Reduced Sensitivity to Charge Noise in Semiconductor Spin Qubits via Symmetric Operation.

We demonstrate improved operation of exchange-coupled semiconductor quantum dots by substantially reducing the sensitivity of exchange operations to charge noise. The method involves biasing a double dot symmetrically between the charge-state anticrossings, where the derivative of the exchange energy with respect to gate voltages is minimized. Exchange remains highly tunable by adjusting the tunnel coupling. We find that this method reduces the dephasing effect of charge noise by more than a factor of 5 in comparison to operation near a charge-state anticrossing, increasing the number of observable exchange oscillations in our qubit by a similar factor. Performance also improves with exchange rate, favoring fast quantum operations.

The National Environmental Respiratory Center (NERC) experiment in multi-pollutant air quality health research: II. Comparison of responses to diesel and gasoline engine exhausts, hardwood smoke and simulated downwind coal emissions.

The NERC Program conducted identically designed exposure-response studies of the respiratory and cardiovascular responses of rodents exposed by inhalation for up to 6 months to diesel and gasoline exhausts (DE, GE), wood smoke (WS) and simulated downwind coal emissions (CE). Concentrations of the four combustion-derived mixtures ranged from near upper bound plausible to common occupational and environmental hotspot levels. An "exposure effect" statistic was created to compare the strengths of exposure-response relationships and adjustments were made to minimize false positives among the large number of comparisons. All four exposures caused statistically significant effects. No exposure caused overt illness, neutrophilic lung inflammation, increased circulating micronuclei or histopathology of major organs visible by light microscopy. DE and GE caused the greatest lung cytotoxicity. WS elicited the most responses in lung lavage fluid. All exposures reduced oxidant production by unstimulated alveolar macrophages, but only GE suppressed stimulated macrophages. Only DE retarded clearance of bacteria from the lung. DE before antigen challenge suppressed responses of allergic mice. CE tended to amplify allergic responses regardless of exposure order. GE and DE induced oxidant stress and pro-atherosclerotic responses in aorta; WS and CE had no such effects. No overall ranking of toxicity was plausible. The ranking of exposures by number of significant responses varied among the response models, with each of the four causing the most responses for at least one model. Each exposure could also be deemed most or least toxic depending on the exposure metric used for comparison. The database is available for additional analyses.

Aerosolised 5-azacytidine suppresses tumour growth and reprogrammes the epigenome in an orthotopic lung cancer model.

BACKGROUND: Epigenetic silencing by promoter methylation and chromatin remodelling affects hundreds of genes and is a causal event for lung cancer. Treatment of patients with low doses of the demethylating agent 5-azacytidine in combination with the histone deacetylase inhibitor entinostat has yielded clinical responses. The subcutaneous dosing route for consecutive days and reduced bioavailability of 5-azacytidine because of inactivation by cytidine deaminase may limit the expansion of epigenetic therapy into Phase III trials. To mitigate these barriers, an aerosol of 5-azacytidine was generated and characterised. METHODS: The effect of aerosol vs systemic delivery of 5-azacytidine on tumour burden and molecular response of engrafted lung tumours in the nude rat was compared. RESULTS: Pharmacokinetics revealed major improvement in the half-life of 5-azacytidine in lung tissue with aerosol delivery. Aerosolised 5-azacytidine significantly reduced lung tumour burden and induced global demethylation of the epigenome at one-third of the comparable effective systemic dose. High commonality for demethylation of genes was seen in tumours sampled throughout lung lobes and across treated animals receiving the aerosolised drug. CONCLUSION: Collectively, these findings show that aerosolised 5-azacytidine targets the lung, effectively reprogrammes the epigenome of tumours, and is a promising approach to combine with other drugs for treating lung cancer.

Measurements of quasiparticle tunneling dynamics in a band-gap-engineered transmon qubit.

