@article {199, title = {Towards biomarker-based tests that can facilitate decisions about prevention and management of preeclampsia in low-resource settings.}, journal = {Clin Chem Lab Med}, year = {2015}, month = {2015 May 20}, abstract = {

In recent years, an increasing amount of literature is emerging on candidate urine and blood-based biomarkers associated with incidence and severity of preeclampsia (PE) in pregnant women. While enthusiasm on the usefulness of several of these markers in predicting PE is evolving, essentially all work so far has focused on the needs of high-resource settings and high-income countries, resulting primarily in multi-parameter laboratory assays based on proteomic and metabolomics analysis techniques. These highly complex methods, however, require laboratory capabilities that are rarely available or affordable in low-resource settings (LRS). The importance of quantifying maternal and perinatal risks and identifying which pregnancies can be safely prolonged is also much greater in LRS, where intensive care facilities that can rapidly respond to PE-related health threats for women and infants are limited. For these reasons, simple, low cost, sensitive, and specific point-of-care (POC) tests are needed that can be performed by antenatal health care providers in LRS and that can facilitate decisions about detection and management of PE. Our study aims to provide a comprehensive systematic review of current and emerging blood and urine biomarkers for PE, not only on the basis of their clinical performance, but also of their suitability to be used in LRS-compatible test formats, such as lateral flow and other variants of POC rapid assays.

}, issn = {1434-6621}, doi = {10.1515/cclm-2015-0069}, author = {Acestor, Nathalie and Goett, Jane and Lee, Arthur and Herrick, Tara M and Engelbrecht, Susheela M and Harner-Jay, Claudia M and Howell, Bonnie J and Weigl, Bernhard H} } @article {201, title = {Medical devices and diagnostics for cardiovascular diseases in low-resource settings.}, journal = {J Cardiovasc Transl Res}, volume = {7}, year = {2014}, month = {2014 Nov}, pages = {737-48}, abstract = {

Noncommunicable diseases (NCDs), including cardiovascular diseases and diabetes, have emerged as an underappreciated health threat with enormous economic and public health implications for populations in low-resource settings. In order to address these diseases, devices that are to be used in low-resource settings have to conform to requirements that are generally more challenging than those developed for traditional markets. Characteristics and issues that must be considered when working in low- and middle-income countries (LMICs) include challenging environmental conditions, a complex supply chain, sometimes inadequate operator training, and cost. Somewhat counterintuitively, devices for low-resource setting (LRS) markets need to be of at least as high quality and reliability as those for developed countries to be setting-appropriate and achieve impact. Finally, the devices need to be designed and tested for the populations in which they are to be used in order to achieve the performance that is needed. In this review, we focus on technologies for primary and secondary health-care settings and group them according to the continuum of care from prevention to treatment.

}, keywords = {Biomedical Technology, Blood Chemical Analysis, Cardiovascular Diseases, Cost-Benefit Analysis, Developing Countries, Diabetes Mellitus, Diagnostic Techniques, Cardiovascular, Equipment Design, Health Care Costs, Health Resources, Health Services Accessibility, Health Services Needs and Demand, Humans, Predictive Value of Tests}, issn = {1937-5395}, doi = {10.1007/s12265-014-9591-3}, author = {McGuire, Helen and Weigl, Bernhard H} } @article {203, title = {Field evaluation of a prototype paper-based point-of-care fingerstick transaminase test.}, journal = {PLoS One}, volume = {8}, year = {2013}, month = {2013}, pages = {e75616}, abstract = {

