition, including reduced abundance of short-chain fatty acid-producing taxa, which may impair epithelial barrier integrity and promote systemic immune activation. Increased intestinal permeability and enhanced Th17-driven inflammatory responses are reported in both diseases. Recent studies suggest that dysregulated bile acid metabolism may influence intestinal permeability and immune balance along the gut-skin-thyroid axis, although direct clinical data remain limited. Dietary patterns, particularly anti-inflammatory and Mediterranean diets, are consistently associated with increased microbial diversity, improved metabolic profiles, and reduced systemic inflammation. However, most human evidence is observational. Conclusions: The gut microbiome represents a potential mechanistic link connecting diet, intestinal barrier function, immune regulation, and organ-specific autoimmunity in psoriasis and Hashimoto's thyroiditis. While microbiome-targeted interventions show biological plausibility, well-designed, mechanistically informed randomized controlled trials are required to establish causality and clinical relevance.
Patients with head and neck squamous cell carcinoma (HNSCC) continue to face poor prognosis, highlighting an urgent need for new diagnostic markers and therapeutic targets. While metabolic reprogramming and immune microenvironment dysregulation are crucial drivers of HNSCC progression, the key causal molecular mechanisms linking these processes remain elusive. Post-translational modifications, especially protein lactylation, may serve as a vital interface for this metabolic-immune "crosstalk". We developed an integrative analytical framework merging lactylation proteomics, transcriptomics, and Mendelian randomization (MR). Differential expression analysis was conducted on three public transcriptomic cohorts (53 HNSCC vs. 53 controls), and the resulting genes were overlapped with a systematically compiled set of 2, 124 lactylation-related genes. Causal risk genes were then identified using MR analysis with large-scale genetic instruments (from expression quantitative trait locus data) and HNSCC genome-wide association study summary statistics. The functional roles of candidate genes were explored through enrichment analysis, Gene Set Variation Analysis, and immune deconvolution (CIBERSORT). Experimental validation was performed using quantitative real-time PCR and Western blotting in an independent The Cancer Genome Atlas dataset and in HNSCC cell lines. We identified 212 lactylation-associated differentially expressed genes. MR analysis established CD44 and APP as genetic causal risk factors for HNSCC, with both genes significantly overexpressed in patient tissues. Functional profiling indicated that high CD44 expression correlated with activation of mTOR signaling and ECM-receptor interaction pathways, and was positively associated with M0 macrophage infiltration. Conversely, high APP expression was linked to activated protein secretion and ECM pathways, and showed a positive correlation with M2 macrophage abundance. The marked upregulation of CD44 and APP in HNSCC was consistently confirmed in the independent validation cohort and in cellular models. By pioneering a multi-omics causal inference approach in HNSCC, this study identifies CD44 and APP as genetic causal risk factors for disease susceptibility and progression. These genes connect distinct metabolic pathways with specific immune cell subsets, functioning as central hubs within the HNSCC metabolic-immune crosstalk network. Our work provides a critical theoretical basis for future development of lactylation pathway-based biomarkers and targeted interventions.
We aimed to evaluate 12-y (2012-2024) burden, clinical and microbiological characteristics of Invasive Pneumococcal Disease (IPD) at one large research hospital - IRCCS Fondazione Policlinico San Matteo - in northern Italy, with focus on serotypes' distribution, resistance trends, and vaccination impact on outcomes and costs. The study included 234 IPD cases. Data were obtained from medical records, microbiological reports, and vaccination registries. Statistical analyses included descriptive measures, multivariate regression models for risk factors (adjusted for sex, age group, comorbidities), and comparison of length of stay and costs between vaccinated and unvaccinated patients. Most cases occurred in males aged ≥65. Bacteremia with pneumonia was the most frequent presentation (55.6%). Obesity and splenectomy were associated with higher risk of severe outcome. The most common serotypes overall were 3 and 8. Among vaccinated patients serotypes 15A, 14, 19A, and 15C were more frequent. Macrolide resistance was detected in 26.9% of isolates and beta-lactam resistance in 14.9%. Collectively, 34.5% of cases were caused by serotypes preventable with Pneumococcal Conjugate Vaccine 13 (PCV13), an additional 5.1% by PCV15, 21% by PCV20 and 14.4% by V116 preventable serotypes. Vaccine-preventable serotypes accounted for 64% of cases, mostly (56%) in patients aged ≥65. Vaccinated patients reported shorter hospital stay (median 8 vs 16 d) and lower associated costs (€3313 vs €5101). IPD surveillance is critical to inform prevention strategies. Our findings quantify how much vaccination reduces disease severity and healthcare costs but highlight gaps in vaccine coverage against emerging serotypes due to replacement mechanisms.