We have engineered the band gap profile of transmon qubits by combining oxygen-doped Al for tunnel junction electrodes and clean Al as quasiparticle traps to investigate energy relaxation due to quasiparticle tunneling. The relaxation time T1 of the qubits is shown to be insensitive to this band gap engineering. Operating at relatively low-E(J)/E(C) makes the transmon transition frequency distinctly dependent on the charge parity, allowing us to detect the quasiparticles tunneling across the qubit junction. Quasiparticle kinetics have been studied by monitoring the frequency switching due to even-odd parity change in real time. It shows the switching time is faster than 10 µs, indicating quasiparticle-induced relaxation has to be reduced to achieve T1 much longer than 100 µs.

Realization of three-qubit quantum error correction with superconducting circuits.

Quantum computers could be used to solve certain problems exponentially faster than classical computers, but are challenging to build because of their increased susceptibility to errors. However, it is possible to detect and correct errors without destroying coherence, by using quantum error correcting codes. The simplest of these are three-quantum-bit (three-qubit) codes, which map a one-qubit state to an entangled three-qubit state; they can correct any single phase-flip or bit-flip error on one of the three qubits, depending on the code used. Here we demonstrate such phase- and bit-flip error correcting codes in a superconducting circuit. We encode a quantum state, induce errors on the qubits and decode the error syndrome--a quantum state indicating which error has occurred--by reversing the encoding process. This syndrome is then used as the input to a three-qubit gate that corrects the primary qubit if it was flipped. As the code can recover from a single error on any qubit, the fidelity of this process should decrease only quadratically with error probability. We implement the correcting three-qubit gate (known as a conditional-conditional NOT, or Toffoli, gate) in 63 nanoseconds, using an interaction with the third excited state of a single qubit. We find 85 ± 1 per cent fidelity to the expected classical action of this gate, and 78 ± 1 per cent fidelity to the ideal quantum process matrix. Using this gate, we perform a single pass of both quantum bit- and phase-flip error correction and demonstrate the predicted first-order insensitivity to errors. Concatenation of these two codes in a nine-qubit device would correct arbitrary single-qubit errors. In combination with recent advances in superconducting qubit coherence times, this could lead to scalable quantum technology.

Preparation and measurement of three-qubit entanglement in a superconducting circuit.

Traditionally, quantum entanglement has been central to foundational discussions of quantum mechanics. The measurement of correlations between entangled particles can have results at odds with classical behaviour. These discrepancies grow exponentially with the number of entangled particles. With the ample experimental confirmation of quantum mechanical predictions, entanglement has evolved from a philosophical conundrum into a key resource for technologies such as quantum communication and computation. Although entanglement in superconducting circuits has been limited so far to two qubits, the extension of entanglement to three, eight and ten qubits has been achieved among spins, ions and photons, respectively. A key question for solid-state quantum information processing is whether an engineered system could display the multi-qubit entanglement necessary for quantum error correction, which starts with tripartite entanglement. Here, using a circuit quantum electrodynamics architecture, we demonstrate deterministic production of three-qubit Greenberger-Horne-Zeilinger (GHZ) states with fidelity of 88 per cent, measured with quantum state tomography. Several entanglement witnesses detect genuine three-qubit entanglement by violating biseparable bounds by 830 ± 80 per cent. We demonstrate the first step of basic quantum error correction, namely the encoding of a logical qubit into a manifold of GHZ-like states using a repetition code. The integration of this encoding with decoding and error-correcting steps in a feedback loop will be the next step for quantum computing with integrated circuits.

High-fidelity readout in circuit quantum electrodynamics using the Jaynes-Cummings nonlinearity.

We demonstrate a qubit readout scheme that exploits the Jaynes-Cummings nonlinearity of a superconducting cavity coupled to transmon qubits. We find that, in the strongly driven dispersive regime of this system, there is the unexpected onset of a high-transmission "bright" state at a critical power which depends sensitively on the initial qubit state. A simple and robust measurement protocol exploiting this effect achieves a single-shot fidelity of 87% using a conventional sample design and experimental setup, and at least 61% fidelity to joint correlations of three qubits.

Health effects of subchronic inhalation exposure to gasoline engine exhaust.

