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Influenza A virus (IAV) preferentially infects conducting airway and alveolar epithelial cells in the lung. The outcome of these infections is impacted by the host response, including the production of various cytokines, chemokines, and growth factors. Fibroblast growth factor-9 (FGF9) is required for lung development, can display antiviral activity in vitro, and is upregulated in asymptomatic patients during early IAV infection. We therefore hypothesized that FGF9 would protect the lungs from respiratory virus infection and evaluated IAV pathogenesis in mice that overexpress FGF9 in club cells in the conducting airway epithelium (FGF9-OE mice). However, we found that FGF9-OE mice were highly susceptible to IAV and Sendai virus infection compared to control mice. FGF9-OE mice displayed elevated and persistent viral loads, increased expression of cytokines and chemokines, and increased numbers of infiltrating immune cells as early as 1 day post-infection (dpi). Gene expression analysis showed an elevated type I interferon (IFN) signature in the conducting airway epithelium and analysis of IAV tropism uncovered a dramatic shift in infection from the conducting airway epithelium to the alveolar epithelium in FGF9-OE lungs. These results demonstrate that FGF9 signaling primes the conducting airway epithelium to rapidly induce a localized IFN and proinflammatory cytokine response during viral infection. Although this response protects the airway epithelial cells from IAV infection, it allows for early and enhanced infection of the alveolar epithelium, ultimately leading to increased morbidity and mortality. Our study illuminates a novel role for FGF9 in regulating respiratory virus infection and pathogenesis., Competing Interests: The authors have declared that no competing interests exist.

Chikungunya virus (CHIKV) is an arthritogenic alphavirus that causes both debilitating acute and chronic disease. Previous work has shown that type I interferons (IFNs) play a critical role in limiting CHIKV pathogenesis and that interferon alpha (IFN-α) and interferon beta (IFN-β) control acute CHIKV infection by distinct mechanisms. However, the role of type I IFNs, especially specific subtypes, during chronic CHIKV disease is unclear. To address this gap in knowledge, we evaluated chronic CHIKV pathogenesis in mice lacking IFN-α or IFN-β. We found that IFN-α was the dominant subtype that controls chronic disease. Despite detecting a varying type I IFN response throughout the course of disease, IFN-α acts within the first few days of infection to control the levels of persistent CHIKV RNA. In addition, using a novel CHIKV-3'-Cre tdTomato reporter system that fate maps CHIKV-infected cells, we showed that IFN-α limits the number of cells that survive CHIKV at sites of dissemination, particularly dermal fibroblasts and immune cells. Though myofibers play a significant role in CHIKV disease, they were not impacted by the loss of IFN-α. Our studies highlight that IFN-α and IFN-β play divergent roles during chronic CHIKV disease through events that occur early in infection and that not all cell types are equally dependent on type I IFNs for restricting viral persistence. IMPORTANCE Chikungunya virus (CHIKV) is a reemerging global pathogen with no effective vaccine or antiviral treatment for acute or chronic disease, and the mechanisms underlying chronic disease manifestations remain poorly defined. The significance of our research is in defining IFN-α, but not IFN-β, as an important host regulator of chronic CHIKV pathogenesis that acts within the first 48 hours of infection to limit persistent viral RNA and the number of cells that survive CHIKV infection 1 month post-infection. Loss of IFN-α had a greater impact on immune cells and dermal fibroblasts than myofibers, highlighting the need to delineate cell-specific responses to type I IFNs. Altogether, our work demonstrates that very early events of acute CHIKV infection influence chronic disease. Continued efforts to delineate early host-pathogen interactions may help stratify patients who are at risk for developing chronic CHIKV symptoms and identify therapeutics that may prevent progression to chronic disease altogether.

Type I interferons (IFNs) are critical effector cytokines of the immune system and were originally known for their important role in protecting against viral infections; however, they have more recently been shown to play protective or detrimental roles in many disease states. Type I IFNs consist of IFNα, IFNβ, IFNϵ, IFNκ, IFNω, and a few others, and they all signal through a shared receptor to exert a wide range of biological activities, including antiviral, antiproliferative, proapoptotic, and immunomodulatory effects. Though the individual type I IFN subtypes possess overlapping functions, there is growing appreciation that they also have unique properties. In this review, we summarize some of the mechanisms underlying differential expression of and signaling by type I IFNs, and we discuss examples of differential functions of IFNα and IFNβ in models of infectious disease, cancer, and autoimmunity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest, (Copyright © 2020 Fox, Locke and Lenschow.)

