Readout System Research Articles

FC076: Development of a High-Throughput in Vivo Drug Screening Assay Using a FSGS-Like Zebrafish Model

Abstract BACKGROUND AND AIMS Focal segmental sclerosis (FSGS) is a severe histopathological condition which often results in end-stage renal disease. Loss of podocytes and severe changes of podocyte foot process morphology accompanied by proteinuria are the hallmarks of FSGS. Since no therapeutic agents are available until now, further efforts must be made to identify new drugs to treat this disease. The zebrafish larva is a widely used kidney research model as the morphology and function of zebrafish and mammalian glomeruli are very similar. Since our group has already established a FSGS-like zebrafish injury model based on the nitroreductase-metronidazole cell ablation system, we have developed a high-throughput based in vivo drug screening assay. METHOD We used a zebrafish screening strain that expresses mCherry and the bacterial enzyme nitroreductase in podocytes. Additionally, a circulating vitamin-D-binding eGFP fusion protein with a size of 78 kDa is expressed and serves as a read-out for proteinuria. Incubation with 80 µM metronidazole for 24 h at 4 days post-fertilization (dpf) induces an FSGS-like phenotype in these larvae. A library of 138 epigenetic drugs were screened and the results are presented herein. Groups of 12 larvae received injury induction as well as drug treatment and were transferred individually into 96-well plates prepared with custom agarose molds. Larvae were oriented laterally and imaged with a high-content screening microscope (Acquifer Imaging Machine). The eGFP signal in the caudal vasculature as well as the glomerular mCherry signal served as readout systems. At 6 dpf, the same larvae and regions were imaged again. Custom written FIJI codes automatically segmented and measured the fluorescence intensities of both readouts and timepoints. For each larva, intensity ratios were determined and the ratios of each treatment group served as the input for statistical analysis. RESULTS Treatment for 24 hours with 80 µM metronidazole resulted in a measurable decline of the eGFP signal in the vasculature and of the podocyte mCherry signal compared to the vehicle (DMSO) group. Simultaneous treatment of metronidazole with the 138 drugs in the epigenetics library resulted in beneficial outcomes in varying degrees (9 drugs were positive, 36 compounds were lethal). CONCLUSION This new in vivo semi-automated high-throughput compatible drug screening assay allows rapid identification of FSGS protective drugs. Here we screened 138 epigenetic drugs, which led to the identification of 9 potential drugs which have had a beneficial effect on podocytes and/or the glomerular filtration barrier.

Readout system for a prototype multi-purpose time projection chamber at CSNS Back-n

This paper presents a readout system for a prototype multi-purpose Time Projection Chamber (MTPC), which is developed for the research of neutron-induced light-charged particles emission reaction. The prototype MTPC consists of 1521 readout channels for charge measurements, track reconstruction, and neutron time-of-flight measurement. The main function of the readout system is to perform 1521-channel waveform digitization based on multi-channel analog to digital converters (ADCs). Digital waveform compression, multi-board time synchronization, and many other efforts have been made to ensure system performance and stability. Test results show that the readout system has a time resolution better than 10 ns at a trigger rate of 20 kHz. With a 2.8 pC dynamic range of charge measurement, the noise without any input load is around 0.76 fC (in RMS), and the nonlinearity of each channel is less than 0.35%. A beam test with 6Li target has been carried out at the back-streaming white neutron source (Back-n) of China Spallation Neutron Source. The tracks of particles from neutron-induced reactions have been successfully reconstructed. The time-of-flight distribution of the 6Li(n,α)3H reaction reveals the resonance peak at about 240 keV. These results indicate that the readout system fulfils the requirements of the prototype MTPC.

Ultrasensitive quantitation of circulating miR-195-5p with triple strand displacement amplification cascade.

