Proton-driven plasma wakefield acceleration in AWAKE.

In this article, we briefly summarize the experiments performed during the first run of the Advanced Wakefield Experiment, AWAKE, at CERN (European Organization for Nuclear Research). The final goal of AWAKE Run 1 (2013-2018) was to demonstrate that 10-20 MeV electrons can be accelerated to GeV energies in a plasma wakefield driven by a highly relativistic self-modulated proton bunch. We describe the experiment, outline the measurement concept and present first results. Last, we outline our plans for the future. This article is part of the Theo Murphy meeting issue 'Directions in particle beam-driven plasma wakefield acceleration'.

Experimental Observation of Proton Bunch Modulation in a Plasma at Varying Plasma Densities.

We give direct experimental evidence for the observation of the full transverse self-modulation of a long, relativistic proton bunch propagating through a dense plasma. The bunch exits the plasma with a periodic density modulation resulting from radial wakefield effects. We show that the modulation is seeded by a relativistic ionization front created using an intense laser pulse copropagating with the proton bunch. The modulation extends over the length of the proton bunch following the seed point. By varying the plasma density over one order of magnitude, we show that the modulation frequency scales with the expected dependence on the plasma density, i.e., it is equal to the plasma frequency, as expected from theory.

Experimental Observation of Plasma Wakefield Growth Driven by the Seeded Self-Modulation of a Proton Bunch.

We measure the effects of transverse wakefields driven by a relativistic proton bunch in plasma with densities of 2.1×10^{14} and 7.7×10^{14} electrons/cm^{3}. We show that these wakefields periodically defocus the proton bunch itself, consistently with the development of the seeded self-modulation process. We show that the defocusing increases both along the bunch and along the plasma by using time resolved and time-integrated measurements of the proton bunch transverse distribution. We evaluate the transverse wakefield amplitudes and show that they exceed their seed value (<15 MV/m) and reach over 300 MV/m. All these results confirm the development of the seeded self-modulation process, a necessary condition for external injection of low energy and acceleration of electrons to multi-GeV energy levels.

Acceleration of electrons in the plasma wakefield of a proton bunch.

High-energy particle accelerators have been crucial in providing a deeper understanding of fundamental particles and the forces that govern their interactions. To increase the energy of the particles or to reduce the size of the accelerator, new acceleration schemes need to be developed. Plasma wakefield acceleration1-5, in which the electrons in a plasma are excited, leading to strong electric fields (so called 'wakefields'), is one such promising acceleration technique. Experiments have shown that an intense laser pulse6-9 or electron bunch10,11 traversing a plasma can drive electric fields of tens of gigavolts per metre and above-well beyond those achieved in conventional radio-frequency accelerators (about 0.1 gigavolt per metre). However, the low stored energy of laser pulses and electron bunches means that multiple acceleration stages are needed to reach very high particle energies5,12. The use of proton bunches is compelling because they have the potential to drive wakefields and to accelerate electrons to high energy in a single acceleration stage13. Long, thin proton bunches can be used because they undergo a process called self-modulation14-16, a particle-plasma interaction that splits the bunch longitudinally into a series of high-density microbunches, which then act resonantly to create large wakefields. The Advanced Wakefield (AWAKE) experiment at CERN17-19 uses high-intensity proton bunches-in which each proton has an energy of 400 gigaelectronvolts, resulting in a total bunch energy of 19 kilojoules-to drive a wakefield in a ten-metre-long plasma. Electron bunches are then injected into this wakefield. Here we present measurements of electrons accelerated up to two gigaelectronvolts at the AWAKE experiment, in a demonstration of proton-driven plasma wakefield acceleration. Measurements were conducted under various plasma conditions and the acceleration was found to be consistent and reliable. The potential for this scheme to produce very high-energy electron bunches in a single accelerating stage20 means that our results are an important step towards the development of future high-energy particle accelerators21,22.

Molecular Characterization and Computational Modelling of New Delhi Metallo-ß-Lactamase-5 from an Escherichia coli Isolate (KOEC3) of Bovine Origin.

