Central Reading of Ulcerative Colitis Clinical Trial Videos Using Neural Networks.

BACKGROUND AND AIMS: Endoscopic disease activity scoring in ulcerative colitis (UC) is useful in clinical practice but done infrequently. It is required in clinical trials, where it is expensive and slow because human central readers are needed. A machine learning algorithm automating the process could elevate clinical care and facilitate clinical research. Prior work using single-institution databases and endoscopic still images has been promising. METHODS: Seven hundred and ninety-five full-length endoscopy videos were prospectively collected from a phase 2 trial of mirikizumab with 249 patients from 14 countries, totaling 19.5 million image frames. Expert central readers assigned each full-length endoscopy videos 1 endoscopic Mayo score (eMS) and 1 Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score. Initially, video data were cleaned and abnormality features extracted using convolutional neural networks. Subsequently, a recurrent neural network was trained on the features to predict eMS and UCEIS from individual full-length endoscopy videos. RESULTS: The primary metric to assess the performance of the recurrent neural network model was quadratic weighted kappa (QWK) comparing the agreement of the machine-read endoscopy score with the human central reader score. QWK progressively penalizes disagreements that exceed 1 level. The model's agreement metric was excellent, with a QWK of 0.844 (95% confidence interval, 0.787-0.901) for eMS and 0.855 (95% confidence interval, 0.80-0.91) for UCEIS. CONCLUSIONS: We found that a deep learning algorithm can be trained to predict levels of UC severity from full-length endoscopy videos. Our data set was prospectively collected in a multinational clinical trial, videos rather than still images were used, UCEIS and eMS were reported, and machine learning algorithm performance metrics met or exceeded those previously published for UC severity scores.

A Phase 2 Randomized Controlled Multisite Study Using Omalizumab-facilitated Rapid Desensitization to Test Continued vs Discontinued Dosing in Multifood Allergic Individuals.

BACKGROUND: As there is limited data on the sustainability of desensitization of multifood-oral immunotherapy (multifood-OIT), we conducted a multisite multifood-OIT study to compare the efficacy of successful desensitization with sustained dosing vs discontinued dosing after multifood-OIT. METHODS: We enrolled 70 participants, aged 5-22 years with multiple food allergies confirmed by double-blind placebo-controlled food challenges (DBPCFCs). In the open-label phase of the study, all participants received omalizumab (weeks 1-16) and multi-OIT (2-5 allergens; weeks 8-30) and eligible participants (on maintenance dose of each allergen by weeks 28-29) were randomized 1:1:1 to 1 g, 300 mg, or 0 mg arms (blinded, weeks 30-36) and then tested by food challenge at week 36. Success was defined as passing 2 g food challenge to at least 2 foods in week 36. FINDINGS: Most participants were able to reach a dose of 2 g or higher of each of 2, 3, 4, and 5 food allergens (as applicable to the participant's food allergens in OIT) in week 36 food challenges. Using an intent-to-treat analysis, we did not find evidence that a 300 mg dose was effectively different than a 1 g dose in maintaining desensitization, and both together were more effective than OIT discontinuation (0 mg dose) (85% vs 55%, P = 0.03). Fifty-five percent of the intent-to-treat participants and 69% of per protocol participants randomized to the 0 mg arm showed no objective reactivity after 6 weeks of discontinuation. Cross-desensitization was found between cashew/pistachio and walnut/pecan when only one of the foods was part of OIT. No statistically significant safety differences were found between the three arms. INTERPRETATION: These results suggest that sustained desensitization after omalizumab-facilitated multi-OIT best occurs through continued maintenance OIT dosing of either 300 mg or 1 g of each food allergen as opposed to discontinuation of multi-OIT. FUNDING: Sean N. Parker Center for Allergy and Asthma Research at Stanford University, Jeff and MacKenzie Bezos, NIAID AADCRC U19AI104209. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number, NCT02626611.

Food allergy and omics.

