Correction: Itaconate and derivatives reduce interferon responses and inflammation in influenza A virus infection.

[This corrects the article DOI: 10.1371/journal.ppat.1010219.].

Itaconate and derivatives reduce interferon responses and inflammation in influenza A virus infection.

Excessive inflammation is a major cause of morbidity and mortality in many viral infections including influenza. Therefore, there is a need for therapeutic interventions that dampen and redirect inflammatory responses and, ideally, exert antiviral effects. Itaconate is an immunomodulatory metabolite which also reprograms cell metabolism and inflammatory responses when applied exogenously. We evaluated effects of endogenous itaconate and exogenous application of itaconate and its variants dimethyl- and 4-octyl-itaconate (DI, 4OI) on host responses to influenza A virus (IAV). Infection induced expression of ACOD1, the enzyme catalyzing itaconate synthesis, in monocytes and macrophages, which correlated with viral replication and was abrogated by DI and 4OI treatment. In IAV-infected mice, pulmonary inflammation and weight loss were greater in Acod1-/- than in wild-type mice, and DI treatment reduced pulmonary inflammation and mortality. The compounds reversed infection-triggered interferon responses and modulated inflammation in human cells supporting non-productive and productive infection, in peripheral blood mononuclear cells, and in human lung tissue. All three itaconates reduced ROS levels and STAT1 phosphorylation, whereas AKT phosphorylation was reduced by 4OI and DI but increased by itaconate. Single-cell RNA sequencing identified monocytes as the main target of infection and the exclusive source of ACOD1 mRNA in peripheral blood. DI treatment silenced IFN-responses predominantly in monocytes, but also in lymphocytes and natural killer cells. Ectopic synthesis of itaconate in A549 cells, which do not physiologically express ACOD1, reduced infection-driven inflammation, and DI reduced IAV- and IFNγ-induced CXCL10 expression in murine macrophages independent of the presence of endogenous ACOD1. The compounds differed greatly in their effects on cellular gene homeostasis and released cytokines/chemokines, but all three markedly reduced release of the pro-inflammatory chemokines CXCL10 (IP-10) and CCL2 (MCP-1). Viral replication did not increase under treatment despite the dramatically repressed IFN responses. In fact, 4OI strongly inhibited viral transcription in peripheral blood mononuclear cells, and the compounds reduced viral titers (4OI>Ita>DI) in A549 cells whereas viral transcription was unaffected. Taken together, these results reveal itaconates as immunomodulatory and antiviral interventions for influenza virus infection.

The Impact of Hidradenitis Suppurativa on Work Productivity and Performance: a Systematic Review and Meta-Analysis.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disorder affecting the skinfold regions. There is growing appreciation of the need for socioeconomic factors to be included in multidisciplinary assessments of HS. However, knowledge regarding HS and workplace function is limited. OBJECTIVES: To assess the relationship between HS and workplace function. METHODS: Cinahl, Embase, MedLine, PsycInfo and PubMed were systematically searched to collect data from studies in which validated surveys of workplace function were administered to HS patients. RESULTS: Out of 1,932 publications, twelve studies were included in this review and seven reported sufficient data for meta-analysis. Included studies encompassed 5,187 HS patients and no controls. All studies employed the Work Productivity and Activity Impairment questionnaire, reporting percentage scores for absenteeism, presenteeism, total work productivity impairment (TWPI) and total activity impairment (TAI). Pooled mean scores for HS were calculated as 10.17% (95%CI 8.68-11.66) for absenteeism, 31.13% (95%CI 25.02-37.23) for presenteeism, 34.25% (95%CI 29.37-39.14) for TWPI, and 42.23% (95%CI 38.56-45.89) for TAI. Significant heterogeneity was identified and most studies were of 'poor' to 'fair' quality. CONCLUSIONS: Current evidence suggests considerable impairment of workplace functioning in HS patients. Our findings point to a significant unmet treatment need with respect to improving working capability in HS. The extant literature is inadequate to reliably assess the mechanisms underlying this effect or to comparatively assess the capabilities of HS therapies to improve workplace function.

Ethics Principles for Artificial Intelligence-Based Telemedicine for Public Health.

The use of artificial intelligence (AI) in the field of telemedicine has grown exponentially over the past decade, along with the adoption of AI-based telemedicine to support public health systems. Although AI-based telemedicine can open up novel opportunities for the delivery of clinical health and care and become a strong aid to public health systems worldwide, it also comes with ethical risks that should be detected, prevented, or mitigated for the responsible use of AI-based telemedicine in and for public health. However, despite the current proliferation of AI ethics frameworks, thus far, none have been developed for the design of AI-based telemedicine, especially for the adoption of AI-based telemedicine in and for public health. We aimed to fill this gap by mapping the most relevant AI ethics principles for AI-based telemedicine for public health and by showing the need to revise them via major ethical themes emerging from bioethics, medical ethics, and public health ethics toward the definition of a unified set of 6 AI ethics principles for the implementation of AI-based telemedicine. (Am J Public Health. 2023;113(5):577-584. https://doi.org/10.2105/AJPH.2023.307225).

The Risk of Meningitis After Cochlear Implantation: A Systematic Review and Meta-Analysis.

