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.

Study into the spread of heat from thermo-optic silicon photonic elements.

Phase modulators based upon the thermo-optic effect are used widely in silicon photonics for low speed applications such as switching and tuning. The dissipation of the heat produced to drive the device to the surrounding silicon is a concern as it can dictate how compact and tightly packed components can be without concerns over thermal crosstalk. In this paper we study through modelling and experiment, on various silicon on insulator photonic platforms, how close waveguides can be placed together without significant thermal crosstalk from adjacent devices.

Improved survival prediction for oropharyngeal cancer beyond TNMv8.

PURPOSE: For oropharynx squamous cell carcinoma (OPSCC) this study aimed to: (i) compare 5-year overall survival (OS) stratification by AJCC/UICC TNM versions 7 (TNMv7) and 8 (TNMv8), (ii) determine whether changes to T and N stage groupings improve prognostication and (iii) develop and validate a model incorporating additional clinical characteristics to improve 5-year OS prediction. MATERIAL AND METHODS: All OPSCC treated with curative-intent at our institution between 2011 and 2017 were included. The primary endpoint was 5-year OS. Survival curves were produced for TNMv7 and TNMv8. A three-way interaction between T, N stage and p16 status was evaluated for improved prognostication. Cox proportional hazards modelling was used to derive a new predictive model. RESULTS: Of 750 OPSCC cases, 574 (77%) were p16-positive. TNMv8 was more prognostic than TNMv7 (concordance probability estimate [CPE] ±â€¯SE = 0.72 ±â€¯0.02 vs 0.53 ±â€¯0.02). For p16-positive disease, TNMv8 discriminated stages II vs I (HR 2.32, 95% CI 1.47-3.67) and III vs II (HR 1.75, 95% CI 1.13-2.72). For p16-negative disease, TNMv7 and TNMv8 demonstrated poor hazard discrimination. Different T, N stage and p16-status combinations did not improve prognostication after adjusting for other factors (CPE = 0.79 vs 0.79, p = 0.998). A model for p16-positive and p16-negative OPSCC including additional clinical characteristics improved 5-year OS prediction beyond TNMv8 (c-index 0.76 ±â€¯0.02). CONCLUSIONS: TNMv8 is superior to TNMv7 for p16-positive OPSCC, but both performed poorly for p16-negative disease. A novel model incorporating additional clinical characteristics improved 5-year OS prediction for both p16-positive and p16-negative disease.

Integration of low loss vertical slot waveguides on SOI photonic platforms for high efficiency carrier accumulation modulators.

Silicon accumulation type modulators offer prospects of high power efficiency, large bandwidth and high voltage phase linearity making them promising candidates for a number of advanced electro-optic applications. A significant challenge in the realisation of such a modulator is the fabrication of the passive waveguide structure which requires a thin dielectric layer to be positioned within the waveguide, i.e. slotted waveguides. Simultaneously, the fabricated slotted waveguide should be integrated with conventional rib waveguides with negligible optical transition losses. Here, successful integration of polysilicon and silicon slot waveguides enabling a low propagation loss 0.4-1.2 dB/mm together with an ultra-small optical mode conversion loss 0.04 dB between rib and slot waveguides is demonstrated. These fabricated slot waveguide with dielectric thermal SiO2 layer thicknesses around 6 nm, 8 nm and 10 nm have been characterized under transmission electron microscopy allowing for strong carrier accumulation effects for MOS-capacitor electro-optic modulators.

Nonconservative Coupling in a Passive Silicon Microring Resonator.

The authors report on nonconservative coupling in a passive silicon microring between its clockwise and counterclockwise resonance modes. The coupling coefficient is adjustable using a thermo-optic phase shifter. The resulting resonance of the supermodes due to nonconservative coupling is predicted in theory and demonstrated in experiments. This Letter paves the way for fundamental studies of on-chip lasers and quantum photonics, and their potential applications.

Ultra-sharp asymmetric Fano-like resonance spectrum on Si photonic platform.

