A new analytic tool for assessing the impact of the US Food and Drug Administration regulatory actions.

PURPOSE: Develop and test a flexible, scalable tool using interrupted time series (ITS) analysis to assess the impact of Food and Drug Administration (FDA) regulatory actions on drug use. METHODS: We applied the tool in the Sentinel Distributed Database to assess the impact of FDA's 2010 drug safety communications (DSC) concerning the safety of long-acting beta2-agonists (LABA) in adult asthma patients. We evaluated changes in LABA use by measuring the initiation of LABA alone and concomitant use of LABA and asthma controller medications (ACM) after the DSCs. The tool generated ITS graphs and used segmented regression to estimate baseline slope, level change, slope change, and absolute and relative changes at up to two user-specified time point (s) after the intervention. We tested the tool and compared our results against prior analyses that used similar measures. RESULTS: Initiation of LABA alone declined among asthma patients aged 18-45 years before FDA DSCs (-0.10% per quarter; 95%CI: -0.11% to -0.09%) and the downward trend continued after. Concomitant use of LABA and ACM was stable before FDA DSCs. After FDA DSCs, there was a small trend decrease of 0.006% per quarter (95% CI, -0.008% to -0.003%). We found similar results among those aged 46-64 years and patients with poorly-controlled asthma. Our results were consistent with previous studies, confirming the performance of the new tool. CONCLUSIONS: We developed and tested a reusable ITS tool in real-world databases formatted to the Sentinel Common Data Model that can assess the impact of regulatory actions on drug use.

Assessing medical product safety during pregnancy using parameterizable tools in the sentinel distributed database.

PURPOSE: The US Food and Drug Administration established the Sentinel System to monitor the safety of medical products. A component of this system includes parameterizable analytic tools to identify mother-infant pairs and evaluate infant outcomes to enable the routine monitoring of the utilization and safety of drugs used in pregnancy. We assessed the feasibility of using the data and tools in the Sentinel System by assessing a known association between topiramate use during pregnancy and oral clefts in the infant. METHODS: We identified mother-infant pairs using the mother-infant linkage table from six data partners contributing to the Sentinel Distributed Database from January 1, 2000, to September 30, 2015. We compared mother-infant pairs with first-trimester exposure to topiramate to mother-infant pairs that were topiramate-unexposed or lamotrigine-exposed and used a validated algorithm to identify oral clefts in the infant. We estimated adjusted risk ratios through propensity score stratification. RESULTS: There were 2007 topiramate-exposed and 1 066 086 unexposed mother-infant pairs in the main comparison. In the active-comparator analysis, there were 1996 topiramate-exposed and 2859 lamotrigine-exposed mother-infant pairs. After propensity score stratification, the odds ratio for oral clefts was 2.92 (95% CI: 1.43, 5.93) comparing the topiramate-exposed to unexposed groups and 2.72 (95% CI: 0.75, 9.93) comparing the topiramate-exposed to lamotrigine-exposed groups. CONCLUSIONS: We found an increased risk of oral clefts after topiramate exposure in the first trimester in the Sentinel database. These results are similar to prior published observational study results and demonstrate the ability of Sentinel's data and analytic tools to assess medical product safety in cohorts of mother-infant pairs in a timely manner.

A neuroglobin-based high-affinity ligand trap reverses carbon monoxide-induced mitochondrial poisoning.

