Interleukin-2-Dependent Allergen-Specific Tissue-Resident Memory Cells Drive Asthma.

Exposure to inhaled allergens generates T helper 2 (Th2) CD4(+) T cells that contribute to episodes of inflammation associated with asthma. Little is known about allergen-specific Th2 memory cells and their contribution to airway inflammation. We generated reagents to understand how endogenous CD4(+) T cells specific for a house dust mite (HDM) allergen form and function. After allergen exposure, HDM-specific memory cells persisted as central memory cells in the lymphoid organs and tissue-resident memory cells in the lung. Experimental blockade of lymphocyte migration demonstrated that lung-resident cells were sufficient to induce airway hyper-responsiveness, which depended upon CD4(+) T cells. Investigation into the differentiation of pathogenic Trm cells revealed that interleukin-2 (IL-2) signaling was required for residency and directed a program of tissue homing migrational cues. These studies thus identify IL-2-dependent resident Th2 memory cells as drivers of lung allergic responses.

Removing T-cell epitopes with computational protein design.

Immune responses can make protein therapeutics ineffective or even dangerous. We describe a general computational protein design method for reducing immunogenicity by eliminating known and predicted T-cell epitopes and maximizing the content of human peptide sequences without disrupting protein structure and function. We show that the method recapitulates previous experimental results on immunogenicity reduction, and we use it to disrupt T-cell epitopes in GFP and Pseudomonas exotoxin A without disrupting function.

A Clinician's Guide to Running Custom Machine-Learning Models in an Electronic Health Record Environment.

We recently brought an internally developed machine-learning model for predicting which patients in the emergency department would require hospital admission into the live electronic health record environment. Doing so involved navigating several engineering challenges that required the expertise of multiple parties across our institution. Our team of physician data scientists developed, validated, and implemented the model. We recognize a broad interest and need to adopt machine-learning models into clinical practice and seek to share our experience to enable other clinician-led initiatives. This Brief Report covers the entire model deployment process, starting once a team has trained and validated a model they wish to deploy in live clinical operations.

Extrinsic MAVS signaling is critical for Treg maintenance of Foxp3 expression following acute flavivirus infection.

Given the rapid spread of flaviviruses such as West Nile virus (WNV) and Zika virus, it is critical that we develop a complete understanding of the key mediators of an effective anti-viral response. We previously demonstrated that WNV infection of mice deficient in mitochondrial antiviral-signaling protein (MAVS), the signaling adaptor for RNA helicases such as RIG-I, resulted in increased death and dysregulated immunity, which correlated with a failure of Treg expansion following infection. Thus, we sought to determine if intrinsic MAVS signaling is required for participation of Tregs in anti-WNV immunity. Despite evidence of increased Treg cell division, Foxp3 expression was not stably maintained after WNV infection in MAVS-deficient mice. However, intrinsic MAVS signaling was dispensable for Treg proliferation and suppressive capacity. Further, we observed generation of an effective anti-WNV immune response when Tregs lacked MAVS, thereby demonstrating that Treg detection of the presence of WNV through the MAVS signaling pathway is not required for generation of effective immunity. Together, these data suggest that while MAVS signaling has a considerable impact on Treg identity, this effect is not mediated by intrinsic MAVS signaling but rather is likely an effect of the overproduction of pro-inflammatory cytokines generated in MAVS-deficient mice after WNV infection.

Identifying barriers to follow-up eye care for children after failed vision screening in a primary care setting.

PURPOSE: To identify barriers to follow-up eye care in children who failed a visual acuity screening conducted by their primary care provider. METHODS: Children aged 3-14 years who failed a visual acuity screening were identified. A phone survey with the parent of every child was conducted 4 months after the screening. Family demographics, parental awareness of childhood eye diseases and eye care for children, and barriers to follow-up eye care were assessed. RESULTS: Of 971 children sampled, 199 (20.5%) failed a visual acuity screening. The survey was completed by the parents of 58 children (29.1%), of whom 27 (46.6%) presented for follow-up examination. The most common reason for failure to follow-up was parental unawareness of screening results (29.3%). Follow-up rates were higher in children with previous eye examinations than in those without (81% versus 17%; P = 0.005) and in children who waited <2 months for a follow-up appointment than in those who had to wait longer (100% versus 63%; P = 0.024). Child's sex, ethnicity, and health insurance status, parent's marital, education and employment status, household income, and transportation access were not associated with statistically significant different follow-up rates. CONCLUSIONS: Parental unawareness of a failed visual acuity screening is an important barrier to obtaining follow-up. Strategies to improve follow-up rates after a failed visual acuity screening may include communicating the results clearly and consistently, providing education about the importance of timely follow-up, and offering logistic support for accessing eye appointments to families.

Cytotoxicity evaluation of methacrylate-based resins for clinical endodontics in vitro.

This study examines the cytotoxicity of Super-Bond C&B (SB-C&B), Super-Bond RC Sealer (SB-RC), MetaSEAL (Meta), and AH Plus Sealer (AH+). Freshly mixed and set materials (100 mg) were prepared in vitro and placed in cell culture medium (1 mL) for the working time and for 6 h, respectively. L929 cells seeded into 96-well plates at 5,000 cells/well were incubated with the eluted medium (200 µL) for 24 h. Cells cultured with medium alone served as the control. Cytotoxicity was evaluated by MTS assay and analyzed with ANOVA. In the freshly mixed group, the average ± SD (%) for cell viability were 66.0 ± 13.6, 55.5 ± 15.6, 10.6 ± 0.7, and 8.9 ± 2.2 for SB-C&B, SB-RC, Meta, and AH+, respectively. In the set group, the average ± SD (%) for cell viability were 100 ± 21.9, 81.8 ± 38.5, 24.9 ± 7.9, and 23.6 ± 10.0 for SB-C&B, SB-RC, Meta, and AH+, respectively. SB-C&B and SB-RC are less cytotoxic than are Meta and AH+.