Hitting the Target: Developing High-quality Evidence for Proton Beam Therapy Through Randomised Controlled Trials.

The National Health Service strategy for the delivery of proton beam therapy (PBT) in the UK provides a unique opportunity to deliver high-quality evidence for PBT through randomised controlled trials (RCTs). We present a summary of three UK PBT RCTs in progress, including consideration of their key design characteristics and outcome assessments, to inform and support future PBT trial development. The first three UK multicentre phase III PBT RCTs (TORPEdO, PARABLE and APPROACH), will compare PBT with photon radiotherapy for oropharyngeal squamous cell carcinoma, breast cancer and oligodendroglioma, respectively. All three studies were designed by multidisciplinary teams, which combined expertise from clinicians, clinical trialists and scientists with strong patient advocacy and guidance from national radiotherapy research networks and international collaborators. Consistent across all three studies is a focus on the reduction of long-term radiotherapy-related toxicities and an evaluation of patient-reported outcomes and health-related quality of life, which will address key uncertainties regarding the clinical benefits of PBT. Innovative translational components will provide insights into mechanisms of toxicity and help to frame the key future research questions regarding PBT. The UK radiotherapy research community is developing and delivering an internationally impactful PBT research portfolio. The combination of data from RCTs with prospectively collected data from a national PBT outcomes registry will provide an innovative, high-quality repository for PBT research and the platform to design and deliver future trials of PBT.

The detection of germline and somatic BRCA1/2 genetic variants through parallel testing of patients with high-grade serous ovarian cancer: a national retrospective audit.

OBJECTIVE: To determine the frequency of germline and somatic pathogenic BRCA1 and BRCA2 variants in patients with high-grade serous ovarian cancer tested by next-generation sequencing (NGS), with the aim of defining the best strategy to be implemented in future routine testing. DESIGN: National retrospective audit. SETTING: The All Wales Medical Genomics Service (AWMGS). POPULATION: Patients with high-grade serous ovarian/fallopian tube/peritoneal cancer referred by oncologists to the AWMGS between February 2015 and February 2021 for germline and/or tumour testing of the BRCA1 and BRCA2 genes by NGS. METHODS: Analysis of NGS data from germline and/or tumour testing. MAIN OUTCOME MEASURES: Frequency of BRCA1 and BRCA2 pathogenic variants. RESULTS: The overall observed germline/somatic pathogenic variant detection rate was 11.6% in the 844 patients included in this study, with a 9.2% (73/791) germline pathogenic variant detection rate. Parallel tumour and germline testing was carried out for 169 patients and the overall pathogenic variant detection rate for this cohort was 14.8%, with 6.5% (11/169) shown to have a somatic pathogenic variant. Two BRCA1 dosage variants were found during germline screens, representing 2.0% (2/98) of patients with a pathogenic variant that would have been missed through tumour testing alone. CONCLUSIONS: Parallel germline and tumour BRCA1 and BRCA2 testing maximises the detection of pathogenic variants in patients with high-grade serous ovarian cancer. TWEETABLE ABSTRACT: Parallel germline and tumour testing maximises BRCA pathogenic variant detection in ovarian cancer.

Production of Plant-Associated Volatiles by Select Model and Industrially Important Streptomyces spp.

The Streptomyces produce a great diversity of specialized metabolites, including highly volatile compounds with potential biological activities. Volatile organic compounds (VOCs) produced by nine Streptomyces spp., some of which are of industrial importance, were collected and identified using gas chromatography-mass spectrometry (GC-MS). Biosynthetic gene clusters (BGCs) present in the genomes of the respective Streptomyces spp. were also predicted to match them with the VOCs detected. Overall, 33 specific VOCs were identified, of which the production of 16 has not been previously reported in the Streptomyces. Among chemical classes, the most abundant VOCs were terpenes, which is consistent with predicted biosynthetic capabilities. In addition, 27 of the identified VOCs were plant-associated, demonstrating that some Streptomyces spp. can also produce such molecules. It is possible that some of the VOCs detected in the current study have roles in the interaction of Streptomyces with plants and other higher organisms, which might provide opportunities for their application in agriculture or industry.

Demographic studies of owned dogs in the Northern Peninsula Area, Australia, to inform population and disease management strategies.

