Holdout-Based Empirical Assessment of Mixed-Type Synthetic Data.

AI-based data synthesis has seen rapid progress over the last several years and is increasingly recognized for its promise to enable privacy-respecting high-fidelity data sharing. This is reflected by the growing availability of both commercial and open-sourced software solutions for synthesizing private data. However, despite these recent advances, adequately evaluating the quality of generated synthetic datasets is still an open challenge. We aim to close this gap and introduce a novel holdout-based empirical assessment framework for quantifying the fidelity as well as the privacy risk of synthetic data solutions for mixed-type tabular data. Measuring fidelity is based on statistical distances of lower-dimensional marginal distributions, which provide a model-free and easy-to-communicate empirical metric for the representativeness of a synthetic dataset. Privacy risk is assessed by calculating the individual-level distances to closest record with respect to the training data. By showing that the synthetic samples are just as close to the training as to the holdout data, we yield strong evidence that the synthesizer indeed learned to generalize patterns and is independent of individual training records. We empirically demonstrate the presented framework for seven distinct synthetic data solutions across four mixed-type datasets and compare these then to traditional data perturbation techniques. Both a Python-based implementation of the proposed metrics and the demonstration study setup is made available open-source. The results highlight the need to systematically assess the fidelity just as well as the privacy of these emerging class of synthetic data generators.

Myocarditis Following Immunization With mRNA COVID-19 Vaccines in Members of the US Military.

Importance: Myocarditis has been reported with COVID-19 but is not clearly recognized as a possible adverse event following COVID-19 vaccination. Objective: To describe myocarditis presenting after COVID-19 vaccination within the Military Health System. Design, Setting, and Participants: This retrospective case series studied patients within the US Military Health System who experienced myocarditis after COVID-19 vaccination between January and April 2021. Patients who sought care for chest pain following COVID-19 vaccination and were subsequently diagnosed with clinical myocarditis were included. Exposure: Receipt of a messenger RNA (mRNA) COVID-19 vaccine between January 1 and April 30, 2021. Main Outcomes and Measures: Clinical diagnosis of myocarditis after COVID-19 vaccination in the absence of other identified causes. Results: A total of 23 male patients (22 currently serving in the military and 1 retiree; median [range] age, 25 [20-51] years) presented with acute onset of marked chest pain within 4 days after receipt of an mRNA COVID-19 vaccine. All military members were previously healthy with a high level of fitness. Seven received the BNT162b2-mRNA vaccine and 16 received the mRNA-1273 vaccine. A total of 20 patients had symptom onset following the second dose of an appropriately spaced 2-dose series. All patients had significantly elevated cardiac troponin levels. Among 8 patients who underwent cardiac magnetic resonance imaging within the acute phase of illness, all had findings consistent with the clinical diagnosis of myocarditis. Additional testing did not identify other etiologies for myocarditis, including acute COVID-19 and other infections, ischemic injury, or underlying autoimmune conditions. All patients received brief supportive care and were recovered or recovering at the time of this report. The military administered more than 2.8 million doses of mRNA COVID-19 vaccine in this period. While the observed number of myocarditis cases was small, the number was higher than expected among male military members after a second vaccine dose. Conclusions and Relevance: In this case series, myocarditis occurred in previously healthy military patients with similar clinical presentations following receipt of an mRNA COVID-19 vaccine. Further surveillance and evaluation of this adverse event following immunization is warranted. Potential for rare vaccine-related adverse events must be considered in the context of the well-established risk of morbidity, including cardiac injury, following COVID-19 infection.

Incomplete digestion of codfish represents a risk factor for anaphylaxis in patients with allergy.

BACKGROUND: Fish represents one of the most important allergenic foods causing severe allergic reactions. Nevertheless, it has been shown that gastric digestion significantly reduces its allergenic capacity. OBJECTIVE: In this study, we assessed the absorption kinetics of fish proteins and investigated the clinical reactivity of patients with fish allergy to codfish digested at physiological or elevated gastric pH. METHODS: Healthy individuals were openly challenged with codfish and blood samples were evaluated by histamine release for absorbed fish allergens. Patients with allergy were recruited on the basis of previously diagnosed codfish allergy. Fish extracts were digested with gastric enzymes at pH 2.0 and 3.0 and used for histamine release, skin prick tests, and titrated double-blind placebo-controlled food challenges. RESULTS: Ingestion experiments in subjects without allergy revealed absorption of biologically active fish allergens only 10 minutes after ingestion with maximal serum levels after 1 to 2 hours. Incubation of fish proteins with digestive enzymes at pH 2.0 resulted in a fragmentation of the proteins leading to a reduced biological activity evidenced by a significantly smaller wheal reaction and reduced histamine release. Fish digested at pH 3.0 revealed comparable reactivity patterns as undigested extracts. Moreover, these test materials triggered reactions at 10-fold to 30-fold lower cumulated challenge doses in patients with allergy. CONCLUSION: Our data indicate the paramount importance of gastric digestion for fish allergens because the quantitatively significant absorption and elicitation of symptoms seemed to take place in the intestine. CLINICAL IMPLICATIONS: Hindered digestion puts patients with fish allergy at risk to develop severe allergic reactions at minute amounts of allergens.