Gasoline engine emissions are a ubiquitous source of exposure to complex mixtures of particulate matter (PM) and non-PM pollutants; yet their health hazards have received little study in comparison with those of diesel emissions. As a component of the National Environmental Respiratory Center (NERC) multipollutant research program, F344 and SHR rats and A/J, C57BL/6, and BALBc mice were exposed 6 h/day, 7 days/week for 1 week to 6 months to exhaust from 1996 General Motors 4.3-L engines burning national average fuel on a simulated urban operating cycle. Exposure groups included whole exhaust diluted 1:10, 1:15, or 1:90, filtered exhaust at the 1:10 dilution, or clean air controls. Evaluations included organ weight, histopathology, hematology, serum chemistry, bronchoalveolar lavage, cardiac electrophysiology, micronuclei in circulating cells, DNA methylation and oxidative injury, clearance of Pseudomonas aeruginosa from the lung, and development of respiratory allergic responses to ovalbumin. Among the 120 outcome variables, only 20 demonstrated significant exposure effects. Several statistically significant effects appeared isolated and were not supported by related variables. The most coherent and consistent effects were those related to increased red blood cells, interpreted as likely to have resulted from exposure to 13-107 ppm carbon monoxide. Other effects supported by multiple variables included mild lung irritation and depression of oxidant production by alveolar macrophages. The lowest exposure level caused no significant effects. Because only 6 of the 20 significant effects appeared to be substantially reversed by PM filtration, the majority of effects were apparently caused by non-PM components of exhaust.

Ankylosing spondylitis: an Australian experience.

BACKGROUND: The purpose of this study was to characterize an Australian cohort of ankylosing spondylitis (AS) patients and examine predictors of important disease outcomes. METHODS: Cross-sectional study of first visit data among patients referred to the Austin Spondylitis Clinic from rheumatology or general practices. We obtained clinical and laboratory data and validated composite indices through self-reported questionnaire. RESULTS: Delay in AS diagnosis averaged 8.1 years and was higher among women and younger-onset disease. Cervicothoracic mobility was better in women although they showed more entheseal tender points and greater impairment of quality of life. Those with long-standing AS had similar disease activity to recent onset disease but had greater functional disability. Current smoking was associated with worse outcomes although there was no association between cumulative exposure and AS outcomes. CONCLUSION: The clinical expression of AS in this first-described Australian cohort is similar to previously described cohorts. We observed greater cervicothoracic mobility and a higher enthesitis index among women perhaps contributing to longer delay to diagnosis.

Potential pharmacokinetic basis for zolpidem dosing in children with sleep difficulties.

The pharmacokinetics of zolpidem was assessed in this open-label, dose-escalation study in children with insomnia. Twenty-one children, seven per age group (2-6, >6 to 12, >12 to 18 years), received a single dose of zolpidem at one of the three dose levels (0.125, 0.25, or 0.50 mg/kg (20 mg maximum dose)). Multiple pharmacokinetic measures were assessed at nine post-dose intervals and pharmacodynamics was assessed by polysomnography and actigraphy. Significant pharmacokinetic effects by dose were observed only as linear increases in maximum concentration (C(max), P<0.001) and area under the plasma concentration-time curve (AUC, P<0.001). Significant pharmacokinetic effects by age group included an increase in AUC (P=0.02), half-life (P=0.04), and mean residence time (P=0.01), whereas total body clearance decreased (P=0.01) and steady-state volume of distribution was variable. Pharmacodynamic measures were independent of the pharmacokinetic estimates. Overall, zolpidem was well tolerated and a pediatric dose of 0.25 mg/kg is recommended for future efficacy studies.

Considerations in the rational design and conduct of phase I/II pediatric clinical trials: avoiding the problems and pitfalls.

Over the past decade, there has been a heightened awareness of the need to include children in the drug development process. With this awareness has come an expansion of the infrastructure for conducting studies in children and an increase in the sponsorship of pediatric clinical trials. However, the growth in pediatric research has, in many cases, not been accompanied by an increase in the involvement of trained pediatric investigators when it comes to trial design and/or interpretation. Pediatric phase I/II protocols continue to span a spectrum from those that are carefully constructed to those that are poorly designed. This paper highlights the basic elements of phase I/II protocols that merit unique consideration when the clinical trial involves children. Illustrations are provided from our experience, which highlight problems that may arise when trials are not designed with the pediatric patient in mind.

