MECs: "Building Blocks" for Creating Biological and Chemical Instruments.

The development of new biological and chemical instruments for research and diagnostic applications is often slowed by the cost, specialization, and custom nature of these instruments. New instruments are built from components that are drawn from a host of different disciplines and not designed to integrate together, and once built, an instrument typically performs a limited number of tasks and cannot be easily adapted for new applications. Consequently, the process of inventing new instruments is very inefficient, especially for researchers or clinicians in resource-limited settings. To improve this situation, we propose that a family of standardized multidisciplinary components is needed, a set of "building blocks" that perform a wide array of different tasks and are designed to integrate together. Using these components, scientists, engineers, and clinicians would be able to build custom instruments for their own unique needs quickly and easily. In this work we present the foundation of this set of components, a system we call Multifluidic Evolutionary Components (MECs). "Multifluidic" conveys the wide range of fluid volumes MECs operate upon (from nanoliters to milliliters and beyond); "multi" also reflects the multiple disciplines supported by the system (not only fluidics but also electronics, optics, and mechanics). "Evolutionary" refers to the design principles that enable the library of MEC parts to easily grow and adapt to new applications. Each MEC "building block" performs a fundamental function that is commonly found in biological or chemical instruments, functions like valving, pumping, mixing, controlling, and sensing. Each MEC also has a unique symbol linked to a physical definition, which enables instruments to be designed rapidly and efficiently using schematics. As a proof-of-concept, we use MECs to build a variety of instruments, including a fluidic routing and mixing system capable of manipulating fluid volumes over five orders of magnitude, an acid-base titration instrument suitable for use in schools, and a bioreactor suitable for maintaining and analyzing cell cultures in research and diagnostic applications. These are the first of many instruments that can be built by researchers, clinicians, and students using the MEC system.

High-sensitivity cardiac troponin I assay to screen for acute rejection in patients with heart transplant.

BACKGROUND: A noninvasive biomarker that could accurately diagnose acute rejection (AR) in heart transplant recipients could obviate the need for surveillance endomyocardial biopsies. We assessed the performance metrics of a novel high-sensitivity cardiac troponin I (cTnI) assay for this purpose. METHODS AND RESULTS: Stored serum samples were retrospectively matched to endomyocardial biopsies in 98 cardiac transplant recipients, who survived ≥3 months after transplant. AR was defined as International Society for Heart and Lung Transplantation grade 2R or higher cellular rejection, acellular rejection, or allograft dysfunction of uncertain pathogenesis, leading to treatment for presumed rejection. cTnI was measured with a high-sensitivity assay (Abbott Diagnostics, Abbott Park, IL). Cross-sectional analyses determined the association of cTnI concentrations with rejection and International Society for Heart and Lung Transplantation grade and the performance metrics of cTnI for the detection of AR. Among 98 subjects, 37% had ≥1 rejection episode. cTnI was measured in 418 serum samples, including 35 paired to a rejection episode. cTnI concentrations were significantly higher in rejection versus nonrejection samples (median, 57.1 versus 10.2 ng/L; P<0.0001) and increased in a graded manner with higher biopsy scores (P(trend)<0.0001). The c-statistic to discriminate AR was 0.82 (95% confidence interval, 0.76-0.88). Using a cut point of 15 ng/L, sensitivity was 94%, specificity 60%, positive predictive value 18%, and negative predictive value 99%. CONCLUSIONS: A high-sensitivity cTnI assay seems useful to rule out AR in cardiac transplant recipients. If validated in prospective studies, a strategy of serial monitoring with a high-sensitivity cTnI assay may offer a low-cost noninvasive strategy for rejection surveillance.

Neurological and chest symptoms following sclerotherapy: a single centre experience.

OBJECTIVES: Documentation and analysis of adverse neurological and chest symptoms in a large single centre series of sclerotherapy treatments. METHOD: In this retrospective study, patient-reported adverse events occurring during liquid or foam sclerotherapy were recorded over a 30 month period and subsequently analyzed. The relevant patient records were reviewed to determine patient characteristics, treatment details and results of subsequent investigations. RESULTS: A total of 1744 ultrasound guided sclerotherapy treatments were performed during the study period. Almost all treatments were done with air-based sodium tetradecyl sulphate foam. During the same time period, 6504 direct vision surface vein sclerotherapy treatments were completed. Approximately 1/4 of these utilized air-based foam in varying concentrations. There were 14 adverse events in 14 patients involving neurological or chest symptoms for an incidence of 0.17%. Five patients injected with foam complained of isolated chest discomfort, tightness or shortness of breath. Nine patients reported various brief neurological symptoms. These events occurred with both liquid and foam, although the majority involved foam. More neurological events were associated with direct vision sclerotherapy of smaller superficial veins than with ultrasound guided injection of intrafascial truncular veins. Seven patients who experienced neurological symptoms had a history of migraine. Five of the patients who had neurological events were investigated for right to left shunts and found to be positive. CONCLUSIONS: These events were uncommon and brief. The incidence of neurological and chest symptoms was higher with foam sclerotherapy than with liquid. A history of migraine with aura was associated with an increased risk of post-treatment neurological symptoms. Events occurred with both large vein and small vein treatment. Some events were associated with liquid sclerotherapy rather than foam and with carbon dioxide based foam as well as air foam. There were no long-term adverse consequences.

MECs: building blocks for custom microfluidic diagnostics in the developing world.

Microfluidic diagnostics for use in the developing world face a number of unique challenges. Doctors and nurses in developing countries are best suited to addresses these challenges, but they lack the resources and training needed to develop their own microfluidic diagnostics. To address this need, we are developing a system of Multifluidic Evolutionary Components or MECs, "building blocks" that can be snapped together by healthcare providers in resource-limited settings to build custom diagnostic instruments. MECs operate on multiple scales of fluid volumes (from nanoliters to milliliters) and include not only fluidic but also optical, mechanical, and electronic functions. In this work we share several prototype MECs and use them to build a demonstration instrument capable of measuring the pH of a sample.

Do established biomarkers such as B-type natriuretic peptide and troponin predict rejection?

PURPOSE OF REVIEW: Acute cardiac allograft rejection surveillance has historically been based on serial endomyocardial biopsy (EMB). Limitations with this approach have stimulated interest in identifying noninvasive surrogate markers of rejection. This review summarizes the evidence assessing the use of direct cardiac markers B-type natriuretic peptide (BNP) and cardiac troponins in detecting acute allograft rejection. RECENT FINDINGS: BNP, its amino-terminal fragment NT-proBNP, and cardiac troponins T and I have all been extensively evaluated for this purpose, and so far have demonstrated inadequate diagnostic accuracy to replace EMB. Longitudinal surveillance of BNP and NT-proBNP appears to offer promise for improved accuracy, but has not been adequately evaluated in prospective studies. Preliminary investigations into highly sensitive troponin assays suggest a potential role in rejection surveillance, but prospective validation in larger studies is needed. SUMMARY: EMB remains the gold standard for cardiac allograft rejection surveillance. However, recent data indicate potential clinical utility for serial monitoring of natriuretic peptides. If further investigation into highly sensitive troponin assays confirms the positive data so far reported, further efforts directed toward a longitudinal-based rejection surveillance algorithm incorporating both troponin and BNP may identify a strategy that could serve as an alternative to EMB.