Monitoring for drug-induced liver injury (DILI) via serial transaminase measurements in patients on potentially hepatotoxic medications (e.g., for HIV and tuberculosis) is routine in resource-rich nations, but often unavailable in resource-limited settings. Towards enabling universal access to affordable point-of-care (POC) screening for DILI, we have performed the first field evaluation of a paper-based, microfluidic fingerstick test for rapid, semi-quantitative, visual measurement of blood alanine aminotransferase (ALT). Our objectives were to assess operational feasibility, inter-operator variability, lot variability, device failure rate, and accuracy, to inform device modification for further field testing. The paper-based ALT test was performed at POC on fingerstick samples from 600 outpatients receiving HIV treatment in Vietnam. Results, read independently by two clinic nurses, were compared with gold-standard automated (Roche Cobas) results from venipuncture samples obtained in parallel. Two device lots were used sequentially. We demonstrated high inter-operator agreement, with 96.3\% (95\% C.I., 94.3-97.7\%) agreement in placing visual results into clinically-defined "bins" (<3x, 3-5x, and >5x upper limit of normal), >90\% agreement in validity determination, and intraclass correlation coefficient of 0.89 (95\% C.I., 0.87-0.91). Lot variability was observed in \% invalids due to hemolysis (21.1\% for Lot 1, 1.6\% for Lot 2) and correlated with lots of incorporated plasma separation membranes. Invalid rates <1\% were observed for all other device controls. Overall bin placement accuracy for the two readers was 84\% (84.3\%/83.6\%). Our findings of extremely high inter-operator agreement for visual reading-obtained in a target clinical environment, as performed by local practitioners-indicate that the device operation and reading process is feasible and reproducible. Bin placement accuracy and lot-to-lot variability data identified specific targets for device optimization and material quality control. This is the first field study performed with a patterned paper-based microfluidic device and opens the door to development of similar assays for other important analytes.

}, keywords = {Alanine Transaminase, Blood Chemical Analysis, Developing Countries, Drug Monitoring, Drug-Induced Liver Injury, Humans, Liver Function Tests, Microfluidics, Observer Variation, Paper, Point-of-Care Systems, Vietnam}, issn = {1932-6203}, doi = {10.1371/journal.pone.0075616}, author = {Pollock, Nira R and McGray, Sarah and Colby, Donn J and Noubary, Farzad and Nguyen, Huyen and Nguyen, The Anh and Khormaee, Sariah and Jain, Sidhartha and Hawkins, Kenneth and Kumar, Shailendra and Rolland, Jason P and Beattie, Patrick D and Chau, Nguyen V and Quang, Vo M and Barfield, Cori and Tietje, Kathy and Steele, Matt and Weigl, Bernhard H} } @article {205, title = {Instrument-free exothermic heating with phase change temperature control for paper microfluidic devices.}, journal = {Proc SPIE Int Soc Opt Eng}, volume = {8615}, year = {2013}, month = {2013 Mar 9}, pages = {86150R}, abstract = {

Many infectious diseases, as well as some cancers, that affect global health are most accurately diagnosed through nucleic acid amplification and detection. There is a great need to simplify nucleic acid-based assay systems for use in global health in low-resource settings as well as in settings that do not have convenient access to laboratory staff and equipment such as doctors{\textquoteright} offices and home care settings. In developing countries, unreliable electric power, inadequate supply chains, and lack of maintenance for complex diagnostic instruments are all common infrastructure shortfalls. Many elements of instrument-free, disposable, nucleic acid amplification assays have been demonstrated in recent years. However, the problem of instrument-free, low-cost, temperature-controlled chemical heating remains unsolved. In this paper we present the current status and results of work towards developing disposable, low-cost, temperature-controlled heaters designed to support isothermal nucleic acid amplification assays that are integrated with a two-dimensional paper network. Our approach utilizes the heat generated through exothermic chemical reactions and controls the heat through use of engineered phase change materials to enable sustained temperatures required for nucleic acid amplification. By selecting appropriate exothermic and phase change materials, temperatures can be controlled over a wide range, suitable for various isothermal amplification methods, and maintained for over an hour at an accuracy of +/- 1{\textdegree}C.

