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Biomedical subjects

John Clarke

Publications and source records attributed to John Clarke.

At least 19 recordsLinked to original sources
PubMed2006

Solid-state qubits with current-controlled coupling.

The ability to switch the coupling between quantum bits (qubits) on and off is essential for implementing many quantum-computing algorithms. We demonstrated such control with two flux qubits coupled together through their mutual inductances and through the dc superconducting quantum interference device (SQUID) that reads out their magnetic flux states. A bias current applied to the SQUID in the zero-voltage state induced a change in the dynamic inductance, reducing the coupling energy controllably to zero and reversing its sign.

Journal Article↗
PubMed2006

Static nuclear spin polarization induced in a liquid by a rotating magnetic field.

We demonstrate that protons in a liquid acquire a static polarization perpendicular to the plane of a rotating magnetic field. The rotating field was reduced adiabatically to zero, transforming the static polarization in the rotating frame to the laboratory frame. The application of a small magnetic field perpendicular to the polarization induced a free induction decay (FID) that was detected by a superconducting quantum interference device. The results agree with the predictions of the modified Bloch equations. The FID remained observable in the presence of magnetic material, suggesting that this technique may find practical applications.

Journal Article↗
PubMed2006

Stabilizing superconductivity in nanowires by coupling to dissipative environments.

We present a theory for a finite-length superconducting nanowire coupled to an environment. We show that in the absence of dissipation quantum phase slips always destroy superconductivity, even at zero temperature. Dissipation stabilizes the superconducting phase. We apply this theory to explain the "antiproximity effect" recently seen by Tian et al. in zinc nanowires.

Journal Article↗
PubMed2006

Discordances between interpretation algorithms for genotypic resistance to protease and reverse transcriptase inhibitors of human immunodeficiency virus are subtype dependent.

The major limitation of drug resistance genotyping for human immunodeficiency virus remains the interpretation of the results. We evaluated the concordance in predicting therapy response between four different interpretation algorithms (Rega 6.3, HIVDB-08/04, ANRS [07/04], and VGI 8.0). Sequences were gathered through a worldwide effort to establish a database of non-B subtype sequences, and demographic and clinical information about the patients was gathered. The most concordant results were found for nonnucleoside reverse transcriptase (RT) inhibitors (93%), followed by protease inhibitors (84%) and nucleoside RT inhibitor (NRTIs) (76%). For therapy-naive patients, for nelfinavir, especially for subtypes C and G, the discordances were driven mainly by the protease (PRO) mutational pattern 82I/V + 63P + 36I/V for subtype C and 82I + 63P + 36I + 20I for subtype G. Subtype F displayed more discordances for ritonavir in untreated patients due to the combined presence of PRO 20R and 10I/V. In therapy-experienced patients, subtype G displayed a lot of discordances for saquinavir and indinavir due to mutational patterns involving PRO 90 M and 82I. Subtype F had more discordance for nelfinavir attributable to the presence of PRO 88S and 82A + 54V. For the NRTIs lamivudine and emtricitabine, CRF01_AE had more discordances than subtype B due to the presence of RT mutational patterns 65R + 115 M and 118I + 215Y, respectively. Overall, the different algorithms agreed well on the level of resistance scored, but some of the discordances could be attributed to specific (subtype-dependent) combinations of mutations. It is not yet known whether therapy response is subtype dependent, but the advice given to clinicians based on a genotypic interpretation algorithm differs according to the subtype.

Algorithms↗
PubMed2005

SQUID-detected microtesla MRI in the presence of metal.

In magnetic resonance imaging performed at fields of 1 T and above, the presence of a metal insert can distort the image because of susceptibility differences within the sample and modification of the radiofrequency fields by screening currents. Furthermore, it is not feasible to perform nuclear magnetic resonance (NMR) spectroscopy or acquire a magnetic resonance image if the sample is enclosed in a metal container. Both problems can be overcome by substantially lowering the NMR frequency. Using a microtesla imaging system operating at 2.8 kHz, with a superconducting quantum interference device as the signal detector, we have obtained distortion-free images of a phantom containing a titanium bar and three-dimensional images of an object enclosed in an aluminum can; in both cases high-field images are inaccessible.