Carbon monoxide (CO) remains the most common cause of human poisoning. The consequences of CO poisoning include cardiac dysfunction, brain injury, and death. CO causes toxicity by binding to hemoglobin and by inhibiting mitochondrial cytochrome c oxidase (CcO), thereby decreasing oxygen delivery and inhibiting oxidative phosphorylation. We have recently developed a CO antidote based on human neuroglobin (Ngb-H64Q-CCC). This molecule enhances clearance of CO from red blood cells in vitro and in vivo Herein, we tested whether Ngb-H64Q-CCC can also scavenge CO from CcO and attenuate CO-induced inhibition of mitochondrial respiration. Heart tissue from mice exposed to 3% CO exhibited a 42 ± 19% reduction in tissue respiration rate and a 33 ± 38% reduction in CcO activity compared with unexposed mice. Intravenous infusion of Ngb-H64Q-CCC restored respiration rates to that of control mice correlating with higher electron transport chain CcO activity in Ngb-H64Q-CCC-treated compared with PBS-treated, CO-poisoned mice. Further, using a Clark-type oxygen electrode, we measured isolated rat liver mitochondrial respiration in the presence and absence of saturating solutions of CO (160 µm) and nitric oxide (100 µm). Both CO and NO inhibited respiration, and treatment with Ngb-H64Q-CCC (100 and 50 µm, respectively) significantly reversed this inhibition. These results suggest that Ngb-H64Q-CCC mitigates CO toxicity by scavenging CO from carboxyhemoglobin, improving systemic oxygen delivery and reversing the inhibitory effects of CO on mitochondria. We conclude that Ngb-H64Q-CCC or other CO scavengers demonstrate potential as antidotes that reverse the clinical and molecular effects of CO poisoning.

Changes in Cigarettes per Day and Biomarkers of Exposure Among US Adult Smokers in the Population Assessment of Tobacco and Health Study Waves 1 and 2 (2013-2015).

INTRODUCTION: Some studies have found some reduction in tobacco exposure and tobacco-related disease risk with decreased numbers of cigarettes smoked per day (CPD), but biomarker of exposure estimates by change in CPD are generally unavailable for the US population. METHODS: We analyzed biomarker of exposure data by smoking status from over 1100 adult exclusive daily cigarette smokers in Wave 1 of the Population Assessment of Tobacco and Health (PATH) Study who were either exclusive daily smokers or had quit tobacco use entirely at Wave 2. Wave 1 smoking categories consisted of "very light" (1-4 CPD), "light" (5-9 CPD), "moderate" (10-19 CPD), and "heavy" (20+ CPD), and Wave 2 categories were "quitters" (stopped smoking entirely), exclusive cigarette "reducers" (CPD decreased ≥ 50%), "maintainers" (CPD within 50%-150% of Wave 1 value), and "increasers" (CPD increased ≥ 50%). RESULTS: Complete quitters had significantly lower levels of TNE-2, NNAL, NNN, 2-Fluorene, HPMA, CYMA, and MHB3 at Wave 2 for all Wave 1 CPD categories, and decreases were often large. Moderate "reducers" had lower levels of NNAL and 1-Hydroxypyrene at Wave 2, and heavy "reducers" had lower levels of NNAL, 2-Fluorene, and MHB3. Light "increasers" had higher levels of TNE-2, NNAL, 2-Fluorene, CYMA, and cadmium at Wave 2, and heavy "increasers" had higher levels of NNAL and HPMA. CONCLUSIONS: Smoking "reducers" and "increasers" had changes in some biomarker of tobacco exposure levels, but reductions were much greater and more consistent for complete quitters. IMPLICATIONS: PATH longitudinal cohort study data show that some exclusive daily cigarette smokers increase or decrease CPD over time. These differences may result in moderate changes in the levels of some biomarkers such as NNAL. Even so, however, reductions in biomarker levels are much greater with complete smoking cessation.

Loss of GCN5L1 in cardiac cells disrupts glucose metabolism and promotes cell death via reduced Akt/mTORC2 signaling.