Health effects of subchronic exposure to diesel-water-methanol emulsion emission.

The U.S. Environmental Protection Agency's National Ambient Air Quality Standards for ozone and particulate matter (PM) require urban non-attainment areas to implement pollution-reduction strategies for anthropogenic source emissions. The type of fuel shown to decrease combustion emissions components versus traditional diesel fuel, is the diesel emulsion. The Lubrizol Corporation, in conjunction with Lovelace Respiratory Research Institute and several subcontracting laboratories, recently conducted a health assessment of the combustion emissions of PuriNOx diesel fuel emulsion (diesel-water-methanol) in rodents. Combustion emissions from either of two, 2002 model Cummins 5.9L ISB engines, were diluted with charcoal-filtered air to exposure concentrations of 125, 250 and 500 microg total PM/m3. The engines were operated on a continuous, repeating, heavy-duty certification cycle (U.S. Code of Federal Regulations, Title 40, Chapter I) using Rotella-T 15W-40 engine oil. Nitrogen oxide (NO) and PM were reduced when engines were operated on PuriNOx versus California Air Resources Board diesel fuel under these conditions. Male and female F344 rats were housed in Hazleton H2000 exposure chambers and exposed to exhaust atmospheres 6 h/day, five days/week for the first 11 weeks and seven days/week thereafter. Exposures ranged from 61 to 73 days depending on the treatment group. Indicators of general toxicity (body weight, organ weight, clinical pathology and histopathology), neurotoxicity (glial fibrillary acidic protein assay), genotoxicity (Ames assay, micronucleus, sister chromatid exchange), and reproduction and development were measured. Overall, effects observed were mild. Emulsion combustion emissions were not associated with neurotoxicity, reproductive/developmental toxicity, or in vivo genotoxicity. Small decreases in serum cholesterol in the 500-microg/m3 exposure group were observed. PM accumulation within alveolar macrophages was evident in all exposure groups. The latter findings are consistent with normal physiological responses to particle inhalation. Other statistically significant effects were present in some measured parameters of other exposed groups, but were not clearly attributed to emissions exposure. Positive mutagenic responses in several strains of Salmonella typhimurium were observed subsequent to treatment with emulsion emissions subfractions. Based on the cholesterol results, it can be concluded that the 250-microg/m3 exposure level was the no observed effect level. In general, biological findings in exposed rats and bacteria were consistent with exposure to petroleum diesel exhaust in the F344 rat and Ames assays.

Health effects of subchronic exposure to environmental levels of hardwood smoke.

Hardwood smoke is a contributor to both ambient and indoor air pollution. As part of a general health assessment of multiple anthropogenic source emissions conducted by the National Environmental Respiratory Center, a series of health assays was conducted on rodents exposed to environmentally relevant levels of hardwood smoke. This article summarizes the study design and exposures, and reports findings on general indicators of toxicity, bacterial clearance, cardiac function, and carcinogenic potential. Hardwood smoke was generated from an uncertified wood stove, burning wood of mixed oak species. Animals were exposed to clean air (control) or dilutions of whole emissions based on particulate (30, 100, 300, and 1000 micromg/m3). F344 rats, SHR rats, strain A/J mice, and C57BL/6 mice were exposed by whole-body inhalation 6 h/day, 7 days/wk, for either 1 wk or 6 mo. Effects of exposure on general indicators of toxicity, bacterial clearance, cardiac function, and carcinogenic potential were mild. Exposure-related effects included increases in platelets and decreases in blood urea nitrogen and serum alanine aminotransferase. Several other responses met screening criteria for significant exposure effects but were not consistent between genders or exposure times and were not corroborated by related parameters. Pulmonary histopathology revealed very little accumulation of hardwood smoke particulate matter. Parallel studies demonstrated mild exposure effects on bronchoalveolar lavage parameters and in a mouse model of asthma. In summary, the results reported here show few and only modest health hazards from short-term to subchronic exposures to realistic concentrations of hardwood smoke.