}, issn = {0277-786X}, doi = {10.1117/12.2005928}, author = {Singleton, Jered and Zentner, Chris and Buser, Josh and Yager, Paul and LaBarre, Paul and Weigl, Bernhard H} } @article {204, title = {Molecular diagnostics in a teacup: Non-Instrumented Nucleic Acid Amplification (NINA) for rapid, low cost detection of Salmonella enterica.}, journal = {Chin Sci Bull}, volume = {58}, year = {2013}, month = {2013 Apr}, pages = {1162-1168}, abstract = {

We report on the use of a novel non-instrumented platform to enable a Loop Mediated isothermal Amplification (LAMP) based assay for Salmonella enterica. Heat energy is provided by addition of a small amount (<150 g) of boiling water, and the reaction temperature is regulated by storing latent energy at the melting temperature of a lipid-based engineered phase change material. Endpoint classification of the reaction is achieved without opening the reaction tube by observing the fluorescence of sequence-specific FRET-based assimilating probes with a simple handheld fluorometer. At or above 22{\textdegree}C ambient temperature the non-instrumented devices could maintain reactions above a threshold temperature of 61{\textdegree}C for over 90 min-significantly longer than the 60 min reaction time. Using the simple format, detection limits were less than 20 genome copies for reactions run at ambient temperatures ranging from 8 to 36{\textdegree}C. When used with a pre-enrichment step and non-instrumented DNA extraction device, trace contaminations of Salmonella in milk close to 1 CFU/mL could be reliably detected. These findings illustrate that the non- instrumented amplification approach is a simple, viable, low-cost alternative for field-based food and agricultural diagnostics or clinical applications in developing countries.

}, issn = {1001-6538}, author = {Kubota, Ryo and LaBarre, Paul and Weigl, Bernhard H and Li, Yong and Haydock, Paul and Jenkins, Daniel M} } @article {202, title = {Point-of-Care Diagnostics in Low-Resource Settings and Their Impact on Care in the Age of the Noncommunicable and Chronic Disease Epidemic.}, journal = {J Lab Autom}, volume = {19}, year = {2013}, month = {2013 Dec 23}, pages = {248-257}, abstract = {

The emergence of point-of-care (POC) diagnostics specifically designed for low-resource settings coupled with the rapid increase in need for routine care of patients with chronic diseases should prompt reconsideration of how health care can be delivered most beneficially and cost-effectively in developing countries. Bolstering support for primary care to provide rapid and appropriate integrated acute and chronic care treatment may be a possible solution. POC diagnostics can empower local and primary care providers and enable them to make better clinical decisions. This article explores the opportunity for POC diagnostics to strengthen primary care and chronic disease diagnosis and management in a low-resource setting (LRS) to deliver appropriate, consistent, and integrated care. We analyze the requirements of resource-appropriate chronic disease care, the characteristics of POC diagnostics in LRS versus the developed world, the many roles of diagnostics in the care continuum in LRS, and the process and economics of developing LRS-compatible POC diagnostics.

}, issn = {2211-0682}, doi = {10.1177/2211068213515246}, author = {Weigl, Bernhard H and Neogi, Tina and McGuire, Helen} } @article {206, title = {The Value of Clinical Needs Assessments for Point-of-Care Diagnostics.}, journal = {Point Care}, volume = {11}, year = {2012}, month = {2012 Jun}, pages = {108-113}, abstract = {

Most entrepreneurial ventures fail long before the core technology can be brought to the marketplace because of disconnects in performance and usability measures such as accuracy, cost, complexity, assay stability, and time requirements between technology developers{\textquoteright} specifications and needs of the end-users. By going through a clinical needs assessment (CNA) process, developers will gain vital information and a clear focus that will help minimize the risks associated with the development of new technologies available for use within the health care system. This article summarizes best practices of the principal investigators of the National Institute of Biomedical Imaging and Bioengineering point-of-care (POC) centers within the National Institute of Biomedical Imaging and Bioengineering POC Technologies Research Network. Clinical needs assessments are particularly important for product development areas that do not sufficiently benefit from traditional market research, such as grant-funded research and development, new product lines using cutting-edge technologies developed in start-up companies, and products developed through product development partnerships for low-resource settings. The objectives of this article were to (1) highlight the importance of CNAs for development of POC devices, (2) discuss methods applied by POC Technologies Research Network for assessing clinical needs, and (3) provide a road map for future CNAs.