GCN5L1 regulates protein acetylation and mitochondrial energy metabolism in diverse cell types. In the heart, loss of GCN5L1 sensitizes the myocardium to injury from exposure to nutritional excess and ischemia/reperfusion injury. This phenotype is associated with the reduced acetylation of metabolic enzymes and elevated mitochondrial reactive oxygen species (ROS) generation, although the direct molecular targets of GCN5L1 remain largely unknown. In this study, we sought to determine the mechanism by which GCN5L1 impacts energy substrate utilization and mitochondrial health. We find that hypoxia and reoxygenation (H/R) leads to a reduction in cell viability and Akt phosphorylation in GCN5L1 knockdown AC16 cardiomyocytes, in parallel with elevated glucose utilization and impaired fatty acid use. We demonstrate that glycolysis is uncoupled from glucose oxidation under normoxic conditions in GCN5L1-depleted cells. We show that GCN5L1 directly binds to the Akt-activating mTORC2 component Rictor, and that loss of Rictor acetylation is evident in GCN5L1 knockdown cells. Finally, we show that restoring Rictor acetylation in GCN5L1-depleted cells reduces mitochondrial ROS generation and increases cell survival in response to H/R. These studies suggest that GCN5L1 may play a central role in energy substrate metabolism and cell survival via the regulation of Akt/mTORC2 signaling.

Cardiac-specific deletion of GCN5L1 restricts recovery from ischemia-reperfusion injury.

GCN5L1 regulates mitochondrial protein acetylation, cellular bioenergetics, reactive oxygen species (ROS) generation, and organelle positioning in a number of diverse cell types. However, the functional role of GCN5L1 in the heart is currently unknown. As many of the factors regulated by GCN5L1 play a major role in ischemia-reperfusion (I/R) injury, we sought to determine if GCN5L1 is an important nexus in the response to cardiac ischemic stress. Deletion of GCN5L1 in cardiomyocytes resulted in impaired myocardial post-ischemic function and increased infarct development in isolated work-performing hearts. GCN5L1 knockout hearts displayed hallmarks of ROS damage, and scavenging of ROS restored cardiac function and reduced infarct volume in vivo. GCN5L1 knockdown in cardiac-derived AC16 cells was associated with reduced activation of the pro-survival MAP kinase ERK1/2, which was also reversed by ROS scavenging, leading to restored cell viability. We therefore conclude that GCN5L1 activity provides an important protection against I/R induced, ROS-mediated damage in the ischemic heart.

US Adult Cigar Smoking Patterns, Purchasing Behaviors, and Reasons for Use According to Cigar Type: Findings From the Population Assessment of Tobacco and Health (PATH) Study, 2013-2014.

Introduction: The US cigar market is diverse, yet until recently most research studies and tobacco surveillance systems have not reported behavioral and related outcomes by cigar type. Methods: The 2013-2014 Population Assessment of Tobacco and Health Study collected data separately for filtered cigars (FCs), cigarillos, and traditional cigars, which were further distinguished as premium or nonpremium. Descriptive statistics for adult established current smokers of each cigar type and cigarettes were calculated for demographic characteristics, tobacco use patterns, purchasing behaviors and reasons for use. Adjusted prevalence ratios (APRs) using a marginal predictions approach with logistic regression assessed correlates of dual cigar and cigarette smoking. Results: Age, sex, race/ethnicity, education level, and poverty status of smokers varied according to cigar type. Daily cigar smoking prevalence and number of cigars smoked per day were higher for FCs (37.3%; median: 1.6 cigars/day, respectively), than all other cigar types (6.7%-25.3%, all p < .01; 0.1-0.4 cigars/day, all p < .01, respectively); daily smoking and cigars per day were similar for nonpremium cigars and cigarillos (p = .11; p = .33, respectively). Cigarette smoking was twice as common among smokers of nonpremium cigars, cigarillos, and FCs (58.0%-66.0%) than among premium cigars (29.9%). Among current cigar smokers, FC smokers (APR = 1.23, 95% confidence interval [CI] = 1.09-1.39), other tobacco product users (APR = 1.27, 95% CI = 1.15-1.41), and those with a GED/high school diploma or less (APR = 1.20, 95% CI = 1.09-1.33) were more likely to also smoke cigarettes. Conclusion: User characteristics, cigar smoking patterns, and dual smoking with cigarettes varied by cigar type highlighting the importance of adequately describing the cigar type studied and, where appropriate, differentiating results by cigar type. Implications: Despite the diversity of the cigar market place, historically many research studies and tobacco surveillance systems have treated cigars as a single product type. This study describes similarities and differences in the user characteristics, tobacco use patterns, and purchasing behaviors of premium, nonpremium, cigarillo, and filtered cigar smokers. To enhance tobacco regulatory science, sufficient descriptions of the cigar type(s) studied and, where appropriate, differentiation of the particular cigar type(s) studied should be undertaken to improve the interpretation of study findings, understanding of cigar use patterns and related behaviors and future approaches to reducing cigar-attributable morbidity and mortality.

