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Public Health Consequences of E-Cigarettes (2018)

Chapter: Appendix B Search Strategy and Quality Assessment

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Suggested Citation:"Appendix B Search Strategy and Quality Assessment." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"Appendix B Search Strategy and Quality Assessment." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"Appendix B Search Strategy and Quality Assessment." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"Appendix B Search Strategy and Quality Assessment." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"Appendix B Search Strategy and Quality Assessment." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"Appendix B Search Strategy and Quality Assessment." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"Appendix B Search Strategy and Quality Assessment." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"Appendix B Search Strategy and Quality Assessment." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"Appendix B Search Strategy and Quality Assessment." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"Appendix B Search Strategy and Quality Assessment." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"Appendix B Search Strategy and Quality Assessment." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"Appendix B Search Strategy and Quality Assessment." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

B Search Strategy and Quality Assessment The Statement of Task charges the committee with conducting a “comprehensive and systematic assessment and review of the litera- ture” on the health effects of e-cigarettes. The committee’s approach was informed by published guidelines for conducting systematic reviews as well as the approaches taken by prior National Academies committees (CRD, 2009; Higgins and Green, 2011; IOM, 2008, p. 45, 2011a, pp. 10–24, 2011b, 2016, pp. 8–10; NASEM, 2017; NRC, 2014; OHAT, 2015; Sena et al., 2014; ­ hiting et al., 2016). For its assessment on the health effects W of e-cigarettes, the committee conducted structured reviews of the lit- erature on the effects of e-cigarette exposure on any biological outcome (whether human, animal, or in vitro). Because assessment of the overall public health impact of e-cigarettes requires understanding the relation- ship between e-cigarettes and combustible tobacco cigarettes, the com- mittee also undertook comprehensive literature reviews of the effects of e-cigarette use on combustible tobacco cigarette smoking initiation and cessation. The committee did not systematically review the health effects of known constituents and contaminants of e-cigarette devices or their refill solutions (e.g., nicotine, certain metals). Because many of these con- stituents have been widely studied in other settings, the committee draws on existing bodies of evidence to describe potential health effects of these constituent parts. This appendix describes the committee’s strategy for identifying and reviewing literature in detail. 665

666 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES LITERATURE SEARCH The committee conducted a series of searches in six databases— PubMed, Scopus, Web of Science, PsycINFO (ProQuest), MEDLINE (Ovid), and Embase (Ovid)—between February 1, 2017, and August 31, 2017, to identify all literature on e-cigarettes. Due to e-pub ahead of print and online first articles, 2018 citations were captured. In addition, a few 2016 and 2017 studies may not have been captured due to lags and dis- crepancies in database indexing. The committee applied no limits on date, language, or country to any of its searches. The following sections describe the committee’s search strategies to identify literature on the health effects of e-cigarettes and on the e-cigarettes and smoking transitions. Health Effects of E-Cigarettes Because the committee is interested primarily in the effects of e-cigarettes as a whole product, rather than the effects of their individual constituent parts, the committee conducted a search to identify litera- ture on human, animal, and in vitro exposure to e-cigarettes. Human epidemiological evidence provides the strongest evidence, but due to the lack of available human studies, the committee also chose to review animal and in vitro exposure to e-cigarettes from which they could draw informed inferences. The committee’s initial search included all literature pertaining to e-cigarette exposures and was conducted as a series of six searches between February 1, 2017, and February 6, 2017. The search was conducted in five databases—PubMed, Scopus, Web of Science, PsycINFO (ProQuest), and MEDLINE (Ovid). All literature on e-cigarettes used the following key words and phrases: e-cigarette, e-cigarettes, “electronic cig- arette,” “electronic cigarettes,” “electronic nicotine delivery,” “electronic nicotine device,” vape, vaping, and e-liquid. (The committee excluded the term “e-liquid” from searches in Scopus and Web of Science, which are multidisciplinary databases, where the term “e-liquid” produced results related to geothermal energy.) Searches in PubMed and MEDLINE also used the Medical Subject Headings (MeSH) term “electronic cigarettes.” This initial series of searches identified 3,494 unique results. The com- plete search syntax can be found in Boxes B-1A through B-1F. Titles and abstracts for all references were reviewed using inclusion criteria devel- oped through a preliminary title and abstract review process. The final inclusion criteria for human, animal, and in vitro studies are listed in Box B-2. The committee conducted a special search to identify literature on e-cigarette use and dependence. The search was conducted between July 14, 2017, and August 31, 2017, in the same five databases as the initial search. In addition to the e-cigarette terms described above, the

APPENDIX B 667 committee added the following terms: dependence, withdrawal, craving, appeal, addition, “abuse liability,” “subjective effects, “smoking urge,” “urge to smoke,” “smoking desire,” and “desire to smoke.” In PubMed and MEDLINE, they also used the MeSH terms “tobacco use disorder,” “substance withdrawal syndrome,” and “craving.” The complete search syntax can be found in Box B-3. This initial search identified 957 unique results. Titles and abstracts were reviewed for all literature that included an assessment of dependence using a validated instrument. E-Cigarettes and Transitions to and from Combustible Tobacco Cigarette Smoking To identify literature on the effects of e-cigarette use on smoking transitions (initiation and cessation), the committee conducted a series of subsearches within its initial search to identify epidemiological and experimental data on these smoking transitions. To do so, the committee added terms to the original search to restrict results to smoking transi- tion outcomes of interest. Additionally, because there are many recent, systematic reviews on the effects of e-cigarettes on smoking initiation and cessation but few original studies, the committee chose to assess first these review articles rather than duplicating these efforts. The committee then complemented the evidence identified through these reviews with new studies published after the search dates of the most recent literature reviews, and also met the most rigorous inclusion/exclusion criteria used in the existing, prior systematic reviews. To identify literature on smoking initiation, the key terms “smoking initiation” and “initiation” were added to the e-cigarette terms described in the section above. This search included all literature published through May 4, 2017, in six databases—PubMed, Scopus, Web of Science, PsycINFO (ProQuest), MEDLINE (Ovid), and Embase (Ovid). The complete search syntax can be found in Box B-4. The committee applied no limits on date, language, or country, and the search yielded 138 unique studies. The committee conducted two searches on smoking cessation, one limited to reviews, and one limited to original, peer-reviewed research. The search of systematic reviews published through March 1, 2017, was conducted in seven databases—PubMed, Scopus, Web of Science, PsycINFO (ProQuest), MEDLINE (Ovid), Embase (Ovid), and Cochrane (Ovid). The key terms “smoking cessation” and “cessation,” and the MeSH term “smoking cessation” were added to the e-cigarette terms described above. The committee applied no limits on date, language, or country. This search produced 209 unique results. The search of primary literature published through May 3, 2017, was conducted in six data- bases—PubMed, Scopus, Web of Science, PsycINFO, MEDLINE (Ovid),