Background: Malignant gliomas have disproportionally high morbidity and mortality. Heterozygous mutations in the isocitrate dehydrogenase 1 (IDH1) gene are most common in glioma, resulting in predominantly arginine to histidine substitution at codon 132. Because IDH1 R132H requires a wild-type allele to produce (D)-2-hydroxyglutarate for epigenetic reprogramming, loss of IDH1 R132H heterozygosity is associated with glioma progression in an IDH1-wildtype-like phenotype. Although previous studies have reported that transgenic IDH1 R132H induces the expression of nestin-a neural stem-cell marker, the underlying mechanism remains unclear. Furthermore, this finding seems at odds with better outcome of IDH1 R132H glioma because of a negative association of nestin with overall survival., Methods: Gene expression was compared between IDH1 R132H -hemizygous and IDH1 R132H -heterozygous glioma cells under adherent and spheroid growth conditions. The results were validated for (D)-2-hydroxyglutarate responsiveness by pharmacologic agents, associations with DNA methylation by bioinformatic analysis, and associations with overall survival. Bisulfite DNA sequencing, chromatin immunoprecipitation, and pharmacological approach were used., Findings: Neural stem-cell marker genes, including CD44, NES, and PROM1, are generally downregulated in IDH-mutant gliomas and IDH1 R132H -heterozygous spheroid growth compared respectively with IDH-wildtype gliomas and IDH1 R132H -hemizygous spheroid growth, in agreement with their negative associations with patient outcome. In contrast, CD24 is specifically upregulated and apparently associated with better survival. CD24 and NES expression respond differentially to alteration of (D)-2-hydroxyglutarate levels. CD24 upregulation is associated with histone and DNA demethylation as opposed to hypermethylation in the downregulated genes., Interpretation: The better outcome of IDH-mutant glioma is orchestrated exquisitely through epigenetic reprogramming that directs bidirectional expression of neural stem-cell marker genes., Competing Interests: Declaration of competing interest None., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Type I interferons (IFNs) are key mediators of the innate immune response. Although members of this family of cytokines signal through a single shared receptor, biochemical and functional variation exists in response to different IFN subtypes. While previous work has demonstrated that type I IFNs are essential to control infection by chikungunya virus (CHIKV), a globally emerging alphavirus, the contributions of individual IFN subtypes remain undefined. To address this question, we evaluated CHIKV pathogenesis in mice lacking IFN-β (IFN-β knockout [IFN-β-KO] mice or mice treated with an IFN-β-blocking antibody) or IFN-α (IFN regulatory factor 7 knockout [IRF7-KO] mice or mice treated with a pan-IFN-α-blocking antibody). Mice lacking either IFN-α or IFN-β developed severe clinical disease following infection with CHIKV, with a marked increase in foot swelling compared to wild-type mice. Virological analysis revealed that mice lacking IFN-α sustained elevated infection in the infected ankle and in distant tissues. In contrast, IFN-β-KO mice displayed minimal differences in viral burdens within the ankle or at distal sites and instead had an altered cellular immune response. Mice lacking IFN-β had increased neutrophil infiltration into musculoskeletal tissues, and depletion of neutrophils in IFN-β-KO but not IRF7-KO mice mitigated musculoskeletal disease caused by CHIKV. Our findings suggest disparate roles for the IFN subtypes during CHIKV infection, with IFN-α limiting early viral replication and dissemination and IFN-β modulating neutrophil-mediated inflammation. IMPORTANCE Type I interferons (IFNs) possess a range of biological activity and protect against a number of viruses, including alphaviruses. Despite signaling through a shared receptor, there are established biochemical and functional differences among the IFN subtypes. The significance of our research is in demonstrating that IFN-α and IFN-β both have protective roles during acute chikungunya virus (CHIKV) infection but do so by distinct mechanisms. IFN-α limits CHIKV replication and dissemination, whereas IFN-β protects from CHIKV pathogenesis by limiting inflammation mediated by neutrophils. Our findings support the premise that the IFN subtypes have distinct biological activities in the antiviral response., (Copyright © 2019 American Society for Microbiology.)

Chikungunya virus (CHIKV) is an arthritogenic alphavirus that acutely causes fever as well as severe joint and muscle pain. Chronic musculoskeletal pain persists in a substantial fraction of patients for months to years after the initial infection, yet we still have a poor understanding of what promotes chronic disease. While replicating virus has not been detected in joint-associated tissues of patients with persistent arthritis nor in various animal models at convalescent time points, viral RNA is detected months after acute infection. To identify the cells that might contribute to pathogenesis during this chronic phase, we developed a recombinant CHIKV that expresses Cre recombinase (CHIKV-3'-Cre). CHIKV-3'-Cre replicated in myoblasts and fibroblasts, and it induced arthritis during the acute phase in mice. Importantly, it also induced chronic disease, including persistent viral RNA and chronic myositis and synovitis similar to wild-type virus. CHIKV-3'-Cre infection of tdTomato reporter mice resulted in a population of tdTomato+ cells that persisted for at least 112 days. Immunofluorescence and flow cytometric profiling revealed that these tdTomato+ cells predominantly were myofibers and dermal and muscle fibroblasts. Treatment with an antibody against Mxra8, a recently defined host receptor for CHIKV, reduced the number of tdTomato+ cells in the chronic phase and diminished the levels of chronic viral RNA, implicating these tdTomato+ cells as the reservoir of chronic viral RNA. Finally, isolation and flow cytometry-based sorting of the tdTomato+ fibroblasts from the skin and ankle and analysis for viral RNA revealed that the tdTomato+ cells harbor most of the persistent CHIKV RNA at chronic time points. Therefore, this CHIKV-3'-Cre and tdTomato reporter mouse system identifies the cells that survive CHIKV infection in vivo and are enriched for persistent CHIKV RNA. This model represents a useful tool for studying CHIKV pathogenesis in the acute and chronic stages of disease., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: MSD is a consultant for Inbios and on the Scientific Advisory Board of Moderna, and has filed a provisional patent on Mxra8 antibodies and related proteins.

