Emittance preservation in a plasma-wakefield accelerator.

Radio-frequency particle accelerators are engines of discovery, powering high-energy physics and photon science, but are also large and expensive due to their limited accelerating fields. Plasma-wakefield accelerators (PWFAs) provide orders-of-magnitude stronger fields in the charge-density wave behind a particle bunch travelling in a plasma, promising particle accelerators of greatly reduced size and cost. However, PWFAs can easily degrade the beam quality of the bunches they accelerate. Emittance, which determines how tightly beams can be focused, is a critical beam quality in for instance colliders and free-electron lasers, but is particularly prone to degradation. We demonstrate, for the first time, emittance preservation in a high-gradient and high-efficiency PWFA while simultaneously preserving charge and energy spread. This establishes that PWFAs can accelerate without degradation-an essential step toward energy boosters in photon science and multistage facilities for compact high-energy particle colliders.

Discrimination of consonants in quiet and in noise in Mandarin-speaking children with normal hearing.

OBJECTIVE: Given the critical role of consonants in speech perception and the lack of knowledge on consonant perception in noise in Mandarin-speaking children, the current study aimed to investigate Mandarin consonant discrimination in normal-hearing children, in relation to the effects of age and signal-to-noise ratios (S/N). DESIGN: A discrimination task consisting of 33 minimal pairs in monosyllabic words was designed to explore the development of consonant discrimination in five test conditions: 0, -5, -10, -15 dB S/Ns, and quiet. STUDY SAMPLE: Forty Mandarin-speaking, normal-hearing children aged from 4;0 to 8;9 in one-year-age increment were recruited and their performance was compared to 10 adult listeners. RESULTS: A significant main effect of age, test conditions, and an interaction effect between these variables was noted. Consonant discrimination in quiet and in noise improved as children became older. Consonants that were difficult to discriminate in quiet and in noise were mainly velar contrasts. Noise seemed to have less effect on the discrimination of affricates and fricatives, and plosives appeared to be to be more difficult to discriminate in noise than in quiet. Place contrasts between alveolar and palato-alveolar consonants were difficult in quiet. CONCLUSIONS: The findings were the first to reveal typical perceptual development of Mandarin consonant discrimination in children and can serve as a reference for comparison with children with disordered perceptual development, such as those with hearing loss.

Recovery time of a plasma-wakefield accelerator.

The interaction of intense particle bunches with plasma can give rise to plasma wakes1,2 capable of sustaining gigavolt-per-metre electric fields3,4, which are orders of magnitude higher than provided by state-of-the-art radio-frequency technology5. Plasma wakefields can, therefore, strongly accelerate charged particles and offer the opportunity to reach higher particle energies with smaller and hence more widely available accelerator facilities. However, the luminosity and brilliance demands of high-energy physics and photon science require particle bunches to be accelerated at repetition rates of thousands or even millions per second, which are orders of magnitude higher than demonstrated with plasma-wakefield technology6,7. Here we investigate the upper limit on repetition rates of beam-driven plasma accelerators by measuring the time it takes for the plasma to recover to its initial state after perturbation by a wakefield. The many-nanosecond-level recovery time measured establishes the in-principle attainability of megahertz rates of acceleration in plasmas. The experimental signatures of the perturbation are well described by simulations of a temporally evolving parabolic ion channel, transferring energy from the collapsing wake to the surrounding media. This result establishes that plasma-wakefield modules could be developed as feasible high-repetition-rate energy boosters at current and future particle-physics and photon-science facilities.

A practical evaluation of machine learning for classification of ultrasound images of ovarian development in channel catfish (Ictalurus punctatus).