In this paper, we report the generation of an ultra-sharp asymmetric resonance spectrum through Fano-like interference. This generation is accomplished by weakly coupling a high-quality factor (Q factor) Fabry-Pérot (FP) cavity and a low-Q factor FP cavity through evanescent waves. The high-Q FP cavity is formed by Sagnac loop mirrors, whilst the low-Q one is built by partially transmitting Sagnac loop reflectors. The working principle has been analytically established and numerically modelled by using temporal coupled-mode-theory (CMT), and verified using a prototype device fabricated on the 340 nm silicon-on-insulator (SOI) platform, patterned by deep ultraviolet (DUV) lithography. Pronounced asymmetric resonances with slopes up to 0.77 dB/pm have been successfully measured, which, to the best of our knowledge, is higher than the results reported in state-of-the-art devices in on-chip integrated Si photonic studies. The established theoretical analysis method can provide excellent design guidelines for devices with Fano-like resonances. The design principle can be applied to ultra-sensitive sensing, ultra-high extinction ratio switching, and more applications.

Silicon-on-insulator free-carrier injection modulators for the mid-infrared.

Experimental demonstrations of silicon-on-insulator waveguide-based free-carrier effect modulators operating at 3.8 µm are presented. PIN diodes are used to inject carriers into the waveguides, and are configured to (a) use free-carrier electroabsorption to create a variable optical attenuator with 34 dB modulation depth and (b) use free-carrier electrorefraction with the PIN diodes acting as phase shifters in a Mach-Zehnder interferometer, achieving a VπLπ of 0.052 V·mm and a DC modulation depth of 22 dB. Modulation is demonstrated at data rates up to 125 Mbit/s.

49.6 Gb/s direct detection DMT transmission over 40 km single mode fibre using an electrically packaged silicon photonic modulator.

We present the characterization of a silicon Mach-Zehnder modulator with electrical packaging and show that it exhibits a large third-order intermodulation spurious-free dynamic range (> 100 dB Hz2/3). This characteristic renders the modulator particularly suitable for the generation of high spectral efficiency discrete multi-tone signals and we experimentally demonstrate a single-channel, direct detection transmission system operating at 49.6 Gb/s, exhibiting a baseband spectral efficiency of 5 b/s/Hz. Successful transmission is demonstrated over various lengths of single mode fibre up to 40 km, without the need of any amplification or dispersion compensation.

Dielectrophoresis study of temporal change in internal conductivity of single CHO cells after electroporation by pulsed electric fields.

Applying sufficiently strong pulsed electric fields to a cell can permeabilize the membrane and subsequently affect its dielectric properties. In this study, we employ a microfluidic dielectrophoresis cytometry technique to simultaneously electroporate and measure the time-dependent dielectric response of single Chinese hamster ovary cells. Using experimental measurements along with numerical simulations, we present quantitative results for the changes in the cytoplasm conductivity of single cells within seconds after exposure to 100 µs duration pulsed electric fields with various intensities. It is shown that, for electroporation in a medium with conductivity lower than that of the cell's cytoplasm, the internal conductivity of the cell decreases after the electroporation on a time scale of seconds and stronger pulses cause a larger and more rapid decrease. We also observe that, after the electroporation, the cell's internal conductivity is constrained to a threshold. This implies that the cell prevents some of the ions in its cytoplasm from diffusing through the created pores to the external medium. The temporal change in the dielectric response of each individual cell is continuously monitored over minutes after exposure to pulsed electric fields. A time constant associated with the cell's internal conductivity change is observed, which ranges from seconds to tens of seconds depending on the applied pulse intensity. This experimental observation supports the results of numerical models reported in the literature.

Dielectric model for Chinese hamster ovary cells obtained by dielectrophoresis cytometry.

