SummaryTo transit between hosts, intracellular Legionella pneumophila transform into a motile, infectious, transmissive state. Here we exploit the pathogen's life cycle to examine how guanosine tetraphosphate (ppGpp) and DksA cooperate to govern bacterial differentiation. Transcriptional profiling revealed that during transmission alarmone accumulation increases the mRNA for flagellar and Type IV-secretion components, secreted host effectors and regulators, and decreases transcripts for translation, membrane modification and ATP synthesis machinery. DksA is critical for differentiation, since mutants are defective for stationary phase survival, flagellar gene activation, lysosome avoidance and macrophage cytotoxicity. The roles of ppGpp and DksA depend on the context. For macrophage transmission, ppGpp is essential, whereas DksA is dispensable, indicating that ppGpp can act autonomously. In broth, DksA promotes differentiation when ppGpp levels increase, or during fatty acid stress, as judged by flaA expression and evasion of degradation by macrophages. For flagella morphogenesis, DksA is required for basal fliA (s 28 ) promoter activity. When alarmone levels increase, DksA cooperates with ppGpp to generate a pulse of Class II rod RNA or to amplify the Class III sigma factor and Class IV flagellin RNAs. Thus, DksA responds to the level of ppGpp and other stress signals to co-ordinate L. pneumophila differentiation.

Background Given increasing numbers of people experiencing transitions in health insurance due to declines in employer-sponsored insurance and changes in health policy, the understanding and application of health insurance terms and concepts (health insurance literacy) may be important for navigating use of health care. The study objective was to systematically review evidence on the relationship between health insurance literacy and health care utilization. Methods Medline, SCOPUS, Web of Science, CINAHL, PsychInfo, Cochrane Library, and reference lists of published literature were searched in August 2019. Quantitative, qualitative, and intervention studies that assessed the association of health insurance literacy as the exposure and health care utilization as the outcome were identified, without language or date restrictions. Outcomes were independently assessed by 2–3 reviewers. Results Twenty-one studies including a total of 62,416 subjects met inclusion criteria: three interventional trials, two mixed-methods studies, and sixteen cross-sectional studies. Ten of thirteen preventive care studies suggested that higher health insurance literacy was associated with greater utilization of primary care and other preventive services. Eight of nine studies of care avoidance demonstrated that individuals with lower health insurance literacy were more likely to delay or avoid care. A few studies had mixed results regarding the utilization of emergency department, inpatient, and surgical care. Discussion The emerging literature in this area suggests that health insurance literacy is an important factor that can enable effective utilization of health care, including primary care and preventive services. However, the literature is limited by a paucity of studies using validated tools that broadly measure health insurance literacy (rather than testing knowledge of specific covered services). Improving health insurance literacy of the general public and increasing plain language communication of health insurance plan features at the point of health care navigation may encourage more effective and cost-conscious utilization. Supplementary Information The online version contains supplementary material available at 10.1007/s11606-021-06819-0.

Although first patented in 1965, electronic cigarettes did not enter significant domestic use until circa 2010. Subsequently, adult use of electronic nicotine delivery system (ENDS) products, including electronic cigarettes and vaporizers, has grown, with an estimated 2.8% of adults engaged in daily use. 1 The launch of flavored ENDS corresponded with a rise in adolescent use, triggering increased skepticism in the public health community and congressional oversight. It is within this environment that the US Food and Drug Administration (FDA) has struggled to regulate the ENDS product marketplace within the confines of its statutory authority and strike a balance between limiting new users while offering current smokers the benefits of reduced-risk products, deploying ENDS products as a harm-reduction product. 2 In this Viewpoint, we review recent challenges in ENDS product regulation, the history of FDA user fees in other product markets, and the potential benefit of modeling ENDS product user fees after pharmaceutical product and device user fees. Recent Tobacco Regulatory ChallengesDespite being available for domestic purchase for more than a decade, the first ENDS device did not receive marketing authorization from the FDA's Center for Tobacco Products (CTP) until October 2021, when CTP authorized RJ Reynolds' Vuse product after nearly 2 years of review. Shortly thereafter-and after 3 years of review-CTP granted marketing authorization to 4 oral smokeless tobacco products, with critics noting that sales ceased 2 years prior. Moreover, CTP failed to meet a court-ordered deadline of September 9, 2021, to complete review of more than 6 million previously submitted ENDS premarket tobacco product applications, 3 inclusive of a decision on Juul's products, the leading seller in the ENDS market. These regulatory challenges have not occurred in a vacuum. Product sales for ENDS accelerated in conjunction with increased past 30-day use by high schoolers from 2.8% in 2012 4 to 13.3% in 2018, 5 coinciding with decreasing combustible cigarette use. Domestically, combustible tobacco use accounts for more annual mortality than 2020 COVID-19 deaths through its contribution to 3 of the 4 leading causes of death: heart disease, cancer, and chronic obstructive pulmonary disease. Thus, cessation and harm reduction remain a continued concern for 34 million cigarette smokers in the US.In this setting, ENDS products, while controversial, may-if regulated appropriately-represent another form of consumer-driven harm reduction 6 or even cessation for adult smokers. 7 Thus, it is no surprise that public health advocates and industry alike find themselves increasingly frustrated by the status quo, with the FDA's lack of timeliness and transparency around regulatory decisions that affect the public health and ambiguous product standards required for market entry impeding access to appropriately regulated reduced-risk products. The History of FDA User FeesUser fees were born in the early 1990s in an environment where lengthy review times,...

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