IntroductionUS tobacco control policies to reduce cigarette use have been effective, but their impact has been relatively slow. This study considers a strategy of switching cigarette smokers to e-cigarette use (‘vaping’) in the USA to accelerate tobacco control progress.MethodsA Status Quo Scenario, developed to project smoking rates and health outcomes in the absence of vaping, is compared with Substitution models, whereby cigarette use is largely replaced by vaping over a 10-year period. We test an Optimistic and a Pessimistic Scenario, differing in terms of the relative harms of e-cigarettes compared with cigarettes and the impact on overall initiation, cessation and switching. Projected mortality outcomes by age and sex under the Status Quo and E-Cigarette Substitution Scenarios are compared from 2016 to 2100 to determine public health impacts.FindingsCompared with the Status Quo, replacement of cigarette by e-cigarette use over a 10-year period yields 6.6 million fewer premature deaths with 86.7 million fewer life years lost in the Optimistic Scenario. Under the Pessimistic Scenario, 1.6 million premature deaths are averted with 20.8 million fewer life years lost. The largest gains are among younger cohorts, with a 0.5 gain in average life expectancy projected for the age 15 years cohort in 2016.ConclusionsThe tobacco control community has been divided regarding the role of e-cigarettes in tobacco control. Our projections show that a strategy of replacing cigarette smoking with vaping would yield substantial life year gains, even under pessimistic assumptions regarding cessation, initiation and relative harm.

Mammalian neurotransmitter-gated receptors can be conjugated to photoswitchable tethered ligands (PTLs) to enable photoactivation, or photoantagonism, while preserving normal function at neuronal synapses. "MAG" PTLs for ionotropic and metabotropic glutamate receptors (GluRs) are based on an azobenzene photoswitch that is optimally switched into the liganding state by blue or near-UV light, wavelengths that penetrate poorly into the brain. To facilitate deep-tissue photoactivation with near-infrared light, we measured the efficacy of two-photon (2P) excitation for two MAG molecules using nonlinear spectroscopy. Based on quantitative characterization, we find a recently designed second generation PTL, , to have a favorable 2P absorbance peak at 850 nm, enabling efficient 2P activation of the GluK2 kainate receptor, LiGluR. We also achieve 2P photoactivation of a metabotropic receptor, LimGluR3, with a new mGluR-specific PTL, D-MAG0 460 . 2P photoswitching is efficiently achieved using digital holography to shape illumination over single somata of cultured neurons. Simultaneous Ca 2+ -imaging reports on 2P photoswitching in multiple cells with high temporal resolution. The combination of electrophysiology or Ca 2+ imaging with 2P activation by optical wavefront shaping should make second generation PTL-controlled receptors suitable for studies of intact neural circuits.optogenetics | pharmacology | multiphoton | photoswitch | azobenzene M odern neurobiology relies heavily on optical microscopy to observe, and, increasingly, to manipulate (1, 2), biological processes in live tissue. Among these methods, 2-photon-excited fluorescence microscopy (2PM) with near-infrared (NIR) light has emerged as an important technique for extending optical microscopy to highly scattering tissue (3, 4). Remarkably, barely 25 years after the first 2P-excited fluorescence image was published (5), 2PM is now performed in awake, behaving animals (4, 6-8). Naturally, optical manipulations in the brain can benefit from the many advantages of 2PM (9). In particular, the inherent spatial confinement of 2P absorption is critical for optical manipulation of individual cells (10) in the intact mammalian brain, where it is difficult to control the spatial extent of gene expression or confine soluble reagents. However, 2P-excited optogenetics is not yet as widespread in adoption as 2PM, being widely perceived to require sophisticated optical techniques (11-13) or reagent concentrations that compromise pharmacological specificity (2, 14).The rapid time to adoption of 2PM owes at least some credit to the availability of spectroscopic data on the 2P-excited efficacy, or brightness, of synthetic and genetically encoded fluorophores (15-17). Brightness, defined for fluorophores as the product of absorption cross-section and fluorescence quantum yield, gives the experimenter an objective metric to assess fluorescent reporters and identify appropriate optical parameters, such as the optimal excitation wavelength and range of light intensities (18). By ...