Transfer of the hematopoietic stem cell transplant patient to the intensive care unit: does it really matter?

We critically reviewed published English language literature and concluded that from 1998 onward the survival of hematopoietic stem cell transplant (SCT) patients who experienced intensive care unit (ICU) transfer has improved. The factors associated with increased mortality during ICU stay included increased patient age, allogeneic transplant, intubation/mechanical ventilation, multiorgan system failure (MOSF), presumed/documented infection, graft-versus-host disease, and higher APACHE and O-PRISM score at ICU transfer. This encouraging outcome trend reflects evolving advances such as use of recombinant hematopoietic growth factors, use of mobilized blood cells rather than marrow, protective strategies for acute lung injury and early goal-directed therapy for sepsis syndrome. Patient selection bias (which patients were transferred and which were not sent to an ICU) also plays a role in ICU survival rates. New strategies to improve upon SCT patient outcome include use of a scoring system to predict mortality, better therapies for MOSF and integration of ICU components and multispecialist involvement earlier in the clinical course to prevent severe complications such as respiratory failure. SCT recipients comprise a heterogeneous group; to further advance this field, prospective multicenter trials involving larger populations from many centers are needed to reduce the biases of retrospective and single-center reports.

Health effects of subchronic exposure to diesel-water emulsion emission.

The U.S. Environmental Protection Agency (EPA) National Ambient Air Quality Standards for ozone and particulate matter are requiring urban nonattainment areas to implement pollution-reduction strategies for anthropogenic source emissions. A type of fuel shown to decrease combustion emissions components versus traditional diesel fuels is the diesel-water emulsion. The Lubrizol Corporation in conjunction with Lovelace Respiratory Research Institute and several subcontracting laboratories recently conducted a rodent health assessment of inhaled combustion emissions of PuriNO(x) diesel fuel emulsion. Combustion emissions from either of two 2001 model Cummins 5.9-L ISB engines were diluted with charcoal-filtered air to exposure concentrations of 100, 200, and 400 microg total particulate matter/m(3). The engines were operated on a continuously repeating, heavy-duty certification cycle (U.S. Code of Federal Regulations, Title 40, Chapter I) using Rotella-T 15W-40 engine oil. Nitrogen oxide and particulate matter were reduced when engines were operated on PuriNO(x) versus California Air Resources Board diesel fuel under these conditions. Male and female F344 rats were housed in Hazleton H2000 exposure chambers and exposed to exhaust atmospheres 6 h/day, 5 days/wk for the first 11 wk and 7 days/wk threafter. Exposures ranged from 58 to 70 days, depending on the treatment group. Indicators of general toxicity (body weight, organ weight, clinical pathology, and histopathology), neurotoxicity (glial fibrillary acidic protein assay), genotoxicity (Ames assay, micronucleus, sister chromatid exchange), and reproduction and development were measured. Overall, effects observed were mild. Emulsion combustion emissions were not associated with neurotoxicity, reproductive/developmental toxicity, or in vivo genotoxicity. Small decreases in serum cholesterol and small increases in platelet values in some groups of exposed animals were observed. Particulate matter accumulation within alveolar macrophages was evident in all exposure groups. These findings are consistent with normal physiological responses to particle inhalation. Other statistically significant effects were present in some measured parameters of other exposed groups but were not clearly attributed to emissions exposure. Positive mutagenic responses in several strains of Salmonella typhimurium were observed subsequent to treatment with emulsion emissions subfractions. Based on the cholesterol and platelet results, it can be concluded that the 100 microg/m(3) exposure level was the no-observed-effect level. In general, biological findings in diesel emulsion emission-exposed animals and bacteria were consistent with exposure to petroleum diesel exhaust in the F344 rat and Ames assays.

Improving drug use for children in the developing world.

