\r\n\tIt has been established that energy/nutrient depletion, calcium flux injury, or oxidative stress disrupt endoplasmic reticulum homeostasis and even induce accumulation of misfolded/unfolded proteins leading to endoplasmic reticulum stress. Under endoplasmic reticulum stress conditions, an adaptive mechanism of coordinated signaling pathways, defined unfolded protein response (UPR), is activated to return the endoplasmic reticulum to its healthy functioning state. The aging causes a decrease of the protective adaptive response of the UPR and an increase of the pro-apoptotic pathway together with endoplasmic reticulum ultrastructural injury. Controlling endoplasmic reticulum stress response, maintaining the appropriate endoplasmic reticulum ultrastructure and homeostasis, and retaining mitochondria interplay are crucial aspects for cellular health.
\r\n
\r\n\tThis book presents a comprehensive overview of endoplasmic reticulum, including, but not limited to, endoplasmic reticulum ultrastructural anatomy, MAMs, endoplasmic reticulum stress, and their implication in health and diseases. Additionally, identifying perturbations in the endoplasmic reticulum stress response could lead to early detection of age-related disease and may help develop therapeutic approaches.
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\n
1. Introduction
\n
The emergence of less risky novel or “next generation” tobacco products such as e-cigarettes and heat-not-burn devices coincided with new regulatory authority provided to the US Food and Drug Administration (FDA), the health agency in charge of regulating the safety of consumer products such as food, drugs, medical devices, and cosmetics, under the Family Smoking Prevention and Tobacco Control Act (Tobacco Control Act), which amended the existing Food, Drug, and Cosmetic Act (FDCA or Act). Pursuant to this new law, FDA now has the authority to regulate the manufacture, distribution, and marketing of tobacco products in the United States [1].
\n
When it was signed into law in June 2009, the Tobacco Control Act provided FDA with immediate authority only over four categories of tobacco products, that is, cigarettes, cigarette tobacco, smokeless tobacco, and roll-your-own tobacco. Subsequently, in 2016, FDA finalized its “Deeming Rule,” 81 Fed. Reg. 28974 (May 10, 2016), which deemed all products that meet the tobacco product definition (including, but not limited to, e-cigarettes, heat-not-burn, cigars, hookah/waterpipe, and pipe tobacco products) to be subject to its Tobacco Control Act authority. Now, newly deemed products are subject to a host of federal requirements including, among other things, premarket authorization for new products, ingredient reporting, manufacturing establishment registration, harmful constituent testing, and sales and marketing restrictions.
\n
Rising underage use of e-cigarettes has underscored the need for increased FDA enforcement of the Tobacco Control Act requirements, and has resulted in new policies aimed at restricted youth access to flavored e-cigarettes. This paper provides a comprehensive review of the regulatory requirements applicable to manufacturers and addresses how FDA’s most recent policy announcements could impact the industry moving forward.
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\n
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2. Overview of major Tobacco Control Act requirements
\n
The Tobacco Control Act requires tobacco product manufacturers to, among other things, register their US manufacturing establishments with FDA, submit a list of US manufactured products, report the ingredients used in their products, submit certain health documents in their possession, test their products for specific harmful and potentially harmful constituents (HPHCs), include nicotine addiction warnings and certain other information on their labels and, most critically, obtain premarket authorization for any new products. Manufacturers are also subject to the adulteration and misbranding provision of the Act and are prohibited from making modified risk claims about their products without specific FDA authorization.
\n
\n
2.1 Marketing and sales restrictions
\n
With respect to the sales and marketing of deemed products, FDA’s Deeming Rule bans claims of reduced or “modified” risk and free samples to consumers, sets the minimum purchase age to 18 years, requires photo-ID verification at the point-of-sale, restricts vending machine sales of covered tobacco products to adult-only facilities, and requires nicotine addiction warnings on labels and advertising [2]. Furthermore, it is illegal to market or distribute any tobacco product whose packaging or labeling is misbranded under Section 903 of the FDCA, or deceptive and misleading under Section 5 of the Federal Trade Commission (FTC) Act.
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\n
\n
2.2 US establishment registration and product listing
\n
Section 905(b) of the Tobacco Control Act requires every person who owns or operates any establishment in the United States that manufactures, prepares, compounds, or processes finished tobacco products to register such establishment with FDA and submit a product list, which must be updated biannually (every December 31 and June 30) [3]. Foreign establishments are not presently required to register with FDA, but the agency has the authority to promulgate a regulation requiring them to do so. Here, the phrase “manufacture, preparation, compounding, or processing” includes repackaging or otherwise changing the container, wrapper, or labeling of any tobacco product package in furtherance of the distribution of the tobacco product. US importers of tobacco products do not register with FDA unless they are also engaged in a manufacturing activity in the United States.
\n
As noted, at the time of registration, registrants must submit to FDA a detailed list of all products that are being manufactured, prepared, compounded, or processed for commercial distribution in the United States, along with all labeling, and a representative sampling of advertisements. The term “commercial distribution” includes any distribution of a tobacco product to consumers or to another person for further manufacturing through sale or otherwise [4]. Registrants must also file a biannual report of certain changes to their product lists [5].
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Registered establishments are subject to FDA inspection every 2 years [6]. FDA may inspect factories, warehouses, and other establishments in which tobacco products are manufactured, processed, packed, or held, as well as any vehicle being used to transport or hold such products [7].
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\n
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2.3 Ingredient reporting
\n
Section 904(a)(1)-(2) of the Tobacco Control Act requires that a manufacturer or importer submit a listing of all ingredients, as well as a description of the content, delivery, and form of nicotine in each tobacco product [8]. “Ingredients” here includes “tobacco, substances, compounds, and additives” [9]—that are added to any component or part of the products (e.g., to the tobacco, paper, filter, or other part). Products must be identified by brand and sub-brand and the ingredients by quantity in each brand and sub-brand. Manufacturers and importers are also required to submit information whenever any additive, or the quantity of any additive, is changed [10]. This requirement applies to all manufacturers no matter where they are located.
\n
However, on April 13, 2018, FDA published a Revised Guidance for Industry which clarified that, at this time, FDA is effectively exempting e-cigarette device and hardware component/part manufacturers from the ingredient listing requirement [11]. Rather, FDA only intends to enforce the Section 904 ingredient listing requirement with respect to those tobacco products that are (1) made or derived from tobacco, or (2) made with consumable ingredients that are burned, aerosolized or ingested when the tobacco product is being used. Specifically, for e-cigarettes, FDA is now only seeking ingredient information on e-liquids, and not any hardware or components/parts such as:
Electrical components including, but not limited to, batteries, charging systems, circuit boards, wiring, and connectors
System software
Digital display, lights, and buttons to adjust settings
Connection adapters
Cartomizers
Coils
Wicks
Tanks
Mouthpieces
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2.4 Reporting health documents
\n
Section 904 obligates tobacco product manufacturers and importers to submit certain health information to FDA. Specifically, manufacturers and importers are also required to submit all documents relating to the health, toxicological, behavioral, or physiologic effects of current or future tobacco products, constituents, ingredients, components, and additives (collectively, “Health Documents”). The term “documents” is defined broadly and includes “writings, drawings, graphs, charts, photographs, sound recordings, images, and other data or data compilations—stored in any medium from which information can be obtained either directly or, if necessary, after translation by the responding party into a reasonably usable form.” At this time, however, FDA is only requesting health documents developed between June 23, 2009 and December 31, 2009. Companies that may not have been in business, or who were not producing health documents on their tobacco products at that time, are still required to notify FDA that they do not have any relevant health documents in their possession [12].
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2.5 Harmful constituent testing
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Section 904(a)(3) requires manufacturers and importers to report quantities of HPHCs found in tobacco products or tobacco smoke by brand and sub-brand. Out of more than 7000 such constituents, FDA has established a list of 93 HPHCs that tobacco companies will ultimately be required to report for every regulated tobacco product sold in the USA [13]. However, in recognition of current testing limitations for certain constituents on FDA’s list, FDA has created representative or “abbreviated” lists of constituents for cigarettes, roll-your-own, and smokeless tobacco for which testing methods are well established and widely available [14].
\n
With respect to e-cigarettes, as of the date of this writing, FDA has not provided any guidance or initiated rulemaking, so it is unclear whether HPHCs will need to be tested in the e-liquids themselves or in the vapor/aerosol formed when used in a device. In August 2016 FDA published a revised guidance document expanding the definition of HPHC to specifically include substances in the vapor (aerosol) produced by e-cigarettes. As defined by FDA in the guidance, an HPHC now includes any chemical or chemical compound in a tobacco product or in tobacco smoke that: (a) is, or potentially is, inhaled, ingested, or absorbed into the body, including as an aerosol (vapor) or any other emission; and (b) causes or has the potential to cause direct or indirect harm to users or non-users of tobacco products” [14].
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FDA is expected to issue formal guidance and regulations for the testing and reporting of HPHCs, ingredients, additives and other constituents pursuant to Section 915 [15].
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2.6 Label requirements
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The Deeming Rule extended a number of labeling requirements to deemed tobacco products. Specifically, by August 10, 2018, all deemed tobacco products must include the following on the labels of all products marketed in the United States:
The name and place of business of the manufacturer, packer, or distributor;
An accurate statement of the quantity of the contents in terms of weight, measure, or numerical count; and
The statement “Sale only allowed in the United States”.
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In addition, all nicotine-containing products must include the following warning on their labels “WARNING: This product contains nicotine. Nicotine is an addictive chemical” [16]. That warning label must comply with the specific requirements set forth in 21 C.F.R. § 1143.3(a). The nicotine addiction warning requirement, however, does not apply to products that are not sold with or contain nicotine [17]. Rather, covered tobacco products that do not contain nicotine (i.e., zero-nicotine e-cigarettes that contain another tobacco-derived ingredient), must include the following statement on their label in lieu of the nicotine addiction warning: “This product is made from tobacco.” Manufacturers of such products are further required to submit a statement to FDA certifying that the product does not contain nicotine.
