Study of diffusion weighted MRI as a predictive biomarker of response during radiotherapy for high and intermediate risk squamous cell cancer of the oropharynx: The MeRInO study

Introduction and background: A significant proportion of patients with intermediate and high risk squamous cell cancer of the oropharynx (OPSCC) continue to relapse locally despite radical chemoradiotherapy (CRT). The toxicity of the current combination of intensified dose per fraction radiotherapy and platinum based chemotherapy limits further uniform intensification. If a predictive biomarker for outcomes from CRT can be identified during treatment then individualised and adaptive treatment strategies may be employed. Methods/design: The MeRInO study is a prospective observational imaging study of patients with intermediate and high risk, locally advanced OPSCC receiving radical RT or concurrent CRT Patients undergo diffusion weighted MRI prior to treatment (MRI_1) and during the third week of RT (MRI_2). Apparent diffusion coefficient (ADC) measurements will be made on each scan for previously specified target lesions (primary and lymph nodes) and change in ADC calculated. Patients will be followed up and disease status for each target lesion noted. The primary aim of the MeRInO study is to determine the threshold change in ADC from baseline to week 3 of RT that may identify the sub-group of non-responders during treatment. Discussion: The use of DW-MRI as a predictive biomarker during RT for SCC H&N is in its infancy but studies to date have found that response to treatment may indeed be predicted by comparison of DW-MRI carried out before and during treatment. However, previous studies have included all sub-sites and biological sub-types. Establishing ADC thresholds that predict for local failure is an essential step towards using DW-MRI to improve the therapeutic ratio in treating SCC H&N. This would be done most robustly in a specific H&N sub-site and in sub-types with similar biological behaviour. The MeRInO study will help establish these thresholds in OPSCC

Self-trapping and excited state absorption in fluorene homo-polymer and copolymers with benzothiadiazole and tri-phenylamine

We thank the EPSRC [EP/J009318/1 and EP/J009016/1] for funding. MJP thanks the European Research Council (ERC) for funding under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC Grant No. 258990.Excited state absorption (ESA) is studied using time-dependent density functional theory and compared with experiments performed in dilute solutions. The molecules investigated are a fluorene pentamer, polyfluorene F8, the alternating F8 copolymer with benzothiadiazole F8BT, and two blue-emitting random copolymers F8PFB and F8TFB. Calculated and measured spectra show qualitatively comparable results. The ESA cross-section of co-polymers at its maximum is about three times lower than that of F8. The ESA spectra are found to change little upon structural relaxation of the excited state, or change in the order of sub-units in a co-polymer, for all studied molecules. In all these molecules, the strongest ESA transition is found to arise from the same electronic process, exhibiting a reversal of the charge parity. In addition, F8PFB and F8TFB are found to possess almost identical electronic behaviour.Publisher PDFPeer reviewe

Current- and Wave-Generated Bedforms on Mixed Sand–Clay Intertidal Flats:A New Bedform Phase Diagram and Implications for Bed Roughness and Preservation Potential

The effect of bedforms on frictional roughness felt by the overlying flow is crucial to the regional modelling of estuaries and coastal seas. Bedforms are also a key marker of palaeoenvironments. Experiments have shown that even modest biotic and abiotic cohesion in sand inhibits bedform formation, modifies bedform size, and slows bedform development, but this has rarely been tested in nature. The present study used a comprehensive dataset recorded over a complete spring–neap cycle on an intertidal flat to investigate bedform dynamics controlled by a wide range of wave and current conditions, including the effects of wave–current angle and bed cohesion. A detailed picture of different bedform types and their relationship to the flow, be they equilibrium, non-equilibrium, or relict, was produced, and captured in a phase diagram that integrates wave-dominated, current-dominated, and combined wave–current bedforms. This bedform phase diagram incorporates a substantially wider range of flow conditions than previous phase diagrams, including bedforms related to near-orthogonal wave–current angles, such as ladderback ripples. Comparison with laboratory-derived bedform phase diagrams indicates that washed-out ripples, lunate interference ripples and upper-stage plane beds replace the subaqueous dune field; such bedform distributions may be a key characteristic of intertidal flats. The field data also provide a means of predicting the dimensions of these bedforms, which can be transferred to other areas and grain sizes. We show that an equation for the prediction of equilibrium bedform size is sufficient to predict the roughness, even though the bedforms are highly variable in character and only in equilibrium with the flow for approximately half the time. Whilst the effect of cohesive clay is limited under more active spring conditions, clay does play a role in reducing the bedform dimensions under more quiescent neap conditions. We also investigated which combinations of waves, currents, and bed clay contents in the intertidal zone have the highest potential for bedform preservation in the geological record. This shows that combined wave–current bedforms have the lowest preservation potential and equilibrium current ripples have the highest preservation potential, even in the presence of moderate and storm waves. Hence, the absence of wave ripples and combined-flow bedforms and their primary stratification in sedimentary successions cannot be taken as evidence that waves were absent at the time of deposition

Albuminuria Changes and Cardiovascular and Renal Outcomes in Type 1 Diabetes: The DCCT/EDIC Study.