668 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES BOX B-1A Search Strategy for E-Cigarettes in Human Populations PubMed: “e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping” OR “e-liquid” OR “Electronic Cigarettes” [MeSH] Limit: Humans Limit: Peer-Reviewed Journal Article Results: 1,060 Scopus: TITLE-ABS-KEY (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping”) AND NOT TITLE-ABS-KEY (animal OR animals OR mice OR mouse OR rat OR rats) Source Type: Journal Document Type: Article, Review, Article in Press, Erratum Note: Scopus is a multidisciplinary database. The term “e-liquid” produced results related to geothermal energy. Results: 1,724 Web of Science: TS=(“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic ciga- rettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping”) NOT TS=(animal OR animals OR mice OR mouse OR rat OR rats) Document Type: Article Note: Web of Science is a multidisciplinary database. The term “e-liquid” produced results related to geothermal energy. Results: 1,036

APPENDIX B 669 PsycINFO (ProQuest): “e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping” OR “e-liquid” OR SU.EXACT (“Electronic Cigarettes”) Population: Human Source Type: Scholarly Journals; Peer-Reviewed Record Type: Include: Journal, Peer-Reviewed Journal, Journal Article Exclude: Comment/Reply, Editorial, Letter, Column/Opinion, Review-Book Results: 617 MEDLINE (Ovid): Search No. Search Syntax 1  (e-cigarette or e-cigarettes or electronic cigarette or electronic ciga- rettes or electronic nicotine delivery or electronic nicotine device or vape or vaping or e-liquid).ti,ab. 2 Electronic Cigarettes/ 3 1 or 2 4 3 5 limit 4 to humans 6  limit 5 to (case reports or clinical study or clinical trial, all or clinical trial, phase i or clinical trial, phase ii or clinical trial, phase iii or clini- cal trial, phase iv or clinical trial or comparative study or controlled clinical trial or “corrected and republished article” or evaluation studies or historical article or introductory journal article or journal article or meta-analysis or multicenter study or observational study or pragmatic clinical trial or published erratum or randomized con- trolled trial or “review” or “scientific integrity review” or systematic reviews or technical report or twin study or validation studies) Results: 1,058 Totals: Citations Downloaded: 5,495 After Removing Duplicates: 2,094

670 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES BOX B-1B Search Strategy for E-Cigarettes in In Vivo Animal Populations PubMed: “e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping” OR “e-liquid” OR “Electronic Cigarettes” [MeSH] Limit: Other Animals Limit: Peer-Reviewed Journal Article Results: 68 Scopus: TITLE-ABS-KEY (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping”) AND TITLE-ABS-KEY (animal OR animals OR mice OR mouse OR rat OR rats) Note: Scopus is a multidisciplinary database. The term “e-liquid” produced results related to geothermal energy. Source Type: Journal Document Type: Article, Review, Article in Press, Erratum Results: 88 Web of Science: TS=(“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic ciga- rettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping”) AND TS=(animal OR animals OR mice OR mouse OR rat OR rats) Note: Web of Science is a multidisciplinary database. The term “e-liquid” produced results related to geothermal energy Document Type: Article Results: 62

APPENDIX B 671 PsycINFO (ProQuest): “e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping” OR “e-liquid” OR SU.EXACT (“Electronic Cigarettes”) Population: Animal Source Type: Scholarly Journals; Peer-Reviewed Record Type: Include: Journal, Peer-Reviewed Journal, Journal Article Exclude: Comment/Reply, Editorial, Letter, Column/Opinion, Review-Book Results: 21 MEDLINE (Ovid): Search No. Search Syntax 1  (e-cigarette or e-cigarettes or electronic cigarette or electronic ciga- rettes or electronic nicotine delivery or electronic nicotine device or vape or vaping or e-liquid).ti,ab. 2 Electronic Cigarettes/ 3 1 or 2 4 3 5  limit 4 to (animals and (case reports or clinical study or clinical trial, all or clinical trial, phase i or clinical trial, phase ii or clinical trial, phase iii or clinical trial, phase iv or clinical trial or compara- tive study or controlled clinical trial or “corrected and republished article” or duplicate publication or evaluation studies or historical ar- ticle or introductory journal article or journal article or meta-analysis or multicenter study or observational study or pragmatic clinical trial or published erratum or randomized controlled trial or “review” or “scientific integrity review” or systematic reviews or technical report or twin study or validation studies)) Results: 56 Totals: Citations Downloaded: 295 After Removing Duplicates: 133