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2.7 Premarket authorization for new tobacco products
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The Tobacco Control Act requires that FDA authorize the marketing of any new tobacco product through a lengthy and complicated application process. If a product was on the market as of February 15, 2007 it is considered “grandfathered” and exempt from FDA premarket review. If a tobacco product was introduced (or is intended to be introduced) after the February 15, 2007 “grandfather date,” or if it was modified in any way after that date, it is a new product. Product modifications include, but are not limited to changes to a product’s design, ingredients, components, parts, delivery mechanism, type of nicotine, etc. Changes to a product’s labeling (including brand name, logos, colors, etc.), however, do not trigger the premarket review requirements [18].
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The substantial equivalence (SE) report and the premarket tobacco application (PMTA) are the primary pathways for new tobacco product. The minor modification or SE exemption pathway is another option but only applies to changes in additives so is rarely utilized.
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If a manufacturer can demonstrate, through the submission of an SE report, that its new product is substantially equivalent to a “predicate” product it may be authorized for sale. A “predicate” product is either a grandfathered tobacco product (that was on the market as of February 15, 2007), or tobacco product that, although not itself grandfathered, has been determined to be substantially equivalent to another grandfathered product. To demonstrate substantial equivalence, the manufacturer must provide evidence (such as data showing similarities in consumer perception, clinical data, abuse liability data, and toxicology) that the new product has the same (identical) “characteristics” as the predicate tobacco product or, if it has different characteristics, that the new product “does not raise different questions of public health.” In other words, FDA may find a new tobacco product to be substantially equivalent to the identified predicate if the new characteristics do not create different public health concerns compared to the predicate. Public health concerns may include the potential to increase tobacco use initiation or decrease cessation.
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For a PMTA, on the other hand, a predicate product is not needed. Rather, the manufacturer must demonstrate that the new product meets a very high public health standard. Specifically, it must be shown that the product, if made available in the United States, would be “appropriate for the protection of the public health.” This requires assessing the product’s potential impact on the population, including its impact on overall tobacco product cessation rates (i.e., the likelihood that people will stop using tobacco products), as well as initiation rates (i.e., the likelihood that people will start using tobacco products) [19].
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To meet this high standard, FDA has recommended PMTAs include detailed scientific literature reviews, as well as numerous non-clinical, clinical (i.e., human), and long-term studies be performed, including, but not limited to, in-vitro and in-vivo (i.e., animal) toxicological studies (e.g., genotoxicity and cytotoxicity), as well as clinical and population-level studies to assess consumer perceptions, likelihood of initiation and cessation, product use patterns, abuse liability, and health outcomes [19].
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2.7.1 Compliance policy for deemed tobacco products
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As noted, in the final Deeming Rule FDA chose not to amend the February 15, 2007 grandfather date for deemed products, forcing all next generation products to go through pre-market authorization (because there are no known grandfathered e-cigarettes or heat-not-burn products). Moreover, as a result, the SE Report pathway (which, as noted above, requires a manufacturer to compare a new product to a predicate product) is unavailable, forcing all next generation products to go through the much more onerous and expensive PMTA.
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FDA instead established a compliance policy that would allow any finished deemed tobacco product marketed after the grandfather date and prior to August 8, 2016 (the rule’s effective date), to remain on the market for 2 years (without premarket authorization) until August 8, 2018, at which time PMTAs would need to be submitted. Products subject to such PMTAs that are accepted by FDA for review would be permitted to remain on the market for an additional year, until August 8, 2019 (the “sunset period”), at which point they would have to be removed from market and wait for FDA authorization (which, of course, is not guaranteed and could take years).
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Lawsuits were filed challenging FDA’s failure to change the grandfather date and the seemingly arbitrary 2-year PMTA compliance policy, and there has been an intense lobbying effort to get Congress to change the grandfather date—so far, to no avail [20].
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However, on July 28, 2017, FDA announced a new “comprehensive regulatory plan to shift the trajectory of tobacco-related disease, death” that refocuses the agency’s implementation of the Tobacco Control Act and the Deeming Rule [21]. While the focus of the announcement was to highlight the agency’s long-term plan to potentially reduce nicotine in cigarettes to “non-addictive” levels, the agency also discussed the potential harm-reduction benefits of deemed products like e-cigarettes, and appeared to recognize that a “continuum of risk” of tobacco and nicotine-containing products exists.
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In this regard, as part of its comprehensive policy announcement, FDA delayed the Deeming Rule’s compliance policy deadlines to submit premarket authorization applications” (i.e., PMTAs or SE reports) for newly deemed tobacco products that were on the market on August 8, 2016. Under the new timelines, applications for previously marketed (but not grandfathered) combustible products, such as cigars, pipe tobacco and hookah tobacco, are now due by August 8, 2021, and applications for previously marketed non-combustibles, such as e-cigarettes, e-liquids and heat-not-burn products are due by August 8, 2022. FDA also indicated that it would be revising the sunset policy so that existing products under review can remain on the market pending review of their applications. New products intended to enter the market after August 8, 2016 must still obtain FDA marketing authorization before entering the market.
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This new compliance policy delaying premarket review provided the industry, which was facing a de facto ban in 2018, much needed breathing room on the most complicated and expensive regulatory requirement. Critical to ensuring that such ban is not simply delayed until 2022 will depend, in part, on whether FDA provides more guidance and clarity on the PMTA process and requirements—particularly how to satisfy the population-level public health standard.
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In addition to extending the premarket review deadlines for deemed products, FDA announced that it will publish advance notices of proposed rulemaking (ANPRMs) to seek (1) input on the potential public health benefits and possible adverse effects of lowering the level of nicotine in cigarettes to non-addictive levels, (2) public comments on the role of flavored tobacco products in terms of youth initiation and harm reduction, and (3) scientific data related to the patterns of use and resulting public health impacts from premium cigars. FDA also indicated that it would develop product standards to address public health risks, such as, e-cigarette battery safety issues, and exposure to liquid nicotine by children, as well as examine ways to increase access and use of FDA-approved medicinal nicotine products intended to help smokers quit [21].
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2.8 New FDA policy to address increase in underage e-cigarette use
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In April 2018 FDA launched its Youth Tobacco Prevention Plan to address the sudden rise in underage use of certain types of e-cigarettes: pre-filled cartridge-based e-cigarettes sold mainly in convenience stores, gas stations and similar all-age retail outlets. FDA stated that between June and September 2018 nearly 1300 retailers across the country had received warning letters and/or monetary penalties for selling products to minors [22]. FDA also requested manufacturers of these popular cartridge-based e-cigarettes to submit proposals on how they plan to curtail the increasing youth-use of their products.
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Subsequently, on November 15, 2018, FDA announced a new policy aimed at preventing youth access to flavored e-cigarettes [23]. First, FDA announced that all flavored e-cigarette products (other than tobacco, mint, and menthol flavors, or non-flavored products) will be required to be sold in age-restricted, in-person locations, or else potentially be subjected to a revised premarket review compliance policy deadline. This policy revision would apply to all e-cigarettes, including e-liquids, cartridge-based systems and cigalikes, in flavors except tobacco, mint, and menthol, sold in physical locations where people under age 18 are permitted. However, the new restrictions would not apply to e-cigarettes sold exclusively in age-restricted locations (e.g., a stand-alone tobacco retailer) that either prevent minors (individuals under age 18) from entering the facility at any time, or establish a walled-off adult-only section of the facility where flavored e-cigarettes can be viewed and purchased by persons 18 and older.
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Second, FDA announced that it would seek to curtail the sale of flavored e-cigarettes (other than tobacco, mint and menthol) that are sold online without “heightened age verification” processes. To advance this goal, FDA plans to identify and publish a list of best practices for online retailers [23].
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Third, FDA announced that flavored cigars will no longer be subject to the extended compliance date for premarket authorization (which currently sets the premarket application deadline for cigars on the market on August 8, 2016 to be August 8, 2021). However, this policy does not apply to the entire product category, as certain flavored cigars are considered “grandfathered” and exempt from premarket review if they were on the market as of February 15, 2007, as discussed above. To address this gap in regulatory authority, FDA plans to propose a product standard that would ban all flavored cigars [23].
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Fourth, FDA announced plans to publish a Proposed Rule in the Federal Register that would seek to ban menthol in combustible tobacco products, including cigarettes and cigars [23].
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The Commissioner also noted that FDA plans to continue to aggressively pursue removing e-cigarettes marketed to children and/or appealing to youth from the market. These marketing practices may include “using popular children’s cartoon or animated characters” or “names of products favored by kids like brands of candy or soda.”
\n
On March 13, 2019 FDA published a new draft guidance document entitled, Modifications to Compliance Policy for Certain Deemed Tobacco Products [24]. The draft guidance formalizes the November 2018 proposal from FDA discussed above, but makes several changes. More specifically, the draft guidance eliminates the compliance policy for flavored e-cigarettes (other than tobacco, mint, menthol and unflavored products) sold or marketed in a manner that is (a) targeted to minors or likely to promote ENDS use by minors, or (b) offered for sale in ways that pose a greater risk of minor access. Such products will be subject to immediate enforcement.
\n
In terms of targeting minors, the guidance states that FDA is evaluating how companies may utilize social media to market to minors, as well as radio and television (which are platforms that are prohibited for cigarette advertising). FDA further implied that products with labeling and/or advertising that use “youth appealing cartoons as well as the use of minors or people who appear to be minors in multimedia advertisements” could be the subject of enforcement. The draft guidance also identifies the following circumstances which pose a “greater risks of minor access”:
Products sold in locations that minors are able to enter at any time (e.g., the entire establishment or an area within the establishment);
Products sold through retail establishments and online retail locations that have sold to minors—as indicated by FDA’s searchable retailer inspection database—after issuance of the final guidance document;
Products sold online without a limit on the quantity of product that a customer may purchase within a given period of time; or
Products sold online without independent, third-party age-and identity-verification services that compare customer information against third-party data sources, such as public records.
\n
The draft guidance also shortens the compliance policy by 1 year for all flavored ENDS (other than tobacco, mint, menthol and unflavored products), even if such products are marketed responsibly to adults. If the draft guidance is finalized, such flavored products on the market on August 8, 2016 will have until August 8, 2021 to submit PMTAs (which must be accepted by FDA for substantive review).
\n
Finally, the guidance keeps in place, for the time being, the existing compliance policy for tobacco, mint, menthol and unflavored ENDS on the market as of August 8, 2016. Accordingly, these products still have until August 8, 2022 to submit premarket applications.
