STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti–IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder.

Recurrent incidents of economically motivated adulteration have long-lasting and devastating effects on public health, economy, and society. With the current food authentication methods being target-oriented, the lack of an effective methodology to detect unencountered adulterants can lead to the next melamine-like outbreak. In this study, an ensemble machine-learning model that can help detect unprecedented adulteration without looking for specific substances, that is, in a non-targeted approach, is proposed. Using raw milk as an example, the proposed model achieved an accuracy and F1 score of 0.9924 and 0. 0.9913, respectively, when the same type of adulterants was presented in the training data. Cross-validation with spiked contaminants not routinely tested in the food industry and blinded from the training data provided an F1 score of 0.8657. This is the first study that demonstrates the feasibility of non-targeted detection with no a priori knowledge of the presence of certain adulterants using data from standard industrial testing as input. By uncovering discriminative profiling patterns, the ensemble machine-learning model can monitor and flag suspicious samples; this technique can potentially be extended to other food commodities and thus become an important contributor to public food safety.

The high effectiveness of the third dose of BNT162b2 in healthy adolescents against Omicron BA.1 has been reported in some studies, but immune responses conferring this protection are not yet elucidated. In this analysis, our study (NCT04800133) aims to evaluate the humoral and cellular responses against wild-type and Omicron (BA.1, BA.2 and/or BA.5) SARS-CoV-2 before and after a third dose of BNT162b2 in healthy adolescents. At 5 months after 2 doses, S IgG, S IgG Fc receptor-binding, and neutralising antibody responses waned significantly, yet neutralising antibodies remained detectable in all tested adolescents and S IgG avidity increased from 1 month after 2 doses. The antibody responses and S-specific IFN-γ⁺ and IL-2⁺ CD8⁺ T cell responses were significantly boosted in healthy adolescents after a homologous third dose of BNT162b2. Compared to adults, humoral responses for the third dose were non-inferior or superior in adolescents. The S-specific IFN-γ⁺ and IL-2⁺ CD4⁺ and CD8⁺ T cell responses in adolescents and adults were comparable or non-inferior. Interestingly, after 3 doses, adolescents had preserved S IgG, S IgG avidity, S IgG FcγRIIIa-binding, against Omicron BA.2, as well as preserved cellular responses against BA.1 S and moderate neutralisation levels against BA.1, BA.2 and BA.5. Sera from 100 and 96% of adolescents tested at 1 and 5 months after two doses could also neutralise BA.1. Our study found high antibody and T cell responses, including potent cross-variant reactivity, after three doses of BNT162b2 vaccine in adolescents in its current formulation, suggesting that current vaccines can be protective against symptomatic Omicron disease.

Mast cells are the major effector cells that mediate IgE-dependent allergic reactions. We sought to use integrated network analysis to identify genomic biomarkers associated with high response in IgE-mediated activation of primary human mast cells. Primary human mast cell cultures derived from 262 normal donors were categorized into High, Average and Low responder groups according to their activation response profiles. Transcriptome analysis was used to identify genes that were differentially expressed in different responder cultures in their baseline conditions, and the data were analyzed by constructing a personalized perturbed profile (PEEP). For upregulated genes, the construction of PEEP for each individual sample of all three responder groups revealed that High responders exhibited a higher percentage of “perturbed” samples whose PEEP values lay outside the normal range of expression. Moreover, the integration of PEEP of four selected upregulated genes into distinct sets of combinatorial profiles demonstrated that the specific pattern of upregulated expression of these four genes, in a tandem combination, was observed exclusively among the High responders. In conclusion, this combinatorial approach was useful in identifying a set of genomic biomarkers that are associated with high degranulation response in human mast cell cultures derived from the blood of a cohort of normal donors.

Background: Patients with kidney diseases are at risk of severe complications from COVID-19, yet little is known about the effectiveness of COVID-19 vaccines in children and adolescents with kidney diseases. Methods: We investigated the immunogenicity and safety of an accelerated, 3-dose primary series of COVID-19 vaccines among 64 pediatric chronic kidney disease patients (mean age 12.2; 32 male) with or without immunosuppression, dialysis, or kidney transplant. CoronaVac was given to those aged <5 years, 0.1ml BNT162b2 to those aged 5-11 years, and 0.3ml BNT162b2 to those aged 11-18 years. Results: Antibody responses including S-RBD IgG (90.9-100% seropositive) and surrogate virus neutralization (geometric mean sVNT% level, 78.6-94.0%) were significantly elicited by 3 doses of any vaccine. T cell responses were also elicited. Weaker neutralization responses were observed among kidney transplant recipients and non-dialysis children receiving rituximab for glomerular diseases. Neutralization was reduced against Omicron BA.1 compared to wild-type (post-dose 3 sVNT% level; 84% vs 27.2%; p<0.0001). However, T cell response against Omicron BA.1 was preserved, which likely confer protection against severe COVID-19. Hybrid immunity was observed after vaccination in infected patients, as evidenced by higher Omicron BA.1 neutralization response among infected patients receiving 2 doses than those uninfected. Generally mild or moderate adverse reactions following vaccines were reported. Conclusions: Our findings support that an accelerated 3-dose primary series with CoronaVac and BNT162b2 is safe and immunogenic in young children and adolescents with kidney diseases. TRIAL REGISTRATION: Clinicaltrials.gov NCT04800133 SIGNIFICANCE STATEMENT: Little is known about the effectiveness of COVID-19 vaccines in children and adolescents with kidney diseases. This paper describes the antibody and T cell responses of 3 doses of CoronaVac or BNT162b2, the top 2 COVID-19 vaccines distributed worldwide, by an accelerated regimen in patients with kidney diseases aged 1-18 years. Antibody and T cell responses were significantly elicited by either vaccine. Neutralization was reduced against Omicron while T cell response was preserved, which likely confer protection against severe COVID-19. Rate of severe adverse reactions was low in the study. Results confirm that accelerated 3-dose primary series with CoronaVac and BNT162b2 is safe and immunogenic in young children and adolescents with kidney diseases.