Metabolomics on integrated circuit

We have demonstrated a chip-based diagnostics tool for the quantification of metabolites, using specific enzymes, to study enzyme kinetics and calculate the Michaelis-Menten constant. An array of 256×256 ion-sensitive field effect transistors (ISFETs) fabricated in a complementary metal oxide semiconductor (CMOS) process is used for this prototype. We have used hexokinase enzyme reaction on the ISFET CMOS chip with glucose concentration in the physiological range of 0.05 mM – 231 mM and successfully studied the enzyme kinetics of hexokinase in detail. This will promote future research towards multiplexing enzyme-based metabolite quantification on a single chip, ultimately opening a pathway towards a personal metabolome machine

Anti-self-dual conformal structures with null Killing vectors from projective structures

Using twistor methods, we explicitly construct all local forms of four--dimensional real analytic neutral signature anti--self--dual conformal structures $(M,[g])$ with a null conformal Killing vector. We show that $M$ is foliated by anti-self-dual null surfaces, and the two-dimensional leaf space inherits a natural projective structure. The twistor space of this projective structure is the quotient of the twistor space of $(M,[g])$ by the group action induced by the conformal Killing vector. We obtain a local classification which branches according to whether or not the conformal Killing vector is hyper-surface orthogonal in $(M, [g])$. We give examples of conformal classes which contain Ricci--flat metrics on compact complex surfaces and discuss other conformal classes with no Ricci--flat metrics.Comment: 43 pages, 4 figures. Theorem 2 has been improved: ASD metrics are given in terms of general projective structures without needing to choose special representatives of the projective connection. More examples (primary Kodaira surface, neutral Fefferman structure) have been included. Algebraic type of the Weyl tensor has been clarified. Final version, to appear in Commun Math Phy

An integrated circuit for chip-based analysis of enzyme kinetics and metabolite quantification

We have created a novel chip-based diagnostic tools based upon quantification of metabolites using enzymes specific for their chemical conversion. Using this device we show for the first time that a solid-state circuit can be used to measure enzyme kinetics and calculate the Michaelis-Menten constant. Substrate concentration dependency of enzyme reaction rates is central to this aim. Ion-sensitive field effect transistors (ISFET) are excellent transducers for biosensing applications that are reliant upon enzyme assays, especially since they can be fabricated using mainstream microelectronics technology to ensure low unit cost, mass-manufacture, scaling to make many sensors and straightforward miniaturisation for use in point-of-care devices. Here, we describe an integrated ISFET array comprising 216 sensors. The device was fabricated with a complementary metal oxide semiconductor (CMOS) process. Unlike traditional CMOS ISFET sensors that use the Si3N4 passivation of the foundry for ion detection, the device reported here was processed with a layer of Ta2O5 that increased the detection sensitivity to 45 mV/pH unit at the sensor readout. The drift was reduced to 0.8 mV/hour with a linear pH response between pH 2 – 12. A high-speed instrumentation system capable of acquiring nearly 500 fps was developed to stream out the data. The device was then used to measure glucose concentration through the activity of hexokinase in the range of 0.05 mM – 231 mM, encompassing glucose’s physiological range in blood. Localised and temporal enzyme kinetics of hexokinase was studied in detail. These results present a roadmap towards a viable personal metabolome machine

A colorimetric CMOS-based platform for rapid total serum cholesterol quantification

Elevated cholesterol levels are associated with a greater risk of developing cardiovascular disease and other illnesses, making it a prime candidate for detection on a disposable biosensor for rapid point of care diagnostics. One of the methods to quantify cholesterol levels in human blood serum uses an optically mediated enzyme assay and a bench top spectrophotometer. The bulkiness and power hungry nature of the equipment limits its usage to laboratories. Here, we present a new disposable sensing platform that is based on a complementary metal oxide semiconductor process for total cholesterol quantification in pure blood serum. The platform that we implemented comprises readily mass-manufacturable components that exploit colorimetric changes of cholesterol oxidase and cholesterol esterase reactions. We have shown that our quantification results are comparable to that obtained by a bench top spectrophotometer. Using the implemented device, we have measured cholesterol concentration in human blood serum as low as 29 μM with a limit of detection at 13 μM, which is approximately 400 times lower than average physiological range, implying that our device also has the potential to be used for applications that require greater sensitivity

Disposable paper-on-CMOS platform for real-time simultaneous detection of metabolites