\n
FDA indicated that the reason it is modifying the compliance policy for e-cigarettes in the manner described above is (i) “to encourage more prompt filing of premarket submissions for certain ENDS products”; (ii) “to focus the Agency’s enforcement resources where there is a greater threat to public health”; and (iii) “to balance that public health threat against the potential benefit to providing adult smokers noncombustible options to allow them to completely switch from the use of combustible products.”
\n
While it is unclear how FDA will enforce the new compliance policy if it becomes effective, the draft guidance expressly places the onus on manufacturers to control distribution and sale of their products to retail customers by, among other things, “requiring terms, conditions, or controls in their contracts with downstream distributors (wholesalers, distributors, importers and/or retailers) to prevent youth access.”
\n
\n
\n
\n
3. Conclusion
\n
The e-cigarette industry has grown rapidly in the United States since the products were first introduced to the market in 2007. Regulators have struggled to keep up with the evolving technology and are still grappling with the public health consequences—both pro and con. In the USA, the FDA’s new authority over traditional tobacco products such as cigarettes was extended to cover e-cigarettes and other novel products. Now, newly deemed tobacco products are subject to the Tobacco Control Act requirements including, among other things, premarket authorization for new products, ingredient reporting, manufacturing establishment registration, harmful constituent testing, and sales and marketing restrictions. Regulators also continue to adopt policies and regulations to address new issues that emerge (i.e., underage use).
\n
Manufacturers of flavored e-cigarettes should be most concerned with complying with FDA’s recently revised premarket review compliance policy. In this regard, to potentially avoid being subject to immediate enforcement, and to remain eligible for the August 8, 2021 PMTA compliance date, manufacturers of flavored e-cigarettes must work with their retailers and distributors to ensure that their products are not sold in (1) all-age retailers (i.e., non-adult only facilities such as convenience stores and gas stations) that do not have separate walled-off section for flavored products, (2) online stores that do not have a limit on bulk purchases or third-party age and identity verification services, or (3) brick-and-mortar and online stores that have previously been cited for selling products to minors.
\n
Manufacturers must further ensure that their products are not viewed as targeting or promoting use to minors. Companies should review their labeling, packaging, social media, websites, and advertising/marketing materials with the understanding that FDA could broadly argue that the use of certain flavors, descriptive flavor names, packaging and label colors, images of food, fruit, or desert, cartoon images or illustrations, playful characters, or young models, among other things, might trigger immediate enforcement under the modified compliance policy.
\n
Finally, even if manufacturers can avoid immediate enforcement against their flavored e-cigarettes, the August 8, 2021 compliance date is fast approaching. It is critical that companies start working to prepare PMTAs sooner rather than later to have any chance of meeting that deadline.
\n
\n
\n
Conflict of interest
\n
Author Azim Chowdhury is a Partner at Keller and Heckman LLP in Washington, DC. In his law practice he represents tobacco and e-cigarettes companies in matters of regulatory compliance. He is also counsel to the Right to be Smoke-Free Coalition, a trade association of e-cigarette businesses that are challenging FDA’s Deeming Rule in court.
\n
\n',keywords:"FDA, e-cigarette, tobacco, nicotine, Deeming, Tobacco Control Act, flavors, PMTA, premarket review, continuum of risk",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/67506.pdf",chapterXML:"https://mts.intechopen.com/source/xml/67506.xml",downloadPdfUrl:"/chapter/pdf-download/67506",previewPdfUrl:"/chapter/pdf-preview/67506",totalDownloads:761,totalViews:0,totalCrossrefCites:0,totalDimensionsCites:0,totalAltmetricsMentions:6,impactScore:0,impactScorePercentile:39,impactScoreQuartile:2,hasAltmetrics:1,dateSubmitted:"September 10th 2018",dateReviewed:"May 2nd 2019",datePrePublished:"June 7th 2019",datePublished:"October 9th 2019",dateFinished:"June 4th 2019",readingETA:"0",abstract:"In the United States, the manufacture, distribution and marketing of tobacco products is regulated by the US Food and Drug Administration (FDA), pursuant to authority extended to the agency in 2009 with the enactment of the Family Smoking Prevention and Tobacco Control Act (Tobacco Control Act). While that law initially gave FDA authority over certain categories of tobacco products (e.g., cigarettes, smokeless tobacco and roll-your-own tobacco), in August 2016, FDA’s “Deeming Rule” extended that authority to all products that are made from or contain tobacco-derived substances, such as nicotine. Now, products such as cigars, pipe tobacco, shisha/hookah and electronic cigarettes (e-cigarettes) are subject to the Tobacco Control Act and FDA’s authority. But regulators have struggled to keep up with the evolving technology and are still grappling with the public health consequences—both pro and con—and continue to adopt policies and regulations to address new issues that emerge (i.e., underage use and flavors).",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/67506",risUrl:"/chapter/ris/67506",book:{id:"7939",slug:"smoking-prevention-cessation-and-health-effects"},signatures:"Azim Chowdhury",authors:[{id:"273786",title:"Mr.",name:"Azim",middleName:null,surname:"Chowdhury",fullName:"Azim Chowdhury",slug:"azim-chowdhury",email:"chowdhury@khlaw.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Overview of major Tobacco Control Act requirements",level:"1"},{id:"sec_2_2",title:"2.1 Marketing and sales restrictions",level:"2"},{id:"sec_3_2",title:"2.2 US establishment registration and product listing",level:"2"},{id:"sec_4_2",title:"2.3 Ingredient reporting",level:"2"},{id:"sec_5_2",title:"2.4 Reporting health documents",level:"2"},{id:"sec_6_2",title:"2.5 Harmful constituent testing",level:"2"},{id:"sec_7_2",title:"2.6 Label requirements",level:"2"},{id:"sec_8_2",title:"2.7 Premarket authorization for new tobacco products",level:"2"},{id:"sec_8_3",title:"2.7.1 Compliance policy for deemed tobacco products",level:"3"},{id:"sec_10_2",title:"2.8 New FDA policy to address increase in underage e-cigarette use",level:"2"},{id:"sec_12",title:"3. Conclusion",level:"1"},{id:"sec_13",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Prior to the Tobacco Control Act, the Federal Trade Commission (FTC) had primary jurisdiction over the advertising and marketing of traditional tobacco products, such as cigarettes and smokeless tobacco'},{id:"B2",body:'Technically, the minimum purchase age, nicotine addiction warning and vending machine sale restriction only apply to deemed “covered” tobacco products, which is defined in the Deeming Rule to mean any tobacco product deemed to be subject to the Tobacco Control Act, but excludes any component or part that is not made or derived from tobacco. 21 C.F.R. § 1140.3. 2018'},{id:"B3",body:'A “finished” tobacco product is defined in the Deeming Rule as “a tobacco product, including all components and parts, sealed in final packaging intended for consumer use”'},{id:"B4",body:'FDA. Guidance for Industry: Registration and Product Listing for Owners and Operators of Domestic Tobacco Product Establishments [Internet]. 2014. Available from: http://www.fda.gov/downloads/TobaccoProducts/GuidanceComplianceRegulatoryInformation/UCM191940.pdf [Accessed: December 10, 2018]'},{id:"B5",body:'Food, Drug, and Cosmetic Act, 21 U.S.C. § 905(i)(3)'},{id:"B6",body:'Food, Drug, and Cosmetic Act, 21 U.S.C. § 905(g)'},{id:"B7",body:'Food, Drug, and Cosmetic Act, 21 U.S.C. § 704'},{id:"B8",body:'Food, Drug, and Cosmetic Act, 21 U.S.C. § 904(a)(1)-(2)'},{id:"B9",body:'For purposes of this reporting requirement, an additive means “any substance the intended use of which results or may reasonably be expected to result, directly or indirectly, in its becoming a component or otherwise affecting the characteristic of any tobacco product (including any substances intended for use as a flavoring or coloring or in producing, manufacturing, packing, processing, preparing, treating, packaging, transporting, or holding), except that such term does not include tobacco or a pesticide chemical residue in or on raw tobacco or a pesticide chemical”'},{id:"B10",body:'Food, Drug, and Cosmetic Act, 21 U.S.C. § 904(a)(3)'},{id:"B11",body:'FDA. Guidance for Industry: Listing of Ingredients in Tobacco Products (Revised)* [Internet]. 2018. Available from: https://www.fda.gov/downloads/TobaccoProducts/Labeling/RulesRegulationsGuidance/UCM527044.pdf [Accessed: December 10, 2018]'},{id:"B12",body:'FDA. Guidance for Industry: Health Document Submission Requirements for Tobacco Products (Revised)* [Internet]. 2017. Available from: https://www.fda.gov/downloads/tobaccoproducts/labeling/rulesregulationsguidance/ucm208916.pdf [Accessed: January 18, 2019]'},{id:"B13",body:'77 Fed. Reg. 20,034 (April 3, 2012)'},{id:"B14",body:'FDA. Draft Guidance for Industry: Reporting Harmful and Potentially Harmful Constituents in Tobacco Products and Tobacco Smoke Under Section 904(a)(3) of the Federal Food, Drug, and Cosmetic Act [Internet]. 2012. Available from: http://www.fda.gov/downloads/TobaccoProducts/GuidanceComplianceRegulatoryInformation/UCM297828.pdf [Accessed: December 10, 2018]'},{id:"B15",body:'Food, Drug, and Cosmetic Act, 21 U.S.C. § 915'},{id:"B16",body:'21 C.F.R. § 1143.3(a) (2018)'},{id:"B17",body:'81 Fed. Reg. 28979 (May 10, 2016)'},{id:"B18",body:'Phillip Morris USA Inc., et al. v. United States Food and Drug Administration, et al., 202 F. Supp. 3d, 31 (D.D.C. 2016)'},{id:"B19",body:'21 U.S.C. § 387j(c) (2018)'},{id:"B20",body:'On July 21, 2017, the U.S. District Court for the District of Columbia ruled in the Nicopure Labs, LLC v. Food and Drug Administration lawsuit brought by the e-cigarette industry challenging aspects of the Deeming Rule. The court ruled entirely in favor of the FDA granting the agency’s motion for summary judgment and holding that: (1) FDA acted within the scope of its statutory authority; namely, that it was legally permitted to e-cigarettes as tobacco products subject to regulation; (2) it was not arbitrary and capricious for the agency to subject e-cigarettes to premarket review and labeling requirements; (3) the new rules being applied to e-cigarettes do not violate the First or the Fifth Amendments to the Constitution; and (4) the agency was not required to undertake a formal cost-benefit analysis when promulgated the Deeming Rule. That decision has been appealed to the U.S. Court of Appeals for the District of Columbia Circuit'},{id:"B21",body:'FDA. FDA Announces Comprehensive Regulatory Plan to Shift Trajectory of Tobacco-Related Disease, Death [Internet]. Available from: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm568923.htm?utm_campaign=CTP%20News%3A%20NAS%20Report%20-%2012318&utm_medium=email&utm_source=Eloqua&elqTrackId=eee7ad075ae24d0b86dee239fd30bd01&elq=aa6a287fc5c44ef29e6f0e9b81140760&elqaid=2177&elqat=1&elqCampaignId=1520 [Accessed: December 10, 2018]'},{id:"B22",body:'FDA. FDA, Warning Letters and Civil Money Penalties Issued to Retailers for Selling JUUL and Other E-Cigarettes to Minors [Internet]. 2018. Available from: https://www.fda.gov/tobaccoproducts/newsevents/ucm605278.htm [Accessed: December 10, 2018]'},{id:"B23",body:'FDA. FDA, Statement From FDA Commissioner Scott Gottlieb, M.D., on Proposed New Steps to Protect Youth by Preventing Access to Flavored Tobacco Products and Banning Menthol in Cigarettes [Internet]. 2018. Available from: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm625884.htm [Accessed: December 10, 2018]'},{id:"B24",body:'FDA. Draft Guidance for Industry: Modifications to Compliance Policy for Certain Deemed Tobacco Products [Internet]. 2019. Available from: https://www.fda.gov/downloads/TobaccoProducts/Labeling/RulesRegulationsGuidance/UCM633281.pdf [Accessed: April 15, 2019]'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Azim Chowdhury",address:"chowdhury@khlaw.com",affiliation:'
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1. Introduction
Insertion of intercostal drainage (ICD) tube is a common procedure that is required to drain the abnormal intrapleural collection. As the name implies, it is insertion of a tube through the intercostal space to facilitate the drainage of abnormal collection in the pleural cavity. The procedure is also known as tube thoracostomy and thoracostomy drainage. The earliest reports of thoracic drainage dates back to 5th century BC [1, 2].