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Previous models of VNP use do not incorporate whether youth and young adults initiating VNP would have been likely to have been a smoker in the absence of VNPs. This study provides a decision-theoretic model of VNP use in a young cohort that incorporates tendencies toward smoking and shows that, under most plausible scenarios, VNP use yields public health gains. The model makes explicit the type of surveillance information needed to better estimate the effect of new products and thereby inform public policy.

Objective This report presents tenofovir alafenamide (TAF) and elvitegravir (EVG) fabricated into nanoparticles (NPs) for subcutaneous (SubQ) delivery as prevention strategy. Design Prospective prevention study in hu-BLT mice. Methods Using an oil-in-water emulsion solvent evaporation technique, TAF+EVG drugs were entrapped together into NPs containing poly(lactic-co-glycolic acid) (PLGA). In vitro prophylaxis studies (IC90) compared NPs to drugs in solution. Humanized-BLT (n=5/group) mice were given 200 mg/kg SubQ, and vaginally challenged with HIV-1 (5×105 TCID50) 4 and 14 days (d) post-NP administration (PI). Control mice (n=5) were challenged at 4 d. Weekly plasma viral load (pVL) was performed using RT-PCR. Hu-BLT mice were sacrificed and lymph nodes were harvested for HIV-1 viral RNA detection by in situ hybridization (ISH). In parallel, CD34+ humanized mice (3/time point) compared tenofovir (TFV) and EVG drug levels in vaginal tissues from NPs and solution. TFV and EVG were analyzed from tissue using LC-MS/MS. Results TAF+EVG NPs were < 200 nm in size. In-vitro prophylaxis indicates TAF+EVG NPs IC90 was 0.002 μg/mL and TAF+EVG solution was 0.78 μg/mL. TAF+EVG NPs demonstrated detectable drugs for 14 days and 72 h for solution, respectively. All Hu-BLT control mice became infected within 14 d after HIV-1 challenge. In contrast, hu-BLT mice that received NPs and challenged at 4 d PI, 100% were uninfected, and 60% challenged at 14 d PI were uninfected (p = 0.007; Mantel-Cox test). ISH confirmed these results. Conclusions This proof-of-concept study demonstrated sustained protection for TAF+EVG NPs in a hu-BLT mouse model of HIV vaginal transmission.

Objective Since WHO released the package of six MPOWER measures to assist nations with implementing the WHO Framework Convention for Tobacco Control (FCTC), 88 countries adopted at least one highest level MPOWER measure. We estimated the subsequent reduction in smoking-related deaths from all new highest level measures adopted between 2007 and 2014. Methods Policy effect sizes based on previously validated SimSmoke models were applied to the number of smokers in each nation to determine the reduction in the number of smokers from policy adoption. On the basis of research that half of all smokers die from smoking, we derived the smoking-attributable deaths (SADs) averted of those smokers alive today. Findings In total, 88 countries adopted at least one highest level MPOWER policy between 2007 and 2014, resulting in almost 22 million fewer projected SADs. The largest number of future SADs averted was due to increased cigarette taxes (7.0 million), followed by comprehensive smoke-free laws (5.4 million), large graphic health warnings (4.1 million), comprehensive marketing bans (3.8 million) and comprehensive cessation interventions (1.5 million). Conclusions These findings demonstrate the immense public health impact of tobacco control policies adopted globally since the WHO-FCTC and highlight the importance of more countries adopting highest level MPOWER measures to reduce the global burden of tobacco use. Substantial additional progress could be made, especially if heavily populated nations with high smoking prevalence were to reach highest level MPOWER measures.