Emergence of antimicrobial resistance mediated through New Delhi metallo-ß-lactamases (NDMs) is a serious therapeutic challenge. Till date, 16 different NDMs have been described. In this study, we report the molecular and structural characteristics of NDM-5 isolated from an Escherichia coli isolate (KOEC3) of bovine origin. Using PCR amplification, cloning and sequencing of full blaNDM gene, we identified the NDM type as NDM-5. Cloning of full gene in E. coli DH5α and subsequent assessment of antibiotic susceptibility of the transformed cells indicated possible role of native promoter in expression blaNDM-5. Translated amino acid sequence had two substitutions (Val88Leu and Met154Leu) compared to NDM-1. Theoretically deduced isoelectric pH of NDM-5 was 5.88 and instability index was 36.99, indicating a stable protein. From the amino acids sequence, a 3D model of the protein was computed. Analysis of the protein structure elucidated zinc coordination and also revealed a large binding cleft and flexible nature of the protein, which might be the reason for broad substrate range. Docking experiments revealed plausible binding poses for five carbapenem drugs in the vicinity of metal ions. In conclusion, results provided possible explanation for wide range of antibiotics catalyzed by NDM-5 and likely interaction modes with five carbapenem drugs.

Add-on tests for improving risk-stratification in emergency department patients with chest pain who are at low to moderate risk of 30-day major adverse cardiac events.

BACKGROUND: Chest pain patients commonly present to emergency departments (ED), and require either hospital admission and/or lengthy diagnostic protocols to rule-out myocardial infarction. We aimed to identify the best combination of add-on tests to high-sensitivity cardiac troponin (hs-cTnT) for predicting 30-day major adverse cardiac events (MACE) in adult chest pain patients presenting to an ED with suspected acute coronary syndrome. METHODS: This prospective observational study was conducted in the ED of a tertiary university hospital in Hong Kong, recruiting adult patients with chest pain of less than 24h duration, suspected with acute coronary syndrome (ACS), and had no history of coronary artery bypass grafting or stent insertion. Patients underwent triage assessment, electrocardiography, blood sampling for laboratory hs-cTnT, and Thrombolysis in Myocardial Infarction (TIMI) and HEART score assessment. The primary outcome was the number of patients with 30-day MACE. RESULTS: 602 consecutive patients were recruited and completed 30-day follow-up. A 30-day MACE occurred in 42 (7.0%) patients. Out of 12 possible models for stratifying patients at risk of 30-day MACE within 2h of ED arrival, a combination of electrocardiography (ECG) and one-time hs-cTnT (model 5) provided the simplest and most accurate model. A risk score of 0 to 5 was derived from raw coefficients of model 5. The risk score provided excellent calibration (P=0.91) and discrimination (AUC 0.87, 95% CI: 0.82 to 0.93). CONCLUSION: Appropriate early risk-stratification of patients with chest pain and possible ACS using a combination of ECG and one-time hs-cTnT may improve efficiency of care.

Diffusion-Weighted Imaging of Nasopharyngeal Carcinoma: Can Pretreatment DWI Predict Local Failure Based on Long-Term Outcome?

BACKGROUND AND PURPOSE: Pretreatment prediction of patients with nasopharyngeal carcinoma who will fail conventional treatment would potentially allow these patients to undergo more intensive treatment or closer posttreatment monitoring. The aim of the study was to determine the ability of pretreatment DWI to predict local failure in patients with nasopharyngeal carcinoma based on long-term clinical outcome. MATERIALS AND METHODS: One hundred fifty-eight patients with pretreatment DWI underwent analysis of the primary tumor to obtain the ADC mean, ADC skewness, ADC kurtosis, volume, and T-stage. Univariate and multivariate analyses using logistic regression were performed to compare the ADC parameters, volume, T-stage, and patient age in primary tumors with local failure and those with local control, by using a minimum of 5-year follow-up to confirm local control. RESULTS: Local control was achieved in 131/158 (83%) patients (range, 60.3-117.7 months) and local failure occurred in 27/158 (17%) patients (range, 5.2-79.8 months). Compared with tumors with local control, those with local failure showed a significantly lower ADC skewness (ADC values with the greatest frequencies were shifted away from the lower ADC range) (P = .006) and lower ADC kurtosis (curve peak broader) (P = .024). The ADC skewness remained significant on multivariate analysis (P = .044). There was a trend toward higher tumor volumes in local failure, but the volume, together with T-stage and ADC mean, were not significantly different between the 2 groups. CONCLUSIONS: Pretreatment DWI of primary tumors found that the skewness of the ADC distribution curve was a predictor of local failure in patients with nasopharyngeal carcinoma, based on long-term clinical outcome.