IPF lung fibroblasts have a senescent phenotype.

The mechanisms of aging that are involved in the development of idiopathic pulmonary fibrosis (IPF) are still unclear. Although it has been hypothesized that the proliferation and activation of human lung fibroblasts (hLFs) are essential in IPF, no studies have assessed how this process works in an aging lung. Our goal was to elucidate if there were age-related changes on primary hLFs isolated from IPF lungs compared with age-matched controls. We investigated several hallmarks of aging in hLFs from IPF patients and age-matched controls. IPF hLFs have increased cellular senescence with higher expression of ß-galactosidase, p21, p16, p53, and cytokines related to the senescence-associated secretory phenotype (SASP) as well as decreased proliferation/apoptosis compared with age-matched controls. Additionally, we observed shorter telomeres, mitochondrial dysfunction, and upon transforming growth factor-ß stimulation, increased markers of endoplasmic reticulum stress. Our data suggest that IPF hLFs develop senescence resulting in a decreased apoptosis and that the development of SASP may be an important contributor to the fibrotic process observed in IPF. These results might change the existing paradigm, which describes fibroblasts as aberrantly activated cells, to a cell with a senescence phenotype.

Tobacco Product Use Among Adults - United States, 2015.

Tobacco use remains the leading cause of preventable disease and death in the United States (1). Despite declining cigarette smoking prevalence among U.S. adults, shifts in the tobacco product landscape have occurred in recent years (2,3). Previous estimates of tobacco product use among U.S. adults were obtained from the National Adult Tobacco Survey, which ended after the 2013-2014 cycle. This year, CDC and the Food and Drug Administration (FDA) assessed the most recent national estimates of tobacco product use among adults aged ≥18 years using, for the first time, data from the 2015 National Health Interview Survey (NHIS), an annual, nationally representative, in-person survey of the noninstitutionalized U.S. civilian population. The 2015 NHIS adult core questionnaire included 33,672 adults aged ≥18 years, reflecting a 55.2% response rate. Data were weighted to adjust for differences in selection probability and nonresponse, and to provide nationally representative estimates. In 2015, 20.1 % of U.S. adults currently (every day or some days) used any tobacco product, 17.6% used any combustible tobacco product, and 3.9% used ≥2 tobacco products. By product, 15.1% of adults used cigarettes; 3.5% used electronic cigarettes (e-cigarettes); 3.4% used cigars, cigarillos, or filtered little cigars; 2.3% used smokeless tobacco; and 1.2% used regular pipes, water pipes, or hookahs.* Current use of any tobacco product was higher among males; persons aged <65 years; non-Hispanic American Indian/Alaska natives (AI/AN), whites, blacks, and persons of multiple races; persons living in the Midwest; persons with a General Educational Development (GED) certificate; persons with annual household income of <$35,000; persons who were single, never married, or not living with a partner or divorced, separated, or widowed; persons who were insured through Medicaid or uninsured; persons with a disability; and persons who identified as lesbian, gay, or bisexual (LGB). Current use of any tobacco product was 47.2% among adults with serious psychological distress compared with 19.2% among those without serious psychological distress. Proven population-level interventions that focus on the diversity of tobacco product use are important to reducing tobacco-related disease and death in the United States (1).

The Proapoptotic F-box Protein Fbxl7 Regulates Mitochondrial Function by Mediating the Ubiquitylation and Proteasomal Degradation of Survivin.