672 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES BOX B-1C Search Strategy for E-Cigarettes in In Vitro Populations PubMed: (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic ciga- rettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping” OR “e-liquid” OR “Electronic Cigarettes” [MeSH]) AND (“In Vitro T ­ echniques” [MeSH] OR “in vitro”) Limit: Other Animals Limit: Peer-Reviewed Journal Article Results: 46 Scopus: TITLE-ABS-KEY (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping”) AND TITLE-ABS-KEY (“in vitro”) Note: Scopus is a multidisciplinary database. The term “e-liquid” produced results related to geothermal energy. Source Type: Journal Document Type: Article, Review, Article in Press, Erratum Results: 40 Web of Science: TS=(“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic ciga- rettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping”) AND TS=(“in vitro”) Note: Web of Science is a multidisciplinary database. The term “e-liquid” produced results related to geothermal energy. Document Type: Article Results: 42

APPENDIX B 673 PsycINFO (ProQuest): (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping” OR “e-liquid” OR SU.EXACT (“Electronic Cigarettes”)) and (“in vitro”) Source Type: Scholarly Journals; Peer-Reviewed Record Type: Include: Journal, Peer-Reviewed Journal, Journal Article Exclude: Comment/Reply, Editorial, Letter, Column/Opinion, Review-Book Results: 6 MEDLINE (Ovid): Search No. Search Syntax 1   (e-cigarette or e-cigarettes or electronic cigarette or electronic ciga- rettes or electronic nicotine delivery or electronic nicotine device or vape or vaping or e-liquid).ti,ab. 2 Electronic Cigarettes/ 3 1 or 2 4 In Vitro Techniques/ 5 in vitro.ti,ab. 6 or/4–5 7 3 and 6 8  limit 7 to (case reports or classical article or clinical study or clinical trial, all or clinical trial, phase i or clinical trial, phase ii or clinical trial, phase iii or clinical trial, phase iv or clinical trial or compara- tive study or controlled clinical trial or “corrected and republished article” or duplicate publication or evaluation studies or histori- cal article or introductory journal article or journal article or meta-­ ­ analysis or multicenter study or observational study or pragmatic clinical trial or published erratum or randomized controlled trial or “review” or “scientific integrity review” or systematic reviews or technical report or twin study or validation studies) Results: 17 Totals: Citations Downloaded: 151 After Removing Duplicates: 73

674 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES BOX B1-D Search Syntax for E-Cigarettes with No Population Limits, Excluding Results from Earlier Searches (Boxes B-1A, B-1B, B-1C) PubMed: No Population Limit: (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping” OR “e-liquid” OR “Electronic Cigarettes” [MeSH]) Limit: Peer-Reviewed Journal Article Results: 1,910 Humans: “e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping” OR “e-liquid” OR “Electronic Cigarettes” [MeSH] Limit: Humans Limit: Peer-Reviewed Journal Article Results: 1,060 Animals: “e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping” OR “e-liquid” OR “Electronic Cigarettes” [MeSH] Limit: Other Animals Limit: Peer-Reviewed Journal Article Results: 68 In Vitro: (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping” OR “e-liquid” OR “Electronic Cigarettes” [MeSH]) AND (“In Vitro Tech- niques” [MeSH] OR “in vitro”) Limit: Peer-Reviewed Journal Article Results: 46 Animals + Humans + In Vitro = 1,174 No Population – (Animals + Humans + In Vitro) = 736 Scopus: No Population Limit: TITLE-ABS-KEY (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping”) Source Type: Journal Document Type: Article, Review, Article in Press, Erratum Results: 1,814

APPENDIX B 675 Humans: TITLE-ABS-KEY (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping”) AND NOT TITLE-ABS-KEY (animal OR animals OR mice OR mouse OR rat OR rats) Source Type: Journal Document Type: Article, Review, Article in Press, Erratum Results: 1,727 Animals: TITLE-ABS-KEY (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping”) AND TITLE-ABS-KEY (animal OR animals OR mice OR mouse OR rat OR rats) Source Type: Journal Document Type: Article, Review, Article in Press, Erratum Results: 87 In Vitro: TITLE-ABS-KEY (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping”) AND TITLE-ABS-KEY (“in vitro”) Source Type: Journal Document Type: Article, Review, Article in Press, Erratum Results: 40 Animals + Humans + In Vitro = 1,854 No Population – (Animals + Humans + In Vitro) = no additional results Web of Science: No Population: TS=(“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping”) Document Type: Article Results: 1,101 Animals: TS=(“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic ciga- rettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping”) AND TS=(animal OR animals OR mice OR mouse OR rat OR rats) Document Type: Article Results: 62 Humans: TS=(“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic ciga- rettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping”) NOT TS=(animal OR animals OR mice OR mouse OR rat OR rats) Document Type: Article Results: 1,039 continued

676 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES BOX B1-D  Continued In Vitro: TS=(“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic ciga- rettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping”) AND TS=(“in vitro”) Document Type: Article Results: 42 Animals + Humans + In Vitro = 1,140 No Population – (Animals + Humans + In Vitro) = no additional results PsycINFO (ProQuest): No Population: “e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping” OR “e-liquid” OR SU.EXACT (“Electronic Cigarettes”) Source Type: Scholarly Journals; Peer-Reviewed Results: 779 Animals: “e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping” OR “e-liquid” OR SU.EXACT (“Electronic Cigarettes”) Population: Animal Results: 21 Humans: “e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping” OR “e-liquid” OR SU.EXACT (“Electronic Cigarettes”) Population: Human Source Type: Scholarly Journals; Peer-Reviewed Results: 721 In Vitro: (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping” OR “e-liquid” OR SU.EXACT (“Electronic Cigarettes”)) and (“in vitro”) Source Type: Scholarly Journals; Peer-Reviewed Results: 6