Objective: Early stage diagnosis of sepsis without overburdening health services is essential to improving patient outcomes. Methods: A fast and simple-to-use platform that combines an integrated circuit with paper microfluidics for simultaneous detection of multiple-metabolites appropriate for diagnostics was presented. Paper based sensors are a primary candidate for widespread deployment of diagnostic or test devices. However, the majority of devices today use a simple paper strip to detect a single marker using the reflectance of light. However, for many diseases such as sepsis, one biomarker is not sufficient to make a unique diagnosis. In this work multiple measurements are made on patterned paper simultaneously. Using laser ablation to fabricate microfluidic channels on paper provides a flexible and direct approach for mass manufacture of disposable paper strips. A reusable photodiode array on a complementary metal oxide semiconductor chip is used as the transducer. Results: The system measures changes in optical absorbance in the paper to achieve a cost-effective and easily implemented system that is capable of multiple simultaneous assays. Potential sepsis metabolite biomarkers glucose and lactate have been studied and quantified with the platform, achieving sensitivity within the physiological range in human serum. Conclusion: We have detailed a disposable paper-based CMOS photodiode sensor platform for real-time simultaneous detection of metabolites for diseases such as sepsis. Significance: A combination of a low-cost paper strip with microfluidic channels and a sensitive CMOS photodiode sensor array makes our platform a robust portable and inexpensive biosensing device for multiple diagnostic tests in many different applications

Multimodal integrated sensor platform for rapid biomarker detection

Precision metabolomics and quantification for cost-effective, rapid diagnosis of disease are key goals in personalized medicine and point-of-care testing. Presently, patients are subjected to multiple test procedures requiring large laboratory equipment. Microelectronics has already made modern computing and communications possible by integration of complex functions within a single chip. As More than Moore technology increases in importance, integrated circuits for densely patterned sensor chips have grown in significance. Here, we present a versatile single CMOS chip forming a platform to address personalized needs through on-chip multimodal optical and electrochemical detection that will reduce the number of tests that patients must take. The chip integrates interleaved sensing subsystems for quadruple-mode colorimetric, chemiluminescent, surface plasmon resonance and hydrogen ion measurements. These subsystems include a photodiode array and a single photon avalanche diode array, with some elements functionalized to introduce a surface plasmon resonance mode. The chip also includes an array of ion sensitive field effect transistors. The sensor arrays are distributed uniformly over an active area on the chip surface in a scalable and modular design. Bio-functionalization of the physical sensors yields a highly selective simultaneous multiple-assay platform in a disposable format. We demonstrate its versatile capabilities through quantified bioassays performed on-chip for glucose, cholesterol, urea and urate, each within their naturally occurring physiological range

Cost and Outcome of Behavioural Activation versus Cognitive Behavioural Therapy for Depression (COBRA): a randomised, controlled, non-inferiority trial

Background Depression is a common, debilitating, and costly disorder. Many patients request psychological therapy, but the best-evidenced therapy—cognitive behavioural therapy (CBT)—is complex and costly. A simpler therapy—behavioural activation (BA)—might be as effective and cheaper than is CBT. We aimed to establish the clinical efficacy and cost-effectiveness of BA compared with CBT for adults with depression. Methods In this randomised, controlled, non-inferiority trial, we recruited adults aged 18 years or older meeting Diagnostic and Statistical Manual of Mental Disorders IV criteria for major depressive disorder from primary care and psychological therapy services in Devon, Durham, and Leeds (UK). We excluded people who were receiving psychological therapy, were alcohol or drug dependent, were acutely suicidal or had attempted suicide in the previous 2 months, or were cognitively impaired, or who had bipolar disorder or psychosis or psychotic symptoms. We randomly assigned participants (1:1) remotely using computer-generated allocation (minimisation used; stratified by depression severity [Patient Health Questionnaire 9 (PHQ-9) score of <19 vs ≥19], antidepressant use, and recruitment site) to BA from junior mental health workers or CBT from psychological therapists. Randomisation done at the Peninsula Clinical Trials Unit was concealed from investigators. Treatment was given open label, but outcome assessors were masked. The primary outcome was depression symptoms according to the PHQ-9 at 12 months. We analysed all those who were randomly allocated and had complete data (modified intention to treat [mITT]) and also all those who were randomly allocated, had complete data, and received at least eight treatment sessions (per protocol [PP]). We analysed safety in the mITT population. The non-inferiority margin was 1·9 PHQ-9 points. This trial is registered with the ISCRTN registry, number ISRCTN27473954. Findings Between Sept 26, 2012, and April 3, 2014, we randomly allocated 221 (50%) participants to BA and 219 (50%) to CBT. 175 (79%) participants were assessable for the primary outcome in the mITT population in the BA group compared with 189 (86%) in the CBT group, whereas 135 (61%) were assessable in the PP population in the BA group compared with 151 (69%) in the CBT group. BA was non-inferior to CBT (mITT: CBT 8·4 PHQ-9 points [SD 7·5], BA 8·4 PHQ-9 points [7·0], mean difference 0·1 PHQ-9 points [95% CI −1·3 to 1·5], p=0·89; PP: CBT 7·9 PHQ-9 points [7·3]; BA 7·8 [6·5], mean difference 0·0 PHQ-9 points [–1·5 to 1·6], p=0·99). Two (1%) non-trial-related deaths (one [1%] multidrug toxicity in the BA group and one [1%] cancer in the CBT group) and 15 depression-related, but not treatment-related, serious adverse events (three in the BA group and 12 in the CBT group) occurred in three [2%] participants in the BA group (two [1%] patients who overdosed and one [1%] who self-harmed) and eight (4%) participants in the CBT group (seven [4%] who overdosed and one [1%] who self-harmed). Interpretation We found that BA, a simpler psychological treatment than CBT, can be delivered by junior mental health workers with less intensive and costly training, with no lesser effect than CBT. Effective psychological therapy for depression can be delivered without the need for costly and highly trained professionals. Funding National Institute for Health Research