Circulating miR-195-5p has been proposed as a promising peripheral biomarker for the diagnosis, prognosis and severity assessment of various diseases. However, the demand for its sensitive and convenient quantification has not been met yet. Herein, we proposed a one-pot isothermal approach, in which the target signal acquisition, amplification and conversion (fluorescence read-out) system was integrated by a triple strand displacement amplification (SDA) cascade. Using this triple SDA strategy, miR-195-5p can be at least detected at 1 aM, and the linear dynamic range (from 100 aM to 1 pM) is wide enough to meet the detection needs of clinical miRNA level. A proof-of-principle study, using this novel methodology to directly analyze the spiking serum samples with different levels of miR-195-5p, demonstrated the potential of circulating miR-195-5p detection for clinical point-of-care assay. This one-pot isothermal triple SDA approach, we believe, will be a simple and feasible tool for ultrasensitive quantification of circulating miR-195-5p, and may promote the wide application of this potential biomarker in non-invasive clinical diagnosis.

The JUNO experiment and its electronics readout system

The main goal of the Jiangmen Underground Neutrino Observatory (JUNO) under construction in China is to determine the neutrino mass hierarchy and to measure oscillation parameters to the sub-percent level. The detector consists of 20 ktons of liquid scintillator instrumented by 17612 20-inch photo-multiplier tubes, and 25600 3-inch small PMTs, with photo-cathode coverage of 77%. The electronics system is separated into two main parts. The front-end system, sitting under water, performs analog signal processing. The back-end electronics system, sitting outside water, consists of the DAQ and the trigger. The current production status of the experiment as well as the design of the electronics system will be reported in the presentation.

Aptamer Functionalized Hydrogel Nanocomposite for Electrochemical Sensing of Progesterone

Among the numerous analytical techniques, electrochemical devices have emerged as a cost-effective tool for point-of-care (POC) diagnosis. Electrochemical biosensing devices combine the peculiar features of the bioreceptors, such as selectivity and specificity, with a cost-effective and miniaturised electronic readout system. In this work, aptamer functionalised AuNCs integrated with a hybrid hydrogel employed as a reliable aptamer modified sensing platform for detecting progesterone (p4). The binding features of the p4 sensor are studied using square wave voltammetry. The p4 sensor was responsive to p4 concentration ranging from 1 to 100 nM with a detection limit of 0.3 ng/mL.

Development of glass-based nuclear emulsion plate as an ultra-high precision tracking detector in the era of fully automated readout systems

The positional accuracy of a nuclear emulsion can reach a submicrometric resolution owing to the size of its detection elements, i.e., 200 nm sized AgBr crystals. However, when used as a film in an experimental environment, the film is deformed by temperature and various mechanical stresses, and it becomes difficult to maintain the accuracy of the submicrometric absolute position throughout the detector. In this study, we attempted to solve this problem by using a glass base instead of a plastic base, which has been widely used thus far. To evaluate the deformation effect, sets of nuclear emulsion plates with a size of 10cm×12.5cm using various base materials were exposed to 5GeV/c pion beams. The magnitude of the deformation between the two films was evaluated using the beam pattern discrepancy. For the commonly used 180 μm thick polystyrene base, the magnitude of the deformation within the 3cm×4cm region was evaluated to be 1.77 μm on average, whereas for the 500 μm thick glass base, it was improved to 0.31 μm. This was approximately the same level as the measurement accuracy of the fully automated nuclear emulsion readout system, and the effect of the film deformation can be ignored. Through an analysis of this experiment, it became clear that the angle of the track had a systematic correlation with the material of the base. Because it can be inferred that the origin is owing to the difference between the refractive index of the base and the designed refractive index of the optical system of the readout system, an equation for correcting this systematic error was proposed. Nuclear emulsions with glass supporting bases are suitable for applications that require submicrometric positional accuracy throughout the detector, such as the precise measurement of momentum using a magnetic field and multiple scattering, and for use in outdoor experiments where the temperature changes widely.

A biosensor based on a thermal camera using infrared radiance as the signal probe

Flexible-type signal probes and their detection methods are increasingly being applied in biosensors. Among these, temperature-based signal probes represent a novel research direction. These sensors convert immunoassay signals into temperature signals, which are then detected using a thermometer or thermal infrared reader. However, from a physical viewpoint, we know that the temperature measured directly using a thermal infrared camera is the infrared radiance temperature, which is proportional to both the true temperature and emissivity. Herein, we design a novel sensing method that uses infrared radiance rather than true temperature as the signal probe. We convert the immunoassay to an infrared radiation temperature measurement by controlling an aluminum plate in constant temperature whose infrared radiation temperature varied significantly with immunoassay-based the amount of the target. We then develop two readout systems: one is based on a scientific-grade infrared camera, and the other uses a smartphone-based thermal camera, which is more portable, flexible, and can be used as an in-pocket sensor. The sensors are verified via detecting exemplary biomarker human IgG, and show excellent quantitative model performances in 0–100 ng mL−1 concentration range with the detection limit estimated as low as 0.54 ng mL−1. The excellent quantitative results demonstrate the powerful detection performance of this sensing method.