APPENDIX B 677 Animals + Humans + In Vitro = 748 No Population – (Animals + Humans + In Vitro) = 31 MEDLINE (Ovid): No Population: Search No. Search Syntax 1  (e-cigarette or e-cigarettes or electronic cigarette or electronic ciga- rettes or electronic nicotine delivery or electronic nicotine device or vape or vaping or e-liquid).ti,ab. 2 Electronic Cigarettes/ 3 1 or 2 4 3 5  limit 4 to (case reports or clinical study or clinical trial, all or clinical trial, phase i or clinical trial, phase ii or clinical trial, phase iii or clini- cal trial, phase iv or clinical trial or comparative study or controlled clinical trial or “corrected and republished article” or evaluation studies or historical article or introductory journal article or journal article or meta-analysis or multicenter study or observational study or pragmatic clinical trial or published erratum or randomized con- trolled trial or “review” or “scientific integrity review” or systematic reviews or technical report or twin study or validation studies) Results: 1,144 Animals: Search No. Search Syntax 1  (e-cigarette or e-cigarettes or electronic cigarette or electronic ciga- rettes or electronic nicotine delivery or electronic nicotine device or vape or vaping or e-liquid).ti,ab. 2 Electronic Cigarettes/ 3 1 or 2 4 3 5  limit 4 to (animals and (case reports or clinical study or clinical trial, all or clinical trial, phase i or clinical trial, phase ii or clinical trial, phase iii or clinical trial, phase iv or clinical trial or comparative study or controlled clinical trial or “corrected and republished arti- cle” or duplicate publication or evaluation studies or historical article ­ or introductory journal article or journal article or meta-analysis or multicenter study or observational study or pragmatic clinical trial or published erratum or randomized controlled trial or “review” or “scientific integrity review” or systematic reviews or technical report or twin study or validation studies)) Results: 56 continued

678 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES BOX B1-D  Continued Humans: Search No. Search Syntax 1  (e-cigarette or e-cigarettes or electronic cigarette or electronic ciga- rettes or electronic nicotine delivery or electronic nicotine device or vape or vaping or e-liquid).ti,ab. 2 Electronic Cigarettes/ 3 1 or 2 4 3 5 limit 4 to humans 6  limit 5 to (case reports or clinical study or clinical trial, all or clinical trial, phase I or clinical trial, phase ii or clinical trial, phase iii or clini- cal trial, phase iv or clinical trial or comparative study or controlled clinical trial or “corrected and republished article” or evaluation studies or historical article or introductory journal article or journal article or meta-analysis or multicenter study or observational study or pragmatic clinical trial or published erratum or randomized con- trolled trial or “review” or “scientific integrity review” or systematic reviews or technical report or twin study or validation studies) Results: 1,058 In Vitro: Search No. Search Syntax 1  (e-cigarette or e-cigarettes or electronic cigarette or electronic ciga- rettes or electronic nicotine delivery or electronic nicotine device or vape or vaping or e-liquid).ti,ab. 2 Electronic Cigarettes/

APPENDIX B 679 3 1 or 2 4 In Vitro Techniques/ 5 in vitro.ti,ab. 6 or/4–5 7 3 and 6 8   limit 7 to (case reports or classical article or clinical study or clinical trial, all or clinical trial, phase i or clinical trial, phase ii or clinical trial, phase iii or clinical trial, phase iv or clinical trial or compara- tive study or controlled clinical trial or “corrected and republished article” or duplicate publication or evaluation studies or historical ar- ticle or introductory journal article or journal article or meta-analysis or multicenter study or observational study or pragmatic clinical trial or published erratum or randomized controlled trial or “review” or “scientific integrity review” or systematic reviews or technical report or twin study or validation studies) Results: 17 Animals + Humans + In Vitro = 1,131 No Population – (Animals + Humans + In Vitro) = 13 EndNote Totals: Animals Exposure: 133 Humans Exposure: 2,094 In Vitro: 73 No Population Limit: 780 After removing duplicates and comparing No Population to Animals, Humans + In Vitro: 265

680 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES BOX B-1E Search Syntax for E-Cigarettes and Dermal and Ingestion Exposure PubMed: (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic ciga- rettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping” OR “e-liquid” OR “Electronic Cigarettes” [MeSH]) AND (“Poisoning” [MeSH] OR dermal OR ingestion OR poison OR poisoning or ingest) Results: 78 Scopus: TITLE-ABS-KEY (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping”) AND TITLE-ABS-KEY (poisoning OR poison OR dermal OR ingestion OR ingest) Results: 63 Web of Science: TS=(“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic ciga- rettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping”) AND TS=(poisoning OR poison OR dermal OR ingestion OR ingest) Results: 58 PsycINFO (ProQuest): “e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping” OR “e-liquid” OR SU.EXACT (“Electronic Cigarettes”) AND (poisoning OR poison OR dermal OR ingestion OR ingest) Results: 21 MEDLINE (Ovid): Search No. Search Syntax 1  (e-cigarette or e-cigarettes or electronic cigarette or electronic ciga- rettes or electronic nicotine delivery or electronic nicotine device or vape or vaping or e-liquid).ti,ab. 2 Electronic Cigarettes/ 3 1 or 2 4 3 5 Poisoning/ 6 (dermal or ingestion or poison or poisoning or ingest).ti,ab. 7 or/5–6 8 4 and 7 Results: 29 Totals: Citations Downloaded: 249 After Removing Duplicates: 124