Machine learning is a powerful tool to improve efficiency of industrial processes, but it has not yet been well utilized in aquacultural and hatchery applications. The goal of the present study was to evaluate the feasibility of using a broad array of machine learning approaches (testing of > 200 vectorization and model combinations, reporting on 20) to classify ultrasound images spanning annual ovarian development (i.e., from undeveloped to mature) of channel catfish (Ictalurus punctatus). The specific objectives were to: 1) establish dataset preprocessing to standardize image features; 2) develop and train image classification models with deep learning methods; 3) develop and train models with traditional machine learning methods; 4) compare performance of deep learning and traditional methods on two classification problems (2-class and 5-class), and 5) propose insights to deploy models in practical aquaculture applications for research and hatchery use. A total of 931 ultrasound images of catfish ovaries were used to train and evaluate models for a 2-class problem (as a 'yes' or 'no' answer) to support hormone-injection decisions for spawning management in hatcheries, and a 5-class problem for classifying gonadal development stages for research. By using feature extraction, cropping, dimension reduction, and histogram normalization, a preprocessing method was created to standardize images to develop traditional (i.e., vector input), and deep learning convolutional neural network (CNN) (i.e., image input) approaches. Traditional machine learning models with image classification achieved 100% median accuracy on the 2-class problem (with the models RN-50 and RN-152), and 96% median accuracy for the 5-class problem (with VGG-19 image vectorization). The deep learning approach for the 2-class problem had a median accuracy of > 98% for 15models. The 5-class deep learning models produced a steady increase in median accuracy with training net size, achievable through expansion of the dataset. These models can be developed further, but traditional models (using CNN architectures to simply calculate image vectors) outperformed the deep learning approach. These models can be directly applicable to aquaculture in hatcheries and reproductive biology research, in addition to a wide variety of other image-based applications.

The emerging role of open technologies for community-based improvement of cryopreservation and quality management for repository development in aquatic species.

Genetic resources of aquatic species are of tremendous value, but worldwide these are maintained almost exclusively as live populations. This is extremely expensive and insecure, and largely results from a pervasive lack of production capability, quality management, and reproducibility in cryopreservation that are barriers in development of germplasm repositories. Community-based technology approaches are emerging that can stimulate research previously limited by a lack of affordable, customizable equipment. Open-access technologies can provide for custom design and fabrication not available through traditional manufacturing. This can assist repository development with robust sample production methods and strong quality management, and can greatly improve reproducibility and standardization. Open technologies can support establishment of new communities of users, makers, and developers that collectively strive to develop open hardware in a distributed (i.e., non-centralized) fashion that can yield aggregate throughput. This occurs through use of consumer-level tools, supplies, software, and equipment, free exchange of designs and modifications, and a shared sense of mission. For cryopreservation and repository development, we have identified 14 categories of open hardware for a processing pathway, and six categories for a quality management pathway. Open hardware offers economic incentives to develop repositories for aquatic species, something that has not occurred despite 70 years of research largely focused on protocol development rather than practical applications. Advanced development of custom scientific hardware enhancing open technologies will be facilitated by interdisciplinary collaboration across biological and engineering fields. This manuscript is a contribution to the Special Issue in memory of Dr. Duane Garner, a leader in the sperm biology.

Improving the handling properties and long-term stability of polyelectrolyte complex by freeze-drying technique for low-dose bone morphogenetic protein 2 delivery.

A variety of controlled release carriers for bone morphogenetic protein 2 (BMP-2) delivery have been developed and tested in animal models. An alginate-based polyelectrolyte complex (PEC) for controlled release of low-dose BMP-2 has shown promising results in preclinical research. However, the poor handling properties and long-term stability of PEC need to be improved for translational applications. This study aimed to address these limitations of alginate-based PEC by employing a freeze-drying technique. The size and structure of freeze-dried PEC (FD-PEC) were maintained with the addition of a cryoprotectant, trehalose. The release profile of BMP-2 from FD-PEC was similar to that of freshly prepared PEC. In vitro bioactivity analysis of the released BMP-2 showed that the carrier performance of PEC was not compromised by freeze-drying up to three-month storage at room temperature. BMP-2-bound FD-PEC induced comparable bone formation to that using freshly prepared regular PEC in a rat posterolateral spinal fusion model. These results suggest that FD-PEC is capable of delivering low-dose BMP-2 and could be developed as an off-the-shelf product for translational applications. The simplicity of this preservation method provides promise for the translational application of PEC.