SRS-based Timepix3 readout system

With the combination of the highly granular pixel ASIC Timepix3 by the Medipix3 collaboration and several technologies we are developing a range of detectors. These technologies are bump bonded sensors, microchannel plates (MCP) and photolithographically postprocessed gas amplification stages (InGrid). For example, we are using the combination of the ASIC and an InGrid for the development of X-ray detectors for X-ray polarimetry and for axion search at IAXO. Based on the combination of the ASIC and silicon sensors we are developing a tracker or respectively a beam telescope. The combination of the ASIC and a microchannel plate will be used for neutron detectors. As this range of detectors has several requirements towards the readout and control system and a wide range of designs from low- to high-rate (Hz to MHz) and from single- to multichip, a versatile readout system is needed which adapts these applications without producing too much overhead for the others. To fulfil these requirements, we are developing a modular and scalable readout and control system based on the basil framework — a modular data acquisition system and system testing framework. The fully open-source implementation uses Verilog for the firmware and Python for the software. The system supports several FPGA boards to offer different applications a range of capabilities. One of these FPGA boards is the Scalable Readout System (SRS) by RD51 which offers scalability in low to medium rate applications. For high-rate applications we are working towards the firmware implementation on Xilinx adaptive compute acceleration platform. Besides the scalability, the system offers an optional monitoring interface via a microcontroller for monitoring chip temperatures and power supply voltages. Additionally, further external sensors could be connected to the monitoring system for example via I2C or SPI. For controlling the full system, the software offers a command line interface and a graphical user interface. Both interfaces also include an online event display to monitor the raw data. Additional meta data and data of the monitoring system is stored in a database and can be visualised with a monitoring dashboard.

QUBIC IV: Performance of TES bolometers and readout electronics

A prototype version of the Q & U bolometric interferometer for cosmology (QUBIC) underwent a campaign of testing in the laboratory atAstroparticle Physics and Cosmology laboratory in Paris (APC). The detection chain is currently made of 256 NbSi transition edge sensors (TES) cooled to 320 mK. The readout system is a 128:1 time domain multiplexing scheme based on 128 SQUIDs cooled at 1 K that are controlled and amplified by a SiGe application specific integrated circuit at 40 K. We report the performance of this readout chain and the characterization of the TES. The readout system has been functionally tested and characterized in the lab and in QUBIC. The low noise amplifier demonstrated a white noise level of 0.3 nV/√Hz. Characterizations of the QUBIC detectors and readout electronics includes the measurement of I-V curves, time constant and the noise equivalent power. The QUBIC TES bolometer array has approximately 80% detectors within operational parameters. It demonstrated a thermal decoupling compatible with a phonon noise of about 5 × 10-17 W/√Hz at 410 mK critical temperature. While still limited by microphonics from the pulse tubes and noise aliasing from readout system, the instrument noise equivalent power is about2 × 10-16 W/√Hz, enough for the demonstration of bolometric interferometry.

Readout electronics for the CMS Phase II Endcap Calorimeter: system overview and prototyping experience

The frontend readout system for the silicon section of the CMS Phase II Endcap Calorimeter faces unique challenges due to the high channel count and associated bandwidth, limited physical space, as well as radiation tolerance requirements. I will give an overview of the frontend electronics design and will discuss the recent experience obtained from the first test system that integrates the HGCROC2 readout ASIC, lpGBT, and VTRX+ in a realistic manner, linking together prototypes of the hexaboard, engine, and wagon boards.