Neuropilins (NRPs), particularly NRP-1, are multifunctional co-receptors involved in neuroinflammatory and neuroprotective processes. Altered NRP expression has been observed in multiple sclerosis (MS) lesions and peripheral circulation, suggesting early involvement in disease progression. This review addresses the dual role of NRPs in MS and experimental autoimmune encephalomyelitis (EAE), emphasizing expression patterns, signaling pathways, and therapeutic interventions. NRP-1 is expressed by endothelial cells, microglia, and macrophages, while Sema3A, a key ligand, is produced by reactive astrocytes and contributes to a non-regenerative microenvironment. NRP-1 is involved in regulating blood-brain barrier (BBB) integrity, contributes to leukocyte trafficking, and modulates inflammatory signaling via the IFN-γ-STAT1-CXCL10 axis. In EAE, endothelial-specific NRP-1 deletion reduces disease severity, demyelination, and immune infiltration. Immunologically, NRP-1 governs interactions among T cells, dendritic cells, and macrophages, facilitating regulatory T cell (Treg) function and peripheral tolerance. Trogocytosis-mediated NRP-1 transfer from dendritic cells to T cells and polysialylated NRP-2 on dendritic cells further influence immune modulation. Tuftsin, a tetrapeptide targeting NRP-1, promotes anti-inflammatory microglial polarization and Treg activation, improving EAE outcomes. Therapeutic interventions, such as Bu-Shen-Yi-Sui Capsule (BSYSC), FTX-101 (a Sema3A-NRP-1 inhibitor), and tuftsin restore BBB function, reduce inflammation, enhance remyelination, and improve clinical scores. NRP-1 signaling thus exhibits context-dependent dual roles: promoting inflammatory cascades while enabling neuroprotection through regulatory immune networks and oligodendrocyte precursor cell support, highlighting NRP-1 as a therapeutic target in MS.
Nutrition in the early years of life plays a fundamental role in newborn growth, immune maturation, metabolic regulation, endocrine signaling, and neurological development, specifically through its interaction with the developing gut microbiota. Breast milk is the biological gold standard for infant nutrition; however, when breastfeeding is not possible, the development of formulations supplemented with bioactive substances can improve functional outcomes in comparison to standard milk formula. This narrative review discusses current evidence on formulas enriched with prebiotics, probiotics, postbiotics, synbiotics, human milk oligosaccharides, and other bioactive molecules. The review focuses on gut microbiota modulation, gastrointestinal function, growth and nutritional adequacy, immune development, infection-related outcomes, safety and tolerability, endocrine signaling, intestinal stem-cell regulation, obesity-related metabolic pathways, and emerging gut-brain axis interactions. Overall, available data indicate that bioactive-supplemented formulas are generally safe, well tolerated, and able to support normal growth, including in selected infants with specific clinical conditions. The most consistent effects are observed in the gastrointestinal tract, where supplementation promotes a more bifidogenic microbial profile, improves stool characteristics, supports intestinal barrier function, and influences microbial metabolic activity. By contrast, evidence regarding systemic immune effects, endocrine modulation, obesity prevention, and neurodevelopmental outcomes remains promising but heterogeneous and is still largely derived from preliminary human studies and experimental models. Therefore, these formulas may be considered a useful option when breastfeeding is not feasible, provided that their use is clinically appropriate and evidence based. Further studies are needed to clarify their long-term functional and clinical implications.
Epithelial ovarian cancer (EOC) remains one of the most lethal gynecologic malignancies, largely owing to advanced-stage presentation, high rates of relapse, and the eventual emergence of therapeutic resistance. Despite the transformative success of immune checkpoint inhibitors (ICIs) across multiple solid tumors, their clinical impact in ovarian cancer has been comparatively modest. This literature review provides a comprehensive synthesis of recent advances in ICI strategies for ovarian cancer (OC), with particular emphasis on phase II and III clinical trials evaluating programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and T cell immunoglobulin and mucin-domain-containing-3 (TIM-3)-directed therapies. Accumulating evidence indicates that PD-1/PD-L1 monotherapy yields limited clinical activity in unselected OC populations, with low objective response rates and minimal survival benefit. Dual checkpoint blockade with PD-1 and CTLA-4 inhibitors demonstrates enhanced antitumor activity, particularly in clear cell ovarian carcinoma (CCOC), albeit at the expense of increased immune-related toxicity. Large randomized trials incorporating ICI into first-line chemotherapy or maintenance settings have largely failed to improve outcomes in biomarker-unselected cohorts. Available evidence demonstrates that combinatorial approaches integrating ICI with anti-angiogenic agents, PARP inhibitors, or neoadjuvant chemotherapy provide modest benefit in selected molecular and histologic subgroups. Early-phase investigations of TIM-3-targeting strategies further expand the immunotherapeutic landscape, although clinical efficacy remains preliminary. Current evidence underscores that OC is not uniformly responsive to immunotherapy and that rational combination strategies, biomarker-driven patient selection, and improved understanding of tumor immune microenvironment heterogeneity are essential to unlocking the full therapeutic potential of ICI in this disease.