We present a dielectric model and its parameters for Chinese hamster ovary (CHO) cells based on a double-shell structure which includes the cell membrane, cytoplasm, nuclear envelope, and nucleoplasm. Employing a dielectrophoresis (DEP) based technique and a microfluidic system, the DEP response of many single CHO cells is measured and the spectrum of the Clausius-Mossotti factor is obtained. The dielectric parameters of the model are then extracted by curve-fitting to the measured spectral data. Using this approach over the 0.6-10 MHz frequency range, we report the values for CHO cells' membrane permittivity, membrane thickness, cytoplasm conductivity, nuclear envelope permittivity, and nucleoplasm conductivity. The size of the cell and its nuclei are obtained using optical techniques.

Angled multimode interferometer for bidirectional wavelength division (de)multiplexing.

We have demonstrated a bidirectional wavelength division (de)multiplexer (WDM) on the silicon-on-insulator platform using two 4-channel angled multimode interferometers (AMMIs) sharing the same multimode interference waveguide. An excellent match of the peak transmission wavelength of each channel between the two AMMIs was achieved. The input and output access waveguides were arranged in a configuration such that the propagation of light of one AMMI in the multimode interference waveguide suffered minimal perturbation by the input and output waveguides of the other AMMI. This type of device is ideal for the WDM system for datacom or telecom applications, e.g. an integrated optical transceiver, where the transmission wavelengths are required to match with the receiving wavelengths. The device also benefits from simple fabrication (as only a single lithography and etching step is required), improved convenience for the transceiver layout design, a reduction in tuning power and circuitry and efficient use of layout space. A low insertion loss of 3-4 dB, and low crosstalk of -15 to -20 dB, was achieved.

Torque-mixing magnetic resonance spectroscopy.

A universal, torque-mixing method for magnetic resonance spectroscopy is presented. In analogy to resonance detection by magnetic induction, the transverse component of a precessing dipole moment can be measured in sensitive broadband spectroscopy, here using a resonant mechanical torque sensor. Unlike induction, the torque amplitude allows equilibrium magnetic properties to be monitored simultaneously with the spin dynamics. Comprehensive electron spin resonance spectra of a single-crystal, mesoscopic yttrium iron garnet disk at room temperature reveal assisted switching between magnetization states and mode-dependent spin resonance interactions with nanoscale surface imperfections. The rich detail allows analysis of even complex three-dimensional spin textures. The flexibility of microelectromechanical and optomechanical devices combined with broad generality and capabilities of torque-mixing magnetic resonance spectroscopy offers great opportunities for development of integrated devices.

Spacing and shape of random peaks in non-parametric spectrum estimates.

In this paper, expressions are derived for the expected number of spurious peaks in a spectrum estimate, that is, crossings above a given significance level per frequency unit, as well as the expected width of these peaks. In numerous scientific applications, spectrum estimates are used for the purpose of identifying sinusoidal or modal components, often thinning large sets of candidate frequencies with coincidence detection. Because one always expects numerous false peaks in a spectrum estimate, knowing the expected rate of false peaks helps to decide whether the number observed is abnormal and hence determine the true nature of the process. An example using solar wind data from the Advanced Composition Explorer is given where spectra display pathological numbers of significant peaks, while temporally permuted versions of the data possess spectra with the number expected for a white, Gaussian process. The permutation test is a valuable diagnostic for processes suspected to contain many line components.

Optical detection and modulation at 2µm-2.5µm in silicon.

Recently the 2µm wavelength region has emerged as an exciting prospect for the next generation of telecommunications. In this paper we experimentally characterise silicon based plasma dispersion effect optical modulation and defect based photodetection in the 2-2.5µm wavelength range. It is shown that the effectiveness of the plasma dispersion effect is dramatically increased in this wavelength window as compared to the traditional telecommunications wavelengths of 1.3µm and 1.55µm. Experimental results from the defect based photodetectors show that detection is achieved in the 2-2.5µm wavelength range, however the responsivity is reduced as the wavelength is increased away from 1.55µm.

Mid-infrared wavelength division (de)multiplexer using an interleaved angled multimode interferometer on the silicon-on-insulator platform.