Installation, integration and first operating experiences of the ALICE ITS upgraded readout system

The ALICE inner tracking system has gone through a significant upgrade for the upcoming third running period of the CERN LHC. The new detector consists of seven layers of high-granularity pixel sensors, while 192 custom FPGA-based readout units control the sensors and transmit the data upstream for analysis. This contribution describes the current system status and the expertise gained by moving from surface commissioning to the installation and throughout the data-taking preparation period, focusing on the intricate integration with other system components. Selected challenges, issues, and lessons learned during the various commissioning periods are presented.

A 0.018 %/V Line Sensitivity Voltage Reference With −82.46 dB PSRR at 100 Hz for Bio-Potential Signals Readout Systems

This brief presents a high power supply ripple rejection (PSRR) and low line sensitivity voltage reference for driving right leg (DgRL) circuits in bio-potential signals readout systems. The proposed voltage reference circuit employs the collector common-mode voltage extraction feedback (CVEF) architecture and the all-sub-threshold-region low line sensitivity (ASLS) circuit to achieve high PSRR and low line sensitivity. A prototype has been taped out using a 0.35- <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$\mu \text{m}$ </tex-math></inline-formula> CMOS technology, and the chip core occupies 0.16 mm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> . The measured reference voltage is about 1.22 V, and its average temperature coefficient (TC) in the range of −40 °C to 125 °C is 12.3 ppm/°C. The measured PSRR of a random chip with 5 V supply voltage is −80.29 dB, −80.16 dB, −82.46 dB, −76.04 dB, −73.17 dB and −38.59 dB at 10 Hz, 50 Hz, 100 Hz, 500 Hz, 1 kHz and 100 kHz, respectively. In the 2–5 V <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$V_{DD}$ </tex-math></inline-formula> range, the line sensitivity of the proposed circuit is 0.018 %/V. The current consumption of the whole circuit is 23.2 <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$\mu \text{A}$ </tex-math></inline-formula> when <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$V_{DD}$ </tex-math></inline-formula> takes the minimum value 2 V at room temperature.

A SiPM photon-counting readout system for Ultra-Fast Astronomy

Very little work has been done searching for astrophysical transient optical emission in the millisecond to nanosecond regime with significant sensitivity. We call this regime "Ultra-Fast Astronomy", or UFA. To investigate transients on as short time scales as possible, we developed our own customized readout system for a silicon photomultiplier (SiPM)-based UFA camera, intended for use on conventional astronomical telescopes. SiPMs, available in array packages for imaging a field, are capable of time-tagged single-photon detection in the visible wavelength range. Our readout system consists of 16 channels of 14-bit data logging. Each channel includes a 50-dB gain pre-amplifier, signal shaping circuits, an analogue front end, an analogue to digital converter, and a Xilinx UltraScale+ Field Programable Gate Array Multipurpose System on Chip (FPGA-MPSoC)board for data-logging. We show that our system successfully read out the data from SiPM at 16 ns intervals with a maximum power consumption of 300 mW per channel and capability to perform concurrent 16 channels readout.

CASCADE: Naked eye-detection of SARS-CoV-2 using Cas13a and gold nanoparticles

The COVID-19 pandemic has brought to light the need for fast and sensitive detection methods to prevent the spread of pathogens. The scientific community is making a great effort to design new molecular detection methods suitable for fast point-of-care applications. In this regard, a variety of approaches have been developed or optimized, including isothermal amplification of viral nucleic acids, CRISPR-mediated target recognition, and read-out systems based on nanomaterials.Herein, we present CASCADE (CRISPR/CAS-based Colorimetric nucleic Acid DEtection), a sensing system for fast and specific naked-eye detection of SARS-CoV-2 RNA. In this approach, viral RNA is recognized by the LwaCas13a CRISPR protein, which activates its collateral RNase activity. Upon target recognition, Cas13a cleaves ssRNA oligonucleotides conjugated to gold nanoparticles (AuNPs), thus inducing their colloidal aggregation, which can be easily visualized. After an exhaustive optimization of functionalized AuNPs, CASCADE can detect picomolar concentrations of SARS-CoV-2 RNA. This sensitivity is further increased to low femtomolar (3 fM) and even attomolar (40 aM) ranges when CASCADE is coupled to RPA or NASBA isothermal nucleic acid amplification, respectively. We finally demonstrate that CASCADE succeeds in detecting SARS-CoV-2 in clinical samples from nasopharyngeal swabs.In conclusion, CASCADE is a fast and versatile RNA biosensor that can be coupled to different isothermal nucleic acid amplification methods for naked-eye diagnosis of infectious diseases.