The influence of precompression on elasticity of thyroid nodules estimated by ultrasound shear wave elastography.

OBJECTIVES: To investigate the influence of variations in resting pressure (precompression) on thyroid ultrasound supersonic shear wave elastography (SWE). METHODS: Thirty-five normal thyroid glands (Norm), 55 benign hyperplastic nodules (BHN), and 17 papillary thyroid cancers (PTC) in 96 subjects underwent thyroid SWE. Four precompression levels were applied manually by the operator, ranging from A (baseline, 0 % strain) to D (high, 22-30 % strain). SWE results at each precompression level were compared using ANOVA tests with P < 0.05 indicating significance. RESULTS: SWE indices were highest in PTC, followed by BHN and Norm at each precompression level (P < 0.05). All tissue types showed successive increases in SWE results as precompression increased, although the rate was higher for PTC than BHN and Norm (Ps < 0.05). SWE values (kPa) of Norm, BHN, and PTC at baseline precompression (A) were 10.3 ± 3.3, 17.7 ± 7.6, and 22.2 ± 11.9 compared with 21.1 ± 4.2, 42.3 ± 16.0, and 97.6 ± 46.8 at high precompression (D). SWE index differences between precompression levels A and D were 10.8 kPa for Norm, 24.6 kPa for BHN, and 75.4 kPa for PTC. CONCLUSION: PTCs show greater SWE stiffening than BHN as precompression rises. Precompression effects on thyroid nodules are not negligible and may account for wide discrepancies in published SWE discriminatory performance results for thyroid malignancy. KEY POINTS: • Increases in resting pressure (precompression) applied by the operator increases thyroid stiffness. • Papillary cancers show greater increases in stiffness (strain hardening) than benign nodules. • Precompression may affect the diagnostic performance of shearwave elastography for thyroid malignancy.

Roles of "Wanting" and "Liking" in Motivating Behavior: Gambling, Food, and Drug Addictions.

The motivation to seek out and consume rewards has evolutionarily been driven by the urge to fulfill physiological needs. However in a modern society dominated more by plenty than scarcity, we tend to think of motivation as fueled by the search for pleasure. Here, we argue that two separate but interconnected subcortical and unconscious processes direct motivation: "wanting" and "liking." These two psychological and neuronal processes and their related brain structures typically work together, but can become dissociated, particularly in cases of addiction. In drug addiction, for example, repeated consumption of addictive drugs sensitizes the mesolimbic dopamine system, the primary component of the "wanting" system, resulting in excessive "wanting" for drugs and their cues. This sensitizing process is long-lasting and occurs independently of the "liking" system, which typically remains unchanged or may develop a blunted pleasure response to the drug. The result is excessive drug-taking despite minimal pleasure and intense cue-triggered craving that may promote relapse long after detoxification. Here, we describe the roles of "liking" and "wanting" in general motivation and review recent evidence for a dissociation of "liking" and "wanting" in drug addiction, known as the incentive sensitization theory (Robinson and Berridge 1993). We also make the case that sensitization of the "wanting" system and the resulting dissociation of "liking" and "wanting" occurs in both gambling disorder and food addiction.

A Comparison of the Diagnostic Accuracy and Reliability of Subjective Grading and Computer-Aided Assessment of Intranodal Vascularity in Differentiating Metastatic and Reactive Cervical Lymphadenopathy.