A New Measurement of Kaonic Hydrogen X rays

The $\bar{K}N$ system at threshold is a sensitive testing ground for low energy QCD, especially for the explicit chiral symmetry breaking. Therefore, we have measured the $K$-series x rays of kaonic hydrogen atoms at the DA$\Phi$NE electron-positron collider of Laboratori Nazionali di Frascati, and have determined the most precise values of the strong-interaction energy-level shift and width of the $1s$ atomic state. As x-ray detectors, we used large-area silicon drift detectors having excellent energy and timing resolution, which were developed especially for the SIDDHARTA experiment. The shift and width were determined to be $\epsilon_{1s} = -283 \pm 36 \pm 6 {(syst)}$ eV and $\Gamma_{1s} = 541 \pm 89 {(stat)} \pm 22 {(syst)}$ eV, respectively. The new values will provide vital constraints on the theoretical description of the low-energy $\bar{K}N$ interaction.Comment: 5 figures, submitted to Physics Letters

Future challenges of occupational safety and health policy-making in the UK

Understanding the changing landscape of occupational safety and health (OSH) regulation and standards and its implications are of central importance for ensuring that OSH outcomes are not compromised and the needs of different types of organizations are met. It is also important for developing appropriate strategies to anticipate and deal with future challenges for OSH policy-making. This paper draws on findings from two qualitative studies with key OSH stakeholders in the UK that were conducted as part of a research programme funded the Institution of Occupational Safety & Health. The aim of the first study was to elicit the views of key stakeholders on changes in the current OSH landscape so as to understand the nature and implications of these changes. The second study explored stakeholder perspectives on how to secure the optimal OSH landscape in the UK by addressing key future challenges for OSH policy-making

NMR and NQR Fluctuation Effects in Layered Superconductors

We study the effect of thermal fluctuations of the s-wave order parameter of a quasi two dimensional superconductor on the nuclear spin relaxation rate near the transition temperature Tc. We consider both the effects of the amplitude fluctuations and the Berezinskii-Kosterlitz-Thouless (BKT) phase fluctuations in weakly coupled layered superconductors. In the treatment of the amplitude fluctuations we employ the Gaussian approximation and evaluate the longitudinal relaxation rate 1/T1 for a clean s-wave superconductor, with and without pair breaking effects, using the static pair fluctuation propagator D. The increase in 1/T1 due to pair breaking in D is overcompensated by the decrease arising from the single particle Green's functions. The result is a strong effect on 1/T1 for even a small amount of pair breaking. The phase fluctuations are described in terms of dynamical BKT excitations in the form of pancake vortex-antivortex (VA) pairs. We calculate the effect of the magnetic field fluctuations caused by the translational motion of VA excitations on 1/T1 and on the transverse relaxation rate 1/T2 on both sides of the BKT transitation temperature T(BKT)<Tc. The results for the NQR relaxation rates depend strongly on the diffusion constant that governs the motion of free and bound vortices as well as the annihilation of VA pairs. We discuss the relaxation rates for real multilayer systems where the diffusion constant can be small and thus increase the lifetime of a VA pair, leading to an enhancement of the rates. We also discuss in some detail the experimental feasibility of observing the effects of amplitude fluctuations in layered s-wave superconductors such as the dichalcogenides and the effects of phase fluctuations in s- or d-wave superconductors such as the layered cuprates.Comment: 38 pages, 12 figure