Type I and Type III Interferons Display Different Dependency on Mitogen-Activated Protein Kinases to Mount an Antiviral State in the Human Gut

Intestinal epithelial cells (IECs) are constantly exposed to commensal flora and pathogen challenges. How IECs regulate their innate immune response to maintain gut homeostasis remains unclear. Interferons (IFNs) are cytokines produced during infections. While type I IFN receptors are ubiquitously expressed, type III IFN receptors are expressed only on epithelial cells. This epithelium specificity strongly suggests exclusive functions at epithelial surfaces, but the relative roles of type I and III IFNs in the establishment of an antiviral innate immune response in human IECs are not clearly defined. Here, we used mini-gut organoids to define the functions of types I and III IFNs to protect the human gut against viral infection. We show that primary non-transformed human IECs, upon viral challenge, upregulate the expression of both type I and type III IFNs at the transcriptional level but only secrete type III IFN in the supernatant. However, human IECs respond to both type I and type III IFNs by producing IFN-stimulated genes that in turn induce an antiviral state. Using genetic ablation of either type I or type III IFN receptors, we show that either IFN can independently restrict virus infection in human IECs. Importantly, we report, for the first time, differences in the mechanisms by which each IFN establishes the antiviral state. Contrary to type I IFN, the antiviral activity induced by type III IFN is strongly dependent on the mitogen-activated protein kinases signaling pathway, suggesting a pathway used by type III IFNs that non-redundantly contributes to the antiviral state. In conclusion, we demonstrate that human intestinal epithelial cells specifically regulate their innate immune response favoring type III IFN-mediated signaling, which allows for efficient protection against pathogens without producing excessive inflammation. Our results strongly suggest that type III IFN constitutes the frontline of antiviral response in the human gut. We propose that mucosal surfaces, particularly the gastrointestinal tract, have evolved to favor type III IFN-mediated response to pathogen infections as it allows for spatial segregation of signaling and moderate production of inflammatory signals which we propose are key to maintain gut homeostasis

Effect of Fatigue Training on Safety, Fatigue, and Sleep in Emergency Medical Services Personnel and Other Shift Workers: A Systematic Review and Meta-Analysis

<p><b>Background</b>: Fatigue training may be an effective way to mitigate fatigue-related risk. We aimed to critically review and synthesize existing literature on the impact of fatigue training on fatigue-related outcomes for Emergency Medical Services (EMS) personnel and similar shift worker groups. <b>Methods</b>: We performed a systematic literature review for studies that tested the impact of fatigue training of EMS personnel or similar shift workers. Outcomes of interest included personnel safety, patient safety, personnel performance, acute fatigue, indicators of sleep duration and quality, indicators of long-term health (e.g., cardiovascular disease), and burnout/stress. A meta-analysis was performed to determine the impact of fatigue training on sleep quality. <b>Results</b>: Of the 3,817 records initially identified for review, 18 studies were relevant and examined fatigue training in shift workers using an experimental or quasi-experimental design. Fatigue training improved patient safety, personal safety, and ratings of acute fatigue and reduced stress and burnout. A meta-analysis of five studies showed improvement in sleep quality (Fixed Effects SMD −0.87; 95% CI −1.05 to −0.69; p < 0.00001; Random Effects SMD −0.80; 95% CI −1.72, 0.12; p < 0.00001). <b>Conclusions</b>: Reviewed literature indicated that fatigue training improved safety and health outcomes in shift workers. Further research is required to identify the optimal components of fatigue training programs to maximize the beneficial outcomes.</p

Reliability and Validity of Survey Instruments to Measure Work-Related Fatigue in the Emergency Medical Services Setting: A Systematic Review

<p><b>Background</b>: This study sought to systematically search the literature to identify reliable and valid survey instruments for fatigue measurement in the Emergency Medical Services (EMS) occupational setting. <b>Methods</b>: A systematic review study design was used and searched six databases, including one website. The research question guiding the search was developed a priori and registered with the PROSPERO database of systematic reviews: “Are there reliable and valid instruments for measuring fatigue among EMS personnel?” (2016:CRD42016040097). The primary outcome of interest was criterion-related validity. Important outcomes of interest included reliability (e.g., internal consistency), and indicators of sensitivity and specificity. Members of the research team independently screened records from the databases. Full-text articles were evaluated by adapting the Bolster and Rourke system for categorizing findings of systematic reviews, and the rated data abstracted from the body of literature as favorable, unfavorable, mixed/inconclusive, or no impact. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology was used to evaluate the quality of evidence. <b>Results</b>: The search strategy yielded 1,257 unique records. Thirty-four unique experimental and non-experimental studies were determined relevant following full-text review. Nineteen studies reported on the reliability and/or validity of ten different fatigue survey instruments. Eighteen different studies evaluated the reliability and/or validity of four different sleepiness survey instruments. None of the retained studies reported sensitivity or specificity. Evidence quality was rated as very low across all outcomes. <b>Conclusions</b>: In this systematic review, limited evidence of the reliability and validity of 14 different survey instruments to assess the fatigue and/or sleepiness status of EMS personnel and related shift worker groups was identified.</p

Shorter Versus Longer Shift Durations to Mitigate Fatigue and Fatigue-Related Risks in Emergency Medical Services Personnel and Related Shift Workers: A Systematic Review

<p><b>Background</b>: This study comprehensively reviewed the literature on the impact of shorter versus longer shifts on critical and important outcomes for Emergency Medical Services (EMS) personnel and related shift worker groups. <b>Methods</b>: Six databases (e.g., PubMed/MEDLINE) were searched, including one website. This search was guided by a research question developed by an expert panel <i>a priori</i> and registered with the PROSPERO database of systematic reviews (2016:CRD42016040099). The critical outcomes of interest were patient safety and personnel safety. The important outcomes of interest were personnel performance, acute fatigue, sleep and sleep quality, retention/turnover, long-term health, burnout/stress, and cost to system. Screeners worked independently and full-text articles were assessed for relevance. Data abstracted from the retained literature were categorized as favorable, unfavorable, mixed/inconclusive, or no impact toward the shorter shift duration. This research characterized the evidence as very low, low, moderate, or high quality according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. <b>Results</b>: The searched yielded <i>n</i> = 21,674 records. Of the 480 full-text articles reviewed, 100 reported comparisons of outcomes of interest by shift duration. We identified 24 different shift duration comparisons, most commonly 8 hours versus 12 hours. No one study reported findings for all 9 outcomes. Two studies reported findings linked to both critical outcomes of patient and personnel safety, 34 reported findings for one of two critical outcomes, and 64 did not report findings for critical outcomes. Fifteen studies were grouped to compare shifts <24 hours versus shifts ≥24 hours. None of the findings for the critical outcomes of patient and personnel safety were categorized as unfavorable toward shorter duration shifts (<24 hours). Nine studies were favorable toward shifts <24 hours for at least one of the 7 important outcomes, while findings from one study were categorized as unfavorable. Evidence quality was low or very low. <b>Conclusions</b>: The quality of existing evidence on the impact of shift duration on fatigue and fatigue-related risks is low or very low. Despite these limitations, this systematic review suggests that for outcomes considered critical or important to EMS personnel, shifts <24 hours in duration are more favorable than shifts ≥24 hours.</p