The Application of Biomedical Engineering Techniques to the Diagnosis and Management of Tropical Diseases: A Review <s> Introduction <s> First generation candidate vaccines against leishmaniasis, prepared using inactivated whole parasites as their main ingredient, were considered as promising because of their relative ease of production and low cost. These vaccines have been the subject of many investigations over several decades and are the only leishmaniasis vaccine candidates which have undergone phase 3 clinical trial evaluation. Although the studies demonstrated the safety of the vaccines and several studies showed reasonable immunogenicity and some indication of protection, an efficacious prophylactic vaccine is yet to be identified. Despite this overall failure, these trials contributed significantly to increasing knowledge on human leishmaniasis immunology. To provide a collective view, this review discusses the methods and findings of field efficacy trials of first generation leishmaniasis vaccine clinical trials conducted in the Old and New Worlds. <s> BIB001 </s> The Application of Biomedical Engineering Techniques to the Diagnosis and Management of Tropical Diseases: A Review <s> Introduction <s> BACKGROUND ::: Cutaneous leishmaniasis (CL) has traditionally been underrecognized and underreported. Improved awareness is warranted as the number of cases has increased as a result of increased travel to endemic countries, the HIV/AIDS pandemic, and the larger number of military and contract workers deployed overseas. ::: ::: ::: OBJECTIVE ::: We sought to present a systematic review of evidence from a gamut of research trials on the treatment efficacy of different regimens and aggregate this knowledge for use as a guide for clinical practice decisions. ::: ::: ::: METHODS ::: We performed a comprehensive search of print and electronic sources to identify the accumulated research information on New World CL. ::: ::: ::: RESULTS ::: Topical treatment of New World CL lesions is generally not recommended. Findings support the systemic administration of pentavalent antimonials as first-line treatment. Exception to this is infection with L guyanensis in French Guiana where systemic pentamidine is suggested as first-line treatment. ::: ::: ::: LIMITATIONS ::: The reliability of the findings of this review of research evidence is dependent on the individual quality and potential bias in its component principal trials. There was a conscious attempt to only include evidence derived from randomized controlled studies, with adequate randomization, adequate patient numbers, and complete follow-up information. However, because of the relatively small number of such studies on New World CL, evidence from nonrandomized studies and case series studies was also considered. ::: ::: ::: CONCLUSIONS ::: The pentavalent antimony compounds remain the first-line treatment choice for the treatment of New World CL. Concerns with cost, availability, poor compliance, and systemic toxicity, however, may compel clinicians to opt for alternative treatment modalities. Some advances in the development of an antileishmanial vaccine have been made but none is yet available for clinic use. The increase, over recent years, in the incidence of CL warrants an enhanced effort to increase awareness of the disease, assure timely diagnosis, and implement effective management and treatment strategies. <s> BIB002 </s> The Application of Biomedical Engineering Techniques to the Diagnosis and Management of Tropical Diseases: A Review <s> Introduction <s> The need for reliable, fast diagnostics is closely linked to the need for safe, effective treatment of the so-called "neglected" diseases. The list of diseases with no field-adapted diagnostic tools includes leishmaniasis, shigella, typhoid, and bacterial meningitis. Leishmaniasis, in particular, is a parasitic disease caused by Leishmania spp. transmitted by infected phlebotomine sandfly, which remains a public health concern in developing countries with ca. 12 million people infected and 350 million at risk of infection. Despite several attempts, methods for diagnosis are still noneffective, especially with regard to specificity due to false positives with Chagas' disease caused by Trypanosoma cruzi . Accepted golden standards for detecting leishmaniasis involve isolation of parasites either microscopically, or by culture, and in both methods specimens are obtained by invasive means. Here, we show that efficient distinction between cutaneous leishmaniasis and Chagas' disease can be obtained with a low-cost biosensor system made with nanostructured films containing specific Leishmania amazonensis and T. cruzi antigens and employing impedance spectroscopy as the detection method. This unprecedented selectivity was afforded by antigen-antibody molecular recognition processes inherent in the detection with the immobilized antigens, and by statistically correlating the electrical impedance data, which allowed distinction between real samples that tested positive for Chagas' disease and leishmaniasis. Distinction could be made of blood serum samples containing 10(-5) mg/mL of the antibody solution in a few minutes. The methods used here are generic and can be extended to any type of biosensor, which is important for an effective diagnosis of many other diseases. <s> BIB003 </s> The Application of Biomedical Engineering Techniques to the Diagnosis and Management of Tropical Diseases: A Review <s> Introduction <s> Background ::: Early detection and confirmation of cholera outbreaks are crucial for rapid implementation of control measures. Because cholera frequently affects regions with limited laboratory resources, rapid diagnostic tests (RDT) designed for field conditions are important to enhance rapid response. Stool culture remains the “gold standard” for cholera diagnosis; however, its lack of sensitivity may lead to underestimation of test specificity. We evaluated the Crystal VC® immunochromatographic test (Span Diagnostics, India) for cholera diagnosis using a modified reference standard that combines culture-dependent and independent assays, or a Bayesian latent class model (LCM) analysis. ::: ::: ::: Methodology/Principal Findings ::: The study was conducted during a cholera epidemic in 2008, in Lubumbashi, Democratic Republic of Congo. Stools collected from 296 patients were used to perform the RDT on site and sent to Institut Pasteur, Paris, for bacterial culture. In comparison with culture as the gold standard, the RDT showed good sensitivity (92.2%; 95% CI: 86.8%–95.9%) but poor specificity when used by a trained laboratory technician (70.6%; 95% CI: 60.7%–79.2%) or by clinicians with no specific test training (60.4%, 95% CI: 50.2%–70.0%). The specificity of the test performed by the laboratory technician increased to 88.6% (95% CI: 78.7–94.9) when PCR was combined with culture results as the reference standard, and to 85.0% (95% CI: 70.4–99.2), when the Bayesian LCM analysis was used for performance evaluation. In both cases, the sensitivity remained high. ::: ::: ::: Conclusion ::: Using an improved reference standard or appropriate statistical methods for diagnostic test evaluations in the absence of a gold standard, we report better performance of the Crystal VC® RDT than previously published. Our results confirm that this test can be used for early outbreak detection or epidemiological surveillance, key components of efficient global cholera control. Our analysis also highlights the importance of improving evaluations of RDT when no reliable gold standard is available. <s> BIB004
The original designation of certain diseases as being tropical can be dated back to the 1898 publication of Sir Patrick Mansonʼs Tropical Diseases: A Manual of the Diseases of Warm Climates  . Tropical diseases (TD) are diseases that are widespread in or unique to the tropical and subtropical regions. TDs are prevalent in hot and humid climates. TDs are caused by pathogenic agents such as bacteria, viruses, parasites or fungi and are most often transmitted through carriers or vectors such as insects and nematodes. These insects may carry a parasite, bacterium or virus that is transmitted via their bite which disperses the infectious agent by subcutaneous blood or saliva exchange in humans and animals. Examples of tropical diseases include malaria, tetanus, hepatitis, American trypanosomiasis (chagas), dengue, yellow fever, cholera, nipah virus, and many others. We will look at some of these where biomedical engineering approaches have contributed to their diagnosis and treatment. Rapid, efficient and inexpensive diagnosis of TDs is vital for the effective treatment and quality management of diseases in tropical regions. Diagnosis of TDs consists of a wide range of methods including serological testing of pathogenic markers such as protein, antigen, and antibody (using the enzyme-linked immunosorbent assay (ELISA) technique and various test kits), x-rays and physical examination, as well as performing bacteria and fungi culture techniques. These methods typically require a sample of bodily fluid, such as blood, sputum, or urine and/or stool samples. However, the management and diagnosis of TDs face several challenges such as prolonged turnaround time for assessment of specimens, high cost, a controlled environment, highly trained personnel, and large blood or bodily fluid samples. Associated measurements are often invasive, and in order to be useful, diagnostic methods must be accurate, simple and affordable for the population for which they are intended. They must also provide a result in time to institute effective treatment and patient isolation when necessary. Current diagnostic methods for TDs are frequently faced with challenges such as inconsistency in specificity and sensitivity, a long turnaround time to receive results, and high cost or specialization (which requires either an advanced and expensive laboratory setup, or skilled technicians and clinicians, or both). Recent research and studies in the past decade have proposed and introduced various biomedical engineering approaches that attempt to address the issues faced in the diagnosis of tropical diseases. This review paper focuses on current biomedical engineering approaches for the more prominent diseases of dengue, malaria, cholera, schistosomiasis, lymphatic filariasis, ebola, leprosy, leishmaniasis, and American trypanosomiasis (chagas). Many of these approaches can be extended to other diseases as well. These diseases were chosen as examples due to their severity and endemic nature and the perceived limitations of the current diagnostic methodology. In recent years outbreaks of dengue have been escalating and spreading geographically throughout the world with high mortality rates when timely treatment is not administered   . The number of infections of malaria and schistosomiasis is in the range of hundreds of millions, with the annual mortality rates in the range of hundreds of thousands  5] . From 2009 to 2010, the number of cases and deaths due to cholera has increased by about 50% BIB004 , while sporadic outbreaks of ebola have been noted to be extremely deadly, killing the patient within 2 days after acquiring the infection  . The disease of lymphatic filariasisis is wide spread, infecting 120 million people and disfiguring 40 million worldwide  , while leprosy has an annual infection rate of 200,000 a year, and causes permanent damage to the skin, nerves, limbs and eyes if untreated [9] . Around the world, millions of people are infected with leishmaniasis and American trypanosomiasis (chagas), and millions more are at risk due to the endemic nature of these diseases BIB002 BIB001 BIB003 . Although the diseases are different, many of the biomedical engineering approaches are common for their diagnosis and treatment. Table 1 presents the relation between the diseases and biomedical engineering approaches for their Diagnosis and Treatment. In the following sections we review biomedical engineering approaches that are currently available for diagnosis and establishing prognosis of the tropical diseases listed in Table 1 . As seen in the table, a wider variety of biomedical engineering approaches have been applied to diseases such as dengue and malaria than some of the diseases on the right side of the table. 