}, issn = {1533-029X}, doi = {10.1097/POC.0b013e31825a241e}, author = {Weigl, Bernhard H and Gaydos, Charlotte A and Kost, Gerald and Beyette, Fred R and Sabourin, Stephanie and Rompalo, Anne and de Los Santos, Tala and McMullan, Jason T and Haller, John} } @article {211, title = {Association of elevated E6 oncoprotein with grade of cervical neoplasia using PDZ interaction-mediated precipitation of E6.}, journal = {J Low Genit Tract Dis}, volume = {15}, year = {2011}, month = {2011 Apr}, pages = {169-76}, abstract = {

OBJECTIVE: To determine the expression of human papillomavirus (HPV) type 16 E6 oncoprotein in cervical specimens of women with and without cervical intraepithelial neoplasia (CIN).

MATERIALS AND METHODS: Cervical specimens from 2,530 unscreened women aged 30 to 54 years from Shanxi, China, were obtained. All women were assessed by liquid-based cytology, high-risk HPV DNA tests, and colposcopy with directed biopsy and endocervical curettage as necessary. Women with abnormal cytologic results or positive HPV DNA results were recalled for colposcopy, 4-quadrant cervical biopsies, and endocervical curettage. Women with biopsy-proven CIN and cancer and a convenience sample of HC2-positive, disease-negative women were tested for the presence of HPV-16 infection via HPV-16 E6 DNA-specific polymerase chain reaction. A PDZ interaction-mediated E6 oncoprotein precipitation method followed by E6-specific Western blot was performed on specimens from women with HPV-16 infections. Associations between elevated expression of E6 oncoprotein and CIN 2 and 3 were determined using logistic regression and a reference category of CIN 1 and disease-negative.

RESULTS: A significant trend for the detection of HPV-16 E6 oncoprotein in specimen of women with proven HPV-16 infection was determined: 0\% (0/12), 12.5\% (1/8), 36.4\% (4/11), and 42.9\% (3/7) of those with negative findings, CIN 1, 2, and 3, respectively (p = .01). Compared with the category combining negative findings and CIN 1, detection of E6 oncoprotein was associated with CIN 2 (odds ratio = 10.9, p = .05) and CIN 3 (odds ratio = 14.3, p = .04).

CONCLUSIONS: There is a significant association between elevated expression of E6 oncoprotein and grade of CIN. This finding seems consistent with the role played by E6 oncoprotein in carcinogenesis.

}, keywords = {Adult, Blotting, Western, Cervical Intraepithelial Neoplasia, Cervix Uteri, China, Female, Human papillomavirus 16, Humans, Immunoprecipitation, Middle Aged, Oncogene Proteins, Viral, Papillomavirus Infections, Repressor Proteins, Up-Regulation, Uterine Cervical Neoplasms}, issn = {1526-0976}, doi = {10.1097/LGT.0b013e3181f6c84d}, author = {Sellors, John W and Schweizer, Johannes G and Lu, Peter S and Liu, Bin and Weigl, Bernhard H and Cui, Jian Feng and Peck, Roger B and Lewis, Kristen and Lim, Jeanette and Howard, Michelle and Mahoney, Charles W and McAllister, Linda and Berard-Bergery, Marthe and Bry, Claire and Labiad, Yassine A and Li, Haimin and Liu, Lilyn and Silver, Jon and Chen, Wen and Qiao, You Lin} } @article {214, title = {Non-Instrumented Nucleic Acid Amplification (NINA) for Rapid Detection of Ralstonia solanacearum Race 3 Biovar 2.}, journal = {Biol Eng Trans}, volume = {4}, year = {2011}, month = {2011}, pages = {69-80}, abstract = {