APPENDIX B 681 BOX B-1F Search Syntax for E-Cigarettes with No Limit on Population or Publication, Excluding Results from Prior Searches (see Boxes B-1A, B-1B, B-1C, B-1D, B-1E) PubMed (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping” OR “e-liquid” OR “Electronic Cigarettes” [MeSH]) Results: 2,304 Scopus: TITLE-ABS-KEY (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping”) Results: 2,597 Web of Science: TS=(“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic ciga- rettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping”) Results: 2,013 PsycINFO (ProQuest): “e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping” OR “e-liquid” OR SU.EXACT (“Electronic Cigarettes”) Results: 804 MEDLINE (Ovid): Search No. Search Syntax 1  (e-cigarette or e-cigarettes or electronic cigarette or electronic ciga- rettes or electronic nicotine delivery or electronic nicotine device or vape or vaping or e-liquid).ti,ab. 2 Electronic Cigarettes/ 3 1 or 2 4 3 Results: 1,493 Totals: Total Citations Downloaded: 9,211 After Removing Duplicates Compared to All Populations, Peer-Reviewed Litera- ture: 805

682 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES BOX B-2 Inclusion Criteria for the Literature Review on the Health Effects of E-Cigarettes Human Studies: • Human subjects • Exposure: e-cigarettes or e-cigarette product/s (e.g., e-liquid, aerosol)— primary, secondary, tertiary • Outcome: Any physiological response or biological effect—such as bio- markers of exposure, biomarkers of risk, adverse events (including self- reported symptoms, injury), disease endpoints (including mental health) • Peer-reviewed, original research Animal Studies: • (Other) animal subjects • Exposure: e-cigarettes or e-cigarette product/s (e.g., e-liquid, aerosol)— primary, secondary, tertiary • Outcome: Any physiological response or biological effect—including biomarkers of exposure, biomarkers of risk, adverse events (including self-reported symptoms, injury), disease endpoints (including behavioral changes) • Peer-reviewed, original research In Vitro Studies: • Human or animal cells • Exposure: e-cigarettes or e-cigarette product/s (e.g., e-liquid, aerosol)— primary, secondary, tertiary • Outcome: Any physiological response or biological effect—cytotoxicity, etc. • Peer-reviewed, original research

APPENDIX B 683 BOX B-3 Search Syntax for E-Cigarettes and Dependence Search Syntax: MEDLINE (Ovid): Search No. Syntax Results 1  (e-cigarette or e-cigarettes or electronic cigarette or electronic cigarettes or electronic nicotine delivery or electronic nicotine device or vape or vaping or e-liquid).ti,ab.    1,668 2 Electronic Cigarettes/   1,306 3 1 or 2    1,787 4 “Tobacco Use Disorder”/   10,292 5 Substance Withdrawal Syndrome/   20,572 6 Craving/    676 7 (dependence or withdrawal or craving or appeal or addiction).ti,ab. 257,569 8 (smok* adj3 urge).ti,ab.    283 9 (smok* adj3 desire).ti,ab.    317 10 “abuse liability”.ti,ab.    970 11 “subjective effects”.ti,ab.   1,686 12 or/4–11 269,923 13 3 and 12    370 14 limit 13 to (comment or editorial or letter)      37 15 13 not 14    333 Embase (Ovid): Search No. Syntax Results 1 (e-cigarette or e-cigarettes or electronic cigarette or electronic cigarettes or electronic nicotine delivery or electronic nicotine device or vape or vaping or e-liquid).ti,ab.    2,749 2 electronic cigarette/   2,754 3 withdrawal syndrome/ or tobacco dependence/   43,252 4 addiction/  49,320 5 (dependence or withdrawal or appeal or addiction).ti,ab. 352,865 6 crav*.ti,ab.  10,313 7 (smok* adj3 urge).ti,ab.    354 8 (smok* adj3 desire).ti,ab.    418 9 “abuse liability”.ti,ab.   1,389 10 “subjective effects”.ti,ab.   2,256 11 1 or 2    3,159 12 or/3–10 406,827 13 11 and 12    722 14 limit 13 to (editorial or letter or note)     136 15 13 not 14    586 continued

684 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES BOX B-3  Continued PubMed: Note: PubMed does not perform adjacency searching (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping” OR “e-liquid” OR “Electronic Cigarettes” [MeSH]) AND (“Tobacco Use Disorder” [MeSH] OR “Substance Withdrawal Syndrome” [MeSH] OR “Craving” [MeSH] OR dependence or withdrawal or craving or appeal or addiction OR “abuse liability” OR “subjective effects” OR “smoking urge” OR “urge to smoke” OR “smok- ing desire” OR “desire to smoke”) Results: 565 Scopus: TITLE-ABS-KEY (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine de- vice” OR “vape” OR “vaping”) AND TITLE-ABS-KEY (dependence OR withdrawal OR craving OR appeal OR addiction OR “abuse liability” OR “subjective effects” OR (smok* w/3 urge) OR (smok* w/3 desire)) Results: 489 Web of Science: TS=(“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic ciga- rettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping”) AND TS=(dependence OR withdrawal OR craving OR appeal OR addiction OR “abuse liability” OR “subjective effects” OR (smok* NEAR/3 urge) OR (smok* NEAR/3 desire)) Results: 341 PsycINFO (ProQuest): (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic ciga- rettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping” OR “e-liquid” OR SU.EXACT (“Electronic Cigarettes”)) AND (ti(dependence OR withdrawal OR craving OR appeal OR addiction OR “abuse liability” OR “subjective effects” OR (smok* NEAR/3 urge) OR (smok* NEAR/3 desire)) OR ab(dependence OR withdrawal OR craving OR appeal OR addiction OR “abuse liability” OR “subjective effects” OR (smok* NEAR/3 urge) OR (smok* NEAR/3 desire))) Results: 246 Total: Results After Removing Duplicates: 957