OBJECTIVE: To generate domestic dog demographic information to aid population and disease management in the Aboriginal and Torres Strait Islander communities of the Northern Peninsula Area, Queensland, Australia. METHODS: Sight-resight surveys using standard and modified methods were conducted to estimate the free-roaming dog population size. A cross-sectional questionnaire of dog owners was used to gather dog demographic information and investigate owners' dog management behaviours. A survey was also conducted to estimate the total dog population size. RESULTS: The mean total dog population size was estimated to be 813 (range, 770-868). The roaming dog population was 430 or 542 (95% confidence interval (CI) 254-608; 95% CI 405-680, standard and modified methods, respectively). Therefore, the roaming population represents 52.8% or 66.7% of the total population based on the sight-resight methodology. We surveyed 65 dog owners who owned 165 dogs (1 : 1 ratio of male : female dogs). Only 14% (95% CI 9-19) of dogs were sterilised and significantly more males were entire (P = 0.02). Although most dogs were pets (65%), hunting dogs were significantly more likely to be taken outside of the resident community (P < 0.001). The birth rate was 2.4 puppies/dog-owning house/year, which was higher than the death rate (1.7 dogs/dog-owning house/year). In the previous 12 months, 90% of the 109 deaths were dogs aged 0-2 years old. CONCLUSION: This study demonstrated that most of the dog population in the NPA is free-roaming and that the population has increased, likely because of a lack of population management strategies such as sterilisation. This information will be used to develop population and disease management strategies in the NPA.

ANITA-An active vibration cancellation system for scanning probe microscopy.

The high sensitivity of scanning probe microscopes poses a barrier to their use in noisy environments. Vibrational noise, whether from structural or acoustic sources, can manifest as relative motion between the probe tip and sample, which then appears in the probe position ("Z") feedback as it tries to cancel this motion. Here we describe an active cancellation process that nullifies the appearance of this vibration by adding a drive signal into the existing Z-feedback loop. The drive is digitally calculated from accelerometer-based vibration measurements. By transferring the vibration cancellation effort to this drive signal, vibration-created noise is significantly reduced. This inexpensive and easy solution requires no major instrumental modifications and is ideal for those looking to place their microscopes in noisier environments, coupled, for example, to active refrigeration systems (e.g., pulse tube cryocoolers) or other high-vibration instruments.

Recurrent Follicular Dendritic Cell Sarcoma of the Parotid Gland Imaged with 18F-FDG PET/CT.

Follicular dendritic cell sarcoma (FDCS) is an extremely rare tumor with only 67 cases of head and neck FDCS reported in the literature. A 65-year-old female had a 6-cm follicular dendritic cell sarcoma resected from the left parotid gland with close margins. It recurred 1 year later as a 5-cm mass that was intensely [18F] fluoro-2-deoxy-D-glucose (18F-FDG) avid on positron emission tomography/computed tomography (PET/CT) and was re-excised. A follow-up PET/CT did not show any metastatic disease. The use of 18F-FDG PET/CT in the management of FDCS warrants further research. We present the 18F-FDG PET/CT imaging findings of this rare tumor.

Surface single-molecule dynamics controlled by entropy at low temperatures.

Configuration transitions of individual molecules and atoms on surfaces are traditionally described using an Arrhenius equation with energy barrier and pre-exponential factor (attempt rate) parameters. Characteristic parameters can vary even for identical systems, and pre-exponential factors sometimes differ by orders of magnitude. Using low-temperature scanning tunnelling microscopy (STM) to measure an individual dibutyl sulfide molecule on Au(111), we show that the differences arise when the relative position of tip apex and molecule changes by a fraction of the molecule size. Altering the tip position on that scale modifies the transition's barrier and attempt rate in a highly correlated fashion, which results in a single-molecular enthalpy-entropy compensation. Conversely, appropriately positioning the STM tip allows selecting the operating point on the compensation line and modifying the transition rates. The results highlight the need to consider entropy in transition rates of single molecules, even at low temperatures.

Suppression of Superfluid Density and the Pseudogap State in the Cuprates by Impurities.