Fbxl7, a component of the Skp1·Cul1·F-box protein type ubiquitin E3 ligase, regulates mitotic cell cycle progression. Here we demonstrate that overexpression of Fbxl7 in lung epithelia decreases the protein abundance of survivin, a member of the inhibitor of apoptosis family. Fbxl7 mediates polyubiquitylation and proteasomal degradation of survivin by interacting with Glu-126 within its carboxyl-terminal α helix. Furthermore, both Lys-90 and Lys-91 within survivin serve as ubiquitin acceptor sites. Ectopically expressed Fbxl7 impairs mitochondrial function, whereas depletion of Fbxl7 protects mitochondria from actions of carbonyl cyanide m-chlorophenylhydrazone, an inhibitor of oxidative phosphorylation. Compared with wild-type survivin, cellular expression of a survivin mutant protein deficient in its ability to interact with Fbxl7 (E126A) and a ubiquitylation-resistant double point mutant (KK90RR/KK91RR) rescued mitochondria to a larger extent from damage induced by overexpression of Fbxl7. Therefore, these data suggest that the Skp1·Cul1·F-box protein complex subunit Fbxl7 modulates mitochondrial function by controlling the cellular abundance of survivin. The results raise opportunities for F-box protein targeting to preserve mitochondrial function.

Platelet bioenergetic screen in sickle cell patients reveals mitochondrial complex V inhibition, which contributes to platelet activation.

Bioenergetic dysfunction, although central to the pathogenesis of numerous diseases, remains uncharacterized in many patient populations because of the invasiveness of obtaining tissue for mitochondrial studies. Although platelets are an accessible source of mitochondria, the role of bioenergetics in regulating platelet function remains unclear. Herein, we validate extracellular flux analysis in human platelets and use this technique to screen for mitochondrial dysfunction in sickle cell disease (SCD) patients, a population with aberrant platelet activation of an unknown mechanism and in which mitochondrial function has never been assessed. We identify a bioenergetic alteration in SCD patients characterized by deficient complex V activity, leading to decreased mitochondrial respiration, membrane hyperpolarization, and augmented oxidant production compared with healthy subjects. This dysfunction correlates with platelet activation and hemolysis in vivo and can be recapitulated in vitro by exposing healthy platelets to hemoglobin or a complex V inhibitor. Further, reproduction of this dysfunction in vitro activates healthy platelets, an effect prevented by attenuation of mitochondrial hyperpolarization or by scavenging mitochondrial oxidants. These data identify bioenergetic dysfunction in SCD patients for the first time and establish mitochondrial hyperpolarization and oxidant generation as potential pathogenic mechanism in SCD as well as a modulator of healthy platelet function.

Tobacco Use Among Middle and High School Students--United States, 2011-2015.

Tobacco use is the leading cause of preventable disease and death in the United States; if current smoking rates continue, 5.6 million Americans aged <18 years who are alive today are projected to die prematurely from smoking-related disease. Tobacco use and addiction mostly begin during youth and young adulthood. CDC and the Food and Drug Administration (FDA) analyzed data from the 2011-2015 National Youth Tobacco Surveys (NYTS) to determine the prevalence and trends of current (past 30-day) use of seven tobacco product types (cigarettes, cigars, smokeless tobacco, electronic cigarettes [e-cigarettes], hookahs [water pipes used to smoke tobacco], pipe tobacco, and bidis [small imported cigarettes wrapped in a tendu leaf]) among U.S. middle (grades 6-8) and high (grades 9-12) school students. In 2015, e-cigarettes were the most commonly used tobacco product among middle (5.3%) and high (16.0%) school students. During 2011-2015, significant increases in current use of e-cigarettes and hookahs occurred among middle and high school students, whereas current use of conventional tobacco products, such as cigarettes and cigars decreased, resulting in no change in overall tobacco product use. During 2014-2015, current use of e-cigarettes increased among middle school students, whereas current use of hookahs decreased among high school students; in contrast, no change was observed in use of hookahs among middle school students, use of e-cigarettes among high school students, or use of cigarettes, cigars, smokeless tobacco, pipe tobacco, or bidis among middle and high school students. In 2015, an estimated 4.7 million middle and high school students were current tobacco product users, and, therefore, continue to be exposed to harmful tobacco product constituents, including nicotine. Nicotine exposure during adolescence, a critical period for brain development, can cause addiction, might harm brain development, and could lead to sustained tobacco product use among youths. Comprehensive and sustained strategies are warranted to prevent and reduce the use of all tobacco products among U.S. youths.