Aluminum↗
PubMed2005

Correction of concomitant gradient artifacts in experimental microtesla MRI.

Magnetic resonance imaging (MRI) suffers from artifacts caused by concomitant gradients when the product of the magnetic field gradient and the dimension of the sample becomes comparable to the static magnetic field. To investigate and correct for these artifacts at very low magnetic fields, we have acquired MR images of a 165-mm phantom in a 66-microT field using gradients up to 350 microT/m. We prepolarize the protons in a field of about 100 mT, apply a spin-echo pulse sequence, and detect the precessing spins using a superconducting gradiometer coupled to a superconducting quantum interference device (SQUID). Distortion and blurring are readily apparent at the edges of the images; by comparing the experimental images to computer simulations, we show that concomitant gradients cause these artifacts. We develop a non-perturbative, post-acquisition phase correction algorithm that eliminates the effects of concomitant gradients in both the simulated and the experimental images. This algorithm assumes that the switching time of the phase-encoding gradient is long compared to the spin precession period. In a second technique, we demonstrate that raising the precession field during phase encoding can also eliminate blurring caused by concomitant phase-encoding gradients; this technique enables one to correct concomitant gradient artifacts even when the detector has a restricted bandwidth that sets an upper limit on the precession frequency. In particular, the combination of phase correction and precession field cycling should allow one to add MRI capabilities to existing 300-channel SQUID systems used to detect neuronal currents in the brain because frequency encoding could be performed within the 1-2 kHz bandwidth of the readout system.

Algorithms↗
PubMed2005

Impact of HIV-1 subtype and antiretroviral therapy on protease and reverse transcriptase genotype: results of a global collaboration.

BACKGROUND: The genetic differences among HIV-1 subtypes may be critical to clinical management and drug resistance surveillance as antiretroviral treatment is expanded to regions of the world where diverse non-subtype-B viruses predominate. METHODS AND FINDINGS: To assess the impact of HIV-1 subtype and antiretroviral treatment on the distribution of mutations in protease and reverse transcriptase, a binomial response model using subtype and treatment as explanatory variables was used to analyze a large compiled dataset of non-subtype-B HIV-1 sequences. Non-subtype-B sequences from 3,686 persons with well characterized antiretroviral treatment histories were analyzed in comparison to subtype B sequences from 4,769 persons. The non-subtype-B sequences included 461 with subtype A, 1,185 with C, 331 with D, 245 with F, 293 with G, 513 with CRF01_AE, and 618 with CRF02_AG. Each of the 55 known subtype B drug-resistance mutations occurred in at least one non-B isolate, and 44 (80%) of these mutations were significantly associated with antiretroviral treatment in at least one non-B subtype. Conversely, of 67 mutations found to be associated with antiretroviral therapy in at least one non-B subtype, 61 were also associated with antiretroviral therapy in subtype B isolates. CONCLUSION: Global surveillance and genotypic assessment of drug resistance should focus primarily on the known subtype B drug-resistance mutations.

Amino Acid Sequence↗
PubMed2005

Long term probability of detection of HIV-1 drug resistance after starting antiretroviral therapy in routine clinical practice.

BACKGROUND: Little is known about the long term risk of development of HIV-1 drug resistance for patients starting antiretroviral therapy (ART) with three or four drug regimens in routine clinical practice. METHODS: We analysed a large cohort study of patients seen in one of six large HIV clinics in and around London, UK. The focus of this analysis was on patients who started ART with two nucleosides plus either a single protease inhibitor (PI), a PI with ritonavir, abacavir or a non-nucleoside reverse transcriptase inhibitor (NNRTI). RESULTS: 4306 patients were followed; 1436 (33%) started with a single PI, 279 (6%) with a PI plus ritonavir, 156 (4%) with triple nucleosides and 2435 (57%) with an NNRTI. The overall cumulative risk of viral load failure was 38% by 6 years. Risk of > or =1 major IAS-USA mutation was 27% by 6 years; risk of mutations from at least two of the three main drug classes was 20% over the same period. These are lower limit estimates as test results were not available for many with viral load failure. Risk of PI mutations being detected in people who started ART with regimens containing a PI with ritonavir was significantly lower than the risk of NNRTI mutations being detected in those starting with NNRTI-containing regimens (relative hazard 0.3195% CI 0.15-0.61; p = 0.0008). CONCLUSION: In routine practice, rates of viral load failure and of resistance detection in patients who started ART with three or four drugs are appreciable.