APPENDIX B 685 BOX B-4 Search Syntax for E-Cigarettes and Combustible Tobacco Cigarette Smoking Initiation Search Strategy: Scopus: TITLE-ABS-KEY (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping”) AND TITLE-ABS-KEY (“smoking initiation” OR initiation) Results: 81 Web of Science: TS=(“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic ciga- rettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping”) AND TS=(“smoking initiation” OR initiation) Results: 86 PsycINFO (ProQuest): (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping” OR “e-liquid” OR SU.EXACT (“Electronic Cigarettes”)) AND (ti(“smoking initiation” OR initiation) OR ab(“smoking initiation” OR initiation)) Results: 46 MEDLINE (Ovid): Search No. Search Syntax Results 1 (e-cigarette or e-cigarettes or electronic cigarette or electronic cigarettes or electronic nicotine delivery or electronic nicotine device or vape or vaping or e-liquid).ti,ab.    1,548 2 Electronic Cigarettes/   1,193 3 1 or 2    1,657 4 3   1,657 5 (smoking adj initiation).ti,ab.    1,179 6 initiation.ti,ab. 175,727 7 or/5–6 175,727 8 4 and 7     42 9 limit 8 to (meta-analysis or “review” or systematic reviews)     12 10 limit 8 to (comment or editorial or letter)       0 11 8 not (9 or 10)      30 Results: 42 continued

686 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES BOX B-4  Continued Embase (Ovid): Search No. Search Syntax Results   1 (e-cigarette or e-cigarettes or electronic cigarette or electronic cigarettes or electronic nicotine delivery or electronic nicotine device or vape or vaping or e-liquid).ti,ab.    2,389  2 Electronic Cigarettes/   1,900  3 1 or 2   2,659  4 3   2,659  5 (smoking adj initiation).ti,ab.   1,410  6 initiation.ti,ab. 247,094  7 or/5–6 247,094  8 4 and 7     77   9 limit 8 to (meta-analysis or “systematic review”)       3 10 limit 8 to (editorial or erratum or letter or note)       1 11 8 not (9 or 10)      73 Results: 77 PubMed: (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping” OR “e-liquid” OR “Electronic Cigarettes” [MeSH]) AND (“smoking initia- tion” OR initiation) Results: 75 Totals: Total Citations Downloaded: 407 After Removing Duplicates: 138 and Embase (Ovid). The key terms “smoking cessation,” “cessation,” “quit,” and “abstinence” and the MeSH term “smoking cessation” were added to the e-cigarette terms from the original search, and the committee applied no limits on date, language, or country. The complete search syn- tax can be found in Boxes B-5 and B-6. This search yielded 1,759 unique results. Finally, the committee conducted a search of literature on e-cigarette exposure and smoking reduction. For this search, the key terms “smok- ing reduction” and “harm reduction” were added to the e-cigarette terms described in the section above. This search included all literature pub- lished through May 4, 2017, in six databases—PubMed, Scopus, Web of Science, PsycINFO (ProQuest), MEDLINE (Ovid), and Embase (Ovid).

APPENDIX B 687 BOX B-5 Search Syntax for Systematic Reviews and Meta- Analyses on E-Cigarettes and Combustible Tobacco Cigarette Smoking Cessation PubMed: (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping” OR “e-liquid” OR “Electronic Cigarettes” [MeSH]) AND (“Smoking Ces- sation” [MeSH] OR “smoking cessation” OR cessation) Limit: Meta-Analysis, Systematic Reviews Results: 53 Scopus: TITLE-ABS-KEY (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping”) AND TITLE-ABS-KEY (“smoking cessation” OR cessation) Source Type: Journal Document Type: Review Results: 143 Web of Science: TS=(“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic ciga- rettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping”) AND TS=(“smoking cessation” OR cessation) Document Type: Review Results: 57 PsycINFO (ProQuest): (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping” OR “e-liquid” OR SU.EXACT (“Electronic Cigarettes”)) AND (SU.EXACT (“Smoking Cessation”) OR “smoking cessation” OR cessation) Source Type: Scholarly Journals; Peer-Reviewed Methodology: Literature Review, Meta-Analysis, Meta-Synthesis, Systematic Review Results: 22 continued

688 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES BOX B-5  Continued MEDLINE, Embase, Cochrane (Ovid): Search No. Search Syntax 1 electronic cigarette/ 2  (e-cigarette or e-cigarettes or electronic cigarette or electronic ciga- rettes or electronic nicotine delivery or electronic nicotine device or vape or vaping or e-liquid).ti,ab. 3 or/1–2 4 smoking cessation/ 5 “smoking cessation”.ti,ab. 6 cessation.ti,ab. 7 or/4–6 8 3 and 7 9 limit 8 to (meta-analysis or systematic reviews) MEDLINE Results: 31 Embase Results: 44 Cochrane Results: 1 Totals: Citations Downloaded: 351 After Removing Duplicates: 209 The complete search syntax can be found in Box B-7. The committee applied no limits on date, language, or country. This search yielded 455 unique results. Literature Updates After the initial searches, the committee continued to collect literature through the end date of August 31, 2017. A total of 641 unique results were identified. QUALITY ASSESSMENT Each relevant study was reviewed and assessed by committee mem- bers. The committee began by identifying what questions the literature addresses and then assessed the extent to which each study was able to answer each question of interest. In their assessment, the committee considered study design, elements of study design, study results, and other potential sources of conflict of interest or bias. Where committee members co-authored studies to be assessed, committee members who