The aim of thoracostomy drainage is to:
Remove fluid and air from pleural cavity as promptly as possible.
Prevent drained air and fluid from returning to pleural cavity.
Restore negative pressure in pleural cavity to help re-expand the lung.
Although, the procedure has been in practice since long, there is still no consensus in the management of chest tubes and there remains great variability in practice. The procedure of inserting a chest tube is simple, definitive in treating a majority of thoracic pathologies and may be life-saving in certain situations. However, improperly placed chest tubes and poor post-procedural care may increase the morbidity and is associated with complications in up to 40% of patients [3, 4]. It is therefore imperative that all clinicians should be well versed with this simple yet life-saving procedure.
In this chapter, we will discuss various aspects of intercostal drainage including the prerequisites, technique of insertion, post-procedural care, complications and common pitfalls in the management of chest tubes in the light of the recent advances and updates.
2. Characteristics of an ideal thoracostomy tube
An ideal thoracostomy tube should:
Allow collected air and fluid to drain out from the chest.
Contain a one-way valve to prevent air and fluid from returning back into the chest.
Allow maintenance of negative intra-pleural pressure (the normal intrapleural pressure is −3 mmHg that decreases further on inspiration).
Have provision for applying higher negative pressure to help in expanding the lung.
Allow accurate measurement of drained fluid and air.
3. Indications for inserting chest tube
Tube thoracostomy is required to drain any abnormal collection in the pleural cavity, that includes:
Air: Pneumothorax
Fluid: Pleural effusion
Blood: Hemothorax
Pus: Empyema
Chyle: Chylothorax
Prophylactically following cardio-thoracic surgery to drain post-operative collection of air, fluid or blood
4. Commercially available chest tubes
The modern, commercially available chest tubes are soft and pliable that are either made up of Polyvinyl chloride (PVC) or silicone (Figure 1).
Figure 1.
Intercostal drainage tube (chest tube).
The red rubber or malecot tube drains (Figure 2) are sometimes used as thoracostomy tubes mostly in resource constraint settings because of their low-cost, however their use is not advisable as they are difficult to retain, get kinked easily, wither rapidly and at times may break.
Figure 2.
Malecot (red rubber) tube drain.
Chest tubes come in various sizes from 6 French gauge (F) to 40 F. Larger the size of the tube, greater is its diameter. One F is equal to 0.033 cm. To know the diameter of the tube from the F size, one need to multiply F size by a factor of 0.033, so a chest tube of size 24 F will have an internal diameter of approximately 0.8 cm.
Some chest tubes are available with metallic trocar that has a pointed end (Figure 3).
Figure 3.
Chest tube with metallic trocar.
These are meant to insert in intercostal space after making a small skin incision, without dissecting the intercostal muscles. Although, this makes the procedure fast, there is a higher risk of injury to the intrathoracic organs and as such use of chest tubes with trocars should be discouraged [3, 5, 6]. Most of the chest tubes are open from one end while the other end is sealed. There are side holes or eyes on the tube and the markings are printed on it. There also is a radiopaque line all along the length of the tube that helps in identifying the position of the chest tube on X-ray (Figures 1 and 4).
Figure 4.
Radiopaque line in the chest tube visible on x-ray (arrow).
5. Before inserting the chest tube- the preparation
5.1 Consent
Insertion of ICD tube is a surgical procedure and like any other surgery, a written informed consent is required prior to the procedure. Consent may not be possible in cases where the patient requires urgent tube thoracostomy as a lifesaving measure and when he/ she is unconscious, unattended or is in extremis.
5.2 Preparing the trolley: Equipment required
Following instruments and equipment are required for inserting the chest tube. One must ensure the availability of all necessary equipment beforehand to avoid any difficulty during the procedure.
5 ml syringe with a suitable local anesthetic. Preferably 2% lidocaine with adrenaline.
Sponge holding forceps
Bowl with solution for painting
Number 11 surgical blade with handle
Sheets for draping
A pair of medium sized curved artery forceps
An appropriately sized chest tube: See the section on ‘selecting the size of chest tube.
Silk No.1 suture on cutting needle
Needle holder
A pair of tooth forceps
Prepared underwater seal bottle or bag.
Gauze pieces
Adhesive tape for dressing
5.3 Selecting the size of chest tube
The chest tubes are available in various sizes ranging from 6 F to 40 F. There is a general understanding that large-bore tubes are required to drain fluid and small-bore tubes are sufficient to drain air. There have been numerous studies on this issue, however there is no conclusive scientific data to support this idea. Large-bore tubes have been related to higher incidence of pain and patient discomfort without any significant advantage in draining the intra-pleural fluid. In various studies, small-bore tubes have been found to be equally effective to drain pleural effusion and hemothorax [7, 8, 9, 10, 11]. This has generated wider interest in use of small-bore tubes for thoracostomy. Conventionally, for most of the clinical conditions requiring tube thoracostomy a 24–32 F chest tube is inserted, depending on the expected underlying pathology, however tubes smaller than 24 F may be sufficient to drain pneumothorax.
5.4 Preparing the under-water seal
The reservoirs for collecting the pleural drainage are available either in the form of bags or single or multiple chambered plastic bottles (Figure 5A and B).
Figure 5.
A: Two chambered plastic bottle and B: ICD bag.
In both of these reservoirs, there are markings for calculation of effluent. In addition, there is also a marking for ‘initial fluid level’. Before connecting the reservoir to the chest tube, a sterile fluid like normal saline should be filled till this mark. As the chest tube is connected with the tube in the reservoir that remains below the ‘initial fluid level’, the air from the environment cannot gain access to the pleural cavity, however the intrapleural collection may egress easily into the reservoir, thus it functions as a one-way valve or ‘under water seal’.
5.5 Local anesthesia: type, amount and technique
Any suitable local anesthetic is appropriate for the procedure. Plain Lidocaine 2% solution and Lidocaine 2% with adrenaline are commonly used drugs for ICD insertion. A volume of nearly 5 ml is sufficient to anesthetize the local site. Local anesthesia may not be required where the patient is obtunded or unconscious and ICD insertion is required urgently.
6. Inserting the chest tube
The step by step procedure is demonstrated in the video supplemented with this article.
Inserting Intercostal drainage tube: step by step.
6.1 Position of the patient
Although the ICD can be inserted while the patient is sitting, leaning forward with the forearms resting over a stool, the supine position is less cumbersome and more comfortable for both patient and the doctor. In addition, the patient may not be able to sit for the procedure due to the underlying clinical condition. We prefer to insert ICD tube in supine position. The patient lies on the table close to the edge with arm abducted over the head if possible.
6.2 Identifying landmarks
The ideal site of inserting ICD is 4th or 5th intercostal space just anterior to the mid axillary line. One may calculate the desired intercostal space by considering sternal angle as landmark. The rib attached to the level of sternal angle is the second rib, subsequent ribs can be counted while palpating the chest wall distally and laterally. There is an alternative way of counting the ribs and the intercostal spaces which is quick and is particularly helpful in obese patients and in presence of subcutaneous emphysema. The level of the nipple in males and inframammary crease in females can be taken as a reference point- a line drawn from this point laterally to a point where it intersects the mid-axillary line is marked and the site for insertion of the chest tube is just anterior to this.
In case, the chest tube is being inserted prophylactically during thoracic surgery, the site of insertion is selected under vision in appropriate intercostal space.
6.3 Steps of the procedure
A wide area around the predetermined site of ICD insertion is painted with a suitable antimicrobial solution (Chlorhexidine or Povidone-iodine) and is draped. If the patient is awake and conscious, 5 ml of local anesthetic solution (preferably 2% lidocaine with adrenaline) is infiltrated in the overlying skin, intercostal muscles and pleura at the site of ICD insertion. Before injecting the local anesthetic, one should ensure that the needle is not in a blood vessel by pulling the plunger of the syringe back. For the adequate effect of local anesthesia, it is prudent to wait for at least 2 minutes before making the incision.