Adult↗
PubMed2005

SQUID-detected MRI at 132 microT with T1-weighted contrast established at 10 microT--300 mT.

T(1)-weighted contrast MRI with prepolarization was detected with a superconducting quantum interference device (SQUID). A spin evolution period in a variable field between prepolarization and detection enabled the measurement of T(1) in fields between 1.7 microT and 300 mT; T(1) dispersion curves of agarose gel samples over five decades in frequency were obtained. SQUID detection at 5.6 kHz drastically reduces the field homogeneity requirements compared to conventional field-cycling methods using Faraday coil detection. This allows T(1) dispersion measurements to be easily combined with MRI, so that T(1) in a wide range of fields can be used for tissue contrast. Images of gel phantoms with T(1)-weighted contrast at four different fields between 10 microT and 300 mT demonstrated dramatic contrast enhancement in low fields. A modified inversion recovery technique further enhanced the contrast by selectively suppressing the signal contribution for a specific value of the low-field T(1).

Humans↗
PubMed2004

Microtesla MRI with a superconducting quantum interference device.

MRI scanners enable fast, noninvasive, and high-resolution imaging of organs and soft tissue. The images are reconstructed from NMR signals generated by nuclear spins that precess in a static magnetic field B0 in the presence of magnetic field gradients. Most clinical MRI scanners operate at a magnetic field B0 = 1.5 T, corresponding to a proton resonance frequency of 64 MHz. Because these systems rely on large superconducting magnets, they are costly and demanding of infrastructure. On the other hand, low-field imagers have the potential to be less expensive, less confining, and more mobile. The major obstacle is the intrinsically low sensitivity of the low-field NMR experiment. Here, we show that prepolarization of the nuclear spins and detection with a superconducting quantum interference device (SQUID) yield a signal that is independent of B0, allowing acquisition of high-resolution MRIs in microtesla fields. Reduction of the strength of the measurement field eliminates inhomogeneous broadening of the NMR lines, resulting in enhanced signal-to-noise ratio and spatial resolution for a fixed strength of the magnetic field gradients used to encode the image. We present high-resolution images of phantoms and other samples and T1-weighted contrast images acquired in highly inhomogeneous magnetic fields of 132 microT; here, T1 is the spin-lattice relaxation time. These techniques could readily be adapted to existing multichannel SQUID systems used for magnetic source imaging of brain signals. Further potential applications include low-cost systems for tumor screening and imaging peripheral regions of the body.

Capsicum↗
PubMed2004

Age and sex dependent variations in the normal magnetocardiogram compared with changes associated with ischemia.

Magnetocardiography is the measurement of the magnetic fields of the heart. Human studies performed in magnetically shielded laboratories have demonstrated that magnetocardiograms (MCGs) can detect ischemia. The aim of this study was to obtain clinically useful MCGs in an unshielded hospital room. Other objectives included understanding the normal variations in MCG during repolarization and determining the MCG parameters that best discriminate patients with ischemia from healthy controls. We measured 51 healthy volunteers of both sexes from 25 to 76 years of age and 11 patients with documented exercise-induced ischemia. Resting and postexercise measurements were taken, and several MCG parameters were defined. For 19 of 29 MCG parameters, there were significant differences between healthy females and males (p < or = 0.05). For nine MCG parameters, there were differences between older and younger healthy subjects (p < 0.01). Therefore the age and sex of a subject should be considered when evaluating the MCG. Thirteen parameters separated the patients from the controls (areas under the receiver operating characteristic curve >80%). The repolarization stabilization interval, a parameter based on the time-evolution of contour maps, performed the best. Magnetocardiography performed in clinical settings is a potential screening tool for ischemia that should be further explored.

Adult↗
PubMed2003

Detection of bacteria in suspension by using a superconducting quantum interference device.