Background: There is a paucity of data providing direct comparison of outcomes, complications, and costs between general and local anesthesia in cutaneous surgery., Objective: Analyze the literature from dermatologic and other specialties to compare outcomes, risks, and costs of general and local anesthesia., Methods: A retrospective analysis of case comparison studies from other specialties comparing outcomes, risks, and/or costs in local versus general anesthesia was performed. A review of the literature from dermatology and other specialties was included., Results: A total of 51 studies were selected; 41 of them directly examined outcomes in procedures performed under local and general anesthesia, and none found a significant difference in outcomes. A total of 41 studies measured adverse effects. Of these, 15 studies (36.6%) report significantly better outcomes between the 2 techniques. Only 2 studies (4.9%) report significantly improved outcomes with use of general anesthesia; 15 of 36 studies (41.7%) report fewer adverse events in local anesthesia. Of the 13 studies that examined costs, all (100%) found significantly decreased costs with use of local anesthesia., Limitations: These data cannot be seamlessly applied to all cases of cutaneous surgery., Conclusion: Local anesthesia techniques provide outcomes equal to or better than general anesthesia and with significantly lower costs., (Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Skin cancer and the surgical treatment thereof have the potential to be sources of great anxiety for patients. Examination of patient satisfaction, anxiety, and contributing factors has the potential to provide information surgeons can use to implement practices that have an impact on patient anxiety and satisfaction regarding dermatologic surgery. This study used a prospective interview to catalog patients' anxiety and experiences before and during the surgical process. Our results indicate that several pre- and perioperative factors have the potential to decrease a patient's overall anxiety. Notably, 33% of surgical patients reported a decrease in anxiety from the time of diagnosis until the day of surgery. Factors that contributed to this included a call discussing the diagnosis and what to expect on the day of surgery as well as reading written material or searching the internet for more information regarding the procedure. Furthermore, a call from the physician compared to a call from a nurse or other team member showed a greater effect on decreasing anxiety. During the surgical procedure, our results highlight several factors that can decrease a patient's anxiety. Most notably, eating, watching TV, bringing a guest, and engaging in small talk with surgeon and staff during the procedure subjectively decreased patients' anxiety. In summary, our results suggest that patients respond to a variety of factors to reduce anxiety and that each patient derives relief from anxiety in different manners. Therefore, offering a spectrum of comforting or distracting activities during the Mohs procedure is ideal and may reduce the need for pharmacologic anxiolytics.

Background: Parkinson's patients, on average, gain weight after deep brain stimulation (DBS)., Objective: To determine potential differences in weight gain when comparing the subthalamic nucleus and the globus pallidus internus target., Methods: A retrospective analysis was performed on the prospective, randomized cohort of National Institutes of Health COMPARE trial DBS patients who received unilateral subthalamic nucleus or globus pallidus internus DBS. Baseline weights were recorded before DBS surgery and at 6, 12, and 18 months postoperatively. Relationships between weight change and changes in Beck Depression Inventory score, Unified Parkinson's Disease Rating Scale (UPDRS) motor score (part III) (also the dyskinesia duration and disability subscores from UPDRS IV), and Hoehn-Yahr stage were determined via Spearman's rank-order correlation coefficients. Regression analyses were performed to investigate the effects of potential factors on weight change over time., Results: Patients in the COMPARE DBS cohort gained a significant amount of weight, a mean of 4.86 lb (standard deviation = 8.73) (P = .001), but there was no significant difference between subthalamic nucleus and globus pallidus internus targets (weight gain of 4.29 ± 6.79 and 5.38 ± 10.32 lb, respectively; P = .68). Weight gain did not correlate with Beck Depression Inventory score change, UPDRS motor score, dyskinesia duration, dyskinesia disability change, or the Hoehn-Yahr stage (P = .62, .21, and .31, respectively). No specific variable was associated with weight gain, and there were no differences in binge eating post-surgery in either target., Conclusion: There were significant changes in weight over time after DBS therapy. However, neither Beck Depression Inventory score change nor UPDRS score change or dyskinesia was correlated with weight gain. No significant factor was associated with the weight change.