The receptors of the tumor necrosis factor (TNF) receptor superfamily (TNFRSF) are of overwhelming scientific and clinical relevance and stand at the center of intensive basic and translational research efforts. TNFRSF receptors (TNFRs) are engaged by membrane-bound ligands of the TNF superfamily (TNFSF) and, in some cases, by soluble ligand molecules released from the membrane-bound TNFSF ligand (TNFL) molecules. The development of recombinant TNFL-based TNFR agonists for research and especially therapeutic purposes is highly "individualized", as ligand type-specific hurdles must be overcome in terms of stability, manufacturability, TNFR-specificity and need for oligomerization. TNFR-specific antibodies can also show agonistic activity, but this agonism typically requires FcγR-binding, resulting in a reciprocal conditional bispecific FcγR/TNFR agonism not useful for the study or exploitation of pure TNFR agonism. Some antibodies trigger intrinsic TNFR agonism independent from FcγR-binding, but the rational development of such antibodies is poorly predictable and furthermore challenging due to isotype- and epitope-requirements and poor specific activity when benchmarked with FcγR-bound anti-TNFR antibodies.Using a series of nanobodies (or single-domain antibodies (sdAbs) or variable heavy domain of heavy chains (VHHs)) specific for the TNFRSF members 41BB, BCMA, CD40, CD95, TRAILR2/DR5, GITR, OX40, TNFR1 and TNFR2, we show here that genetic fusion of single-chain encoded triplets of these nanobodies with oligomerizing protein scaffolds regularly results in potent hexa-, nona- and dodecavalent agonists inducing TNFR signaling with EC50-values in the sub-nanomolar range. The oligovalent nanobody formats described exhibit superior CMC properties and enable the simple generation of highly active TNFR agonists from virtually any TNFR-specific nanobody.
Artificial intelligence (AI) directed computational protein design has emerged as a transformative force in modern therapeutic discovery, reshaping how vaccines and antibody-based interventions are conceived, optimized, and deployed against emerging infectious diseases. The COVID-19 pandemic served as an unprecedented real-world stress test for these technologies, highlighting their potential to accelerate antigen design, guide antibody optimization, and anticipate viral evolution in near real time. AI driven approaches contributed to faster characterization of viral variants, supported vaccine and broadly neutralizing antibodies developments. Despite the significant contributions, the pandemic also revealed important limitations that must be addressed before such approaches can be relied upon as cornerstones of global preparedness. Challenges related to data bias, model interpretability, experimental validation bottlenecks, and integration with existing regulatory frameworks became increasingly apparent. In several cases, the gap between computational promise and translational readiness underscored the need for closer coupling between in silico design, laboratory experimentation, and clinical evaluation. Moreover, the rapid pace of AI innovation often outstripped established regulatory pathways, raising questions about standardization, validation, and long-term safety. This mini review provides a focused overview of recent advances in AI enabled computational protein design, with an emphasis on applications relevant to pandemic response. Drawing on lessons from COVID-19 case studies, it examines translational and regulatory considerations, highlights unresolved controversies, and identifies critical research gaps. Collectively, these insights outline a path toward transitioning AI designed vaccines and antibody therapeutics from reactive emergency tools into proactive, scalable infrastructures for future pandemic preparedness.