We demonstrate a technique for detecting magnetically labeled Listeria monocytogenes and for measuring the binding rate between antibody-linked magnetic particles and bacteria. This sensitive assay quantifies specific bacteria in a sample without the need to immobilize them or wash away unbound magnetic particles. In the measurement, we add 50-nm-diameter superparamagnetic magnetite particles, coated with antibodies, to an aqueous sample containing L. monocytogenes. We apply a pulsed magnetic field to align the magnetic dipole moments and use a high-transition temperature superconducting quantum interference device, an extremely sensitive detector of magnetic flux, to measure the magnetic relaxation signal when the field is turned off. Unbound particles randomize direction by Brownian rotation too quickly to be detected. In contrast, particles bound to L. monocytogenes are effectively immobilized and relax in about 1 s by rotation of the internal dipole moment. This Néel relaxation process is detected by the superconducting quantum interference device. The measurements indicate a detection limit of (5.6 +/- 1.1) x 10(6) L. monocytogenes in our sample volume of 20 microl. If the sample volume were reduced to 1 nl, we estimate that the detection limit could be improved to 230 +/- 40 L. monocytogenes cells. Time-resolved measurements yield the binding rate between the particles and bacteria.

Animals↗
PubMed2003

Performance of two commercially available sequence-based HIV-1 genotyping systems for the detection of drug resistance against HIV type 1 group M subtypes.

The use of genotyping assays for the detection and evaluation of drug resistance mutations within the polymerase gene of human immunodeficiency virus type 1 (HIV-1) is becoming increasingly relevant in the clinical management of HIV-1 infection. However, genotypic resistance assays available currently have been optimised for genetic subtype B strains of the virus and many clinical centres are presented with strains from subtypes A, C, and D. In the present report, we compare the performance of two sequence-based commercially available kits, the ViroSeq Genotyping System (Applied Biosystems, Foster City, CA) and the TruGene HIV-1 Genotyping Kit (Visible Genetics, Toronto, Ontario) against a panel of 35 virus isolates from HIV-1 Group M (subtypes A-J). Full-length consensus sequences were generated by the ViroSeq genotyping system for 26 of 31 (83.8%) of the isolates tested, in contrast to the TruGene genotyping system, which generated 16 of 30 (53%) usable sequences overall. Overall, subtype B isolates were sequenced with a greater degree of success than non-subtype B isolates. Discrepancies were found between the consensus sequences reported by each system for each sample (mean difference 1.0%; range 0.0-3.2%), but these appeared to be random and did not affect interpretation of the major resistance codons. In addition, both systems were able to amplify template RNA from low copy viral load plasma samples (10(2)-10(3) RNA copies/ml) taken from a random selection of patient samples encompassing subtypes A-C. While the availability of these genotyping systems should facilitate studies of HIV-1 drug resistance in countries in which these subtypes are prevalent, the performance against subtypes other than B needs to be improved.

Consensus Sequence↗
PubMed2002

Virological and immunological effects of short-course antiretroviral therapy in primary HIV infection.

BACKGROUND: National and international guidelines call for the treatment of primary HIV infection (PHI) with combination antiretroviral therapy, although the ideal timing and duration of this intervention is unknown. Recent immunological studies of antiretroviral therapy on small numbers of patients with PHI have reported preservation of HIV-specific CD4 T-helper responses, ordinarily lost in the absence of intervention. We sought to investigate whether a short course of antiretroviral therapy (SCART) at PHI was sufficient to preserve HIV-specific cellular immunity. METHODS: Forty-five subjects with confirmed PHI were offered SCART at diagnosis. HIV specific cellular immune responses and virological parameters were assessed at monthly intervals. RESULTS: Thirty-seven of the subjects chose SCART at PHI, and achieved a plasma viral load < 50 RNA copies/ml by a median of 10 weeks (range, 4-32 weeks). Two of the 45 individuals had evidence of genotypic HIV drug resistance at baseline, and none developed new mutations following therapy. All patients who received SCART at PHI showed preservation of HIV-specific CD4 T-helper responses up to 64 weeks off SCART. CONCLUSION: SCART at PHI was safe, did not induce the development of drug resistance, and appeared sufficient to preserve HIV-specific CD4 T-helper responses. However, PHI is highly heterogeneous, and a large-scale randomized trial of SCART at PHI is now needed.

Adult↗