Multi-qubit entanglement and algorithms on a neutral-atom quantum computer.

Gate-model quantum computers promise to solve currently intractable computational problems if they can be operated at scale with long coherence times and high-fidelity logic. Neutral-atom hyperfine qubits provide inherent scalability owing to their identical characteristics, long coherence times and ability to be trapped in dense, multidimensional arrays1. Combined with the strong entangling interactions provided by Rydberg states2-4, all the necessary characteristics for quantum computation are available. Here we demonstrate several quantum algorithms on a programmable gate-model neutral-atom quantum computer in an architecture based on individual addressing of single atoms with tightly focused optical beams scanned across a two-dimensional array of qubits. Preparation of entangled Greenberger-Horne-Zeilinger (GHZ) states5 with up to six qubits, quantum phase estimation for a chemistry problem6 and the quantum approximate optimization algorithm (QAOA)7 for the maximum cut (MaxCut) graph problem are demonstrated. These results highlight the emergent capability of neutral-atom qubit arrays for universal, programmable quantum computation, as well as preparation of non-classical states of use for quantum-enhanced sensing.

Cardiometabolic risk prediction algorithms for young people with psychosis: a systematic review and exploratory analysis.

OBJECTIVE: Cardiometabolic risk prediction algorithms are common in clinical practice. Young people with psychosis are at high risk for developing cardiometabolic disorders. We aimed to examine whether existing cardiometabolic risk prediction algorithms are suitable for young people with psychosis. METHODS: We conducted a systematic review and narrative synthesis of studies reporting the development and validation of cardiometabolic risk prediction algorithms for general or psychiatric populations. Furthermore, we used data from 505 participants with or at risk of psychosis at age 18 years in the ALSPAC birth cohort, to explore the performance of three algorithms (QDiabetes, QRISK3 and PRIMROSE) highlighted as potentially suitable. We repeated analyses after artificially increasing participant age to the mean age of the original algorithm studies to examine the impact of age on predictive performance. RESULTS: We screened 7820 results, including 110 studies. All algorithms were developed in relatively older participants, and most were at high risk of bias. Three studies (QDiabetes, QRISK3 and PRIMROSE) featured psychiatric predictors. Age was more strongly weighted than other risk factors in each algorithm. In our exploratory analysis, calibration plots for all three algorithms implied a consistent systematic underprediction of cardiometabolic risk in the younger sample. After increasing participant age, calibration plots were markedly improved. CONCLUSION: Existing cardiometabolic risk prediction algorithms cannot be recommended for young people with or at risk of psychosis. Existing algorithms may underpredict risk in young people, even in the face of other high-risk features. Recalibration of existing algorithms or a new tailored algorithm for the population is required.

A computational method for NMR-constrained protein threading.

Protein threading provides an effective method for fold recognition and backbone structure prediction. But its application is currently limited due to its level of prediction accuracy and scope of applicability. One way to significantly improve its usefulness is through the incorporation of underconstrained (or partial) NMR data. It is well known that the NMR method for protein structure determination applies only to small proteins and that its effectiveness decreases rapidly as the protein mass increases beyond about 30 kD. We present, in this paper, a computational framework for applying underconstrained NMR data (that alone are insufficient for structure determination) as constraints in protein threading and also in all-atom model construction. In this study, we consider both secondary structure assignments from chemical shifts and NOE distance restraints. Our results have shown that both secondary structure assignments and a small number of long-range NOEs can significantly improve the threading quality in both fold recognition and threading-alignment accuracy, and can possibly extend threading's scope of applicability from homologs to analogs. An accurate backbone structure generated by NMR-constrained threading can then provide a great amount of structural information, equivalent to that provided by many NMR data; and hence can help reduce the number of NMR data typically required for an accurate structure determination. This new technique can potentially accelerate current NMR structure determination processes and possibly expand NMR's capability to larger proteins.

Idiopathic interstitial pneumonitis in children: a national survey in the United Kingdom and Ireland.