Lynch syndrome (LS) is a hereditary cancer syndrome that increases risk for colorectal and other cancers. We hypothesize that vaccines against tumor-associated antigens CEA, MUC1, and brachyury, simultaneously delivered in an adenovirus serotype-5 vector (Tri-Ad5) combined with the immune-enhancing IL-15 receptor superagonist nogapendekin-alfa-inbakicept (NAI) will reduce the incidence of colorectal neoplasms in LS carriers. In this ongoing phase IIB double-blind placebo-controlled trial, two open-label safety phases (SPs) assessed safety of Tri-Ad5 alone (SP1, n=10) and with added NAI (SP2, n=10). A randomized controlled trial (RCT) follows the SPs. After baseline colonoscopy, vaccine dosing occurs at weeks 0, 4 and 8; Tri-Ad5 alone in SP1 and Tri-Ad5 plus NAI in SP2, with identical boosters at Week 52. The RCT phase participants (n=138) were randomized to receive Tri-Ad5 plus NAI or placebo. All participants complete colonoscopy at Weeks 52 and 104 for assessment of the primary endpoint: cumulative colorectal neoplasm incidence. Secondary endpoints include safety, tolerability, and immunogenicity. All 20 SP participants (median age 57.5 (range 42-75), 70% female, 15% minority) received all prime and booster series. SP1 participants reported 139 adverse events (AEs) and SP2 participants reported 178. AEs were predominantly grade 1; no treatment-related serious adverse events (SAEs) occurred. The most common treatment-related AEs were reactogenic events including grade 3 rash (without skin necrosis or breakdown) at NAI injection site (100% of SP2 participants). The RCT phase (n=138) recently completed accrual. In LS carriers without active cancer, the combination of Tri-Ad5 + NAI was well-tolerated; the RCT phase is ongoing. https://clinicaltrials.gov/study/, identifier NCT05419011.
Neutralizing antibodies (NAbs) have long been the principal correlate of antiviral protection. Evidence now indicates that antibody Fc-mediated effector functions play indispensable and context-dependent roles in antiviral immunity. Through interactions between the fragment crystallizable (Fc) domain and Fc receptors (FcRs) or complement components, antibodies mediate a broad spectrum of effector mechanisms, including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular and neutrophil phagocytosis (ADCP and ADNP), and complement activation, contributing to viral control beyond direct neutralization. In this review, we integrate recent evidence on Fc effector biology across major viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza virus, human immunodeficiency virus (HIV), Ebola virus (EBOV), and dengue virus (DENV). We discuss how Fc-FcR interactions shape antiviral immune outcomes, modulate vaccine efficacy, and influence the balance between protective immunity and immunopathology, including antibody-dependent enhancement (ADE). We focus on the experimental strategies used to assess Fc-mediated functions and on the inherent limitations of in vitro assays and animal models in defining their physiological relevance in humans. We explore how different vaccine platforms and immunization strategies shape Fc effector profiles, specifically through antibody subclass selection, Fc glycosylation patterns, and engagement with Fcγ receptors. We also summarize emerging approaches to Fc engineering and glycan modification that aim to enhance antibody efficacy while limiting adverse immune activation. This review summarizes current understanding of Fc effector functions in antiviral immunity and discusses their relevance for the design of next-generation vaccines and antibody-based therapies.
Several medications are available for rapid tranquilisation in psychomotor agitation, but choosing among them varies across local practices and this variation is compounded by inconsistent guidelines. We performed a systematic review with individual participant data network meta-analysis to inform evidence-based recommendations. In this systematic review and individual participant data meta-analysis, we searched multiple databases from database inception to Nov 14, 2025, for randomised trials comparing intramuscular or intravenous treatments for rapid tranquilisation (primary outcome defined as sedation within 15-30 min) in patients with psychomotor agitation in general or psychiatric emergency settings. Anonymised individual participant data were collected and harmonised into a common dataset. Risk of bias was assessed using the RoB 2 tool. We performed Bayesian one-stage random-effects individual participant data network meta-regressions, accounting for between-study heterogeneity, drug classes, prognostic factors, and subgroup effects based on agitation severity. We combined individual participant data and aggregate data to evaluate side-effects. Confidence in the evidence was assessed using the Confidence In Network Meta Analysis (CINeMA) framework. People with lived experience were involved in the design and interpretation of the findings. The protocol was registered with PROSPERO (CRD42023402365). We included 18 trials across eight regions (3411 participants; 1988 [58·3%] men, 1423 [41·7%] women; mean age 36·0 [SD 11·7] years), of which 13 trials (2705 participants) provided individual participant data for antipsychotics, benzodiazepines, and their combination. In moderate agitation, odds of achieving sedation relative to haloperidol monotherapy were higher with antipsychotic-benzodiazepine combinations (odds ratio [OR] 12·93, 95% credible interval [95% CrI] 3·00-50·91; relative risk [RR] 1·58), benzodiazepines (5·52, 1·37-21·02; 1·49), and other antipsychotics (4·54, 1·35-14·45; 1·45). In severe agitation, antipsychotic-benzodiazepine combinations were more effective than haloperidol (4·86, 1·28-17·54; 1·73), whereas results were uncertain for benzodiazepines (2·09, 0·58-6·99; 1·38) and other antipsychotics (1·70, 0·62-4·59; 1·28). Confidence in these estimates was very low, mainly due to imprecision and heterogeneity. Haloperidol monotherapy was associated with higher risk of extrapyramidal side-effects and benzodiazepines, alone or in combination, with hypotension. Antipsychotic-benzodiazepine combinations might be among the most effective options for rapid tranquilisation in patients with psychomotor agitation but carry a risk of hypotension, whereas haloperidol monotherapy appeared among the least effective and is associated with extrapyramidal side-effects. These findings should be contextualised to the specific setting and patient characteristics, including the underlying agitation aetiology. Large trials are needed to provide more precise recommendations. German Ministry of Research, Technology and Space and Swiss National Science Foundation.