Background and objectives In trials of people with type 2 diabetes, albuminuria reduction with renin-angiotensin system inhibitors is associated with lower risks of cardiovascular events and CKD progression. We tested whether progression or remission of microalbuminuria is associated with cardiovascular and renal risk in a well characterized cohort of type 1 diabetes. Design, setting, participants, & measurements We studied 1441 participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study. Albumin excretion rate (AER) was quantified annually or biennially for up to 30 years. For each participant, albuminuria status was defined over time as normoalbuminuria (AER continuously \u3c30 mg/d), sustained microalbuminuria (AER, 30–299 mg/d on two consecutive visits), macroalbuminuria (AER≥300 mg/d), or remitted microalbuminuria (transition from sustained microalbuminuria to AER\u3c30 mg/d on two consecutive visits). We tested associations of time-updated albuminuria status with adjudicated clinical cardiovascular events, the development of reduced GFR (\u3c60 ml/min per 1.73 m2 on two consecutive visits), and subclinical cardiovascular disease. Results At least one cardiovascular event occurred in 184 participants, and 98 participants developed reduced eGFR. Compared with normoalbuminuria, sustained microalbuminuria, remitted microalbuminuria, and macroalbuminuria were each associated with higher risk of cardiovascular events (adjusted hazard ratios [HRs] and 95% confidence intervals [95% CIs]: 1.79 [1.13 to 2.85], 2.62 [1.68 to 4.07], and 2.65 [1.68 to 4.19], respectively) and reduced eGFR (adjusted HRs [95% CIs], 5.26 [2.43 to 11.41], 4.36 [1.80 to 10.57], and 54.35 [30.79 to 95.94], respectively). Compared with sustained microalbuminuria, remission to normoalbuminuria was not associated with reduced risk of cardiovascular events (adjusted HR, 1.33; 95% CI, 0.68 to 2.59) or reduced eGFR (adjusted HR, 1.75; 95% CI, 0.56 to 5.49). Compared with normoalbuminuria, sustained microalbuminuria, remitted microalbuminuria, and macroalbuminuria were associated with greater carotid intima-media thickness, and macroalbuminuria was associated with a greater degree of coronary artery calcification. Conclusions In type 1 diabetes, microalbuminuria and macroalbuminuria are associated with higher risks of cardiovascular disease and reduced eGFR, but achieving a remission of established microalbuminuria to normoalbuminuria does not appear to improve outcomes

Metabolic, inflammatory and haemostatic effects of a low-dose continuous combined HRT in women with type 2 diabetes: potentially safer with respect to vascular risk?

BACKGROUND Conventional hormone replacement therapy (HRT) containing conjugated equine oestrogen (CEE) and medroxyprogesterone acetate (MPA) increases triglyceride, C- reactive protein (CRP) and coagulation Factor VII concentrations, potentially explaining their increased coronary heart disease (CHD) and stroke risk. OBJECTIVE To assess the metabolic effects of a continuous combined HRT containing 1 mg oestradiol and 0.5 mg norethisterone or matching placebo. DESIGN Double-blind, randomized placebo-controlled trial. PATIENTS Fifty women with type 2 diabetes. MEASUREMENTS Classical and novel risk factors for vascular disease. RESULTS Triglyceride concentration was not altered (P = 0.31, change in active arm relative to placebo) and low-density lipoprotein (LDL) cholesterol concentration declined 13% (P = 0.018). IL-6 concentration (mean difference -1.42 pg/ml, 95% CI: -2.55 to - 0.29 IU/dl, P = 0.015), Factor VII (-32 IU/dl, -43 to -21 IU/l, P lt 0.001) and tissue plasminogen activator antigen (by 13%, P = 0.005) concentrations fell, but CRP was not significantly altered (P = 0.62). Fasting glucose (P = 0.026) also declined significantly, but there are no significant effects on HBA1c, Factor IX or APC resistance. CONCLUSIONS HRT containing 1 mg oestradiol and 0.5 mg norethisterone may avoid the adverse metabolic effects potentially implicated in the elevated CHD and stroke risk induced by conventional higher dose HRT. This type of preparation may therefore be more suitable than conventional HRT for women at elevated CHD risk such as those with type 2 diabetes. Large randomized controlled trials of such low dose preparations, powered for cardiovascular end points, are now needed

Current- and wave- generated bedforms on mixed sand-clay intertidal flats : a new bedform phase diagram and implications for bed roughness and preservation potential

