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<h2>Diseases and Applications</h2>


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<strong>Celiac Disease</strong>
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Celiac disease is an autoimmune digestive disorder in which the body reacts to the presence of gluten in the diet by mounting an immune response against the small intestine, damaging and sometimes entirely destroying the villi necessary to absorb nutrients from ingested food1. Estimated to affect 1 in 100 people worldwide, celiac disease is one of the most prevalent genetic autoimmune disorders in the world<sup>1</sup>. It is estimated that 3 million people in the United States have celiac disease<sup>2</sup> with 2.5 million of those people being undiagnosed and therefore at high risk for the common resulting long-term health complications of the disease when it is left untreated including dermatitis herpetiformis (a painful, itchy rash affecting the skin), infertility and miscarriage, osteoporosis, anemia, neurological conditions including epilepsy and migraines, intestinal cancers, and the development of other autoimmune disorders including Type I diabetes and multiple sclerosis (MS)<sup>1</sup>. As it is a genetic disorder, there is no cure for celiac disease, and the only current form of treatment is strict adherence to a gluten-free diet<sup>3</sup>. 
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Despite the importance of patients with celiac disease being able to keep gluten out of their diets, the labeling of food as “gluten-free” has only recently become tightly regulated. On August 2, 2013, the FDA issued a final rule clarifying the use of the term “gluten-free” on packaged food, requiring any packaged food labeled “gluten-free” must contain less than 20 parts per million (ppm) of gluten<sup>4</sup>. There are two main reasons for the designation of this minimum value. First, most patients with celiac disease can tolerate trace amounts of gluten (less than 20 ppm) in their diets without experiencing adverse symptoms<sup>5</sup>. Second, according to the FDA, there are no current methods deemed scientifically reliable that can detect gluten levels below 20 ppm<sup>5</sup>. Part of the difficulty of detecting gluten comes from the fact that gluten is not a single protein but rather a collection of the major storage proteins of dietary grains<sup>6</sup>. Gliadins, the portion of wheat gluten that is soluble in alcohol, and prolamins, the counterpart of gliadins in rye and barley, are typically what a test for gluten ultimately tries to detect<sup>6</sup>. However, gliadins and prolamins are often altered during food processing by processes such as thermal and enzymatic treatments, making them undetectable by current gluten-detection methods and thereby introducing dangerous error into the production of supposedly gluten-free foods<sup>6</sup>. Whereas the current methods of gluten detection rely on enzyme-linked immunosorbent assays (ELISA)<sup>5</sup> which cannot detect some of the modified versions of gluten<sup>6</sup>.
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<strong>Chagas Disease</strong>
<br>
Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi)<sup>7</sup>, is considered to be endemic in much of Mexico, Central America, and South America with an estimated eight million people infected worldwide<sup>7</sup>. The disease is most commonly spread by a vector called the triatomine bug, commonly known as “kissing bug”, which feeds on the blood of both humans and animals<sup>7</sup>. Poor, rural areas are at the highest risk of exposure to the triatomine bug as they are prevalent among housing composed of mud and straw<sup>7</sup>. Despite the fact that the triatomine bug is not common in the United States, the CDC estimates that 300,000 people in the United States are currently living with Chagas disease with most cases having been acquired in endemic countries<sup>7</sup>. The combination of the high prevalence and low awareness of Chagas disease in the United States has qualified it to be considered one of the five Neglected Parasitic Infections (NPIs) of the United States according to the CDC<sup>7</sup>. 
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Chagas disease has two main phases, the acute phase and the chronic phase<sup>7</sup>. The acute phase, which may last anywhere from several weeks to several months<sup>7</sup>, is marked by the presence of the parasite in the bloodstream<sup>8</sup>. An infected individual in the acute phase may be asymptomatic, demonstrate mild symptoms including fever and malaise, or demonstrate severe symptoms including meningoencephalitis and myocarditis<sup>8</sup>. During the chronic phase, the parasite is either absent from or at low concentrations in the blood<sup>8</sup> but has taken up residence in the muscles of the heart and digestive system where it can cause life-threatening cardiac disorders in up to 30% of individuals and digestive disorders in up to 10% of individuals<sup>9</sup>. Early treatment of the disease is crucial as antiparasitic medications may be able to cure an infected individual if administered early enough in the acute phase<sup>9</sup>. If treatment is delayed beyond this point, the disease is lifelong<sup>9</sup>. 