Interstitial lung disease (ILD) of unknown etiology in immunocompetent patients is rare in children. A national survey was carried out in the United Kingdom and Ireland over a 3-year period in order to identify prevalence, age distribution, histopathology, natural history of the illness, and response to current treatment.Forty-six cases were identified, including 29 males and 17 females. Seventy-six percent presented in the first year of life. Nine (16%) occurred within four families. Conventional treatment with pulsed methylprednisolone, prednisolone, or hydroxychloroquine, singly or in combination, resulted in an excellent response in 65% of cases. Seven children died (15%). The recurrence risk for further children within the same family to develop ILD is estimated to be approximately 10%. The prevalence rate of this condition in the United Kingdom and Ireland during the period of study for children aged 0-16 years is estimated to be 3.6 cases/million.

Fibrosing alveolitis and desquamative interstitial pneumonitis.

We report the experience with and evaluation of treatment strategies in fibrosing alveolitis and desquamative interstitial pneumonitis (FA/DIP) over the last 16 years by a review of all cases referred to a tertiary referral center. There were 25 cases, 16 boys and 9 girls (mean age at onset, 2.3 years; range, 7 days to 11.6 years). In each case the diagnosis was confirmed by open lung biopsy at a mean age of 3.3 years (range, 7 weeks to 15.1 years). Presently features were tachypnea (19), cyanosis (15), cough (12), exertional dyspnea (7), recurrent chest infections +/- wheezing (9), and clubbing (8). Four patients recovered without antiinflammatory medication. The others received specific treatment. Of 11 patients given only prednisolone, six improved, two did not, and three died despite treatment. Of five patients receiving only chloroquine, four responded. Five patients received both prednisolone and chloroquine; one died, two responded well. There was poor progress in the remaining two. Of the 10 patients receiving chloroquine six (60%) showed a good response. A younger presentation carried a worse prognosis, but chest radiology at presentation and outcome were not interrelated. Those with mild histological changes all survived, but severe desquamation or fibrosis at biopsy was not related to outcome. In four cases there was a family history (16%). Patients with FA/DIP probably represent a disease spectrum of multiple etiology with a variable prognosis and response to treatment.

Retrospective review of the effects of rhDNase in children with cystic fibrosis.

Trials of rhDNase in mixed groups of adults and children with cystic fibrosis (CF) have demonstrated improvements in lung function and well-being. This has led to many pediatric CF patients receiving regular rhDNase therapy although their response to treatment may not be the same as that seen in adults. We have retrospectively reviewed the effects of rhDNase during the first year of therapy in 65 children receiving the drug at two tertiary referral centers. Outcome measures included changes in lung function, oxygen saturation, use of intravenous antibiotics, and subjective improvement. Median baseline lung function (% of predicted) was 45% for forced expiratory volume in 1 second (FEV1) and 58% for forced vital capacity (FVC). At 3-4 months following initiation of therapy the group demonstrated median (95% CI) increases of 14.2% (95% CI 7.3; 21.1%) in FEV1 and 7% (0; 14%) in FVC. Within this wide scatter of responses, one-quarter of children deteriorated, but almost 50% showed significant improvements of > 10%. A similar pattern was seen at 9 months, with median increases for the group of 11.1% (0; 18.8%) in FEV1 and 5.6% (0; 17%) in FVC, again with approximately one-third of the group deteriorating and one-half improving significantly. Intravenous antibiotic use decreased significantly. Almost all the children (89%), including those with a fall in lung function, described subjective improvement. There were no predictive markers at baseline of a good response to the drug. However, there was a good correlation between lung function response at 3 months and that at 6, 9, and 12 months. Thus, children respond to rhDNase at least as well as adults, and a therapeutic trial is justified in those over 5 years with significantly impaired lung function. Response is highly variable, making careful individual assessment mandatory. Baseline characteristics are not useful in predicting those children who will respond well to treatment, but long-term response to the drug can be predicted on the basis of spirometric improvement at 3 months. Therefore, this would be a useful time period for a therapeutic trial.

Effects of the tissue-air interface in calculations of beta-particle skin dose at a depth of 70 microns.

The effects that the tissue-air interface has on the basal-layer dose at a depth of 70 microns from beta emitters on the skin surface are studied using Monte Carlo calculations. The dose is decreased at small lateral distances from a point source but is increased at large distances.