We use scanning tunneling microscopy (STM) to study magnetic Fe impurities intentionally doped into the high-temperature superconductor Bi_{2}Sr_{2}CaCu_{2}O_{8+δ}. Our spectroscopic measurements reveal that Fe impurities introduce low-lying resonances in the density of states at Ω_{1}≈4 meV and Ω_{2}≈15 meV, allowing us to determine that, despite having a large magnetic moment, potential scattering of quasiparticles by Fe impurities dominates magnetic scattering. In addition, using high-resolution spatial characterizations of the local density of states near and away from Fe impurities, we detail the spatial extent of impurity-affected regions as well as provide a local view of impurity-induced effects on the superconducting and pseudogap states. Our studies of Fe impurities, when combined with a reinterpretation of earlier STM work in the context of a two-gap scenario, allow us to present a unified view of the atomic-scale effects of elemental impurities on the pseudogap and superconducting states in hole-doped cuprates; this may help resolve a previously assumed dichotomy between the effects of magnetic and nonmagnetic impurities in these materials.

Fermi surface and pseudogap evolution in a cuprate superconductor.

The unclear relationship between cuprate superconductivity and the pseudogap state remains an impediment to understanding the high transition temperature (T(c)) superconducting mechanism. Here, we used magnetic field-dependent scanning tunneling microscopy to provide phase-sensitive proof that d-wave superconductivity coexists with the pseudogap on the antinodal Fermi surface of an overdoped cuprate. Furthermore, by tracking the hole-doping (p) dependence of the quasi-particle interference pattern within a single bismuth-based cuprate family, we observed a Fermi surface reconstruction slightly below optimal doping, indicating a zero-field quantum phase transition in notable proximity to the maximum superconducting T(c). Surprisingly, this major reorganization of the system's underlying electronic structure has no effect on the smoothly evolving pseudogap.

Bio-organic materials in the atmosphere and snow: measurement and characterization.

Bio-organic chemicals are ubiquitous in the Earth's atmosphere and at air-snow interfaces, as well as in aerosols and in clouds. It has been known for centuries that airborne biological matter plays various roles in the transmission of disease in humans and in ecosystems. The implication of chemical compounds of biological origins in cloud condensation and in ice nucleation processes has also been studied during the last few decades, and implications have been suggested in the reduction of visibility, in the influence on oxidative potential of the atmosphere and transformation of compounds in the atmosphere, in the formation of haze, change of snow-ice albedo, in agricultural processes, and bio-hazards and bio-terrorism. In this review we critically examine existing observation data on bio-organic compounds in the atmosphere and in snow. We also review both conventional and cutting-edge analytical techniques and methods for measurement and characterisation of bio-organic compounds and specifically for microbial communities, in the atmosphere and snow. We also explore the link between biological compounds and nucleation processes. Due to increased interest in decreasing emissions of carbon-containing compounds, we also briefly review (in an Appendix) methods and techniques that are currently deployed for bio-organic remediation.

Veterinary and human biobanking practices: enhancing molecular sample integrity.

Animal models have historically informed veterinary and human pathophysiology. Next-generation genomic sequencing and molecular analyses using analytes derived from tissue require integrative approaches to determine macroanalyte integrity as well as morphology for imaging algorithms that can extend translational applications. The field of biospecimen science and biobanking will play critical roles in tissue sample collection and processing to ensure the integrity of macromolecules, aid experimental design, and provide more accurate and reproducible downstream genomic data. Herein, we employ animal experiments to combine protein expression analysis by microscopy with RNA integrity number and quantitative measures of morphologic changes of autolysis. These analyses can be used to predict the effect of preanalytic variables and provide the basis for standardized methods in tissue sample collection and processing. We also discuss the application of digital imaging with quantitative RNA and tissue-based protein measurements to show that genomic methods augment traditional in vivo imaging to support biospecimen science. To make these observations, we have established a time course experiment of murine kidney tissues that predicts conventional measures of RNA integrity by RIN analysis and provides reliable and accurate measures of biospecimen integrity and fitness, in particular for time points less than 3 hours post-tissue resection.

Simplified staging laparotomy in FIGO stage 1 epithelial ovarian cancer: follow-up and outcomes in south Wales, U.K.