OBJECTIVE: This study aims to estimate the rate of postoperative meningitis (both immediate and long-term) in patients following cochlear implants (CIs). It aims to do so through a systematic review and meta-analysis of published studies tracking complications after CIs. DATA SOURCES: MEDLINE, Embase, and Cochrane Library. REVIEW METHODS: This review was performed in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies tracking complications following CIs in patients were included. Exclusion criteria included non-English language studies and case series reporting <10 patients. Bias risk was evaluated using the Newcastle-Ottawa Scale. Meta-analysis was performed through DerSimonian and Laird random-effects models. RESULTS: A total of 116/1931 studies met the inclusion criteria and were included in the meta-analysis. Overall, there were 112 cases of meningitis in 58,940 patients after CIs. Meta-analysis estimated an overall rate of postoperative meningitis of 0.07% (95% confidence interval [CIs], 0.03%-0.1%; I2 = 55%). Subgroup meta-analysis showed this rate had 95% CIs crossing 0% in implanted patients who received the pneumococcal vaccine, antibiotic prophylaxis, those with postoperative acute otitis media (AOM), and those implanted less than 5 years. CONCLUSION: Meningitis is a rare complication following CIs. Our estimated rates of meningitis after CIs appear lower than prior estimates based on epidemiological studies in the early 2000s. However, the rate still appears higher than the baseline rate in the general population. The risk was very low in implanted patients who received the pneumococcal vaccine, antibiotic prophylaxis, received unilateral or bilateral implantations, developed AOM, those implanted with a round window or cochleostomy techniques, and those under 5 years.

Inhibition on human liver cytochrome P450 3A4 by constituents of fennel (Foeniculum vulgare): identification and characterization of a mechanism-based inactivator.

Fennel, a seed of Foeniculum vulgare, is used as a culinary spice and traditional medicine. The methanolic extract of fennel showed a characteristic of mechanism-based inactivation on erythromycin N-demethylation mediated by human liver microsomal cytochrome P450 3A4 (CYP3A4). The present study was conducted to identify the fennel constituent having the inhibition. Thirteen compounds have been isolated from a methanol extract of fennel and tested for their inhibition on CYP3A4. Among them, 5-methoxypsoralen (5-MOP) showed the strongest inhibition with an IC50 value of 18.3 microM and a mixed type of inhibition. In addition, with the preincubation time of 20 min only 5-MOP showed preincubation time dependency; the IC50 value decreased from 18.3 microM with a preincubation time of 0 min to 4.6 microM with a preincubation time of 20 min. Further investigation on 5-MOP showed the characteristics of time-dependent inhibition, requirement of NADPH, lack of protecting effect of nucleophiles, and recovery of CYP3A4 activity by the competitive inhibitor. This result suggests that the inhibitory activity of CYP3A4 by 5-MOP was a mechanism-based inactivation. The kinetic parameter for mechanism-based inactivation was characterized by a KI value of 15.0 microM and a kinact value of 0.098 min(-1).

Quantifying Intracranial Plaque Permeability with Dynamic Contrast-Enhanced MRI: A Pilot Study.

BACKGROUND AND PURPOSE: Intracranial atherosclerotic disease plaque hyperintensity and/or gadolinium contrast enhancement have been studied as imaging biomarkers of acutely symptomatic ischemic presentations using single static MR imaging measurements. However, the value in modeling the dynamics of intracranial plaque permeability has yet to be evaluated. The purpose of this study was to use dynamic contrast-enhanced MR imaging to quantify the contrast permeability of intracranial atherosclerotic disease plaques in symptomatic patients and to compare these parameters against existing markers of plaque volatility using black-blood MR imaging pulse sequences. MATERIALS AND METHODS: We performed a prospective study of contrast uptake dynamics in the major intracranial vessels proximal and immediately distal to the circle of Willis using dynamic contrast-enhanced MR imaging, specifically in patients with symptomatic intracranial atherosclerotic disease. Using the Modified Tofts model, we extracted the volume transfer constant (Ktrans) and fractional plasma volume (Vp) parameters from plaque-enhancement curves. Using regression analyses, we compared these parameters against time from symptom onset as well as intraplaque hyperintensity and postcontrast enhancement derived from T1 SPACE, a black-blood MR vessel wall imaging sequence. RESULTS: We completed analysis in 10 patients presenting with symptomatic intracranial atherosclerotic disease. Ktrans and Vp measurements were higher in plaques versus healthy white matter and similar or less than values in the choroid plexus. Only Ktrans correlated significantly with time from symptom onset (P = .02). Dynamic contrast-enhanced MR imaging parameters were not found to correlate significantly with intraplaque enhancement or intraplaque hyperintensity (P = .4 and P = .17, respectively). CONCLUSIONS: Elevated Ktrans and Vp values found in intracranial atherosclerotic disease plaques versus healthy white matter suggest that dynamic contrast-enhanced MR imaging is a feasible technique for studying vessel wall and plaque characteristics in the proximal intracranial vasculature. Significant correlations between Ktrans and symptom onset, which were not observed on T1 SPACE-derived metrics, suggest that Ktrans may be an independent imaging biomarker of acute and symptom-associated pathologic changes in intracranial atherosclerotic disease plaques.