A randomised feasibility study of serial magnetic resonance imaging to reduce treatment times in Charcot neuroarthropathy in people with diabetes (CADOM): A protocol

Background Charcot neuroarthropathy is a complication of peripheral neuropathy associated with diabetes which most frequently affects the lower limb. It can cause fractures and dislocations within the foot, which may progress to deformity and ulceration. Recommended treatment is immobilisation and offloading, with a below knee non-removable cast or boot. Duration of treatment varies from six months to more than one year. Small observational studies suggest that repeated assessment with Magnetic Resonance Imaging improves decision making about when to stop treatment, but this has not been tested in clinical trials. This study aims to explore the feasibility of using serial Magnetic Resonance Imaging without contrast in the monitoring of Charcot neuroarthropathy to reduce duration of immobilisation of the foot. A nested qualitative study aims to explore participants’ lived experience of Charcot neuroarthropathy and of taking part in the feasibility study. Methods We will undertake a two arm, open study, and randomise 60 people with a suspected or confirmed diagnosis of Charcot neuroarthropathy from five NHS, secondary care multidisciplinary Diabetic Foot Clinics across England. Participants will be randomised 1:1 to receive Magnetic Resonance Imaging at baseline and remission up to 12 months, with repeated foot temperature measurements and x-rays (standard care plus), or standard care plus with additional three-monthly Magnetic Resonance Imaging until remission up to 12 months (intervention). Time to confirmed remission of Charcot neuroarthropathy with off-loading treatment (days) and its variance will be used to inform sample size in a full-scale trial. We will look for opportunities to improve the protocols for monitoring techniques and the clinical, patient centred, and health economic measures used in a future study. For the nested qualitative study, we will invite a purposive sample of 10-14 people able to offer maximally varying experiences from the feasibility study to take part in semi-structured interviews to be analysed using thematic analysis. Discussion The study will inform the decision whether to proceed to a full-scale trial. It will also allow deeper understanding of the lived experience of Charcot neuroarthropathy, and factors that contribute to engagement in management and contribute to the development of more effective patient centred strategies. Trial registration ISRCTN, ISRCTN, 74101606. Registered on 6 November 2017, http://www.isrctn.com/ISRCTN74101606?q=CADom&filters=&sort=&offset=1&totalResults=1&page=1&pageSize=10&searchType=basic-searc

Status of the CRESST Dark Matter Search

The CRESST experiment aims for a detection of dark matter in the form of WIMPs. These particles are expected to scatter elastically off the nuclei of a target material, thereby depositing energy on the recoiling nucleus. CRESST uses scintillating CaWO4 crystals as such a target. The energy deposited by an interacting particle is primarily converted to phonons which are detected by transition edge sensors. In addition, a small fraction of the interaction energy is emitted from the crystals in the form of scintillation light which is measured in coincidence with the phonon signal by a separate cryogenic light detector for each target crystal. The ratio of light to phonon energy permits the discrimination between the nuclear recoils expected from WIMPs and events from radioactive backgrounds which primarily lead to electron recoils. CRESST has shown the success of this method in a commissioning run in 2007 and, since then, further investigated possibilities for an even better suppression of backgrounds. Here, we report on a new class of background events observed in the course of this work. The consequences of this observation are discussed and we present the current status of the experiment.Comment: Proceedings of the 13th International Workshop on Low Temperature Detectors, 4 pages, 3 figure

Results from 730 kg days of the CRESST-II Dark Matter Search

The CRESST-II cryogenic Dark Matter search, aiming at detection of WIMPs via elastic scattering off nuclei in CaWO$_4$ crystals, completed 730 kg days of data taking in 2011. We present the data collected with eight detector modules, each with a two-channel readout; one for a phonon signal and the other for coincidently produced scintillation light. The former provides a precise measure of the energy deposited by an interaction, and the ratio of scintillation light to deposited energy can be used to discriminate different types of interacting particles and thus to distinguish possible signal events from the dominant backgrounds. Sixty-seven events are found in the acceptance region where a WIMP signal in the form of low energy nuclear recoils would be expected. We estimate background contributions to this observation from four sources: 1) "leakage" from the e/\gamma-band 2) "leakage" from the \alpha-particle band 3) neutrons and 4) Pb-206 recoils from Po-210 decay. Using a maximum likelihood analysis, we find, at a high statistical significance, that these sources alone are not sufficient to explain the data. The addition of a signal due to scattering of relatively light WIMPs could account for this discrepancy, and we determine the associated WIMP parameters.Comment: 17 pages, 13 figure

The CRESST II Dark Matter Search

Direct Dark Matter detection with cryodetectors is briefly discussed, with particular mention of the possibility of the identification of the recoil nucleus. Preliminary results from the CREEST II Dark Matter search, with 730 kg-days of data, are presented. Major backgrounds and methods of identifying and dealing with them are indicated.Comment: Talk at DSU workshop, ITP Beijing, Oct. 2011. 9 figures, 2 table

Composite CaWO4 Detectors for the CRESST-II Experiment

CRESST-II, standing for Cryogenic Rare Events Search with Superconducting Thermometers phase II, is an experiment searching for Dark Matter. In the LNGS facility in Gran Sasso, Italy, a cryogenic detector setup is operated in order to detect WIMPs by elastic scattering off nuclei, generating phononic lattice excitations and scintillation light. The thermometers used in the experiment consist of a tungsten thin-film structure evaporated onto the CaWO4 absorber crystal. The process of evaporation causes a decrease in the scintillation light output. This, together with the need of a big-scale detector production for the upcoming EURECA experiment lead to investigations for producing thermometers on smaller crystals which are glued onto the absorber crystal. In our Run 31 we tested composite detectors for the first time in the Gran Sasso setup. They seem to produce higher light yields as hoped and could provide an additional time based discrimination mechanism for low light yield clamp events.Comment: Proceedings of the Thirteenth International Workshop on Low Temperature Detectors 4 pages, 9 figure