Inorganic nitrite improves components of the metabolic syndrome independent of weight change in a murine model of obesity and insulin resistance.

Nitrite acts as an endocrine source of bioactive nitric oxide, impacting vascular reactivity, angiogenesis and cytoprotection. Nitrite has recently been shown to have a metabolic role although its effects and mechanisms of action in the obese insulin-resistant state are unknown. We examined glucose tolerance and insulin secretion using the frequently sampled intravenous glucose tolerance test and insulin sensitivity using the hyperinsulinaemic euglycaemic clamp in obese male ob(lep) mice administered nitrite (100 mg kg(-1) day(-1) ) or saline (control) for 7 days and compared responses to the known insulin-sensitizing effects of rosiglitazone (6 mg kg(-1) day(-1) ). Under weight-matched conditions, nitrite lowered blood pressure relative to saline and rosiglitazone, whereas only rosiglitazone was effective at reducing hepatic glucose output and basal blood glucose. Both nitrite and rosiglitazone produced improvements, relative to saline, in glucose tolerance (12,524 ± 602, 12,811 ± 692 vs.14,428 ± 335 mg (dl min)(-1) , respectively; P < 0.05) and insulin sensitivity (8.6 ± 0.7, 7.9 ± 0.3 vs. 6.6 ± 0.5 mg kg(-1) min(-1) , respectively; P < 0.001), but there was no effect on insulin secretion. Nitrite exhibited an uncoupling of mitochondrial respiration and a decrease in ATP generation in muscle that was independent of mitochondrial biogenesis or activation of uncoupling proteins. There was no insulin-stimulated phosphorylation of Akt, but nitrite increased the phosphorylation of AMP-activated protein kinase. We conclude that nitrite improves two key components of the metabolic syndrome, blood pressure and insulin sensitivity, independent of weight and with effectiveness comparable to rosiglitazone.

Inhaled, nebulized sodium nitrite protects in murine and porcine experimental models of hemorrhagic shock and resuscitation by limiting mitochondrial injury.

OBJECTIVE: The cellular injury that occurs in the setting of hemorrhagic shock and resuscitation (HS/R) affects all tissue types and can drive altered inflammatory responses. Resuscitative adjuncts hold the promise of decreasing such injury. Here we test the hypothesis that sodium nitrite (NaNO2), delivered as a nebulized solution via an inhalational route, protects against injury and inflammation from HS/R. METHODS: Mice underwent HS/R to a mean arterial pressure (MAP) of 20 or 25 mmHg. Mice were resuscitated with Lactated Ringers after 90-120 min of hypotension. Mice were randomized to receive nebulized NaNO2 via a flow through chamber (30 mg in 5 mL PBS). Pigs (30-35 kg) were anesthetized and bled to a MAP of 30-40 mmHg for 90 min, randomized to receive NaNO2 (11 mg in 2.5 mL PBS) nebulized into the ventilator circuit starting 60 min into the hypotensive period, followed by initial resuscitation with Hextend. Pigs had ongoing resuscitation and support for up to four hours. Hemodynamic data were collected continuously. RESULTS: NaNO2 limited organ injury and inflammation in murine hemorrhagic shock. A nitrate/nitrite depleted diet exacerbated organ injury, as well as mortality, and inhaled NaNO2 significantly reversed this effect. Furthermore, NaNO2 limited mitochondrial oxidant injury. In porcine HS/R, NaNO2 had no significant influence on shock induced hemodynamics. NaNO2 limited hypoxia/reoxia or HS/R-induced mitochondrial injury and promoted mitochondrial fusion. CONCLUSION: NaNO2 may be a useful adjunct to shock resuscitation based on its limitation of mitochondrial injury.

