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      Paper-based microfluidics for DNA diagnostics of malaria in low resource underserved rural communities

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          Significance

          Populations living in remote rural communities would benefit from rapid, highly sensitive molecular, DNA-based diagnostics to inform the correct and timely treatment of infectious diseases. Such information is also becoming increasingly relevant in global efforts for disease elimination, where the testing of asymptomatic patients is now seen as being important for the identification of disease reservoirs. However, healthcare workers face practical and logistical problems in the implementation of such tests, which often involve complex instrumentation and centralized laboratories. Here we describe innovations in paper microfluidics that enable low-cost, multiplexed DNA-based diagnostics for malaria, delivered, in a first-in-human study, in schools in rural Uganda.

          Abstract

          Rapid, low-cost, species-specific diagnosis, based upon DNA testing, is becoming important in the treatment of patients with infectious diseases. Here, we demonstrate an innovation that uses origami to enable multiplexed, sensitive assays that rival polymerase chain reactions (PCR) laboratory assays and provide high-quality, fast precision diagnostics for malaria. The paper-based microfluidic technology proposed here combines vertical flow sample-processing steps, including paper folding for whole-blood sample preparation, with an isothermal amplification and a lateral flow detection, incorporating a simple visualization system. Studies were performed in village schools in Uganda with individual diagnoses being completed in <50 min (faster than the standard laboratory-based PCR). The tests, which enabled the diagnosis of malaria species in patients from a finger prick of whole blood, were both highly sensitive and specific, detecting malaria in 98% of infected individuals in a double-blind first-in-human study. Our method was more sensitive than other field-based, benchmark techniques, including optical microscopy and industry standard rapid immunodiagnostic tests, both performed by experienced local healthcare teams (which detected malaria in 86% and 83% of cases, respectively). All assays were independently validated using a real-time double-blinded reference PCR assay. We not only demonstrate that advanced, low-cost DNA-based sensors can be implemented in underserved communities at the point of need but also highlight the challenges associated with developing and implementing new diagnostic technologies in the field, without access to laboratories or infrastructure.

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          Most cited references38

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          Diagnostics for the developing world: microfluidic paper-based analytical devices.

          Microfluidic paper-based analytical devices (microPADs) are a new class of point-of-care diagnostic devices that are inexpensive, easy to use, and designed specifically for use in developing countries. (To listen to a podcast about this feature, please go to the Analytical Chemistry multimedia page at pubs.acs.org/page/ancham/audio/index.html.).
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            Isothermal Amplification of Nucleic Acids.

            Isothermal amplification of nucleic acids is a simple process that rapidly and efficiently accumulates nucleic acid sequences at constant temperature. Since the early 1990s, various isothermal amplification techniques have been developed as alternatives to polymerase chain reaction (PCR). These isothermal amplification methods have been used for biosensing targets such as DNA, RNA, cells, proteins, small molecules, and ions. The applications of these techniques for in situ or intracellular bioimaging and sequencing have been amply demonstrated. Amplicons produced by isothermal amplification methods have also been utilized to construct versatile nucleic acid nanomaterials for promising applications in biomedicine, bioimaging, and biosensing. The integration of isothermal amplification into microsystems or portable devices improves nucleic acid-based on-site assays and confers high sensitivity. Single-cell and single-molecule analyses have also been implemented based on integrated microfluidic systems. In this review, we provide a comprehensive overview of the isothermal amplification of nucleic acids encompassing work published in the past two decades. First, different isothermal amplification techniques are classified into three types based on reaction kinetics. Then, we summarize the applications of isothermal amplification in bioanalysis, diagnostics, nanotechnology, materials science, and device integration. Finally, several challenges and perspectives in the field are discussed.
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              A review of malaria diagnostic tools: microscopy and rapid diagnostic test (RDT).