Food allergy (FA) prevalence has been increasing over the last few decades and is now a global health concern. Current diagnostic methods for FA result in a high number of false-positive results, and the standard of care is either allergen avoidance or use of epinephrine on accidental exposure, although currently with no other approved treatments. The increasing prevalence of FA, lack of robust biomarkers, and inadequate treatments warrants further research into the mechanism underlying food allergies. Recent technological advances have made it possible to move beyond traditional biological techniques to more sophisticated high-throughput approaches. These technologies have created the burgeoning field of omics sciences, which permit a more systematic investigation of biological problems. Omics sciences, such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, microbiomics, and exposomics, have enabled the construction of regulatory networks and biological pathway models. Parallel advances in bioinformatics and computational techniques have enabled the integration, analysis, and interpretation of these exponentially growing data sets and opens the possibility of personalized or precision medicine for FA.

Allergen Immunotherapy.

Allergies affect a large proportion of the population. Allergies can adversely affect productivity, sleep, and quality of life and can lead to life-threatening reactions. Allergies can spread to affect multiple organ systems. Allergen immunotherapy is the only therapy that can change the natural history of allergic disease.

Treatment with rituximab and brentuximab vedotin in a patient of common variable immune deficiency-associated classic Hodgkin lymphoma.

BACKGROUND: Patients with common variable immunodeficiency (CVID) have an increased risk of developing lymphoproliferative diseases, including non-Hodgkins lymphoma (Blood 116:1228-1234, 2010; Blood 119:1650-7, 2012). The incidence and prognosis of Hodgkin lymphoma in this population is not clear, with only a few case reports in the literature. Conventional cytotoxic chemotherapy, although highly efficacious in treating Hodgkin lymphoma in immune competent patients, is problematic in patients with CVID due to the increased risk of infectious complications (Ther Umsch 69:687-91, 2012; Pediatr Hematol Oncol 24:337-42, 2012). Rituximab and brentuximab vedotin are both targeted agents used to treat lymphomas that express CD20 and CD30, respectively. Compared to cytotoxic chemotherapy typically used in Hodgkin lymphoma, these agents are better tolerated with minimal side effects. This makes them an attractive option for treating lymphoma in patients who have significant co-morbidities, including those with immune deficiencies. Additionally, rituximab has been used safely to treat autoimmune cytopenias in patients with CVID5. However, the role of these targeted therapies in CVID-associated Hodgkin lymphoma has not been reported. CASE PRESENTATION: Here we report the case of a 25 year old female diagnosed with CVID-associated classic Hodgkin lymphoma, who achieved a complete remission following treatment with rituximab followed by brentuximab vedotin. CONCLUSIONS: We demonstrate that rituximab and brentuximab are likely safe and effective in CVID-associated Hodgkin lymphoma, providing a feasible and potentially optimal treatment option for this patient population.

The Hyper-IgE Syndromes: Lessons in Nature, From Bench to Bedside.

: Hyper-IgE syndrome is a primary immunodeficiency marked by abnormalities in the coordination of cell-cell signaling with the potential to affect TH17 cell, B cell, and neutrophil responses. Clinical manifestations include recurrent skin and lung infections, serum IgE elevation, connective tissue repair and development alterations, and the propensity for vascular abnormalities and tumor development. Signal transducer and activator of transcription 3 (STAT3) signaling, dedicator of cytokinesis 8 (DOCK8) signaling, and tyrosine kinase 2 (TYK2) signaling alterations have been implicated in 3 forms of hyper-IgE syndrome.

Interleukin-13 signaling and its role in asthma.

Asthma affects nearly 300 million people worldwide. The majority respond to inhaled corticosteroid treatment with or without beta-adrenergic agonists. However, a subset of 5 to 10% with severe asthma do not respond optimally to these medications. Different phenotypes of asthma may explain why current therapies show limited benefits in subgroups of patients. Interleukin-13 is implicated as a central regulator in IgE synthesis, mucus hypersecretion, airway hyperresponsiveness, and fibrosis. Promising research suggests that the interleukin-13 pathway may be an important target in the treatment of the different asthma phenotypes.