Flavored Tobacco Product Use Among Middle and High School Students--United States, 2014.

The 2009 Family Smoking Prevention and Tobacco Control Act prohibits "characterizing flavors" (e.g., candy, fruit, and chocolate) other than tobacco and menthol in cigarettes; however, characterizing flavors are not currently prohibited in other tobacco products. Analyses of retail sales data suggest that U.S. consumption of flavored noncigarette tobacco products, including flavored cigars and flavored e-cigarettes, has increased in recent years. There is growing concern that widely marketed varieties of new and existing flavored tobacco products might appeal to youths (2) and could be contributing to recent increases in the use of tobacco products, including e-cigarettes and hookah, among youths. CDC and the Food and Drug Administration (FDA) analyzed data from the 2014 National Youth Tobacco Survey (NYTS) to determine the prevalence of past 30 day use (current use) of flavored e-cigarette, hookah tobacco, cigar, pipe tobacco or smokeless tobacco products, and menthol cigarettes among middle and high school students, and the proportion of current tobacco product users who have used flavored products. An estimated 70.0% (3.26 million) of all current youth tobacco users had used at least one flavored tobacco product in the past 30 days. Among current users, 63.3%, (1.58 million) had used a flavored e-cigarette, 60.6%, (1.02 million) had used flavored hookah tobacco, and 63.5% (910,000) had used a flavored cigar in the past 30 days. Given the millions of current youth tobacco users, it is important for comprehensive tobacco prevention and control strategies to address all forms of tobacco use, including flavored tobacco products, among U.S. youths.

Frequency of Tobacco Use Among Middle and High School Students--United States, 2014.

The use of tobacco products during adolescence increases the risk for adverse health effects and lifelong nicotine addiction. In 2014, an estimated 4.6 million middle and high school students were current users of any tobacco product, of whom an estimated 2.2 million were current users of two or more types of tobacco products. Symptoms of nicotine dependence are increased for multiple tobacco product users compared with single-product users. CDC and the Food and Drug Administration (FDA) analyzed data from the 2014 National Youth Tobacco Survey (NYTS) to determine how frequently (the number of days in the preceding 30 days) U.S. middle school (grades 6­8) and high school (grades 9­12) students used cigarettes, e-cigarettes, cigars, and smokeless tobacco products. Among current users (≥1 day during the preceding 30 days) in high school, frequent use (≥20 days during the preceding 30 days) was most prevalent among smokeless tobacco users (42.0%), followed by cigarette smokers (31.6%), e-cigarette users (15.5%), and cigar smokers (13.1%); a similar pattern was observed for those who used during all 30 days. Among current users in middle school, frequent use was greatest among smokeless tobacco users (29.2%), followed by cigarette smokers (20.0%), cigar smokers (13.2%) and e-cigarette users (11.8%). Current use of two or more types of tobacco products was common, even among students who used tobacco products 1­5 days during the preceding 30 days: 77.3% for cigar smokers, 76.9% for cigarette smokers, 63.4% for smokeless tobacco users, and 54.8% for e-cigarettes users. Preventing youths from initiating the use of any tobacco product is important to tobacco use prevention and control strategies in the United States. Monitoring the frequency and patterns of tobacco use among youths, including the use of two or more tobacco products, is important to inform evidence-based interventions to prevent and reduce all forms of tobacco use among youths.

Tobacco use among middle and high school students - United States, 2011-2014.