An incision measuring nearly 1.5–2 cms is made by a number 11 surgical blade at the predetermined site of ICD insertion along the long axis of the rib in the intercostal space just over the upper border of the lower rib. This is done to prevent injury to the neurovascular bundle that runs along the lower border of the ribs.
Using a medium sized curved hemostatic clamp, the subcutaneous tissues and inter-costal muscles are dissected bluntly till the parietal pleura is reached. By the tip of the closed hemostatic clamp, gentle pressure is then applied till there is a feeling of ‘give way’ which marks the entry into the pleural cavity. The entry into the pleural cavity is also confirmed by the escape of intra-pleural collection like air, fluid or blood (as the case may be). One should be careful enough not to apply undue force while puncturing the pleura as this may cause injury to lungs or mediastinal structures. The jaws of the hemostatic clamp are then opened while withdrawing the instrument to increase the size of the thoracostomy wide enough to allow the entry of index finger. This should be followed by ‘finger thoracostomy’. The index finger is inserted through the thoracostomy site to explore the pleural cavity for presence of any pleuro-pulmonary adhesions. In case they are present, adhesiolysis is performed to create space inside the pleural cavity for the chest tube. This step is important as attempts to insert a chest tube without ensuring space between the lung and the chest wall may injure the lung, cause air leak from the damaged lung parenchyma and such improperly placed tube may fail to drain the intra-pleural collection.
Following finger thoracostomy and ensuring safe space inside the pleural cavity to accommodate the chest tube, an adequately sized chest tube is then taken. The tip of the tube from the open end (the end that should lie inside the thoracic cavity) is held with the tip of the hemostatic clamp and the rest of the tube is held parallel to the instrument. The tube is introduced inside the pleural cavity, the instrument is then released and the tube is inserted gradually by guiding it to lie posteriorly and superiorly by using the same instrument aided by the index finger of the opposite hand to the point till the last eye (hole) on the chest tube is at least 5 cms inside the pleural cavity (this can be confirmed by looking at the markings over the chest tube). The limit to which the ICD tube needs to be put in depends on the build of the patient. In a patient with an average built a length till 8–12 cms inside the chest is sufficient.
The tube is then clamped by using an artery forceps (hemostatic clamp) close to its distal (closed) end. The end of the chest tube is now cut and is connected with the tubing of the underwater seal using the connector provided with the chest tube. The length of the tube of under-water seal apparatus should not be unduly long as the fluid column in the tube will provide resistance to the egress of intrapleural collection compromising the drainage. A good rule is not to allow any loop in the draining tube between the connector and the tubing of the reservoir.
The chest tube is then fixed by silk suture no.1. For better fixity, it should be anchored on either side. While fixing, one must ensure to take deep bites through the soft tissues close to the tube. Fixing the tube by taking superficial bites (including skin only) may leave potential space around the tube at the site of entry in the intercostal space which may lead to subcutaneous emphysema in cases of pneumothorax and may increase morbidity. Some clinicians prefer purse string suture for fixation of the tube but that leaves an ugly scar following removal of the chest tube and as such is not necessary. A dressing is now applied at the ICD site and the tube may then firmly be reinforced at the site by using adhesive tapes. This completes the procedure.
The free drainage of the collected material from the pleural cavity and the movement of the column of the fluid in the tube confirms the adequate position of the chest tube. The chest should now be auscultated, improvement in the breath sounds suggests success of the procedure. A chest X-ray is then performed for confirmation of proper positioning of the tube radiologically.
Some authors advocate creation of an oblique passage or ‘tunnel’ in the chest wall to insert the tube, primarily to decrease the incidence of recurrent pneumothorax following removal of the chest tube [12]. In this technique incision is made one intercostal space below the pre-determined site of thoracostomy, the skin and soft tissues of the chest wall are then bluntly dissected to reach the site of thoracostomy thereby creating a curved passage through the chest wall for introduction of the chest tube. This requires additional time at the expense of no added advantage and therefore is not required.
7. Post-procedural care
7.1 Nursing the patient with chest tube
Utmost care should be exercised while nursing a patient with chest tube. The reservoir should remain below the level of the chest at all times. Raising the reservoir above the chest level may result in passage of the fluid from the reservoir back into the pleural cavity. While turning or shifting the patient, one must ensure that the tube is not held or entangled in the patient’s bed. This may result in accidental displacement or dismantling of the tube. The outlet of the reservoir should remain open at all times especially in patients with pneumothorax or air leak. The closed outlet of the reservoir may lead to failure of decompression of pneumothorax leading to development of life-threatening tension pneumothorax. For the same reason, the tube should not be clamped at any time except while changing the fluid in the reservoir, collecting a sample of effluent or while planning to remove the chest tube. The patient should be closely monitored during this period.
The patient should be motivated for active physiotherapy and incentive spirometry (Figure 6).
Figure 6.
Patient performing incentive spirometry.
This aids in faster resolution of pleural collection and thereby early removal of the ICD tube. In case, the patient is unable to do active physiotherapy, passive physiotherapy should be performed. All efforts must be made to ambulate the patient early. The chest tube must be secured carefully while patient mobilizes and the drainage bag (reservoir) should be kept well below the thoracostomy site.
The ICD site should be carefully examined every day for signs of local infection like peri-tubal inflammation or tenderness. The dressing needs to be changed in case it is soaked. Extreme care must be taken while dressing the ICD site lest the tube is displaced or dismantled. The patient should be clinically monitored every day and the volume of drained fluid should be charted carefully in the patient’s record. The reservoir should be emptied once it is full up to 3/4 of its capacity. A new reservoir with prepared under water seal or disposable reservoir (in case of digital chest tube drainage systems) is kept ready while changing the reservoir. In resource constraint settings the same reservoir may be reused. It is important to follow universal precautions while changing the reservoir. The chest tube is clamped and the filled reservoir is disconnected from the tube, the new reservoir is then connected or fluid is filled up to the ‘initial water level’ mark (or till the outlet tube is at least 2 cms below the water level) in case one contemplates to use the same reservoir. Once the reservoir is reattached, the tube is unclamped. It is important to prepare the equipment beforehand while changing the reservoir to keep the time of occlusion of the chest tube to minimum possible.
The practice of performing daily x-ray has been questioned by many authors and it is suggested that this may not be required if there is pleura to pleura apposition in the post-procedure x-ray and the patient is improving clinically [13].
7.2 Use of analgesics and antibiotics
Appropriate oral or parenteral analgesics are administered depending on the underlying condition for which tube thoracostomy was necessitated. There has been much debate on the use of antibiotics following tube thoracostomy. There is no evidence to support the routine use of prophylactic antibiotic therapy following the procedure [14, 15]. However, the antibiotics may be needed for other associated causes for which tube thoracostomy was performed like in empyema thoracis or in a patient of trauma with soft tissue injuries.
7.3 Use of suction
The use of controlled suction (−10 to −15 cm saline) to the outlet of the reservoir may help in faster resolution of intrapleural collection and promote early pleura to pleura approximation. This is most useful following pulmonary resections and may decrease the incidence of persistent post-operative space problems. In our practice, we apply overnight suction in patients undergoing pulmonary resection surgery (except following pneumonectomy). At times, the application of suction may result in pleural pain, the amount of suction should be decreased in such situations. In case of increased air leak on application of suction, the suction may be decreased or avoided altogether.
7.4 What to do in case the tube is blocked?
Blockage of thoracostomy tube is not uncommon and occur frequently in hemothorax. Careful observation of the ICD tube and the ensuring drainage of the fluid are paramount to detect this complication early. If appropriate measures are taken in time, the possibility of maintaining the tube patency are high.
Various manipulations can be performed to restore the patency of blocked ICD tube. These include tapping, milking and stripping of the tube. These measures are successful only with partial blockage of the tube and should not be performed routinely to prevent blockage. There is theoretical possibility of generation of high intrapleural pressures with stripping and milking. Some authors have raised concern that this may cause pulmonary injury, however we have not observed any clinically significant adverse effects of these procedures. The practice of flushing the blocked tube by instilling sterile solutions should be discouraged as this may increase the chances of introducing infection from outside with resultant increase in the incidence of empyema. Some clinicians have used novel methods like using a fogarty balloon catheter to unblock the chest tube [16] or use of advanced systems to either prevent clot formation inside the tube [17] or wipe the inside of tube to unblock it [18].
7.5 How to collect a sample from the chest tube
A loop is formed in the ICD tube and the intrapleural fluid is allowed to accumulate in this loop. The tube is then clamped proximal to this collected fluid. With all aseptic measures the external surface of the ICD tube near its connection with the tubing of the reservoir is cleaned with alcohol based antiseptic solution. The tube is then disconnected from this end and the sample is collected in a sterile container. The ICD tube is then reconnected with the reservoir tube and is unclamped.
8. Removing the chest tube: when and how?
There are no fixed or universally agreed criteria that applies to all patients for guiding removal of the thoracostomy tube. There is great heterogeneity in practice, however the rule of thumb is that the chest tube should be removed once it has served its purpose. If the patient is clinically well, there is no more air leak than on forced expiration, no expanding subcutaneous emphysema, no blood, pus or chyle in the effluent and the volume of the fluid being drained is less than 250 ml, the tube can be safely removed. In case of residual space following pulmonary resection with persistent low volume air leak (no more than on forced expiration) beyond day 5, the chest tube may be clamped for up to 24 hours and a repeat x-ray is performed. The patient should be closely monitored during this period for tachypnoea or dyspnea. In case the patient remains asymptomatic and the pneumothorax does not worsen, the chest tube may be removed. The same may be done in case of persistent non-expanding effusion. This practice however, carries the risk of serious side effects if the patient monitoring following clamping of the tube is not diligent. The use of digital chest tube drainage devices might obviate this risk. The chest tube may be safely removed if the air leak is <40 ml/ min over 24 hours [19]. Alternatively, in patients with prolonged air leak (beyond day 5), a Heimlich valve may be applied to the chest tube and the patient may be followed on outpatient basis with a plan to remove the tube later allowing more opportunity for the residual lung to expand. We have recently proposed a protocol for removal of chest tubes following thoracic surgery that have enabled us to decrease the chest tube indwelling time [20].