We have conducted a retrospective analysis of FIGO stage 1 ovarian cancer patients in south Wales, who underwent a simplified staging laparotomy without routine nodal sampling and peritoneal biopsies. Patient records from January 2004 to December 2010 were analysed. A total of 116 patients were included in the final analysis. Adjuvant chemotherapy was offered to patients with risk factors for relapse (grade > 1, clear cell histology, or stage > Ia); overall, 89 patients (76.7%) received adjuvant single agent carboplatin (n = 54, 46.5%) or combination chemotherapy (n = 35, 30.2%). After a median follow up of 41 months (range 12-95), 18 patients have relapsed (15.5%), of these 17 had risk factors and 16 had received adjuvant chemotherapy. Eighteen patients have died, of whom 6 of non-cancer related causes without prior relapse. 5-year overall and relapse free survival were 80%. In conclusion, in situations where there are limited resources and operating time constraints, our data suggest that a simplified staging laparotomy approach may be a reasonable compromise in apparently early stage ovarian cancer: this may result in a more aggressive use of chemotherapy, but survival outcomes seem comparable to other series.

Quantum phase transition from triangular to stripe charge order in NbSe2.

The competition between proximate electronic phases produces a complex phenomenology in strongly correlated systems. In particular, fluctuations associated with periodic charge or spin modulations, known as density waves, may lead to exotic superconductivity in several correlated materials. However, density waves have been difficult to isolate in the presence of chemical disorder, and the suspected causal link between competing density wave orders and high-temperature superconductivity is not understood. Here we used scanning tunneling microscopy to image a previously unknown unidirectional (stripe) charge-density wave (CDW) smoothly interfacing with the familiar tridirectional (triangular) CDW on the surface of the stoichiometric superconductor NbSe(2). Our low-temperature measurements rule out thermal fluctuations and point to local strain as the tuning parameter for this quantum phase transition. We use this quantum interface to resolve two longstanding debates about the anomalous spectroscopic gap and the role of Fermi surface nesting in the CDW phase of NbSe(2). Our results highlight the importance of local strain in governing phase transitions and competing phenomena, and suggest a promising direction of inquiry for resolving similarly longstanding debates in cuprate superconductors and other strongly correlated materials.

Scanning tunnelling microscopy imaging of symmetry-breaking structural distortion in the bismuth-based cuprate superconductors.

A complicating factor in unravelling the theory of high-temperature (high-T(c)) superconductivity is the presence of a 'pseudogap' in the density of states, the origin of which has been debated since its discovery. Some believe the pseudogap is a broken symmetry state distinct from superconductivity, whereas others believe it arises from short-range correlations without symmetry breaking. A number of broken symmetries have been imaged and identified with the pseudogap state, but it remains crucial to disentangle any electronic symmetry breaking from the pre-existing structural symmetry of the crystal. We use scanning tunnelling microscopy to observe an orthorhombic structural distortion across the cuprate superconducting Bi(2)Sr(2)Ca(n-1)Cu(n)O(2n+4+x) (BSCCO) family tree, which breaks two-dimensional inversion symmetry in the surface BiO layer. Although this inversion-symmetry-breaking structure can impact electronic measurements, we show from its insensitivity to temperature, magnetic field and doping, that it cannot be the long-sought pseudogap state. To detect this picometre-scale variation in lattice structure, we have implemented a new algorithm that will serve as a powerful tool in the search for broken symmetry electronic states in cuprates, as well as in other materials.

Quality of induced sputum using a human-powered nebuliser in a mobile human immunodeficiency virus testing service in South Africa.

OBJECTIVES: To investigate the quality of induced sputum samples using a human-powered (HPN) and an electric-powered nebuliser (EPN). METHODS: For each participant two sputum samples were induced using the HPN and the EPN. The sequence of the two nebulisers was allocated at random. The proportion of good quality sputum according to different assessment criteria was compared using an exact McNemar test. The difference in time to expectoration was compared using the Wilcoxon matched-pairs signed-rank test. RESULTS: A total of 123 individuals were eligible for the study. Nine individuals refused to participate and five were unable to produce a sputum sample. The proportion of good quality sputum was higher among sputum samples induced by the HPN compared to those obtained using the EPN. The median time to produce a sputum sample was 2.2 min (IQR 1.13-4.1) for the HPN and 2.5 min (IQR 1.4-4.1) for the EPN. CONCLUSION: The HPN induced good quality sputum within 3 min. The device operates without electricity and is suitable not only for remote clinics with unreliable electricity, but also for mobile services and community-based intensified tuberculosis (TB) case finding. Further research needs to investigate the yield of TB in sputum samples induced by the HPN.