Hypoglycemia in Type 1 Diabetic Pregnancy: Role of preconception insulin aspart treatment in a randomized study

Objective: A recent randomized trial compared prandial insulin aspart (IAsp) with human insulin in type 1 diabetic pregnancy. The aim of this exploratory analysis was to investigate the incidence of severe hypoglycemia during pregnancy and compare women enrolled preconception with women enrolled during early pregnancy. Research design and methods: IAsp administered immediately before each meal was compared with human insulin administered 30 min before each meal in 99 subjects (44 to IAsp and 55 to human insulin) randomly assigned preconception and in 223 subjects (113 for IAsp and 110 for human insulin) randomly assigned in early pregnancy (<10 weeks). NPH insulin was the basal insulin. Severe hypoglycemia (requiring third-party assistance) was recorded prospectively preconception (where possible), during pregnancy, and postpartum. Relative risk (RR) of severe hypoglycemia was evaluated with a gamma frailty model. Results: Of the patients, 23% experienced severe hypoglycemia during pregnancy with the peak incidence in early pregnancy. In the first half of pregnancy, the RR of severe hypoglycemia in women randomly assigned in early pregnancy/preconception was 1.70 (95% CI 0.91–3.18, P = 0.097); the RR in the second half of pregnancy was 1.35 (0.38–4.77, P = 0.640). In women randomly assigned preconception, severe hypoglycemia rates occurring before and during the first and second halves of pregnancy and postpartum for IAsp versus human insulin were 0.9 versus 2.4, 0.9 versus 2.4, 0.3 versus 1.2, and 0.2 versus 2.2 episodes per patient per year, respectively (NS). Conclusions: These data suggest that initiation of insulin analog treatment preconception rather than during early pregnancy may result in a lower risk of severe hypoglycemia in women with type 1 diabetes

Acute Modulation of Adipose Tissue Lipolysis by Intravenous Estrogens

Objective: The aim of this study was to determine whether intravenous (IV) conjugated estrogens (EST) acutely enhance the suppression of whole-body or regional subcutaneous adipose tissue (SAT) lipolysis by insulin in postmenopausal women. Research Methods and Procedures: We assessed whole-body lipolysis by [2H5]glycerol rate of appearance (GlycRA) and abdominal and femoral SAT lipolysis (interstitial glycerol; GlycIS) by subcutaneous microdialysis. Postmenopausal women (n = 12) were studied on two occasions, with IV EST or saline control (CON), under basal conditions and during a 3-stage (4, 8, and 40 mU/m2/ min) hyperinsulinemic, euglycemic clamp. Ethanol outflow/inflow ratio and recovery of [13C] glycerol during microdialysis were used to assess blood flow changes and interstitial glycerol concentrations, respectively. Results: Compared with CON, EST did not affect systemic basal or insulin-mediated suppression of lipolysis (GlycRA) or SAT nutritive blood flow. Basal GlycIS in SAT was reduced on the EST day. However, insulin-mediated suppression of lipolysis in SAT was not significantly influenced by EST. Discussion: These findings suggest that estrogens acutely reduce basal lipolysis in SAT through an unknown mechanism but do not alter whole-body or SAT suppression of lipolysis by insulin. Originally published Obesity (Silver Spring), Vol. 14, No. 12, Dec 200

Distributed Dendritic Processing Facilitates Object Detection: A Computational Analysis on the Visual System of the Fly

Hennig P, Möller R, Egelhaaf M. Distributed Dendritic Processing Facilitates Object Detection: A Computational Analysis on the Visual System of the Fly. PLoS ONE. 2008;3(8): e3092.Background: Detecting objects is an important task when moving through a natural environment. Flies, for example, may land on salient objects or may avoid collisions with them. The neuronal ensemble of Figure Detection cells (FD-cells) in the visual system of the fly is likely to be involved in controlling these behaviours, as these cells are more sensitive to objects than to extended background structures. Until now the computations in the presynaptic neuronal network of FD-cells and, in particular, the functional significance of the experimentally established distributed dendritic processing of excitatory and inhibitory inputs is not understood. Methodology/Principal Findings: We use model simulations to analyse the neuronal computations responsible for the preference of FD-cells for small objects. We employed a new modelling approach which allowed us to account for the spatial spread of electrical signals in the dendrites while avoiding detailed compartmental modelling. The models are based on available physiological and anatomical data. Three models were tested each implementing an inhibitory neural circuit, but differing by the spatial arrangement of the inhibitory interaction. Parameter optimisation with an evolutionary algorithm revealed that only distributed dendritic processing satisfies the constraints arising from electrophysiological experiments. In contrast to a direct dendro-dendritic inhibition of the FD-cell (Direct Distributed Inhibition model), an inhibition of its presynaptic retinotopic elements (Indirect Distributed Inhibition model) requires smaller changes in input resistance in the inhibited neurons during visual stimulation. Conclusions/Significance: Distributed dendritic inhibition of retinotopic elements as implemented in our Indirect Distributed Inhibition model is the most plausible wiring scheme for the neuronal circuit of FD-cells. This microcircuit is computationally similar to lateral inhibition between the retinotopic elements. Hence, distributed inhibition might be an alternative explanation of perceptual phenomena currently explained by lateral inhibition networks