A fast, stochastic threading algorithm for proteins.

MOTIVATION: Sequences for new proteins are being determined at a rapid rate, as a result of the Human Genome Project, and related genome research. The ability to predict the three-dimensional structure of proteins from sequence alone would be useful in discovering and understanding their function. Threading, or fold recognition, aims to predict the tertiary structure of a protein by aligning its amino acid sequence with a large number of structures, and finding the best fit. This approach depends on obtaining good performance from both the scoring function, which simulates the free energy for given trial alignments, and the threading algorithm, which searches for the lowest-score alignment. It appears that current scoring functions and threading algorithms need improvement. RESULTS: This paper presents a new threading algorithm. Numerical tests demonstrate that it is more powerful than two popular approximate algorithms, and much faster than exact methods.

Single breath nitrogen washout in pulmonary sarcoidosis.

In 35 patients with pulmonary sarcoidosis we explored the utility of single breath nitrogen washout as a means for detecting abnormalities in airway function and intrapulmonary distribution of air. Closing volume/vital capacity ratio (CV/VC) was 21% (predicted 12.5%) in patients with only hilar adenopathy (stage I). CV/VC was 21% (predicted 13%) in patients with hilar adenopathy and parenchymal infiltration (stage II). Abnormalities in CV/VC were less readily detectable in patients with parenchymal infiltrates only (stage III) or those with bullous lesions and lung retraction (stage IV). Closing capacity was abnormally high in 66% of the cases. The slope of the alveolar plateau (delta N2/L) increased with disease progression. Single breath nitrogen test provides useful information concerning the function of small airways and distribution of pulmonary ventilation in all stages of sarcoidosis.

Treatment of pleural empyema.

OBJECTIVE: To determine the clinical presentation and treatment strategies for children admitted with pleural empyema. METHODOLOGY: Retrospective review of medical and radiological records of 54 patients admitted with pleural empyema between January 1989 and April 1997. RESULTS: Fever (98%), cough (83%), chest pain (38%), clinical cyanosis (17%) and abdominal pain (16%) were common clinical features. The causative organism was identified in 17 patients (31%). Intravenous antibiotics were given for a mean of 18. 2 +/- 7.5 days. Forty-seven (87%) patients had closed chest tube drainage and 21(39%) patients underwent decortication for unsatisfactory response to medical treatment. The chest tube insertion was more likely to be delayed in patients who required decortication, although the difference was not significant (8.1 +/- 5.4 vs 6.3 +/- 5.2 days of illness, P = 0.67). All patients were discharged well, with almost complete resolution of the chest radiograph at 6 months. CONCLUSIONS: Intensive medical management with adequate chest tube drainage and appropriate antibiotics will result in full resolution for most patients. Surgical intervention is important in patients who fail to receive adequate treatment early in the disease.

Effect of human saliva and serum on ion transport by dog tracheal mucosa. Comparison of normal subjects with cystic fibrosis patients.

It has been proposed that cystic fibrosis (CF) saliva or serum contains factors that alter ion transport in various tissues. Since CF frequently affects the lungs, and disturbances in epithelial ion transport has been proposed to contribute to the pathophysiology of pulmonary disease in CF, we investigated whether saliva or serum from CF patients could alter ion transport across airways epithelium. Canine tracheal mucosae were mounted in lucite chamber and perfused on both sides with Krebs-Henseleit solution at 37 degrees C and pH 7.4. Unidirectional fluxes of 22Na and 36Cl were measured in pairs of mucosal tissues under short circuit conditions. Saliva from 5 CF patients stimulated short circuit current (SCC) by 33 +/- 8 microA/cm2 and net Cl secretion by 1.10 +/- 0.33 muEq/cm2 X h (mean +/- SE; p less than 0.05). No change occurred in net Na absorption. Saliva from normal subjects raised SCC by 34 +/- 7 microA/cm2 and increased net Cl secretion by 1.29 +/- 0.46 muEq/cm2 X h (n = 9; p less than 0.02). Serum from both CF patients and control subjects briefly stimulated SCC. Exposure of tracheal mucosa to normal as well as CF saliva, such as by aspiration, or to serum, such as by transudation, stimulates Cl secretion, and therefore water secretion into airway lumen. There appears to be no difference in the effect exerted by CF saliva or serum and that of normal subjects. These findings argue against the presence of a specific circulating or secreted CF factor that could alter ion transport across respiratory epithelia in a way that might contribute to lung disease in CF.