Tobacco use and addiction most often begin during youth and young adulthood. Youth use of tobacco in any form is unsafe. To determine the prevalence and trends of current (past 30-day) use of nine tobacco products (cigarettes, cigars, smokeless tobacco, e-cigarettes, hookahs, tobacco pipes, snus, dissolvable tobacco, and bidis) among U.S. middle (grades 6-8) and high school (grades 9-12) students, CDC and the Food and Drug Administration (FDA) analyzed data from the 2011-2014 National Youth Tobacco Surveys (NYTS). In 2014, e-cigarettes were the most commonly used tobacco product among middle (3.9%) and high (13.4%) school students. Between 2011 and 2014, statistically significant increases were observed among these students for current use of both e-cigarettes and hookahs (p<0.05), while decreases were observed for current use of more traditional products, such as cigarettes and cigars, resulting in no change in overall tobacco use. Consequently, 4.6 million middle and high school students continue to be exposed to harmful tobacco product constituents, including nicotine. Nicotine exposure during adolescence, a critical window for brain development, might have lasting adverse consequences for brain development, causes addiction, and might lead to sustained tobacco use. For this reason, comprehensive and sustained strategies are needed to prevent and reduce the use of all tobacco products among youths in the United States.

E-Cigarette Market Trends in Traditional U.S. Retail Channels, 2012-2013.

INTRODUCTION: E-cigarette sales continue to increase in the United States. To date, little surveillance research has documented the specific product attributes driving growth. This study uses national market scanner data to describe sales trends in traditional U.S. tobacco retail channels between 2012 and 2013 and identifies product features associated with sales increases. METHODS: Data on e-cigarette sales in convenience stores, drug stores, grocery stores, and mass merchandisers in the United States were obtained from the Nielsen Company. Each product was coded for attributes such as brand, flavor, and unit size. Total sales volume, market share, and percent growth were calculated for various product attributes. RESULTS: E-cigarette sales more than doubled between 2012 and 2013, from $273.6 million to $636.2 million, respectively. Growth was particularly strong in the convenience store channel. Blu eCigs quickly emerged as the best-selling brand and in 2013 constituted nearly half (44.1%) of overall sales. Although fruit-flavored and other flavored products experienced marked growth, unflavored and menthol e-cigarettes overwhelmingly dominated the market. Sales of single unit products (likely disposable e-cigarettes) increased by 216.4%, a much faster rate than multi-unit packs and cartridge refills. CONCLUSIONS: In traditional U.S. retail channels, particularly the convenience store channel, sales of e-cigarettes continue to grow, with brands like blu and disposable products as the likely drivers. Given the rapidly-changing market, expanded surveillance is needed to monitor sales not only in traditional retail locations, but sales online and in specialty "vape shops," as well.

Intentions to smoke cigarettes among never-smoking US middle and high school electronic cigarette users: National Youth Tobacco Survey, 2011-2013.

INTRODUCTION: Electronic cigarette (e-cigarette) use is increasing rapidly, and the impact on youth is unknown. We assessed associations between e-cigarette use and smoking intentions among US youth who had never smoked conventional cigarettes. METHODS: We analyzed data from the nationally representative 2011, 2012, and 2013 National Youth Tobacco Surveys of students in grades 6-12. Youth reporting they would definitely not smoke in the next year or if offered a cigarette by a friend were defined as not having an intention to smoke; all others were classified as having positive intention to smoke conventional cigarettes. Demographics, pro-tobacco advertisement exposure, ever use of e-cigarettes, and ever use of other combustibles (cigars, hookah, bidis, kreteks, and pipes) and noncombustibles (chewing tobacco, snuff, dip, snus, and dissolvables) were included in multivariate analyses that assessed associations with smoking intentions among never-cigarette-smoking youth. RESULTS: Between 2011 and 2013, the number of never-smoking youth who used e-cigarettes increased 3-fold, from 79,000 to more than 263,000. Intention to smoke conventional cigarettes was 43.9% among ever e-cigarette users and 21.5% among never users. Ever e-cigarette users had higher adjusted odds for having smoking intentions than never users (adjusted odds ratio = 1.70, 95% confidence interval = 1.24-2.32). Those who ever used other combustibles, ever used noncombustibles, or reported pro-tobacco advertisement exposure also had increased odds for smoking intentions. CONCLUSION: In 2013, more than a quarter million never-smoking youth used e-cigarettes. E-cigarette use is associated with increased intentions to smoke cigarettes, and enhanced prevention efforts for youth are important for all forms of tobacco, including e-cigarettes.