Introduction: Accurate estimates of e-cigarette use are needed to gauge its impact on public health. We compared the results of online and traditional, large scale surveys and provide additional estimates from the Population Assessment of Tobacco and Health (PATH) survey, with the aim of assessing the extent of variation in prevalence estimates. Materials and Methods: We searched the peer-reviewed literature for nationally representative estimates of U.S. adult e-cigarette prevalence, and developed our own estimates from waves one, two, and three of the PATH survey. We compared estimates by age, gender, cigarette smoking status, and e-cigarette use intensity both between online and traditional surveys and among the traditional surveys. Results: For specific years, online surveys generally yielded higher adult use rates than most traditional surveys, but considerable variation was found among traditional surveys. E-cigarette prevalence was greater for less intensive than for more intensive use. Levels of use were higher among current and recent former cigarette smokers than among former smokers of longer quit duration and never smokers, and by those of younger ages. Conclusions: Considerable variation in e-cigarette use estimates was observed even for a specific year. Further study is needed to uncover the source of variation in e-cigarette prevalence measures, with a view towards developing measures that best explain regular use and transitions between the use of e-cigarettes and other tobacco products.

The origins of human immunodeficiency virus type 1 (HIV-1) have been widely accepted to be the consequences of simian immunodeficiency viruses from wild chimpanzees (SIVcpz) crossing over to humans. However, there has not been any in vivo study of SIVcpz infection of humans. Also, it remains largely unknown why only specific SIVcpz strains have achieved crossspecies transmission and what transmission risk might exist for those SIVcpz strains that have not been found to infect humans. Closing this knowledge gap is essential for better understanding cross-species transmission and predicting the likelihood of additional cross-species transmissions of SIV into humans. Here we show that humanized bone marrow, thymus, and liver (hu-BLT) mice are susceptible to all studied strains of SIVcpz, including the inferred ancestral viruses of pandemic and nonpandemic HIV-1 groups M (SIVcpzMB897) and N (SIVcpzEK505) as well as strains that have not been found in humans (SIVcpzMT145 and SIVcpzBF1167). Importantly, the ability of SIVcpz to cross the interspecies barrier to infect humanized mice correlates with their phylogenetic distance to pandemic HIV-1. We also identified mutations of SIVcpzMB897 (Env G411R and G413R) and SIVcpzBF1167 (Env H280Q and Q380R) at 14 weeks postinoculation. Together, our results have recapitulated the events of SIVcpz cross-species transmission to humans and identified mutations that occurred during the first 16 weeks of infection, providing in vivo experimental evidence that the origins of HIV-1 are the consequence of SIVcpz crossing over to humans. This study also revealed that SIVcpz viruses whose inferred descendants have not been found in humans still have the potential to cause an HIV-1-like zoonosis. IMPORTANCEIt is believed that the origins of HIV-1 are the consequence of SIV from wild chimpanzees crossing over to humans. However, the origins of HIV-1 have been linked back to only specific SIVcpz strains. There have been no experiments that directly test the in vivo cross-species transmissibility of SIVcpz strains to humans. This is the first in vivo study of SIVcpz cross-species transmission. With the humanized-BLT mouse model, we have provided in vivo experimental evidence of multiple SIVcpz strains crossing over to humans and identified several important mutations of divergent SIVcpz strains after long-term replication in human cells. We also found that the cross-species transmission barrier of SIVcpz to humans correlates with their phylogenetic distance to pandemic HIV-1 group M. Importantly, this work provides evidence that SIVcpz viruses, whose inferred descendants have not been found in humans, still have the potential to cause a future HIV-1-like zoonotic outbreak. H uman immunodeficiency virus type 1 (HIV-1) infections have claimed millions of human lives since the pandemic began in 1981, and HIV-1 still infects about 2.3 million people every year (1, 2). Based on comparative phylogenetic analyses of HIV-1 and simian immunodeficiency viruses from chimpanzee (SIVcpz), it has ...