APPENDIX B 689 BOX B-6 Search Syntax for Original Studies on E-Cigarettes and Smoking Cessation Search Strategy: PubMed: ((“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic ciga- rettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping” OR “e-liquid” OR “Electronic Cigarettes” [MeSH]) AND (“Smoking Cessation” [MeSH] OR “smoking cessation” OR cessation or quit or abstinence)) Document Type: Editorial, Comment, Letter Results: 148 Document Type: Case Reports, Classical Article, Clinical Study, Clinical Trial, Comparative Study, Controlled Clinical Trial, Evaluation Studies, Government Pub- lications, Historical Article, Introductory Journal Article, Multicenter Study, Random- ized Controlled Trial, Twin Study, Validation Studies, Journal Article Results: 864 Results: 1,012 Scopus: TITLE-ABS-KEY (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping”) AND TITLE-ABS-KEY (“smoking cessation” OR cessation or quit or abstinence) Source Type: Journal Document Type: Note, Letter, Editorial, Erratum: 345 Document Type: Article, Article in Press: 694 Results: 1,039 Web of Science: TS=(“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic ciga- rettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping”) AND TS=(“smoking cessation” OR cessation or quit or abstinence) Document Type: Article: 540 Document Type: Editorial Material, Letter, Note: 78 Results: 618 PsycINFO (ProQuest): (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping” OR “e-liquid” OR SU.EXACT (“Electronic Cigarettes”)) AND (SU.EXACT (“Smoking Cessation”) OR “smoking cessation” OR cessation or quit or abstinence) Source Type: Journal, Journal Article, Peer-Reviewed Journal: 490 Document Type: Comment/reply, Editorial, Letter: 73 Results: 563 continued

690 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES BOX B-6  Continued MEDLINE (OVID): Search No. Search Syntax Results   1 electronic cigarette/ 1,169   2 (e-cigarette or e-cigarettes or electronic cigarette or electronic cigarettes or electronic nicotine delivery or electronic nicotine device or vape or vaping or e-liquid).ti,ab.   1,522  3 or/1–2  1,630   4 smoking cessation/ 24,810   5 “smoking cessation”.ti,ab. 18,167  6 cessation.ti,ab. 57,497   7 quit.ti,ab. 11,598  8 abstinence.ti,ab. 17,729  9 or/4–8 83,943 10 3 and 9    741 11 limit 10 to (comment or editorial or letter)     123 12 limit 10 to (meta-analysis or “review” or systematic reviews)    118 13 10 not (11 or 12)     503 Results: 626 Embase (Ovid): Search No. Search Syntax Results   1 electronic cigarette/ 2,366   2 (e-cigarette or e-cigarettes or electronic cigarette or electronic cigarettes or electronic nicotine delivery or electronic nicotine device or vape or vaping or e-liquid).ti,ab. 2,379  3 or/1–2 2,735   4 smoking cessation/ 47,313   5 “smoking cessation”.ti,ab. 25,202  6 cessation.ti,ab. 78,749   7 quit.ti,ab. 15,339  8 abstinence.ti,ab. 23,856  9 or/4–8 123,500 10 3 and 9   1,263 11 limit 10 to (editorial or letter or note)     322 12 limit 10 to (meta-analysis or “systematic review”)      37 13 10 not (11 or 12)     906 Results: 1,228 Totals: Total Results: 5,086 After Removing Duplicates: 1,759

APPENDIX B 691 BOX B-7 Search Syntax for E-Cigarettes and Combustible Tobacco Cigarette Smoking Reduction Search Strategy: Scopus: TITLE-ABS-KEY (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping”) AND TITLE-ABS-KEY (“smoking reduction” OR “harm reduction”) Results: 327 Web of Science: TS=(“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic ciga- rettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping”) AND TS=(“smoking reduction” OR “harm reduction”) Results: 221 PsycINFO (ProQuest): (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping” OR “e-liquid” OR SU.EXACT (“Electronic Cigarettes”)) AND (ti(“smoking reduction” OR “harm reduction”) OR ab(“smoking reduction” OR “harm reduction”)) Results: 75 MEDLINE (Ovid): Search No. Search Syntax Results   1 (e-cigarette or e-cigarettes or electronic cigarette or electronic cigarettes or electronic nicotine delivery or electronic nicotine device or vape or vaping or e-liquid).ti,ab. 1,548   2 Electronic Cigarettes/ 1,193   3 1 or 2 1,657  4 3 1,657  5 (smoking adj reduction).ti,ab.   486   6 Harm Reduction/ 2,157   7 (harm adj reduction).ti,ab. 2,488  8 or/5–7 4,119  9 4 and 8   156 10 limit 9 to (meta-analysis or “review” or systematic reviews)    26 11 limit 9 to (comment or letter or editorial)     20 12 9 not (10 or 11)    110 Results: 156 continued

692 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES BOX B-7  Continued Embase (Ovid): Search No. Search Syntax Results   1 (e-cigarette or e-cigarettes or electronic cigarette or electronic cigarettes or electronic nicotine delivery or electronic nicotine device or vape or vaping or e-liquid).ti,ab. 2,389   2 Electronic Cigarettes/ 1,900   3 1 or 2 2,659  4 3 2,659  5 (smoking adj reduction).ti,ab.   555   6 Harm Reduction/ 4,026   7 (harm adj reduction).ti,ab. 3,715  8 or/5–7 6,315  9 4 and 8   280 10 limit 9 to (meta analysis or “systematic review”)      9 11 limit 9 to (editorial or erratum or letter or note)     74 12 9 not (10 or 11)    198 Results: 280 PubMed: (“e-cigarette” OR “e-cigarettes” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “electronic nicotine device” OR “vape” OR “vaping” OR “e-liquid” OR “Electronic Cigarettes” [MeSH]) AND (“smoking reduc- tion” OR “harm reduction”) Results: 253 Totals: Total Downloaded: 1,312 Total After Removing Duplicates: 455 did not participate in the study independently reviewed the work, with particular attention to the study design, results, and the interpretation of the results (i.e., conclusions). This section briefly describes these study characteristics; strengths and weaknesses of individual studies are best understood in the context in which they are being used. Thus, consider- ations for optimal study design and special considerations for different outcomes are discussed in each relevant section in the report text.