Application of PROSPECT in CASP4: characterizing protein structures with new folds.

In the Fourth Community Wide Experiment on the Critical Assessment of Techniques for Protein Structure Prediction (CASP4), we predicted all 43 targets using our threading application PROSPECT. PROSPECT guarantees to find an optimal alignment between a protein sequence and a structural fold for a general energy function with pairwise contact potential. For each prediction, it gives a reliability assessment based on a neural network approach. In addition, PROSPECT has been added to the Genomic Integrated Supercomputing Toolkit (GIST) and is deployed on terascale computing resources. Structural predictions in CASP4 included three categories, that is comparative modeling, fold recognition, and prediction for structures with new folds. In the fold recognition category, PROSPECT correctly identified 8 of a total of 22 and finished the sixth in the total scores among 127 assessed groups. In the "new fold" category, it found important structural features for most targets, and its overall performance is among the best of all prediction methods. Our CASP4 performance demonstrates that PROSPECT is a powerful tool to quickly characterize structures with new folds, and it may provide useful structural restraints for ab initio prediction methods.

Product yields from irradiated glycylglycine in oxygen-free solutions: Monte Carlo simulations and comparison with experiments.

The radiation chemistry of photon-irradiated aqueous solutions of biological molecules may be considered under four distinct time regimes: physical transport (< or = 10(-15) s); prechemical conversion of H2O+, H2O*, and subexcitation electrons into free radicals and molecular products (10(-15) s to 10(-12) s); chemical reactions within individual electron tracks (10(-12) s to 10(-6) s); and chemical reactions within overlapping tracks (>10(-6) s). We have previously reported of the use of the Monte Carlo radiation transport/chemistry codes OREC and RADLYS to model the radiolysis of glycylglycine in oxygen-free solution to a time of 1 micros. These simulations successfully predicted the yields of free ammonia, an end product created solely in the reaction of the hydrated electron with the solute within individual tracks. Other measurable products are only partially created during intratrack reactions, and thus one must additionally consider the late, intertrack chemistry of this system. In this paper, we extend our simulations of glycylglycine radiolysis to model for the first time the events which occur during this late chemistry stage. The model considers the product rates of the reactants in bulk solution by using previously available microsecond intratrack yields given by single-track OREC/RADLYS simulations and an x-ray dose rate of 2.80 Gy min(-1) as used in a companion experimental program. These rates are then applied in a series of coupled, differential rate equations that describe the solution chemistry of glycylglycine radiolysis. Product yields are reported as a function of time over a total irradiation period of 10(4) s. Excellent overall agreement is seen between the theoretical predictions and measurements of five radiolysis end products: free ammonia, acetylglycine, diaminosuccinic acid, aspartic acid, and succinic acid. The model also gives the explicit contributions of intratrack and intertrack reactions to the various end products. For example, the model predicts that approximately 56% and 93% of succinic acid and aspartic acid, respectively, are produced during intertrack reactions at a solute concentration of 0.05 M; these contributions drop to 0.07% and 11%, respectively, at 1.2 M.

Protein threading by PROSPECT: a prediction experiment in CASP3.

We present an analysis of the protein fold recognition experiment using PROSPECT in The Third Community Wide Experiment on the Critical Assessment of Techniques for Protein Structure Prediction (CASP3). PROSPECT is a computer program we have recently developed for finding an optimal alignment between a protein sequence and a protein structural fold. Two unique features of PROSPECT are (a) that it guarantees to find the globally optimal sequence-structure alignment and does so in an efficient manner, when the alignment-scoring function consists of three additive terms: (i) a singleton fitness term, (ii) a pairwise contact preference term between residues that are spatially close (