PURPOSE: Ultrasound is a well-established imaging modality in the assessment of malignant cervical lymphadenopathy. With the use of Doppler ultrasound, intranodal vascularity can be evaluated. However, the major limitation of ultrasound is operator dependency. Therefore, this study aimed to evaluate and compare the diagnostic accuracy and reliability of the subjective grading and computer-aided approach in assessing intranodal vascularity for the differentiation of benign and malignant lymph nodes. MATERIALS AND METHODS: The present study retrospectively assessed 99 power Doppler ultrasound images of cervical lymph nodes and evaluated the degree of intranodal vascularity using qualitative subjective grading (QSG) and quantitative computer-aided (QCA) methods. The diagnostic accuracy of the two methods in distinguishing metastatic and reactive nodes and their inter- and intra-rater reliability in assessing intranodal vascularity were evaluated and compared. RESULTS: The results showed that the QCA method was more accurate than the QSG method with a significantly higher sensitivity (67.8 % and 61.9 %, respectively, p < 0.05) and specificity (73.3 % and 57.3 %, respectively, p < 0.05). Using the intranodal vascularity index as determined by the QCA approach, the optimum cut-off to differentiate metastatic and reactive cervical lymph nodes was 32 %. The QCA method showed higher inter- and intra-rater reliability than the QSG method. CONCLUSION: In the assessment of the degree of intranodal vascularity, the QCA method was more accurate and reliable than the QSG method in distinguishing metastatic and reactive lymph nodes.

Detection of Nasopharyngeal Carcinoma by MR Imaging: Diagnostic Accuracy of MRI Compared with Endoscopy and Endoscopic Biopsy Based on Long-Term Follow-Up.

BACKGROUND AND PURPOSE: Our previous nasopharyngeal carcinoma detection study, comparing MR imaging, endoscopy, and endoscopic biopsy, showed that MR imaging is a highly sensitive test that identifies nasopharyngeal carcinomas missed by endoscopy. However, at the close of that study, patients without biopsy-proved nasopharyngeal carcinoma nevertheless had shown suspicious abnormalities on endoscopy and/or MR imaging. The aim of this study was to determine whether there were any patients with undiagnosed nasopharyngeal carcinoma by obtaining long-term follow-up and to use these data to re-evaluate the diagnostic performance of MR imaging. MATERIALS AND METHODS: In the previous study, 246 patients referred to a hospital ear, nose, and throat clinic with suspected nasopharyngeal carcinoma, based on a wide range of clinical indications, had undergone MR imaging, endoscopy, and endoscopic biopsy, and 77 had biopsy-proved nasopharyngeal carcinoma. One hundred twenty-six of 169 patients without biopsy-proved nasopharyngeal carcinoma underwent re-examination of the nasopharynx after a minimum of 3 years, including 17 patients in whom a previous examination (MR imaging = 11; endoscopy = 7) had been positive for nasopharyngeal carcinoma, but the biopsy had been negative for it. Patients with nasopharyngeal carcinoma were identified by biopsy obtained in the previous and this follow-up study; patients without nasopharyngeal carcinoma were identified by the absence of a tumor on re-examination of the nasopharynx. The sensitivity and specificity of the previous investigations were updated and compared by using the Fisher exact test. RESULTS: One patient with a previous positive MR imaging finding was subsequently proved to have nasopharyngeal carcinoma. Nasopharyngeal carcinomas were not found in the remaining 125 patients at follow-up, and the previous positive findings for nasopharyngeal carcinoma on MR imaging and endoscopy were attributed to benign lymphoid hyperplasia. The diagnostic performances for the previous MR imaging, endoscopy, and endoscopic biopsy were 100%, 88%, and 94%, respectively, for sensitivity, and 92%, 94%, and 100%, respectively, for specificity; the differences between MR imaging and endoscopy were significant for sensitivity (P = .003) but not specificity (P = .617). CONCLUSIONS: MR imaging detected the 12% of nasopharyngeal carcinomas that were endoscopically invisible, including 1 cancer that remained endoscopically occult for several years. Lymphoid hyperplasia reduced the specificity of MR imaging.

Primary hepatic angiosarcoma.