<br><br>
Current detection of Chagas disease depends on whether the patient is in the acute or chronic phase. During the acute phase, blood smears allow the blood borne parasite to be visualized, and PCR allows for detection of parasitic DNA8. During the chronic phase, however, there are few to no blood borne parasites, and so the current methods of diagnosis are centered on detecting antibodies against the parasite with serologic tests that most commonly use enzyme-linked immunosorbent assay (ELISA) or immunofluorescent antibody assay (IFA). No single assay, however, is accurate enough by itself, presenting the need for multiple assays that can be cross referenced against one another<sup>8</sup>. Despite the use of multiple assays, false negatives and misdiagnosis are still quite common<sup>10</sup>. 
What lacks in all the current methods of detection is practicality. Given that Chagas disease is most prevalent in poor, rural areas, laboratory equipment and people trained to use it are likely not readily available. This demonstrates the need for inexpensive detection that can be used in the field. Our biosensor, which utilizes aptamers to detect its designated target, can be made to utilize an aptamer that specifically binds to T. cruzi excreted secreted antigens (TESA)<sup>10</sup>, thus demonstrating the presence of the disease. This would allow for one single assay that can reliably and inexpensively diagnose a patient without the need for laboratory equipment or trained individuals to carry out the assay. 
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<strong>Human Papillomavirus (HPV)</strong>
<br>
Human papillomaviruses (HPV) are an extremely common group of DNA viruses that can be transmitted sexually or non-sexually and infect human epithelial tissues resulting in warts<sup>11</sup>. Differing HPV strains cause infections in differing epithelial cells and can determine the severity of the infection. The majority of HPV infections are low-risk and typically only result in the formation of warts on the skin or around the genitalia that will disappear over time. Of the over 200 HPVs discovered, about 40 are known to be easily transmitted through sexual contact.Two sexually transmitted strains of HPV, types 16 and 18, are responsible for the majority of cervical, anal, and oropharyngeal cancers. These high-risk HPV types are characterized by the production of E6 and E7 proteins which interfere with cell-cycle regulatory pathways, causing uncontrollable cell proliferation which, when left untreated, may result in precancerous growths or cancer<sup>12</sup>.
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Diagnostic tools for HPV are highly accurate, effectively detecting the presence of HPV DNA within sample cells. However, these tests trade specificity with accuracy making it nearly impossible to determine whether the strain is a low-risk or high-risk type<sup>13</sup>. More specific tests are limited to high-risk HPV types, specifically to type 16 and it’s links to cervical cancer. Papanicolaou smears, or pap smears, is by far the most commonly used test to detect the presence of type 16 and type 18 HPV. A single smear contains several hundred-thousand cells which will be examined in a lab for any cellular irregularities by a cytologist. However, given the number of samples need to be examined, the number of cells within one sample, and the limited amount of time a cytologist has with a sample, errors using a pap smear is expected and, unfortunately, difficult to prevent<sup>14</sup>. General HPV tests could be used instead of pap smears however, due to the test’s non-specificity the amount of false-positives would be expected to increase. Efforts to improve the pap smear have been made. Various companies have developed automated computer systems to analyse samples with a blue-white light. While these advances improve existing detection methods, the use of an aptapaper system would eliminate the need for microscopy altogether, combining the accuracy of HPV screening with the specificity of pap smears. Wheres the general HPV test tests for the presence of viral DNA and RNA the aptapaper system would detect the presence of the E7 proteins produced when a cell is infected by type 16 HPV<sup>15</sup>.
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<strong>Malaria</strong>
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Malaria, a vector borne disease caused by the Plasmodium parasite, remains a heavy burden on global health. In 2013, there were an estimated 198 million cases of malaria worldwide, killing 584,000, with 90% of those deaths occurring in Africa.  An estimated 3.3. Billion people remain at risk.  Although these numbers are staggering and devastating, Malaria is entirely preventable and treatable.  However, like with NTDs, Malaria disproportionately affects those in impoverished areas without the means to obtain treatment<sup>16</sup>.