A muographic study of a scoria cone from 11 directions using nuclear emulsion cloud chambers

Abstract. One of the key challenges for muographic studies is to reveal the detailed 3D density structure of a volcano by increasing the number of observation directions. 3D density imaging by multi-directional muography requires that the individual differences in the performance of the installed muon detectors are small and that the results from each detector can be derived without any bias in the data analysis. Here we describe a pilot muographic study of the Izu–Omuroyama scoria cone in Shizuoka Prefecture, Japan, from 11 directions, using a new nuclear emulsion detector design optimized for quick installation in the field. We describe the details of the data analysis and present a validation of the results. The Izu–Omuroyama scoria cone is an ideal target for the first multi-directional muographic study, given its expected internal density structure and the topography around the cone. We optimized the design of the nuclear emulsion detector for rapid installation at multiple observation sites in the field, and installed these at 11 sites around the volcano. The images in the developed emulsion films were digitized into segmented tracks with a high-speed automated readout system. The muon tracks in each emulsion detector were then reconstructed. After the track selection, including straightness filtering, the detection efficiency of the muons was estimated. Finally, the density distributions in 2D angular space were derived for each observation site by using a muon flux and attenuation models. The observed muon flux was compared with the expected value in the free sky, and is 88 % ± 4 % in the forward direction and 92 % ± 2 % in the backward direction. The density values were validated by comparison with the values obtained from gravity measurements, and are broadly consistent, except for one site. The excess density at this one site may indicate that the density inside the cone is non-axisymmetric, which is consistent with a previous geological study.

Rate-capability of the VMM3a front-end in the RD51 Scalable Readout System

The VMM3a is an Application Specific Integrated Circuit (ASIC), specifically developed for the readout of gaseous detectors. Originally developed within the ATLAS New Small Wheel (NSW) upgrade, it has been successfully integrated into the Scalable Readout System (SRS) of the RD51 collaboration. This allows, to use the VMM3a also in small laboratory set-ups and mid-scale experiments, which make use of Micro-Pattern Gaseous Detectors (MPGDs). As part of the integration of the VMM3a into the SRS, the readout and data transfer scheme was optimised to reach a high rate-capability of the entire readout system and profit from the VMM3a’s high single-channel rate-capability of 3.6Mhits/s. The optimisation focused mainly on the handling of the data output stream of the VMM3a, but also on the development of a trigger-logic between the front-end cards and the DAQ computer. In this article, two firmware implementations of the non-ATLAS continuous readout mode are presented, as well as the implementation of the trigger-logic. Afterwards, a short overview on X-ray imaging results is presented, to illustrate the high rate-capability from an application point-of-view.

Low-cost remote distance and height sensing analog device for laboratory agriculture environments

This paper introduces a novel simple readout system for infrared distance measurement and transmission in closed environments, for instance small-area agriculture, employing transformation of distance on settable duty cycle variation. This simple analog system utilizes active devices fabricated in 0.35 μm 3.3 V I3T25 ON Semiconductor complementary metal oxide semiconductor process. Analog system generates and transmits the information in form of the duty cycle of square wave signal with frequency of 3 kHz up to 46.6 kHz in full range (duty cycle approximately between 10% and 90%) or half range (above 50%) due to requirements of various types of receivers. There is no requirement for any special processing software. The transmitted waveform is received by a low-cost phototransistor in distance at least 30 mm (case when the transmitter and receiver are placed directly on both sides of dividing glass plate). The proposed concept was tested for distance measurement (up to 70 mm) by commercially available distance sensor connected to the communication system and can be utilized for different use cases (e.g. monitoring of growth of small plants or mushrooms). The measuring range (sensitivity and dynamical range) of the sensing system can be easily adjusted. The experiments indicate error between the transmitted and received value below 5%. The overall error of the system between the evaluated and real measured distance is below 10%. All the presented tests confirmed operationability of the proposed system.