              The absolute necessity for rational therapy in the face of rampant drug resistance places increasing importance on the accuracy of malaria diagnosis. Giemsa microscopy and rapid diagnostic tests (RDTs) represent the two diagnostics most likely to have the largest impact on malaria control today. These two methods, each with characteristic strengths and limitations, together represent the best hope for accurate diagnosis as a key component of successful malaria control. This review addresses the quality issues with current malaria diagnostics and presents data from recent rapid diagnostic test trials. Reduction of malaria morbidity and drug resistance intensity plus the associated economic loss of these two factors require urgent scaling up of the quality of parasite-based diagnostic methods. An investment in anti-malarial drug development or malaria vaccine development should be accompanied by a parallel commitment to improve diagnostic tools and their availability to people living in malarious areas.
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                Author and article information

                Journal
                Proc Natl Acad Sci U S A
                Proc. Natl. Acad. Sci. U.S.A
                pnas
                pnas
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                12 March 2019
                19 February 2019
                19 February 2019
                : 116
                : 11
                : 4834-4842
                Affiliations
                [1] aDivision of Biomedical Engineering, University of Glasgow , G12 8LT Glasgow, United Kingdom;
                [2] bNano Biomedical Research Centre, School of Biomedical Engineering, Shanghai Jiao Tong University , 200030 Shanghai, People’s Republic of China;
                [3] cVector Control Division, Ministry of Health , Kampala, Uganda
                Author notes
                2To whom correspondence should be addressed. Email: jon.cooper@ 123456glasgow.ac.uk .

                Edited by David A. Weitz, Harvard University, Cambridge, MA, and approved December 21, 2018 (received for review July 19, 2018)

                Author contributions: J.R., G.X., M.A., E.M.T., and J.M.C. designed research; J.R., G.X., A.G., M.A., Z.Y., C.R., and J.M.C. performed research; J.R., G.X., A.G., C.R., and J.M.C. analyzed data; and J.R., G.X., M.A., C.R., and J.M.C. wrote the paper.

                1J.R. and G.X. contributed equally to this work.

                Author information
                http://orcid.org/0000-0002-6879-8405
                http://orcid.org/0000-0002-2358-1050
                Article
                201812296
                10.1073/pnas.1812296116
                6421471
                30782834
                4de701cc-88b5-48c9-91a4-e2585718fcda
                Copyright © 2019 the Author(s). Published by PNAS.

                This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).

                History
                Page count
                Pages: 9
                Funding
                Funded by: RCUK | Engineering and Physical Sciences Research Council (EPSRC) 501100000266
                Award ID: EP/R512813/1
                Award Recipient : Julien Reboud Award Recipient : Gaolian Xu Award Recipient : Alice Garrett Award Recipient : Moses Adriko Award Recipient : Edridah M Tukahebwa Award Recipient : Candia Rowell Award Recipient : Jonathan M Cooper
                Funded by: RCUK | Engineering and Physical Sciences Research Council (EPSRC) 501100000266
                Award ID: EP/I017887/1
                Award Recipient : Julien Reboud Award Recipient : Gaolian Xu Award Recipient : Alice Garrett Award Recipient : Moses Adriko Award Recipient : Edridah M Tukahebwa Award Recipient : Candia Rowell Award Recipient : Jonathan M Cooper
                Funded by: EC | FP7 | FP7 Ideas: European Research Council (FP7 Ideas) 100011199
                Award ID: 340117
                Award Recipient : Julien Reboud Award Recipient : Jonathan M Cooper
                Funded by: RCUK | Engineering and Physical Sciences Research Council (EPSRC) 501100000266
                Award ID: EP/R01437X/1
                Award Recipient : Julien Reboud Award Recipient : Gaolian Xu Award Recipient : Alice Garrett Award Recipient : Moses Adriko Award Recipient : Edridah M Tukahebwa Award Recipient : Candia Rowell Award Recipient : Jonathan M Cooper
                Funded by: Scottish Funding Council (SFC) 501100000360
                Award ID: GCRF
                Award Recipient : Julien Reboud Award Recipient : Gaolian Xu Award Recipient : Alice Garrett Award Recipient : Jonathan M Cooper
                Categories
                PNAS Plus
                Physical Sciences
                Engineering
                Biological Sciences
                Biochemistry
                PNAS Plus

                malaria,nucleic acid-based tests,paper microfluidics,low-resource settings,point-of-care diagnostics

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