A low-cost and high-performance wavelength division (de)multiplexing structure in the mid-IR wavelength range is demonstrated on the silicon-on-insulator platform using an interleaved angled multimode interferometer (AMMI). As compared to a single AMMI, the channel count was doubled and the channel spacing halved with negligible extra insertion loss and crosstalk and with only a slight increase in device footprint. The device requires only single lithography and etching steps for fabrication. Potential is also shown for achieving improved performance with further optimized design.

Planar surface implanted diffractive grating couplers in SOI.

Grating couplers are used to efficiently couple light from an optical fibre to a silicon waveguide as they allow light to be coupled into or out from any location on the device without the need for cleaving. However, using the typical surface relief grating fabrication method reduces surface planarity and hence makes further processing more difficult. The ability to manufacture high quality material layers on top of a grating coupler allows multiple active optical layers to be realized for multi-layer integrated optical circuits, and may enable monolithic integration of optical and electronic circuits on separate layers. Furthermore, the nature of the refractive index change may enable removal via rapid thermal annealing for wafer scale testing applications. We demonstrate for the first time a coupling device utilising a refractive index change introduced by lattice disorder. Simulations show 44% of the power can be extracted from the waveguide by using uniform implanted gratings, which is not dissimilar to the performance of typical uniform surface relief gratings currently used. Losses determined empirically, of 5.5 dB per coupler have been demonstrated.

Monitoring the dielectric response of single cells following mitochondrial adenosine triphosphate synthase inhibition by oligomycin using a dielectrophoretic cytometer.

One of the main uses of adenosine triphosphate (ATP) within mammalian cells is powering the Na(+)/K(+) ATPase pumps used to maintain ion concentrations within the cell. Since ion concentrations determine the cytoplasm conductivity, ATP concentration is expected to play a key role in controlling the cytoplasm conductivity. The two major ATP production pathways within cells are via glycolysis within the cytoplasm and via the electron transport chain within the mitochondria. In this work, a differential detector combined with dielectrophoretic (DEP) translation in a microfluidic channel was employed to observe single cell changes in the cytoplasm conductivity. The DEP response was made sensitive to changes in cytoplasm conductivity by measuring DEP response versus media conductivity and using double shell models to choose appropriate frequencies and media conductivity. Dielectric response of Chinese hamster ovary (CHO) cells was monitored following inhibition of the mitochondria ATP production by treatment with oligomycin. We show that in CHO cells following exposure to oligomycin (8 µg/ml) the cytoplasm conductivity drops, with the majority of the change occurring within 50 min. This work demonstrates that dielectric effects due to changes in ATP production can be observed at the single cell level.

High-contrast 40 Gb/s operation of a 500 µm long silicon carrier-depletion slow wave modulator.

In this Letter, we demonstrate a highly efficient, compact, high-contrast and low-loss silicon slow wave modulator based on a traveling-wave Mach-Zehnder interferometer with two 500 µm long slow wave phase shifters. 40 Gb/s operation with 6.6 dB extinction ratio at quadrature and with an on-chip insertion loss of only 6 dB is shown. These results confirm the benefits of slow light as a means to enhance the performance of silicon modulators based on the plasma dispersion effect.

High-resolution imaging of gigahertz polarization response arising from the interference of reflected surface acoustic waves.

The surface polarization caused by traveling SAWs at 1.585 GHz has been imaged using a dynamic homodyne electrostatic force microscope technique. Instead of measuring topographic changes caused by the SAW, the reported technique measures polarization in the piezoelectric substrate arising from mechanical stress caused by the SAW. The polarization associated with this stress field modulates the scanning probe cantilever deflection amplitude, which is extracted using a lock-in-based technique. High-resolution imaging is presented with images of the interference arising from a metal reflector on a SAW device. A mathematical model combining SAW generation and force interactions between the probe and the substrate was used to verify the experimental data. In addition to overcoming the challenge associated with detecting and imaging polarization effects at gigahertz frequencies, this imaging technique will greatly assist the development of SAW-based devices that exploit the reflection and interference of SAWs in areas as diverse as microfluidic mixing, cell sorting, and quantum entanglement.