FLASHForward: plasma wakefield accelerator science for high-average-power applications.

The FLASHForward experimental facility is a high-performance test-bed for precision plasma wakefield research, aiming to accelerate high-quality electron beams to GeV-levels in a few centimetres of ionized gas. The plasma is created by ionizing gas in a gas cell either by a high-voltage discharge or a high-intensity laser pulse. The electrons to be accelerated will either be injected internally from the plasma background or externally from the FLASH superconducting RF front end. In both cases, the wakefield will be driven by electron beams provided by the FLASH gun and linac modules operating with a 10 Hz macro-pulse structure, generating 1.25 GeV, 1 nC electron bunches at up to 3 MHz micro-pulse repetition rates. At full capacity, this FLASH bunch-train structure corresponds to 30 kW of average power, orders of magnitude higher than drivers available to other state-of-the-art LWFA and PWFA experiments. This high-power functionality means FLASHForward is the only plasma wakefield facility in the world with the immediate capability to develop, explore and benchmark high-average-power plasma wakefield research essential for next-generation facilities. The operational parameters and technical highlights of the experiment are discussed, as well as the scientific goals and high-average-power outlook. This article is part of the Theo Murphy meeting issue 'Directions in particle beam-driven plasma wakefield acceleration'.

Particle physics experiments based on the AWAKE acceleration scheme.

New particle acceleration schemes open up exciting opportunities, potentially providing more compact or higher-energy accelerators. The AWAKE experiment at CERN is currently taking data to establish the method of proton-driven plasma wakefield acceleration. A second phase aims to demonstrate that bunches of about 109 electrons can be accelerated to high energy, preserving emittance and that the process is scalable with length. With this, an electron beam of [Formula: see text](50 GeV) could be available for new fixed-target or beam-dump experiments searching for the hidden sector, like dark photons. The rate of electrons on target could be increased by a factor of more than 1000 compared to that currently available, leading to a corresponding increase in sensitivity to new physics. Such a beam could also be brought into collision with a high-power laser and thereby probe the completely unmeasured region of strong fields at values of the Schwinger critical field. An ultimate goal is to produce an electron beam of [Formula: see text](3 TeV) and collide with an Large Hadron Collider proton beam. This very high-energy electron-proton collider would probe a new regime in which the structure of matter is completely unknown. This article is part of the Theo Murphy meeting issue 'Directions in particle beam-driven plasma wakefield acceleration'.

Vitamin D attenuates cerebral artery remodeling through VDR/AMPK/eNOS dimer phosphorylation pathway after subarachnoid hemorrhage in rats.

The role of vitamin D3 (VitD3) in the upregulation of osteopontin (OPN) and eNOS in the endothelium of cerebral arteries after subarachnoid hemorrhage (SAH) is investigated. The endovascular perforation SAH model in Sprague-Dawley rats ( n = 103) was used. The VitD3 pretreatment (30 ng/kg) increased endogenous OPN and eNOS expression in cerebral arteries compared with naïve rats ( n = 5 per group). Neurobehavioral scores were significantly improved in Pre-SAH+VitD3 group compared with the SAH group. The effects of VitD3 were attenuated by intracerebroventricular (i.c.v) injections of siRNA for the vitamin D receptor (VDR) and OPN in Pre-SAH+VitD3+VDR siRNA and Pre-SAH+VitD3+OPN siRNA rats, respectively ( n = 5 per group). The significant increase of VDR, OPN and decrease of C44 splicing in the cerebral arteries of Pre-SAH+VitD3 rats lead to an increase in basilar artery lumen. The increase in VDR expression led to an upregulation and phosphorylation of AMPK and eNOS, especially dimer form, in endothelium of cerebral artery. The results provide that VitD3 pretreatment attenuates cerebral artery remodeling and vasospasm through the upregulation of OPN and phosphorylation of AMPK (p-AMPK) and eNOS (p-eNOS) at Ser1177-Dimer in the cerebral arteries. Vitamin D may be a useful new preventive and therapeutic strategy against cerebral artery remodeling in stroke patients.

