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Type I interferons (IFNs) are essential innate immune proteins that maintain tissue homeostasis through tonic expression and can be upregulated to drive antiviral resistance and inflammation upon stimulation. However, the mechanisms that inhibit aberrant IFN upregulation in homeostasis and the impacts of tonic IFN production on health and disease remain enigmatic. Here, we report that caspase-8 negatively regulates type I IFN production by inhibiting the RIPK1-TBK1 axis during homeostasis across multiple cell types and tissues. When caspase-8 is deleted or inhibited, RIPK1 interacts with TBK1 to drive elevated IFN production, leading to heightened resistance to norovirus infection in macrophages but also early onset lymphadenopathy in mice. Combined deletion of caspase-8 and RIPK1 reduces the type I IFN signaling and lymphadenopathy, highlighting the critical role of RIPK1 in this process. Overall, our study identifies a mechanism to constrain tonic type I IFN during homeostasis which could be targeted for infectious and inflammatory diseases., Competing Interests: Declaration of interests T.-D.K. is a consultant for Pfizer., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the refractive error induced by intraocular administration of silicone oil (SiO) in dogs., Animals: 47 client-owned dogs evaluated for blindness secondary to retinal detachment., Procedures: -3-port pars plana vitrectomy with perfluoro-octane and SiO exchange (1,000- or 5,000-centistoke SiO) was performed in 1 or both eyes for all dogs (n = 63 eyes), depending on which eye or eyes were affected. Dogs were normotensive, had complete oil filling of the eyes, and were examined in a standing position for retinoscopic examination of both eyes (including healthy eyes)., Results: The mean refractive error for SiO-filled phakic and pseudophakic eyes was 2.67 and 3.24 D, respectively. The mean refractive error for SiO-filled aphakic eyes was 6.50 D. Dogs in which 5,000-centistoke SiO was used had consistently greater positive refractive errors (mean, 3.45 D), compared with dogs in which 1,000-centistoke SiO was used (mean, 2.10 D); however, the difference was nonsignificant. There was no significant linear relationship between refractive error and the number of days between surgery and retinoscopy., Conclusions and Clinical Relevance: Hyperopia was observed in all dogs that underwent SiO tamponade, regardless of lens status (phakic, pseudophakic, or aphakic). Aphakic eyes underwent a myopic shift when filled with SiO. Pseudophakic eyes appeared to be more hyperopic than phakic eyes when filled with SiO; however, additional investigation is needed to confirm the study findings.

Managed care's continual rise will impact each Virginia area market uniquely. Although almost all physicians will be affected in some way by managed care, the level and type of impact will vary greatly depending on the physician's geographic location, specialty, practice type, practice size, hospital affiliations and existing managed care affiliations. Staying abreast of the constant changes in the public and private sector will become increasingly crucial for all of Virginia's physicians as management of resources and care plays a larger role in the health care delivery system.

Objective: To determine if a 6-month course of therapy with IMREG-1, a leukocyte-derived immunomodulator, slows disease progression in patients with AIDS-related complex., Design: Randomized, double-blind trial., Setting: Five academic- and three community-based clinics., Patients: Immunocompromised patients (143) with HIV., Interventions: IMREG-1 or placebo every 2 weeks (13 doses)., Main Results: Twelve of forty-eight patients on placebo and 5 of 95 patients on IMREG-1 experienced adverse events (AIDS-defining opportunistic infection or neoplasm, wasting syndrome, HIV-associated encephalopathy, or peripheral sensory neuropathy). Based on an intention-to-treat analysis, Kaplan-Meier event probabilities were 26% for the placebo group and 6% for the IMREG-1 group (P less than 0.001); based on the Cox proportional hazards model, the relative risk for patients on placebo compared with patients on IMREG-1 was 5.1 (95% CI, 1.8 to 14.8). The frequency of symptoms significantly increased from baseline in patients receiving placebo. The mean decrease in CD4+ cells from baseline was 80 x 10(6) cells/L in the placebo group and 29 x 10(6) cells/L in patients on IMREG-1, with 20% (8) and 38% (32) of patients, respectively, showing a trend toward an increase (P = 0.04). In patients receiving IMREG-1, the size and rate of delayed hypersensitivity responses were larger than in the placebo group., Conclusions: Patients with AIDS-related complex experienced fewer adverse events and constitutional symptoms after IMREG-1 treatment. The slower loss of CD4+ cells and increased size and rate of delayed hypersensitivity responses most likely reflect the effect of IMREG-1 on the immune system. No toxicity related to IMREG-1 administration was observed.