The effects of gastric digestion on codfish allergenicity.

BACKGROUND: In a recent murine study, we showed that impaired gastric digestion supports the induction of fish allergy by protecting the digestion-sensitive major allergen parvalbumin and thus enhancing its sensitizing properties. OBJECTIVE: The aim of the present study was to investigate whether impairment of peptic degradation might also play a role in the effector phase of codfish allergy. METHODS: The resistance of cod proteins to digestion by simulated gastric fluid was assessed in vitro . Gastric solutions with pH values ranging from 1.25 to 5.0 were prepared, and the influence of the pH on protein degradation was evaluated by means of SDS-PAGE and IgE immunoblotting. The allergenic potency of digested and undigested cod extract was further characterized in RAST inhibition and basophil histamine release experiments. RESULTS: The digestion experiments revealed that codfish proteins were degraded within 1 minute under physiologic gastric conditions. An only marginal pH shift from 2.5 to 2.75 abrogated completely the digestion of cod allergens. In RAST inhibition experiments digested cod extracts showed a reduced IgE-binding capability that was dependent on the digestion time. Moreover, peptic fragments expressed a 10,000 times reduced allergenic potency, as evaluated on the basis of histamine release from human basophils. CONCLUSION: Codfish allergens have a grossly reduced ability to trigger an intestinal allergic reaction when they are physiologically degraded. Impairment of the physiologic digestion might thus lower the threshold levels of a food allergen in sensitized patients.

High prevalence of autoimmune urticaria in children with chronic urticaria.

BACKGROUND: The etiology of chronic urticaria (CU) in childhood often remains unrecognized. Recently, in adults it has been shown that approximately 40% of patients with CU have autoimmune urticaria (AU); however, no data are available in children. OBJECTIVE: To determine the prevalence and possible risk factors for AU in children with CU. METHODS: Ninety-three consecutive children (52 male; median age, 7.8 years) with CU were evaluated for AU by means of autologous serum skin test (ASST) in all and serum-induced basophil histamine release (HR-urticaria test) in 52. All other known causes of CU were excluded as appropriate. RESULTS: A cause for CU was identified in 44 children (47%), whereas 49 (53%) remained idiopathic. ASST and HR-urticaria test had positive results in 22 of 49 (45%) and in 16 of 31 (52%) children with idiopathic CU compared with 1 of 44 (2%) and 5 of 21 (24%) with CU of a known cause, respectively ( P <.00001; P=.09). Sensitivity, specificity, and positive and negative predictive values of the ASST for diagnosing AU are 78%, 85%, 74%, and 88%. The prevalence of AU in childhood is 31% (15/52; 95% CI, 24%-51%). None of the variables studied were predictive for development of AU. CONCLUSION: Our results demonstrate for the first time that children have the same ability as adults to produce functionally active autoantibodies directed against IgE or IgE receptor and that AU occurs in children in as many as 30% of cases. The addition of screening for AU dramatically decreases the rate of the idiopathic form from 52% to 20%.

Immunochemical and biological quantification of peanut extract.

Biological standardization of allergen extracts is one of the steps in the characterization of an extract. The gold standard for determination of biological potency is the skin prick test, but histamine release (HR) has been used as a convenient ex vivo method for analyzing a large number of samples. We describe the use of rabbit basophils as a tool in biological standardization. Using peanut as a model allergen, it is described how rabbits immunized for production of antiserum may become sensitized and their basophils used for histamine release experiments. It is also possible to use rabbit antiserum to passively sensitize basophils derived from naive rabbits, but the sensitivity of this method is so far 100-1000 times lower than the direct histamine release. The rabbit histamine release results are compared to an ELISA developed by means of the same antisera and by passive sensitization of human basophils using serum from a strongly sensitized peanut-allergic patient. The overall sensitivity of the methods were ELISA > HR-human cells > HR-sensitized rabbit cells > HR-passively sensitized rabbit cells. The use of rabbit basophils for biological standardizations will allow for the use of rabbit antisera.