APPENDIX B 693 Study Design In general, randomized controlled trials (RCTs) are the gold standard for assessing the effectiveness of an intervention compared with nothing or other interventions. For areas where experimental studies are feasible, but RCTs are not available, the committee considered next-best designs— controlled studies (without randomization). In some cases, RCTs are not feasible because they would be unethical, in which case longitudinal observational designs offer the next strongest evidence. These include prospective cohort studies and crossover trials. For all studies, the com- mittee considered multiple elements pertinent for assessing the studies’ internal and external validity. These elements include the study sample, such as sampling methods, basic demographic information (age, gender, and race/ethnicity), as well as study setting. The committee also consid- ered analytical methods, such as statistical tests used, and their appro- priateness. Finally, the committee considered the study results (including adjusted and unadjusted results where available), including the outcomes assessed and how these outcomes were operationalized. Special Considerations for Interventions As described in Chapter 3, the e-cigarette product and how it is used shape e-cigarette aerosol composition, exposure, and thus health effects. Therefore, when assessing experimental studies, the committee consid- ered the device and e-liquid used, the nicotine concentration, the device settings (e.g., power, temperature, resistance), as well as the puffing pro- tocols used. The committee also considered the comparison or control conditions. Special Considerations for Observational Studies Confounding is a challenge inherent in observational studies. Con- founders are a third variable related to both an exposure and an outcome and not in the causal pathway. If confounders are distributed unequally across groups (e.g., e-cigarette users and non-users), they can statistically bias the association between the exposure and outcome (i.e., observed effect or study results). Thus, the committee considered confounders and other covariates controlled for in observational studies. For longitudinal (or cohort) studies, the committee considered follow- up periods and time points assessed. Additionally, loss to follow-up is a challenge in these studies. Because those lost could be systematically different from those who remain in the study, this systematic difference could bias study results. This may be important for the generalizability of findings. Methods exist to account for loss to follow-up. The committee

694 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES therefore considered the treatment of the study sample lost to follow-up in longitudinal studies. External Influences Potential bias in the studies based on sponsorship, particularly by industry, is a concern in the health effects literature on e-cigarettes given the tobacco industry’s history of manipulating evidence to support their interests. The committee recognizes that there is a range of non-scientific influences that affect the ways in which investigators design, conduct, analyze, and interpret their data, including but not limited to research sponsorship and source of employment. The committee focused its assess- ment of the evidence on the quality of the research and the results that were reported, but recognized that financial interests raise concerns to varying degrees with the credibility of the findings. For completeness, the committee documents, in a table available as an online supplement the source of research sponsorship or other external involvement, noting whether each study was funded by industry, government, other (univer- sity, foundation), or not stated. The committee also notes other industry involvement, such as if industry is a source of employment. The table can be downloaded at https://www.nap.edu/catalog/24952. REFERENCES CRD (Centre for Reviews and Dissemination). 2009. Systematic reviews: CRD’s guidance for un- dertaking reviews in health care. https://www.york.ac.uk/crd/SysRev/!SSL!/WebHelp/ SysRev3.htm (accessed November 27, 2017). Higgins, J. P. T., and S. Green, eds. 2011. Cochrane handbook for systematic reviews of interven¬tions version 5.1.0. The Cochrane Collaboration. http://www.handbook.-5-1- cochrane.org (accessed November 27, 2017). IOM (Institute of Medicine). 2008. Treatment of posttraumatic stress disorder: An assessment of the evidence. Washington, DC: The National Academies Press. IOM. 2011a. Adverse effects of vaccines: Evidence and causality. Washington, DC: The National Academies Press. IOM. 2011b. Finding what works in health care: Standards for systematic reviews. Washington, DC: The National Academies Press. IOM. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Acad- emies Press. NASEM (National Academies of Sciences, Engineering, and Medicine). 2017. The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for research. Washington, DC: The National Academies Press. NRC (National Research Council). 2014. Review of EPA’s Integrated Risk Information System (IRIS) process. Washington, DC: The National Academies Press. OHAT (National Toxicology Program Office of Health Assessment and Translation). 2015. Handbook for conducting a literature-based health assessment using OHAT approach for systematic review and evidence integration. https://ntp.niehs.nih.gov/ntp/ohat/pubs/ handbookjan2015_508.pdf (accessed November 27, 2017).

APPENDIX B 695 Sena, E. S., G. L. Currie, S. K. McCann, M. R. Macleod, and D. W. Howells. 2014. System- atic reviews and meta-analysis of preclinical studies: Why perform them and how to a ­ ppraise them critically. Journal of Cerebral Blood Flow & Metabolism 34(5):737–742. Whiting, P., J. Savovic, J. P. Higgins, D. M. Caldwell, B. C. Reeves, B. Shea, P. Davies, J. K ­ leijnen, R. Churchill, and ROBIS Group. 2016. ROBIS: A new tool to assess risk of bias in systematic reviews was developed. Journal of Clinical Epidemiology 69:225–234.

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Millions of Americans use e-cigarettes. Despite their popularity, little is known about their health effects. Some suggest that e-cigarettes likely confer lower risk compared to combustible tobacco cigarettes, because they do not expose users to toxicants produced through combustion. Proponents of e-cigarette use also tout the potential benefits of e-cigarettes as devices that could help combustible tobacco cigarette smokers to quit and thereby reduce tobacco-related health risks. Others are concerned about the exposure to potentially toxic substances contained in e-cigarette emissions, especially in individuals who have never used tobacco products such as youth and young adults. Given their relatively recent introduction, there has been little time for a scientific body of evidence to develop on the health effects of e-cigarettes.

Public Health Consequences of E-Cigarettes reviews and critically assesses the state of the emerging evidence about e-cigarettes and health. This report makes recommendations for the improvement of this research and highlights gaps that are a priority for future research.

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