In some specialties like Colorectal and Gynecological Surgery, the Enhanced Recovery After Surgery (ERAS) protocol has been well established. This has recently been proposed for patients undergoing oncological major lung resection surgery too. The guidelines suggest that chest tubes may safely be removed with a non-chylous fluid output of up to 450 ml/ day in absence of air leak or minimal air leak detected by the digital chest tube drainage systems [21].
The view is equally divided regarding removal of the chest tube during end-inspiration or end-expiration [22, 23]. In a Randomized Controlled Trial by Bell RL et al., there was no significant difference between the complications following removal of the chest tube at either the height of inspiration or expiration and both methods were considered safe [23]. The incidence of recurrent pneumothorax is likely to be multifactorial and correlates poorly to the method of chest tube removal alone [23, 24]. We prefer to remove the chest tube by a swift motion followed immediately by sealing of the thoracostomy wound by appropriate dressing material irrespective of the phase of respiration.
9. Complications
The complications of tube thoracostomy may be divided into 3 phases:
During insertion of the tube:
Hemorrhage from the ICD site
Injury to the lung and the mediastinal structures
Misplacement of the tube
During the indwelling time of the chest tube:
Displacement or dislodgement of the tube
Subcutaneous emphysema
Kinking
Blockage
Fracture of the tube
Empyema thoracis
Wound infection
Re-expansion pulmonary edema
Following removal of the tube
Recurrent pneumothorax or pleural effusion
Thoracostomy site pain
Hemorrhage from the ICD site may be avoided by carefully siting the thoracostomy incision on the upper border of the lower rib in the desired intercostal space. This avoids the damage to the neurovascular bundle that runs along the lower border of the rib. All aseptic measures should be taken while inserting the chest tube and later while handling the tube during the post procedural care to prevent wound infection and empyema. Care should be exercised while nursing and mobilizing the patient with chest tube to prevent accidental displacement or dislodgement of the tube.
To prevent re-expansion pulmonary edema, the pleural cavity should be gradually decompressed. Sudden evacuation of more than one liter of fluid from the thoracic cavity should be avoided. It is desirable to monitor the intrapleural pressure while draining large amount of fluid from the pleural cavity. The intrapleural pressure should not be allowed to fall below −20 cm saline at any point of time.
10. Common pitfalls in chest tube management
A pitfall is different from complication and is defined as a hidden or unsuspected danger or difficulty that may lead to adverse events. The awareness of a pitfall and preparation to act swiftly in such eventuality may help in averting the complication arising from it. Following are the common pitfalls in ICD tube management:
Missed diagnosis: ICD tube placed in a patient with large diaphragmatic hernia suspecting it to be a loculated pneumothorax. A careful history and diligent look at the x-ray will avoid this pitfall (Figure 7A and B).
Placement of ICD on wrong side: One should confirm the side with pathology before putting the chest tube. The history of the patient, clinical notes and the radiological findings should be correlated to correctly identify the side of pathology.
A large thoracostomy incision may result in potential space around the chest tube. This coupled with fixation of the tube by superficial skin suturing results in development of a closed plane in the subcutaneous tissues. Peri-tubal air leak in this situation may lead to massive surgical emphysema with attended morbidity and mortality.
Avoiding digital exploration of the pleural cavity may result in injury to pulmonary parenchyma in addition to improper positioning and kinking of the tube (Figure 8).
One must perform ‘finger thoracostomy’ before inserting the chest tube to avoid this from happening.
Use of tubes with trocar and applying undue force while gaining entry to the pleural cavity may result in injury to various thoracic, mediastinal or intra-abdominal organs.
Poor placement result in a tube that may be:
Too in: may impinge on to the mediastinal structures (Figure 9A and B).
Too out: the eye (hole) of the tube may lie in the subcutaneous tissues with resultant subcutaneous emphysema (Figure 10).
Mispositioned or kinked resulting in poor drainage (Figures 11–14).
Poor fixation of the chest tube may result in accidental displacement or dislodgement (Figure 11). The chest tube should be anchored properly with number 1 silk suture. An additional suture from the opposite side improves the fixation and decreases the chances of this mishap.
Improper filling of the reservoir (under water seal) with sterile solution so that the outlet tube is not beneath the water column may result in pneumothorax.
Raising the reservoir above the level of the chest may result in drainage of the collected material back into the thoracic cavity. The reservoir should remain below the chest level of the patient at all times.
Clamping the tube while shifting or mobilizing the patient may result in tension pneumothorax. The outlet of the reservoir should be kept open at all times to prevent this.
Figure 7.
A: Left sided diaphragmatic hernia with large gastric shadow. B: Chest tube inserted in a patient of diaphragmatic hernia misdiagnosed as hydropneumothorax.
Figure 8.
A kinked chest tube.
Figure 9.
A & B: Chest tube impinging on mediastinal structures.
Figure 10.
Eye of chest tube in subcutaneous tissues with subcutaneous emphysema.
Figure 11.
Chest tube (arrow) about to come out.
Figure 12.
Chest tube lying outside the chest wall.
Figure 13.
Mispositioned tube over the diaphragm (arrow).
Figure 14.
Mispositioned tube lying in abdomen (arrow).
11. Advances in chest tube drainage systems
With the advancement in technology, newer equipment has become available that may help in decreasing some of the complications associated with the tube thoracostomy, make the assessment of drainage more objective and accurate thus helping in better management of ICD tubes. Some of the advancement in the recent times are:
Devices for better fixation of the chest tubes: Some devices are available that claim better fixation of the chest tubes [25], others have been tested on animal models and may soon become available [26].
Digital chest tube drainage systems: This has been perhaps the most significant advancement that is now the part of most modern thoracic surgery units (Figure 15).
Figure 15.
A patient being managed on digital chest tube drainage system following thoracotomy.
The use of these drainage systems has been associated with improved decision-making regarding chest tube management, decrease complications, improved quality of life and reduce the hospital stay [27, 28, 29] These are light weight, portable system with a disposable reservoir that may be replaced once full. The main advantages of this system are:
It does not require an ‘underwater seal’ thus eliminating the risk of accidental pneumothorax and passage of drained material from the reservoir back to the chest.
It allows accurate measurement of drained fluid and air over time and thus helps in assessment of the trend of drainage (Figure 16A & B).
Figure 16.
A & B: Objective depiction of air and fluid drainage and trend of drainage in digital chest tube drainage system.
This may help the clinician in making decision for removal of chest tube more objective and accurately.
Continuous controlled suction may be applied to the chest tube that remains constant irrespective of the position of the drainage system.
The patient may easily carry the device while ambulation without the risk of changes in pressure effecting drainage or accidental drainage of the collected material back in chest.
Chest tube systems with inbuilt mechanism to keep the inside of the tube clean to prevent clogging [16, 18].
Motion activated systems for prevention of clot formation inside the chest tube: This system uses motion-activated energy (vibration) primarily to prevent early adhesion of clots within the internal chest tube surface and thus maintains the patency of the chest tube [17].
12. Conclusion
Insertion of ICD is a common, simple yet lifesaving procedure. All clinicians should be well versed with the appropriate technique of inserting the thoracostomy tube and various aspects of its management. Although simple, it is associated with high rate of complications that primarily occur due to improper technique of insertion or poor post-procedural care. Awareness of these factors will make the procedure safer with improved outcome.
Conflict of interest
There are no conflicts of interest.