Observation of Laser Power Amplification in a Self-Injecting Laser Wakefield Accelerator.

We report on the depletion and power amplification of the driving laser pulse in a strongly driven laser wakefield accelerator. Simultaneous measurement of the transmitted pulse energy and temporal shape indicate an increase in peak power from 187±11 TW to a maximum of 318±12 TW after 13 mm of propagation in a plasma density of 0.9×10^{18} cm^{-3}. The power amplification is correlated with the injection and acceleration of electrons in the nonlinear wakefield. This process is modeled by including a localized redshift and subsequent group delay dispersion at the laser pulse front.

Treatment strategies of spinal arteriovenous fistulas and malformations: timing matters.

Spinal vascular malformations are a rare heterogeneous entity of spinal lesions with abnormal blood vessels. They may occur extra- and intradurally, peri- and intramedullary, with confined or complex configuration, and at various levels of the spine. Associated clinical symptoms are extremely variable and may range from diffuse pain, to progressive myelopathy, and even to acute hemorrhage with severe neurological deficits. Often, the patients present with significant spinal cord injury before the spinal arteriovenous lesions are diagnosed. Early recognition of the pathology is essential to cease potential disease progression and neurological deterioration. Therefore, the purpose of this review was to describe the current findings in spinal arteriovenous lesions focusing on the timing of treatment and treatment modality.

Cantonese-Speaking Children Do Not Acquire Tone Perception before Tone Production-A Perceptual and Acoustic Study of Three-Year-Olds' Monosyllabic Tones.

Models of phonological development assume that speech perception precedes speech production and that children acquire suprasegmental features earlier than segmental features. Studies of Chinese-speaking children challenge these assumptions. For example, Chinese-speaking children can produce tones before two-and-a-half years but are not able to discriminate the same tones until after 6 years of age. This study compared the perception and production of monosyllabic Cantonese tones directly in 3 -year-old children. Twenty children and their mothers identified Cantonese tones in a picture identification test and produced monosyllabic tones in a picture labeling task. To control for lexical biases on tone ratings, the mother- and child-productions were low-pass filtered to eliminate lexical information and were presented to five judges for tone classification. Detailed acoustic analysis was performed. Contrary to the view that children master lexical tones earlier than segmental phonemes, results showed that 3-year-old children could not perceive or produce any Cantonese tone with adult-like proficiency and incorrect tone productions were acoustically different from criterion. In contrast to previous findings that Cantonese-speaking children mastered tone production before tone perception, we observed more accuracy during speech perception than production. Findings from Cantonese-speaking children challenge some of the established tenets in theories of phonological development that have been tested mostly with native English speakers.

Brilliant X-rays using a Two-Stage Plasma Insertion Device.

Particle accelerators have made an enormous impact in all fields of natural sciences, from elementary particle physics, to the imaging of proteins and the development of new pharmaceuticals. Modern light sources have advanced many fields by providing extraordinarily bright, short X-ray pulses. Here we present a novel numerical study, demonstrating that existing third generation light sources can significantly enhance the brightness and photon energy of their X-ray pulses by undulating their beams within plasma wakefields. This study shows that a three order of magnitude increase in X-ray brightness and over an order of magnitude increase in X-ray photon energy is achieved by passing a 3 GeV electron beam through a two-stage plasma insertion device. The production mechanism micro-bunches the electron beam and ensures the pulses are radially polarised on creation. We also demonstrate that the micro-bunched electron beam is itself an effective wakefield driver that can potentially accelerate a witness electron beam up to 6 GeV.

Elucidating the prognostic significance of KRAS, NRAS, BRAF and PIK3CA mutations in Chinese patients with metastatic colorectal cancer.