Primary hepatic angiosarcoma is a rare, aggressive tumor; composed of spindle or pleomorphic cells that line, or grow into, the lumina of pre-existing vascular spaces like sinusoids and terminal hepatic venules; with only about 200 cases diagnosed annually worldwide but it is the most common primary malignant mesenchymal tumor of the liver in adults and accounts for 2% of all primary hepatic malignancies. HAS occurs in association with known chemical carcinogens, but 75% of the tumors have no known etiology. Patients present with vague symptoms like abdominal pain, weight loss, fatigue or an abdominal mass. Hepatic angiosarcoma is usually multicentric and involves both lobes, entire liver may also found to be involved. CD31 is the most reliable marker. These tumors lack specific features on imaging, so, pathological diagnosis is necessary. There are no established treatment guidelines because of low frequency and aggressive nature of tumor, chemotherapy is only palliative, liver resection is indicated for solitary mass and liver transplant is contraindicated. The aim of this article is to comprehensively review all the available literature and to present detailed information and an update on primary hepatic angiosarcoma.

Dissipation pattern and risk assessment of flubendiamide on chili at different agro-climatic conditions in India.

Dissipation pattern and risk assessment of flubendiamide and its metabolite (desiodo flubendiamide) on chili were studied at four different agro-climatic locations of India at the standard and double dose at 60 and 120 g a.i. ha(-1) at 10 days interval. Quantification of residues was done on a high-performance liquid chromatograph (HPLC) with a photo diode array detector. The limit of quantification (LOQ) of this method was found to be 0.01 mg kg(-1) while limit of detection (LOD) being 0.003 mg kg(-1). Residues of flubendiamide were found to be below the determination limit in 15 days at both the dosages in all locations. Half-life of flubendiamide when applied at 60 and 120 g a.i. ha(-1) ranged from 0.85 to 1.80 and from 0.95 to 2.79 days, respectively. On the basis of data generated under the All India Network Project on Pesticide Residues, a preharvest interval (PHI) of 1 day has been recommended and the flubendiamide 480 SC has been registered for use on chili in India by the Central Insecticide Board and Registration Committee, Ministry of Agriculture, Government of India. The maximum residue limit (MRL) of flubendiamide on chili has been fixed by the Food Safety Standard Authority of India, Ministry of Health and Family Welfare, Government of India, as 0.02 µg g(-1) after its risk assessment.

Shear Wave Elastography--A New Quantitative Assessment of Post-Irradiation Neck Fibrosis.

PURPOSE: Shear wave elastography (SWE) is a new technique which provides quantitative assessment of soft tissue stiffness. The aim of this study was to assess the reliability of SWE stiffness measurements and its usefulness in evaluating post-irradiation neck fibrosis. MATERIALS AND METHODS: 50 subjects (25 patients with previous radiotherapy to the neck and 25 sex and age-matched controls) were recruited for comparison of SWE stiffness measurements (Aixplorer, Supersonic Imagine). 30 subjects (16 healthy individuals and 14 post-irradiated patients) were recruited for a reliability study of SWE stiffness measurements. SWE stiffness measurements of the sternocleidomastoid muscle and the overlying subcutaneous tissues of the neck were made. The cross-sectional area and thickness of the sternocleidomastoid muscle and the overlying subcutaneous tissue thickness of the neck were also measured. The post-irradiation duration of the patients was recorded. RESULTS: The intraclass correlation coefficients for the intraoperator and interoperator reliability of deep and subcutaneous tissue SWE stiffness ranged from 0.90-0.99 and 0.77-0.94, respectively. The SWE stiffness measurements (mean +/- SD) of deep and subcutaneous tissues were significantly higher in the post-irradiated patients (64.6 ± 46.8 kPa and 63.9 ± 53.1 kPa, respectively) than the sex and age-matched controls (19.9 ± 7.8 kPa and 15.3 ± 8.37 respectively) (p < 0.001). The SWE stiffness increased with increasing post-irradiation therapy duration in the Kruskal Wallis test (p < 0.001) and correlated with muscle atrophy and subcutaneous tissue thinning (p < 0.01). CONCLUSION: SWE is a reliable technique and may potentially be an objective and specific tool in quantifying deep and subcutaneous tissue stiffness, which in turn reflects the severity of neck fibrosis.