Interleukin-1β (IL-1β) is a key mediator of innate immunity and a central driver of airway inflammation in asthma and chronic obstructive pulmonary disease (COPD). Elevated IL-1β levels in sputum, bronchoalveolar lavage, and airway tissues correlate with neutrophilic inflammation, exacerbation frequency, airflow limitation, and steroid resistance. Mechanistically, IL-1β promotes epithelial activation, epithelial-mesenchymal transition, neutrophil recruitment, inflammasome activation, and immune cell plasticity, particularly driving ILC2 transdifferentiation toward pro-inflammatory phenotypes. Despite strong biological rationale, clinical trials targeting IL-1 signaling through receptor blockade or IL-1β neutralization have yielded limited benefits in certain patient populations. Therapeutic failure is largely attributed to disease heterogeneity, lack of biomarker-guided stratification, redundant inflammatory pathways, and suboptimal timing of intervention. Emerging strategies include precision medicine approaches with biomarker enrichment, upstream NLRP3 inflammasome inhibition, combinatorial cytokine targeting, modulation of signaling intermediates, temporally targeted therapy during exacerbations, and localized airway delivery systems. Integration of multi-omics profiling and endotype-based patient selection may enhance therapeutic responsiveness. Future clinical trials should adopt adaptive designs to validate IL-1-targeted interventions in biologically defined subgroups of patients with asthma or COPD.
Respiratory syncytial virus (RSV) is a leading cause of acute respiratory infection, with substantial morbidity and mortality in older adults, yet its impact in this population remains underrecognized compared with childhood RSV. Despite the availability of effective vaccines, RSV immunization in adults is underutilized, as observed for other vaccines. We summarize the RSV burden in adult populations and present clinical and real-world evidence supporting efficacy/effectiveness and safety of three approved RSV vaccines. We explore barriers to adult vaccine uptake - including limited awareness, lack of reimbursement, mistrust, misinformation, and inconsistent guidance - and highlight broader benefits of adult immunization, including reducing antimicrobial resistance and promoting healthy aging. We conclude that to improve uptake, communication strategies should include messages that emphasize how vaccination prevents severe illness, preserves independence, and supports everyday well-being. We highlight that a life-course immunization strategy, built on trust, is essential to achieve equitable protection across populations. Adult vaccines remain undervalued despite their proven safety and benefits, which extend beyond infection prevention to support healthy aging and reduce antimicrobial resistance. To maximize their impact, strategies such as harmonizing recommendations, improving reimbursement, leveraging digital tools, and addressing vaccine hesitancy through better communication and research are essential. Respiratory syncytial virus (RSV) infection is a real but often overlooked risk for older adults and people with underlying health problems. Vaccines to help prevent severe RSV disease in adults have been available since 2023. However, only a minority of eligible adults are getting vaccinated, similar to what is seen with other adult vaccines. Reasons for low adult vaccine uptake include a lack of knowledge about the diseases and vaccines, and a lack of trust, reinforced by misinformation on social media. This review looks at ways to improve vaccine uptake in adults. First, the benefits of vaccination against RSV and other infectious diseases should be clearly communicated to patients and healthcare providers based on the best scientific evidence. Second, it is important to highlight that adult vaccination, including against RSV, may do more than protect against infections: it may also help prevent acute complications (such as stroke or heart attack), some chronic illnesses or their worsening, and it may help fight antimicrobial resistance. Third, we should develop a strategy for life-long vaccination, based on lessons from childhood vaccination programs and the COVID-19 pandemic. Finally, the success of these strategies depends on building trust at every level: from policy and education to clinical practice. Only then can adult vaccination become a cornerstone of life-long health.