We report on the use of a non-instrumented device for the implementation of a loop-mediated amplification (LAMP) based assay for the select-agent bacterial-wilt pathogen Ralstonia solanacearum race 3 biovar 2. Heat energy is generated within the device by the exothermic hydration of calcium oxide, and the reaction temperature is regulated by storing latent energy at the melting temperature of a renewable lipid-based engineered phase-change material. Endpoint detection of the LAMP reaction is achieved without opening the reaction tube by observing the fluorescence of an innovative FRET-based hybridization probe with a simple custom fluorometer. Non-instrumented devices could maintain reactions near the design temperature of 63{\textdegree}C for at least an hour. Using this approach DNA extracted from the pathogen could be detected at fewer than ten copies within a 25 μL reaction mix, illustrating the potential of these technologies for simple, powerful agricultural diagnostics in the field. Furthermore, the assay was just as reliable when implemented in a tropical environment at 31{\textdegree}C as it was when implemented in an air-conditioned lab maintained at 22{\textdegree}C, illustrating the potential value of the technology for field conditions in the tropics and subtropics.

}, issn = {2162-643X}, doi = {10.13031/2013.38508}, author = {Kubota, Ryo and LaBarre, Paul and Singleton, Jered and Beddoe, Andy and Weigl, Bernhard H and Alvarez, Anne M and Jenkins, Daniel M} } @article {213, title = {Point-of-Care Technologies for Health Care.}, journal = {IEEE Trans Biomed Eng}, volume = {58}, year = {2011}, month = {2011 Mar}, pages = {732-5}, keywords = {Diagnosis, Computer-Assisted, Humans, Monitoring, Physiologic, Point-of-Care Systems}, issn = {1558-2531}, doi = {10.1109/TBME.2011.2109251}, author = {Beyette, Fred R and Gaydos, Charlotte A and Kost, Gerald J and Weigl, Bernhard H} } @article {216, title = {Laboratory operations, specimen processing, and handling for viral load testing and surveillance.}, journal = {J Infect Dis}, volume = {201 Suppl 1}, year = {2010}, month = {2010 Apr 15}, pages = {S27-36}, abstract = {

RNA remains the most informative and accurate biomarker for human immunodeficiency virus type 1 load diagnostics and for surveillance of drug resistance markers. Viral load testing by nucleic acid amplification currently is a complex and expensive test that is restricted to centralized laboratory testing. Successful extension of centralized viral load testing to rural or remote settings is a major challenge. Emerging nucleic acid-based technologies are progressing rapidly toward platforms appropriate for field use in low-resource settings, leaving a growing gap for sample processing technologies that complement them. One area in which new technologies could be applied to improve access is clinical specimen preservation and processing. Novel technologies that extract nucleic acid from clinical specimens and stabilize it at the point of specimen collection could fill this gap. In addition, these technologies may provide alternative viral load detection and surveillance solutions to the current centralized laboratory testing paradigm.

}, keywords = {HIV, HIV Infections, Humans, RNA, Viral, Specimen Handling, Viral Load}, issn = {1537-6613}, doi = {10.1086/650390}, author = {Puren, Adrian and Gerlach, Jay L and Weigl, Bernhard H and Kelso, David M and Domingo, Gonzalo J} } @article {221, title = {A magnetic immunochromatographic strip test for detection of human papillomavirus 16 E6.}, journal = {Clin Chem}, volume = {52}, year = {2006}, month = {2006 Nov}, pages = {2170-2}, keywords = {Antibodies, Monoclonal, Chromatography, Enzyme-Linked Immunosorbent Assay, Female, Human papillomavirus 16, Humans, Magnetics, Oncogene Proteins, Viral, PDZ Domains, Protein Binding, Protein Interaction Mapping, Recombinant Fusion Proteins, Repressor Proteins, Sensitivity and Specificity}, issn = {0009-9147}, author = {Peck, Roger B and Schweizer, Johannes and Weigl, Bernhard H and Somoza, Chamorro and Silver, John and Sellors, John W and Lu, Peter S} } @article {222, title = {Microfluidic diagnostic technologies for global public health.}, journal = {Nature}, volume = {442}, year = {2006}, month = {2006 Jul 27}, pages = {412-8}, abstract = {