AIM: The prognostic significance of KRAS, NRAS, PIK3CA and BRAF mutations was evaluated in Chinese patients with metastatic colorectal cancer (CRC). METHOD: Tumor samples from 183 patients were retrospectively tested for KRAS, NRAS, PIK3CA and BRAF mutations. Multivariate analysis was performed to determine the relationship between mutational status, drug response and survival. RESULT: Over 70% of patients received two or more lines of chemotherapy, 50% had cetuximab and 18% had bevacizumab. The prevalence of KRAS, NRAS, BRAF and PIK3CA mutations was 45, 3.2, 5 and 20%, respectively. For the entire cohort, the median overall survival was 24 months (95% confidence interval [CI] = 20.4-26.4 months). Of the genes tested, only KRAS mutation was an independent prognostic factor with a multivariate hazard ratio of 1.5 (95% CI = 1.05-2.16, P = 0.03). In the subgroup of patients who received cetuximab-based therapy in the first-line setting, KRAS mutation was associated with a lack of response to chemotherapy (28% vs 66%, chi-square, P = 0.01). Patients with KRAS mutant tumors (or KRAS wild-type tumors that harbored BRAF and/or PIK3CA mutations) tended to have lower response rates to chemotherapy and/or cetuximab (P = not significant). The number of NRAS mutant cases was too small to allow any statistical analysis. CONCLUSION: The prevalence of KRAS, NRAS, BRAF and PIK3CA mutations in this cohort is consistent with reports from non-Asian populations, and KRAS mutation has both prognostic and predictive significance in Chinese patients with metastatic CRC.

Haemorrhagic cerebral air embolism from an atrio-oesophageal fistula following atrial fibrillation ablation.

We report the case of a man found unconscious three weeks following atrial fibrillation (AF) ablation. Cranial and thoracic imaging demonstrated multiple areas of pneumo-embolic infarction secondary to an atrio-oesophageal fistula (AEF). AEF is a recognised, but rare, complication of AF ablation.(1-8) Early recognition is critical as the mortality is 100% without surgical intervention. We consider the postulated mechanisms of AEF formation, the spectrum of clinical presentation, investigations and treatment.

Compact laser accelerators for X-ray phase-contrast imaging.

Advances in X-ray imaging techniques have been driven by advances in novel X-ray sources. The latest fourth-generation X-ray sources can boast large photon fluxes at unprecedented brightness. However, the large size of these facilities means that these sources are not available for everyday applications. With advances in laser plasma acceleration, electron beams can now be generated at energies comparable to those used in light sources, but in university-sized laboratories. By making use of the strong transverse focusing of plasma accelerators, bright sources of betatron radiation have been produced. Here, we demonstrate phase-contrast imaging of a biological sample for the first time by radiation generated by GeV electron beams produced by a laser accelerator. The work was performed using a greater than 300 TW laser, which allowed the energy of the synchrotron source to be extended to the 10-100 keV range.

Intermittent versus continuous erlotinib with concomitant modified "XELOX" (q3W) in first-line treatment of metastatic colorectal cancer: correlation with serum amphiregulin and transforming growth factor alpha.

BACKGROUND: This study evaluated the activity of 2 schedules of erlotinib in combination with chemotherapy, and the prognostic significance of serum amphiregulin (AREG) and transforming growth factor alpha (TGFa) in metastatic colorectal cancer. METHODS: A total of 60 untreated patients were randomized to a "continuous" (CON; erlotinib 100 mg daily) or an "intermittent" (INT; erlotinib 150 mg on alternate day on day 2 to 14, then 150 mg daily on days 15 to 21) schedule of erlotinib with a modified XELOX (capecitabine plus oxaliplatin) regimen. Serum levels of AREG and TGFa were determined serially. RESULTS: Baseline characteristics were similar between the 2 arms. Of the 58 patients evaluated for response, there was a nonsignificant trend toward a slightly higher overall response rate in the INT arm (66.7%) versus the CON arm (56.7%). At a median follow-up of 2.8 years, the median overall survival was 18.8 months (95% confidence interval = 11.3-22.9 months) and 20.7 months (95% confidence interval = 12.5-31 months, P = .19) for the CON and INT arm, respectively. KRAS mutation did not predict drug response. The 2 arms did not differ significantly in toxicity. Baseline serum TGFa was an independent predictor of progression-free survival, whereas a drop in serum TGFa and AREG levels following 3 to 4 cycles of treatment were associated with shorter progression-free survival and overall survival, respectively. CONCLUSIONS: The intermittent erlotinib schedule was associated with a higher response rate, although this is not statistically significant. Serum TGFa and AREG levels have prognostic significance in erlotinib-treated patients with colorectal cancer, and further studies are warranted.