Implantable, wireless, self-fixing thermal sensors for continuous measurements of microvascular blood flow in flaps and organ grafts

Vascular pedicle thrombosis after free flap transfer or solid organ transplantation surgeries can lead to flap necrosis, organ loss requiring re-transplantation, or even death. Although implantable flow sensors can provide early warning of malperfusion and facilitate operative salvage, measurements performed with existing technologies often depend on extrinsic conditions such as mounting methods and environmental fluctuations. Furthermore, the mechanisms for fixing such probes to vascular or skeletal structures may disrupt the normal blood flow or cause unnecessary tissue damage. Requirements for wired connections to benchtop readout systems also increase costs, complicate clinical care and constrain movements of the patient. Here, we report a wireless, miniaturized flow sensing system that exploits sub-millimeter scale, multi-nodal thermal probes, with biodegradable barbs that secure the probes to the surrounding tissues in a manner that facilitates removal after a period of use. These smartphone-readable devices, together with experimentally validated analytical models of the thermal transport physics, enable reliable, accurate flow sensing in ways that are largely immune to variations in temperature and mechanical perturbations. In vivo demonstrations of this technology in porcine myocutaneous flap and kidney malperfusion models highlight the essential capabilities in microsurgical and transplantation-related biomedical application scenarios.

Figure of Merit for CRISPR-Based Nucleic Acid-Sensing Systems: Improvement Strategies and Performance Comparison.

Clustered regularly interspaced short palindromic repeats (CRISPR)-based nucleic acid-sensing systems have grown rapidly in the past few years. Nevertheless, an objective approach to benchmark the performances of different CRISPR sensing systems is lacking due to the heterogeneous experimental setup. Here, we developed a quantitative CRISPR sensing figure of merit (FOM) to compare different CRISPR methods and explore performance improvement strategies. The CRISPR sensing FOM is defined as the product of the limit of detection (LOD) and the associated CRISPR reaction time (T). A smaller FOM means that the method can detect smaller target quantities faster. We found that there is a tradeoff between the LOD of the assay and the required reaction time. With the proposed CRISPR sensing FOM, we evaluated five strategies to improve the CRISPR-based sensing: preamplification, enzymes of higher catalytic efficiency, multiple crRNAs, digitalization, and sensitive readout systems. We benchmarked the FOM performances of 57 existing studies and found that the effectiveness of these strategies on improving the FOM is consistent with the model prediction. In particular, we found that digitalization is the most promising amplification-free method for achieving comparable FOM performances (∼1 fM·min) as those using preamplification. The findings here would have broad implications for further optimization of the CRISPR-based sensing.

Point-of-care therapeutic drug monitoring of adalimumab by integrating a FO-SPR biosensor in a self-powered microfluidic cartridge

Disease treatment with advanced biological therapies such as adalimumab (ADM), although largely beneficial, is still costly and suffers from loss of response. To tackle these aspects, therapeutic drug monitoring (TDM) is proposed to improve treatment dosing and efficacy, but is often associated with long sampling-to-result workflows. Here, we present an in-house constructed ADM-sensor, allowing TDM of ADM at the doctor's office. This biosensor brings fiber optic surface plasmon resonance (FO-SPR), combined with self-powered microfluidics, to a point of care (POC) setting for the first time. After developing a rapid FO-SPR sandwich bioassay for ADM detection on a commercial FO-SPR device, this bioassay was implemented on the fully-integrated ADM-sensor. For the latter, we combined (I) a gold coated fiber optic (FO) probe for bioassay implementation and (II) an FO-SPR readout system with (III) the self-powered iSIMPLE microfluidic technology empowering plasma sample and reagent mixing on the-cartridge as well as connection to the FO-SPR readout system. With a calculated limit of detection (LOD) of 0.35 μg/mL in undiluted plasma, and a total time-to-result (TTR) within 12 min, this innovative biosensor demonstrated a comparable performance to existing POC biosensors for ADM quantification in patient plasma samples, while requiring only 1 μL of plasma. Whereas this study demonstrates great potential for FO-SPR biosensing at the POC using ADM as a model case, it also shows huge potential for bedside TDM of other drugs (e.g. other immunosuppressants, anti-epileptics and antibiotics), as the bioassay is highly amenable to adaptation.