\n',keywords:"Chest tube, Tube thoracostomy, intercostal drainage tube, ICD tube, Thoracentesis, Thoracostomy drainage",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/78585.pdf",chapterXML:"https://mts.intechopen.com/source/xml/78585.xml",downloadPdfUrl:"/chapter/pdf-download/78585",previewPdfUrl:"/chapter/pdf-preview/78585",totalDownloads:126,totalViews:0,totalCrossrefCites:0,dateSubmitted:"April 9th 2021",dateReviewed:"August 22nd 2021",datePrePublished:"September 14th 2021",datePublished:null,dateFinished:"September 14th 2021",readingETA:"0",abstract:"Insertion of intercostal drainage (ICD) tube is one of the commonest surgical procedure that is life saving in certain circumstances. Although the procedure is being used for long, yet there is no consensus in its management. The procedure is simple to perform but the incidence of the complications, which primarily occur due to improper positioning of the tube and poor post-procedural care, is as high as 40%. It is therefore essential that all clinicians should be familiar with this simple, common and lifesaving procedure. 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PMID: 29929649.'},{id:"B26",body:'Eisenkraft A, Gavish L, Wagnert-Avraham L, Gertz SD, Milner I, Shaylor R, Kushnir D, Kedar A, Mintz Y. Novel self-fixation chest drain device tested in a swine model of pneumo-hemothorax. Minim Invasive Ther Allied Technol. 2021;30(1):40-46. doi: 10.1080/13645706.2019.1671456. Epub 2019 Sep 30. PMID: 31566510.'},{id:"B27",body:'Chiappetta M, Lococo F, Nachira D, Ciavarella LP, Congedo MT, Porziella V, Meacci E, Margaritora S. Digital Devices Improve Chest Tube Management: Results from a Prospective Randomized Trial. Thorac Cardiovasc Surg. 2018;66(7):595-602. doi: 10.1055/s-0037-1607443. Epub 2017 Oct 27. PMID: 29078230.'},{id:"B28",body:'Wang H, Hu W, Ma L, Zhang Y. Digital chest drainage system versus traditional chest drainage system after pulmonary resection: a systematic review and meta-analysis. J Cardiothorac Surg. 2019;14(1):13. doi: 10.1186/s13019-019-0842-x. PMID: 30658680; PMCID: PMC6339372.'},{id:"B29",body:'Miller DL, Helms GA, Mayfield WR. Digital Drainage System Reduces Hospitalization After Video-Assisted Thoracoscopic Surgery Lung Resection. Ann Thorac Surg. 2016;102(3):955-961. doi: 10.1016/j.athoracsur.2016.03.089. Epub 2016 May 25. PMID: 27234573.'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Mohit Kumar Joshi",address:"drmohitjoshi@gmail.com",affiliation:'
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In this context, this chapter presents key subjects while implementing a quality management system at materials science laboratories and some considerations on strategies for effectively implementing such systems.",book:{id:"5486",slug:"quality-control-and-assurance-an-ancient-greek-term-re-mastered",title:"Quality Control and Assurance",fullTitle:"Quality Control and Assurance - An Ancient Greek Term Re-Mastered"},signatures:"Rodrigo S. Neves, Daniel P. Da Silva, Carlos E. C. Galhardo, Erlon H.\nM. Ferreira, Rafael M. Trommer and Jailton C. Damasceno",authors:[{id:"20571",title:"Prof.",name:"Erlon H.",middleName:null,surname:"Martins Ferreira",slug:"erlon-h.-martins-ferreira",fullName:"Erlon H. 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The quality practices or quality management systems adopted by industries will further evolve due to the changes of quality concepts as time goes by. This chapter discusses the change of quality concepts and the related revolution of quality management systems in the past century. The quality concepts were gradually changed from the achievement of quality standards, satisfaction of customer needs, and expectations to customer delight. Since merely satisfying customers is not enough to ensure customer loyalty, the enterprises gradually focus on customers’ emotional responses and their delight in order to pursue their loyalty. The emotion of “delight” is composed of “joy” and “surprise,” which can be achieved as the customers’ latent requirements are satisfied. Thus, the concept of “customer delight” and the means to provide the innovative quality so as to meet the unsatisfied customers’ latent needs are elaborated on. Finally, a framework of innovation creation is developed that is based on the mining of customer's latent requirements. This outline will manifest the essential elements of the related operation steps.",book:{id:"5486",slug:"quality-control-and-assurance-an-ancient-greek-term-re-mastered",title:"Quality Control and Assurance",fullTitle:"Quality Control and Assurance - An Ancient Greek Term Re-Mastered"},signatures:"Ching-Chow Yang",authors:[{id:"11862",title:"Prof.",name:"Ching-Chow",middleName:null,surname:"Yang",slug:"ching-chow-yang",fullName:"Ching-Chow Yang"}]},{id:"62915",title:"Advanced Methods of PID Controller Tuning for Specified Performance",slug:"advanced-methods-of-pid-controller-tuning-for-specified-performance",totalDownloads:3439,totalCrossrefCites:10,totalDimensionsCites:16,abstract:"This chapter provides a concise survey, classification and historical perspective of practice-oriented methods for designing proportional-integral-derivative (PID) controllers and autotuners showing the persistent demand for PID tuning algorithms that integrate performance requirements into the tuning algorithm. The proposed frequency-domain PID controller design method guarantees closed-loop performance in terms of commonly used time-domain specifications. One of its major benefits is universal applicability for both slow and fast-controlled plants with unknown mathematical model. Special charts called B-parabolas were developed as a practical design tool that enables consistent and systematic shaping of the closed-loop step response with regard to specified performance and dynamics of the uncertain controlled plant.",book:{id:"6323",slug:"pid-control-for-industrial-processes",title:"PID Control for Industrial Processes",fullTitle:"PID Control for Industrial Processes"},signatures:"Štefan Bucz and Alena Kozáková",authors:[{id:"21933",title:"Ms.",name:"Alena",middleName:null,surname:"Kozakova",slug:"alena-kozakova",fullName:"Alena Kozakova"},{id:"213658",title:"Dr.",name:"Štefan",middleName:null,surname:"Bucz",slug:"stefan-bucz",fullName:"Štefan Bucz"}]},{id:"75699",title:"Data Clustering for Fuzzyfier Value Derivation",slug:"data-clustering-for-fuzzyfier-value-derivation",totalDownloads:279,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The fuzzifier value m is improving significant factor for achieving the accuracy of data. Therefore, in this chapter, various clustering method is introduced with the definition of important values for clustering. To adaptively calculate the appropriate purge value of the gap type −2 fuzzy c-means, two fuzzy values m1 and m2 are provided by extracting information from individual data points using a histogram scheme. Most of the clustering in this chapter automatically obtains determination of m1 and m2 values that depended on existent repeated experiments. Also, in order to increase efficiency on deriving valid fuzzifier value, we introduce the Interval type-2 possibilistic fuzzy C-means (IT2PFCM), as one of advanced fuzzy clustering method to classify a fixed pattern. In Efficient IT2PFCM method, proper fuzzifier values for each data is obtained from an algorithm including histogram analysis and Gaussian Curve Fitting method. Using the extracted information form fuzzifier values, two modified fuzzifier value m1 and m2 are determined. 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He\nreceived a short-term scholarship to carry out his post-doctoral\nstudies abroad, from Japan International Cooperation Agency\n(JICA), in coordination with the Egyptian government. Dr.\nShalaby speaks fluent English and his native Arabic. He has 77\ninternationally published research papers, has attended 15 international conferences, and has contributed to 18 international books and chapters.\nDr. Shalaby works as a reviewer on over one hundred international journals and is\non the editorial board of more than twenty-five international journals. He is a member of seven international specialized scientific societies, besides his local one, and\nhe has won seven prizes.",institutionString:"Cairo University",institution:{name:"Cairo University",institutionURL:null,country:{name:"Egypt"}}}]}]},openForSubmissionBooks:{},onlineFirstChapters:{},subseriesFiltersForOFChapters:[],publishedBooks:{},subseriesFiltersForPublishedBooks:[],publicationYearFilters:[],authors:{paginationCount:617,paginationItems:[{id:"158492",title:"Prof.",name:"Yusuf",middleName:null,surname:"Tutar",slug:"yusuf-tutar",fullName:"Yusuf Tutar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/158492/images/system/158492.jpeg",biography:"Prof. Dr. Yusuf Tutar conducts his research at the Hamidiye Faculty of Pharmacy, Department of Basic Pharmaceutical Sciences, Division of Biochemistry, University of Health Sciences, Turkey. He is also a faculty member in the Molecular Oncology Program. He obtained his MSc and Ph.D. at Oregon State University and Texas Tech University, respectively. He pursued his postdoctoral studies at Rutgers University Medical School and the National Institutes of Health (NIH/NIDDK), USA. His research focuses on biochemistry, biophysics, genetics, molecular biology, and molecular medicine with specialization in the fields of drug design, protein structure-function, protein folding, prions, microRNA, pseudogenes, molecular cancer, epigenetics, metabolites, proteomics, genomics, protein expression, and characterization by spectroscopic and calorimetric methods.",institutionString:"University of Health Sciences",institution:null},{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180528/images/system/180528.jpg",biography:"Hiroyuki Kagechika received his bachelor’s degree and Ph.D. in Pharmaceutical Sciences from the University of Tokyo, Japan, where he served as an associate professor until 2004. 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He has developed various compounds including a drug for acute promyelocytic leukemia.",institutionString:"Tokyo Medical and Dental University",institution:{name:"Tokyo Medical and Dental University",country:{name:"Japan"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNVJQA4/Profile_Picture_2022-03-07T13:23:04.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Associate Prof.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/15648_n.jpg",biography:"Dr. Mohd Aftab Siddiqui is currently working as Assistant Professor in the Faculty of Pharmacy, Integral University, Lucknow for the last 6 years. He has completed his Doctor in Philosophy (Pharmacology) in 2020 from Integral University, Lucknow. He completed his Bachelor in Pharmacy in 2013 and Master in Pharmacy (Pharmacology) in 2015 from Integral University, Lucknow. He is the gold medalist in Bachelor and Master degree. He qualified GPAT -2013, GPAT -2014, and GPAT 2015. His area of research is Pharmacological screening of herbal drugs/ natural products in liver and cardiac diseases. He has guided many M. Pharm. research projects. He has many national and international publications.",institutionString:"Integral University",institution:null},{id:"255360",title:"Dr.",name:"Usama",middleName:null,surname:"Ahmad",slug:"usama-ahmad",fullName:"Usama Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255360/images/system/255360.png",biography:"Dr. Usama Ahmad holds a specialization in Pharmaceutics from Amity University, Lucknow, India. He received his Ph.D. degree from Integral University. Currently, he’s working as an Assistant Professor of Pharmaceutics in the Faculty of Pharmacy, Integral University. From 2013 to 2014 he worked on a research project funded by SERB-DST, Government of India. He has a rich publication record with more than 32 original articles published in reputed journals, 3 edited books, 5 book chapters, and a number of scientific articles published in ‘Ingredients South Asia Magazine’ and ‘QualPharma Magazine’. He is a member of the American Association for Cancer Research, International Association for the Study of Lung Cancer, and the British Society for Nanomedicine. Dr. Ahmad’s research focus is on the development of nanoformulations to facilitate the delivery of drugs that aim to provide practical solutions to current healthcare problems.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"30568",title:"Prof.",name:"Madhu",middleName:null,surname:"Khullar",slug:"madhu-khullar",fullName:"Madhu Khullar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/30568/images/system/30568.jpg",biography:"Dr. Madhu Khullar is a Professor of Experimental Medicine and Biotechnology at the Post Graduate Institute of Medical Education and Research, Chandigarh, India. She completed her Post Doctorate in hypertension research at the Henry Ford Hospital, Detroit, USA in 1985. She is an editor and reviewer of several international journals, and a fellow and member of several cardiovascular research societies. Dr. Khullar has a keen research interest in genetics of hypertension, and is currently studying pharmacogenetics of hypertension.",institutionString:"Post Graduate Institute of Medical Education and Research",institution:{name:"Post Graduate Institute of Medical Education and Research",country:{name:"India"}}},{id:"223233",title:"Prof.