Children differ significantly from adults in the way they absorb, metabolise, and excrete drugs. These parameters also vary as children grow from neonates through to adolescence. The practical implications and challenges that this presents are well know to anyone who is involved in the medical management of sick children. The importance of paediatric medication safety and efficacy has been gaining increasing attention in the developed world over the past decade. The United States has introduced a carrot and stick approach to increase research into medications for children with the "paediatric exclusivity provision" and the "paediatric rule". The European Union is also investigating ways of improving the availability of medications for children. Unfortunately, this increased focus on appropriate medicines for children, which has occurred in the developed world, has not been mirrored in developing nations. Currently more than 10 million children under the age of 5 years die each year, with only six countries accounting for 50% of these deaths. The majority of these deaths are from treatable or preventable diseases. The developed world has a moral and ethical obligation to share its gains with the children of the world.

Health effects of subchronic exposure to environmental levels of diesel exhaust.

Diesel exhaust is a public health concern and contributor to both ambient and occupational air pollution. As part of a general health assessment of multiple anthropogenic source emissions conducted by the National Environmental Respiratory Center (NERC), a series of health assays was conducted on rats and mice exposed to environmentally relevant levels of diesel exhaust. This article summarizes the study design and exposures, and reports findings on several general indicators of toxicity and carcinogenic potential. Diesel exhaust was generated from a commonly used 2000 model 5.9-L, 6-cylinder turbo diesel engine operated on a variable-load heavy-duty test cycle burning national average certification fuel. Animals were exposed to clean air (control) or four dilutions of whole emissions based on particulate matter concentration (30, 100, 300, and 1000 microg/m(3)). Male and female F344 rats and A/J mice were exposed by whole-body inhalation 6 h/day, 7 days/wk, for either 1 wk or 6 mo. Exposures were characterized in detail. Effects of exposure on clinical observations, body and organ weights, serum chemistry, hematology, histopathology, bronchoalveolar lavage, and serum clotting factors were mild. Significant exposure-related effects occurring in both male and female rats included decreases in serum cholesterol and clotting Factor VII and slight increases in serum gamma-glutamyl transferase. Several other responses met screening criteria for significant exposure effects but were not consistent between genders or exposure times and were not corroborated by related parameters. Carcinogenic potential as determined by micronucleated reticulocyte counts and proliferation of adenomas in A/J mice were unaffected by 6 mo of exposure. Parallel studies demonstrated effects on cardiac function and resistance to viral infection; however, the results reported here show few and only modest health hazards from subchronic or shorter exposures to realistic concentrations of contemporary diesel emissions.

The pharmacokinetics of colistin in patients with cystic fibrosis.

The safety and pharmacokinetics of colistin were determined after first dose (n = 30) and again under steady-state conditions (n = 27) in 31 patients with cystic fibrosis receiving the drug as a component of their treatment for an acute pulmonary exacerbation of their disease. Patients ranged in age from 14 to 53 years and received colistin for 6 to 35 days. Each patient was started on colistin 5 to 7 mg/kg/day administered intravenously in three equally divided doses. Elimination half-life (t1/2), mean residence time (MRT), steady-state volume of distribution (Vdss), total body clearance (Cl), and renal clearance (Clr) after first-dose administration averaged 3.4 hours, 4.4 hours, 0.09 l/kg, and 0.35 and 0.24 ml/min/kg, respectively. No differences in colistin disposition characteristics between first-dose and steady-state evaluations were observed. Sputum sampling was incomplete and confounded by previous aerosol administration but revealed colistin concentrations that markedly exceeded observed plasma concentrations. Twenty-one patients experienced one or more side effects attributed to colistin administration. The most common reactions involved reversible neurologic manifestations, including oral and perioral paresthesias (n = 16), headache (n = 5), and lower limb weakness (n = 5). All of these apparent colistin-induced neurologic adverse effects, though bothersome, were benign and reversible. Intermittent proteinuria was observed on urinalysis in 14 patients, and 1 patient developed reversible, colistin-induced nephrotoxicity. No relationship between the occurrence of any colistin-associated adverse effect and plasma colistin concentration or colistin pharmacokinetic parameter estimate was observed. These data provide no basis for routine monitoring of colistin plasma concentrations to guide dosing for patient safety and suggest slow upward dose titration to minimize the incidence and severity of associated side effects.