Supportive care needs in Hong Kong Chinese women confronting advanced breast cancer.

BACKGROUND: Women with advanced breast cancer (ABC) are living longer, so understanding their needs becomes important. This cross-sectional study investigated the type and extent of unmet supportive care needs in Hong Kong Chinese women with advanced breast cancer. METHODS: Face-to-face interviews were conducted among women with stage III or stage IV disease mostly awaiting chemotherapy (76%) to identify unmet needs using the Supportive Care Needs Survey Short Form, psychological morbidity using the Hospital Anxiety and Depression Scale, symptom distress using the Memorial Symptom Assessment Scale, and satisfaction with care using the Patient satisfaction questionnaire (PSQ-9). RESULTS: About 27-72% of 198/220 (90%) women (mean age = 53.4 ± 9.74 (standard deviation) years) identified needs from the health system, information, and patient support (HSIPS) domain as the top 15 most prevalent unmet needs. 'having one member of hospital staff with whom you can talk to about all aspect of your condition, treatment, and follow-up' was most cited by 72% of the patients, with remaining unmet needs addressing mostly desire for information. Unmet need strength did not differ between women with stage III and stage IV disease, whereas women with first time diagnosis reported greater health system and information unmet needs compared with women with recurrent disease. Stepwise multiple regression analyses revealed that symptom distress was consistently positively associated with all but sexuality need domains, whereas low satisfaction with care was associated with HSIPS (ß = 3.270, p < 0.001) and physical and daily living (ß = 2.810, p < 0.01) domains. DISCUSSIONS: Chinese women with ABC expressed need for continuity of care and improved information provision. High symptom distress was associated with lower levels of satisfaction with care. These unmet needs appear to reflect current care services shortcomings.

Fiddling with the pacemaker: Twiddler's syndrome in a Parkinsonian patient.

We describe the case report of an 86-year-old Afro-Caribbean Parkinsonian gentleman with intermittent Mobitz II heart block and syncope who received a DDD pacemaker. Due to Parkinson's syndrome, the patient rotated the atrial lead around the pacemaker, causing the famous "Twiddler's syndrome", a rare clinical issue which can easily be diagnosed with a simple chest X-ray.

Prospective Predictors of Patellofemoral Pain Syndrome: A Systematic Review With Meta-analysis.

CONTEXT: Patellofemoral pain syndrome (PFPS) is one of the most common overuse injuries. OBJECTIVE: To assess the collective evidence of predisposing factors to PFPS. DATA SOURCES: MEDLINE (1960-June 2010), EMBASE (1980-June 2010), and CINAHL (1982-June 2010). STUDY SELECTION: Studies were included if patients were asymptomatic at baseline testing (free of PFPS) and were prospectively followed for the development of the disorder. Only studies that assessed at least 1 variable that can be measured at a typical clinic were included. After duplicates were removed, 973 studies were assessed from their titles or abstracts, 20 from the full text, and from these, 7 met the inclusion criteria. DATA EXTRACTION: Data were extracted for age, weight, height, sample size, patient type (military vs civilian), follow-up periods, diagnostic methods, and diagnostic criteria. Means and standard deviations were extracted for all outcome variables. RESULTS: Meta-analyses were performed for height, weight, leanness, Q angle, number of sit-ups, knee extension strength, and peak knee valgus angle during landing. Lower knee extension strength was the only variable that was predictive of PFPS (P < 0.01). Other variables that were identified as predictive of PFPS by single studies were vertical jump, push-ups, knee flexion and hip abduction strength, thumb-to-forearm flexibility, quadriceps and gastrocnemius flexibility, genu varum, navicular drop, knee valgus moment at initial contact during landing, social support, and palliative reaction. CONCLUSIONS: It appears that anthropometric variables are not associated with PFPS, while knee extension strength deficits appear to be predictors of PFPS.