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/223233/images/system/223233.png",biography:"Xianquan Zhan received his MD and Ph.D. in Preventive Medicine at West China University of Medical Sciences. He received his post-doctoral training in oncology and cancer proteomics at the Central South University, China, and the University of Tennessee Health Science Center (UTHSC), USA. He worked at UTHSC and the Cleveland Clinic in 2001–2012 and achieved the rank of associate professor at UTHSC. Currently, he is a full professor at Central South University and Shandong First Medical University, and an advisor to MS/PhD students and postdoctoral fellows. He is also a fellow of the Royal Society of Medicine and European Association for Predictive Preventive Personalized Medicine (EPMA), a national representative of EPMA, and a member of the American Society of Clinical Oncology (ASCO) and the American Association for the Advancement of Sciences (AAAS). He is also the editor in chief of International Journal of Chronic Diseases & Therapy, an associate editor of EPMA Journal, Frontiers in Endocrinology, and BMC Medical Genomics, and a guest editor of Mass Spectrometry Reviews, Frontiers in Endocrinology, EPMA Journal, and Oxidative Medicine and Cellular Longevity. He has published more than 148 articles, 28 book chapters, 6 books, and 2 US patents in the field of clinical proteomics and biomarkers.",institutionString:"Shandong First Medical University",institution:{name:"Affiliated Hospital of Shandong Academy of Medical Sciences",country:{name:"China"}}},{id:"297507",title:"Dr.",name:"Charles",middleName:"Elias",surname:"Assmann",slug:"charles-assmann",fullName:"Charles Assmann",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/297507/images/system/297507.jpg",biography:"Charles Elias Assmann is a biologist from Federal University of Santa Maria (UFSM, Brazil), who spent some time abroad at the Ludwig-Maximilians-Universität München (LMU, Germany). He has Masters Degree in Biochemistry (UFSM), and is currently a PhD student at Biochemistry at the Department of Biochemistry and Molecular Biology of the UFSM. His areas of expertise include: Biochemistry, Molecular Biology, Enzymology, Genetics and Toxicology. He is currently working on the following subjects: Aluminium toxicity, Neuroinflammation, Oxidative stress and Purinergic system. Since 2011 he has presented more than 80 abstracts in scientific proceedings of national and international meetings. Since 2014, he has published more than 20 peer reviewed papers (including 4 reviews, 3 in Portuguese) and 2 book chapters. He has also been a reviewer of international journals and ad hoc reviewer of scientific committees from Brazilian Universities.",institutionString:"Universidade Federal de Santa Maria",institution:{name:"Universidade Federal de Santa Maria",country:{name:"Brazil"}}},{id:"217850",title:"Dr.",name:"Margarete Dulce",middleName:null,surname:"Bagatini",slug:"margarete-dulce-bagatini",fullName:"Margarete Dulce Bagatini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217850/images/system/217850.jpeg",biography:"Dr. Margarete Dulce Bagatini is an associate professor at the Federal University of Fronteira Sul/Brazil. She has a degree in Pharmacy and a PhD in Biological Sciences: Toxicological Biochemistry. She is a member of the UFFS Research Advisory Committee\nand a member of the Biovitta Research Institute. She is currently:\nthe leader of the research group: Biological and Clinical Studies\nin Human Pathologies, professor of postgraduate program in\nBiochemistry at UFSC and postgraduate program in Science and Food Technology at\nUFFS. She has experience in the area of pharmacy and clinical analysis, acting mainly\non the following topics: oxidative stress, the purinergic system and human pathologies, being a reviewer of several international journals and books.",institutionString:"Universidade Federal da Fronteira Sul",institution:{name:"Universidade Federal da Fronteira Sul",country:{name:"Brazil"}}},{id:"226275",title:"Ph.D.",name:"Metin",middleName:null,surname:"Budak",slug:"metin-budak",fullName:"Metin Budak",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226275/images/system/226275.jfif",biography:"Metin Budak, MSc, PhD is an Assistant Professor at Trakya University, Faculty of Medicine. He has been Head of the Molecular Research Lab at Prof. Mirko Tos Ear and Hearing Research Center since 2018. His specializations are biophysics, epigenetics, genetics, and methylation mechanisms. He has published around 25 peer-reviewed papers, 2 book chapters, and 28 abstracts. He is a member of the Clinical Research Ethics Committee and Quantification and Consideration Committee of Medicine Faculty. His research area is the role of methylation during gene transcription, chromatin packages DNA within the cell and DNA repair, replication, recombination, and gene transcription. His research focuses on how the cell overcomes chromatin structure and methylation to allow access to the underlying DNA and enable normal cellular function.",institutionString:"Trakya University",institution:{name:"Trakya University",country:{name:"Turkey"}}},{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",slug:"anca-pantea-stoian",fullName:"Anca Pantea Stoian",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",biography:"Anca Pantea Stoian is a specialist in diabetes, nutrition, and metabolic diseases as well as health food hygiene. She also has competency in general ultrasonography.\n\nShe is an associate professor in the Diabetes, Nutrition and Metabolic Diseases Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania. She has been chief of the Hygiene Department, Faculty of Dentistry, at the same university since 2019. Her interests include micro and macrovascular complications in diabetes and new therapies. Her research activities focus on nutritional intervention in chronic pathology, as well as cardio-renal-metabolic risk assessment, and diabetes in cancer. She is currently engaged in developing new therapies and technological tools for screening, prevention, and patient education in diabetes. \n\nShe is a member of the European Association for the Study of Diabetes, Cardiometabolic Academy, CEDA, Romanian Society of Diabetes, Nutrition and Metabolic Diseases, Romanian Diabetes Federation, and Association for Renal Metabolic and Nutrition studies. She has authored or co-authored 160 papers in national and international peer-reviewed journals.",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",country:{name:"Romania"}}},{id:"279792",title:"Dr.",name:"João",middleName:null,surname:"Cotas",slug:"joao-cotas",fullName:"João Cotas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279792/images/system/279792.jpg",biography:"Graduate and master in Biology from the University of Coimbra.\n\nI am a research fellow at the Macroalgae Laboratory Unit, in the MARE-UC – Marine and Environmental Sciences Centre of the University of Coimbra. My principal function is the collection, extraction and purification of macroalgae compounds, chemical and bioactive characterization of the compounds and algae extracts and development of new methodologies in marine biotechnology area. \nI am associated in two projects: one consists on discovery of natural compounds for oncobiology. The other project is the about the natural compounds/products for agricultural area.\n\nPublications:\nCotas, J.; Figueirinha, A.; Pereira, L.; Batista, T. 2018. An analysis of the effects of salinity on Fucus ceranoides (Ochrophyta, Phaeophyceae), in the Mondego River (Portugal). Journal of Oceanology and Limnology. in press. DOI: 10.1007/s00343-019-8111-3",institutionString:"Faculty of Sciences and Technology of University of Coimbra",institution:null},{id:"279788",title:"Dr.",name:"Leonel",middleName:null,surname:"Pereira",slug:"leonel-pereira",fullName:"Leonel Pereira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279788/images/system/279788.jpg",biography:"Leonel Pereira has an undergraduate degree in Biology, a Ph.D. in Biology (specialty in Cell Biology), and a Habilitation degree in Biosciences (specialization in Biotechnology) from the Faculty of Science and Technology, University of Coimbra, Portugal, where he is currently a professor. In addition to teaching at this university, he is an integrated researcher at the Marine and Environmental Sciences Center (MARE), Portugal. His interests include marine biodiversity (algae), marine biotechnology (algae bioactive compounds), and marine ecology (environmental assessment). Since 2008, he has been the author and editor of the electronic publication MACOI – Portuguese Seaweeds Website (www.seaweeds.uc.pt). He is also a member of the editorial boards of several scientific journals. Dr. Pereira has edited or authored more than 20 books, 100 journal articles, and 45 book chapters. He has given more than 100 lectures and oral communications at various national and international scientific events. He is the coordinator of several national and international research projects. In 1998, he received the Francisco de Holanda Award (Honorable Mention) and, more recently, the Mar Rei D. Carlos award (18th edition). He is also a winner of the 2016 CHOICE Award for an outstanding academic title for his book Edible Seaweeds of the World. In 2020, Dr. Pereira received an Honorable Mention for the Impact of International Publications from the Web of Science",institutionString:"University of Coimbra",institution:{name:"University of Coimbra",country:{name:"Portugal"}}},{id:"61946",title:"Dr.",name:"Carol",middleName:null,surname:"Bernstein",slug:"carol-bernstein",fullName:"Carol Bernstein",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/61946/images/system/61946.jpg",biography:"Carol Bernstein received her PhD in Genetics from the University of California (Davis). She was a faculty member at the University of Arizona College of Medicine for 43 years, retiring in 2011. Her research interests focus on DNA damage and its underlying role in sex, aging and in the early steps of initiation and progression to cancer. In her research, she had used organisms including bacteriophage T4, Neurospora crassa, Schizosaccharomyces pombe and mice, as well as human cells and tissues. She authored or co-authored more than 140 scientific publications, including articles in major peer reviewed journals, book chapters, invited reviews and one book.",institutionString:"University of Arizona",institution:{name:"University of Arizona",country:{name:"United States of America"}}},{id:"182258",title:"Dr.",name:"Ademar",middleName:"Pereira",surname:"Serra",slug:"ademar-serra",fullName:"Ademar Serra",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/182258/images/system/182258.jpeg",biography:"Dr. Serra studied Agronomy on Universidade Federal de Mato Grosso do Sul (UFMS) (2005). He received master degree in Agronomy, Crop Science (Soil fertility and plant nutrition) (2007) by Universidade Federal da Grande Dourados (UFGD), and PhD in agronomy (Soil fertility and plant nutrition) (2011) from Universidade Federal da Grande Dourados / Escola Superior de Agricultura Luiz de Queiroz (UFGD/ESALQ-USP). Dr. Serra is currently working at Brazilian Agricultural Research Corporation (EMBRAPA). His research focus is on mineral nutrition of plants, crop science and soil science. Dr. Serra\\'s current projects are soil organic matter, soil phosphorus fractions, compositional nutrient diagnosis (CND) and isometric log ratio (ilr) transformation in compositional data analysis.",institutionString:"Brazilian Agricultural Research Corporation",institution:{name:"Brazilian Agricultural Research Corporation",country:{name:"Brazil"}}}]}},subseries:{item:{id:"12",type:"subseries",title:"Human Physiology",keywords:"Anatomy, Cells, Organs, Systems, Homeostasis, Functions",scope:"Human physiology is the scientific exploration of the various functions (physical, biochemical, and mechanical properties) of humans, their organs, and their constituent cells. The endocrine and nervous systems play important roles in maintaining homeostasis in the human body. Integration, which is the biological basis of physiology, is achieved through communication between the many overlapping functions of the human body's systems, which takes place through electrical and chemical means. 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