Gemcitabine and carboplatin in the treatment of transitional cell carcinoma of the urothelium: a single centre experience and review of the literature.

The objectives of this study are to evaluate patient outcomes in clinical practice using gemcitabine and carboplatin (GCarbo) as first-line treatment in metastatic transitional cell carcinoma (TCC) of the urothelium, and to review the published evidence on the use of GCarbo in this setting. From July 2003, all cases of metastatic TCC of the urothelium referred to a single consultant were treated using 3-weekly gemcitabine 1200 mg/m(2) i.v. days 1 and 8 plus carboplatin AUC 5-6 i.v. day 1 to a maximum of six cycles. Fifteen patients (median age 67 years) were treated. Grade 3 or 4 toxicity included neutropenia (47%), anaemia (27%) and thrombocytopenia (20%). No patients required admission for neutropenic pyrexia/sepsis, and there were no treatment-related deaths. The overall response rate was 67%. The median survival was 9 months (95% CI 7.4-10.6), and 1-year survival 42%. Gemcitabine and carboplatin is well tolerated, and has activity as first-line treatment in metastatic TCC of the urothelium. However, there is now evidence suggesting that gemcitabine and cisplatin may be more efficacious, and until the appropriate randomized phase 3 trials have been carried out, gemcitabine and cisplatin should probably remain the preferred first-line therapy. Gemcitabine and carboplatin is an effective alternative in those patients not deemed fit enough for cisplatin.

Induction chemotherapy followed by chemoradiation in locally advanced pancreatic cancer: an effective and well-tolerated treatment.

AIMS: The treatment of locally advanced pancreatic cancer varies enormously both within the UK and internationally. Although chemoradiation is the treatment of choice in the USA, in the UK this modality is used infrequently because of concerns regarding both its efficacy and its toxicity. We reviewed our experience with induction chemotherapy and selective chemoradiation in an attempt to show that it is a well-tolerated treatment that may be superior to chemotherapy alone. MATERIALS AND METHODS: Case notes of patients with locally advanced pancreatic cancer referred to the Velindre Cancer Centre between 1 March 2005 and 31 October 2007 were reviewed. Data on patient demographics, tumour characteristics, treatment and overall survival were collected retrospectively. Toxicity data during chemoradiation were collected prospectively. Patients who had non-progressive disease after 3 months of chemotherapy were planned for chemoradiation using three-dimensional conformal radiotherapy to a total dose of 4500-5040cGy in 25-28 daily fractions with gemcitabine as a radiosensitiser. RESULTS: Of the 91 referrals, 69 (76%) were fit for active oncological treatment; 43/69 (62%) patients were considered for induction chemotherapy followed by chemoradiation and 16/43 (37%) patients received chemoradiation. The median overall survival for patients receiving primary chemotherapy (n=26) was 9.2 (6.8-11.9) months and was 15.3 (11.6-upper limit not reached) months for patients who received chemoradiation (n=16). During the induction chemotherapy 8/16 (50%) patients experienced grade 3/4 toxicity and there were five hospital admissions. During chemoradiation there were 6/16 (37.5%) cases of grade 3/4 toxicity and two hospital admissions. There were no treatment-related deaths. Overall, 94.5% of the intended radiotherapy dose and 84% of the concurrent chemotherapy dose was delivered. CONCLUSIONS: In this UK network, about half of patients were considered for chemoradiation, but only 18% received it. Survival and treatment-related toxicity are consistent with data from other chemoradiation trials and in our series chemoradiation was tolerated better than chemotherapy alone. This supports the view that 'consolidation' chemoradiation is a viable treatment option that should be considered in selected patients with locally advanced non-metastatic pancreatic cancer.

An auxiliary capacitor based ultrafast drive circuit for shear piezoelectric motors.

Shear piezoelectric motors frequently require large voltage changes on very short time scales. Since piezos behave electrically as capacitors, this requires a drive circuit capable of quickly sourcing or sinking a large amount of current at high voltages. Here we describe a novel circuit design using a high voltage amplifier, transistor switching stage, and auxiliary capacitor. This circuit can drive piezoelectric motors at higher speeds and lower costs than conventional methods and with greater flexibility for computer automation. We illustrate its application in a controller for a scanning tunneling microscope coarse approach mechanism and discuss other possible applications and modifications of this circuit.