Severe Malaria can progress rapidly, making early diagnosis key to preventing fatalities<sup>16</sup>. It was demonstrated that DNA aptamers selected against Plasmodium falciparum lactate dehydrogenase could potentially aid in the early detection of malaria7. These aptamers were found to bind to PfLDH with high specificity and affinity, without cross reaction to human lactate dehydrogenase<sup>17</sup>. Incorporated into our Aptapaper system, we can help facilitate the early detection of malaria.
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<p><strong>References:</strong></p>
<ol class="second">
    <li>What is Celiac Disease? Celiac Disease Foundation. <a href="https://celiac.org/celiac-disease/what-is-celiac-disease/">https://celiac.org/celiac-disease/what-is-celiac-disease/</a>https://celiac.org/celiac-disease/what-is-celiac-disease/. Accessed September 2, 2015.</li>
    <li>Gluten-Free Labeling of Foods. U.S. Food and Drug Administration. http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/Allergens/ucm362510.htm. Updated June 15, 2015. Accessed September 2, 2015.</li>
    <li>Celiac Disease Symptoms. Celiac Disease Foundation. https://celiac.org/celiac-disease/symptomssigns/. Accessed September 2, 2015.</li>
    <li>Foods Labeled Gluten-Free Must Now Meet FDA's Definition. U.S. Food and Drug Administration. http://www.fda.gov/Food/NewsEvents/ConstituentUpdates/ucm407867.htm. Published August 5, 2014. Updated August 5, 2014. Accessed September 2, 2015.
    <li>Questions and Answers: Gluten-Free Food Labeling Final Rule. U.S. Food and Drug Administration. http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/Allergens/ucm362880.htm. Updated June 16, 2015. Accessed September 2, 2015. 
    <li>Amaya-González S, de-Los-Santos-Álvarez N, Miranda-Ordieres AJ, Lobo-Castañón MJ. Sensitive gluten determination in gluten-free foods by an electrochemical aptamer-based assay. Anal. Bioanal. Chem. 2015; 407(20): 6021 – 6029. 
    <li>Parasites – American Trypanosomiasis (also known as Chagas Disease). Centers for Disease Control and Prevention. http://www.cdc.gov/parasites/chagas/. Updated July 19, 2013. Accessed August 31, 2015. 
    <li>Bern C. Chagas’ Disease. N. Engl. J. Med. 2015; 373: 456 – 466. 
    <li>Chagas disease (American trypanosomiasis). World Health Organization. http://www.who.int/mediacentre/factsheets/fs340/en/. Updated March 2015. Accessed August 31, 2015. 
    <li>Nagarkatti R, de Araujo FF, Gupta C, Debrabant A. Aptamer Based, Non-PCR, Non-Serological Detection of Chagas Disease Biomarkers in Trypanosoma cruzi Infected Mice. PLoS Neglected Trop. Dis. 2014; 8(1): e2650. doi: 10.1371/journal.pntd.0002650 
    <li>"Genital HPV Infection - Fact Sheet." Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 23 Feb. 2015. Web. 12 Sept. 2015. 
    <li>"HPV and Cancer." National Cancer Institute. National Cancer Institute, n.d. Web. 12 Sept. 2015. 
    <li>http://ajcp.ascpjournals.org/content/supplements/114/Suppl_1/S48.full.pdf 
    <li>http://www.cancer.gov/about-cancer/causes-prevention/risk/infectious-agents/hpv-fact-sheet 
    <li>Arbyn M, Buntinx F, Van Ranst M, Paraskevaidis E, Martin-Hirsch P, Dillner J; Buntinx; Van Ranst; Paraskevaidis; Martin-Hirsch; Dillner (2004). "Virologic versus cytologic triage of women with equivocal Pap smears: a meta-analysis of the accuracy to detect high-grade intraepithelial neoplasia". J. Natl. Cancer Inst. 96 (4): 280–93. 
    <li>Trampuz A, Jereb M, Muzlovic I, Prabhu RM. Clinical review: Severe malaria. Crit Care. 2003;7(4):315-323. doi:10.1186/cc2183. 
    <li>Cheung Y-W, Kwok J, Law AWL, Watt RM, Kotaka M, Tanner J a. Structural basis for discriminatory recognition of Plasmodium lactate dehydrogenase by a DNA aptamer. Proc Natl Acad Sci U S A. 2013;110(40):15967-15972. doi:10.1073/pnas.1309538110.</li> 
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