The developing world does not have access to many of the best medical diagnostic technologies; they were designed for air-conditioned laboratories, refrigerated storage of chemicals, a constant supply of calibrators and reagents, stable electrical power, highly trained personnel and rapid transportation of samples. Microfluidic systems allow miniaturization and integration of complex functions, which could move sophisticated diagnostic tools out of the developed-world laboratory. These systems must be inexpensive, but also accurate, reliable, rugged and well suited to the medical and social contexts of the developing world.

}, keywords = {Developing Countries, Diagnostic Tests, Routine, Humans, Internationality, Microfluidics, Public Health}, issn = {1476-4687}, doi = {10.1038/nature05064}, author = {Yager, Paul and Edwards, Thayne and Fu, Elain and Helton, Kristen and Nelson, Kjell and Tam, Milton R and Weigl, Bernhard H} } @article {223, title = {Lab-on-a-chip for drug development.}, journal = {Adv Drug Deliv Rev}, volume = {55}, year = {2003}, month = {2003 Feb 24}, pages = {349-77}, abstract = {

Significant advances have been made in the development of micro-scale technologies for biomedical and drug discovery applications. The first generation of microfluidics-based analytical devices have been designed and are already functional. Microfluidic devices offer unique advantages in sample handling, reagent mixing, separation, and detection. We introduce and review microfluidic concepts, microconstruction techniques, and methods such as flow-injection analysis, electrokinesis, and cell manipulation. Advances in micro-device technology for proteomics, sample preconditioning, immunoassays, electrospray ionization mass spectrometry, and polymerase chain reaction are also reviewed.

}, keywords = {Animals, Humans, Microchemistry, Technology, Pharmaceutical}, issn = {0169-409X}, author = {Weigl, Bernhard H and Bardell, Ron L and Cabrera, Catherine R} } @article {226, title = {Lab-on-a-chip-based separation and detection technology for clinical diagnostics.}, journal = {Am Clin Lab}, volume = {21}, year = {2002}, month = {2002 Mar}, pages = {8-13}, keywords = {Chemistry, Clinical, Cytological Techniques, Humans, Miniaturization}, issn = {1041-3235}, author = {Weigl, Bernhard H and Hedine, Karen} } @article {225, title = {Microfluidic technologies in clinical diagnostics.}, journal = {Clin Chim Acta}, volume = {321}, year = {2002}, month = {2002 Jul}, pages = {1-10}, abstract = {

BACKGROUND: Laboratory instrumentation and analytical devices are becoming smaller, simpler, and smarter. This trend to miniaturization extends to fluid handling and fluid analysis. However, fluid behavior undergoes significant changes as geometric scale decreases. The laminar flow behavior of fluids in microfluidic devices must be accommodated in the design and development of clinical and bio-clinical miniaturized systems.

CONCLUSION: The scale of chemical and clinical analysis systems will continue to decrease. The capability to manufacture smaller fluidic devices and to quantitatively monitor smaller volumes of liquids bring this process of miniaturization into the domain of laminar flow. New and enabling technologies are being developed using the unique diffusion-based characteristics of the laminar flow domain for sample preparation and analysis. These new analytical systems will have a significant impact on the future of clinical diagnostics.

}, keywords = {Biomechanical Phenomena, Body Fluids, Chemistry, Clinical, Chromatography, High Pressure Liquid, Diffusion, Humans, Microchemistry, Miniaturization}, issn = {0009-8981}, author = {Schulte, Thomas H and Bardell, Ron L and Weigl, Bernhard H} }