Funding: This work was supported by the United Kingdom’s Natural Environment Research Council (NERC) under Grant NE/I027223/1 (COHBED). JM, Julie Hope, and Daniel Parsons were partially funded by a Horizon 2020 European Research Council Consolidator Award (GEOSTICK, Grant 725955). The GEOSTICK project also kindly contributed the article processing fees. Andrew Manning’s contribution toward this research was partly supported by the National Science Foundation grants OCE-1924532 and OCE-1736668, TKI-MUSA project 11204950-000-ZKS-0002, and the HR Wallingford company research project FineScale (Grant Nos. ACK3013_62). DP received funding from the MASTS pooling initiative (The Marine Alliance for Science and Technology for Scotland) and their support is gratefully acknowledged. MASTS is funded by the Scottish Funding Council (Grant reference HR09011) and contributing institutions.The effect of bedforms on frictional roughness felt by the overlying flow is crucial to the regional modelling of estuaries and coastal seas. Bedforms are also a key marker of palaeoenvironments. Experiments have shown that even modest biotic and abiotic cohesion in sand inhibits bedform formation, modifies bedform size, and slows bedform development, but this has rarely been tested in nature. The present study used a comprehensive dataset recorded over a complete spring–neap cycle on an intertidal flat to investigate bedform dynamics controlled by a wide range of wave and current conditions, including the effects of wave–current angle and bed cohesion. A detailed picture of different bedform types and their relationship to the flow, be they equilibrium, non-equilibrium, or relict, was produced, and captured in a phase diagram that integrates wave-dominated, current-dominated, and combined wave–current bedforms. This bedform phase diagram incorporates a substantially wider range of flow conditions than previous phase diagrams, including bedforms related to near-orthogonal wave–current angles, such as ladderback ripples. Comparison with laboratory-derived bedform phase diagrams indicates that washed-out ripples, lunate interference ripples and upper-stage plane beds replace the subaqueous dune field; such bedform distributions may be a key characteristic of intertidal flats. The field data also provide a means of predicting the dimensions of these bedforms, which can be transferred to other areas and grain sizes. We show that an equation for the prediction of equilibrium bedform size is sufficient to predict the roughness, even though the bedforms are highly variable in character and only in equilibrium with the flow for approximately half the time. Whilst the effect of cohesive clay is limited under more active spring conditions, clay does play a role in reducing the bedform dimensions under more quiescent neap conditions. We also investigated which combinations of waves, currents, and bed clay contents in the intertidal zone have the highest potential for bedform preservation in the geological record. This shows that combined wave–current bedforms have the lowest preservation potential and equilibrium current ripples have the highest preservation potential, even in the presence of moderate and storm waves. Hence, the absence of wave ripples and combined-flow bedforms and their primary stratification in sedimentary successions cannot be taken as evidence that waves were absent at the time of deposition.Publisher PDFPeer reviewe

Fragmentation and shear band formation by slow compression of brittle porous media

Localized fragmentation is an important phenomenon associated with the formation of shear bands and faults in granular media. It can be studied by empirical observation, by laboratory experiment, or by numerical simulation. Here we investigate the spatial structure and statistics of fragmentation using discrete element simulations of the strain-controlled uniaxial compression of cylindrical samples of different finite size. As the system approaches failure, damage localizes in a narrow shear band or synthetic fault "gouge" containing a large number of poorly sorted noncohesive fragments on a broad bandwidth of scales, with properties similar to those of natural and experimental faults. We determine the position and orientation of the central fault plane, the width of the shear band, and the spatial and mass distribution of fragments. The relative width of the shear band decreases as a power law of the system size, and the probability distribution of the angle of the central fault plane converges to around 30 degrees, representing an internal coefficient of friction of 0.7 or so. The mass of fragments is power law distributed, with an exponent that does not depend on scale, and is near that inferred for experimental and natural fault gouges. The fragments are in general angular, with a clear self-affine geometry. The consistency of this model with experimental and field results confirms the critical roles of preexisting heterogeneity, elastic interactions, and finite system size to grain size ratio on the development of shear bands and faults in porous media. © 2016 American Physical Society

A method for phase reconstruction from measurements obtained using a configured detector with a scanning transmission X-ray microscope

Abstract We developed a technique for performing quantitative phase reconstructions from differential phase contrast images obtained using a configured detector in a scanning transmission X-ray microscope geometry. The technique uses geometric optics to describe the interaction of the X-ray beam with the specimen, which allows interpretation of the measured intensities in terms of the derivative of the phase thickness. Integration of the resulting directional derivatives is performed using a Fourier integration technique. We demonstrate the approach by reconstructing simulated measurements of a 0:5Àmm-diameter gold sphere at 7-keV photon energy. Published by Elsevier B.V