The continuous erythropoietin receptor activator (C.E.R.A.) corrects anemia at extended administration intervals in patients with chronic kidney disease not on dialysis:results of a phase II study

This study was designed to assess the potential of the continuous erythropoietin receptor activator (C.E.R.A.) to correct anemia at extended administration intervals in erythropoiesis-stimulating agent-naīve patients with chronic kidney disease (CKD) not on dialysis and to determine its optimal starting dose.

Speed of processing in the primary motor cortex: A continuous theta burst stimulation study

‘Temporally urgent’ reactions are extremely rapid, spatially precise movements that are evoked following discrete stimuli. The involvement of primary motor cortex (M1) and its relationship to stimulus intensity in such reactions is not well understood. Continuous theta burst stimulation (cTBS) suppresses focal regions of the cortex and can assess the involvement of motor cortex in speed of processing. The primary objective of this study was to explore the involvement of M1 in speed of processing with respect to stimulus intensity. Thirteen healthy young adults participated in this experiment. Behavioral testing consisted of a simple button press using the index finger following median nerve stimulation of the opposite limb, at either high or low stimulus intensity. Reaction time was measured by the onset of electromyographic activity from the first dorsal interosseous (FDI) muscle of each limb. Participants completed a 30 min bout of behavioral testing prior to, and 15 min following, the delivery of cTBS to the motor cortical representation of the right FDI. The effect of cTBS on motor cortex was measured by recording the average of 30 motor evoked potentials (MEPs) just prior to, and 5 min following, cTBS. Paired t-tests revealed that, of thirteen participants, five demonstrated a significant attenuation, three demonstrated a significant facilitation and five demonstrated no significant change in MEP amplitude following cTBS. Of the group that demonstrated attenuated MEPs, there was a biologically significant interaction between stimulus intensity and effect of cTBS on reaction time and amplitude of muscle activation. This study demonstrates the variability of potential outcomes associated with the use of cTBS and further study on the mechanisms that underscore the methodology is required. Importantly, changes in motor cortical excitability may be an important determinant of speed of processing following high intensity stimulation.

Intermittent chemotherapy plus either intermittent or continuous cetuximab for first-line treatment of patients with KRAS wild-type advanced colorectal cancer (COIN-B): a randomised phase 2 trial

Background: Advanced colorectal cancer is treated with a combination of cytotoxic drugs and targeted treatments. However, how best to minimise the time spent taking cytotoxic drugs and whether molecular selection can refine this further is unknown. The primary aim of this study was to establish how cetuximab might be safely and effectively added to intermittent chemotherapy.

Methods: COIN-B was an open-label, multicentre, randomised, exploratory phase 2 trial done at 30 hospitals in the UK and one in Cyprus. We enrolled patients with advanced colorectal cancer who had received no previous chemotherapy for metastases. Randomisation was done centrally (by telephone) by the Medical Research Council Clinical Trials Unit using minimisation with a random element. Treatment allocation was not masked. Patients were assigned (1:1) to intermittent chemotherapy plus intermittent cetuximab or to intermittent chemotherapy plus continuous cetuximab. Chemotherapy was FOLFOX (folinic acid and oxaliplatin followed by bolus and infused fluorouracil). Patients in both groups received FOLFOX and weekly cetuximab for 12 weeks, then either had a planned interruption (those taking intermittent cetuximab) or planned maintenance by continuing on weekly cetuximab (continuous cetuximab). On RECIST progression, FOLFOX plus cetuximab or FOLFOX was recommenced for 12 weeks followed by further interruption or maintenance cetuximab, respectively. The primary outcome was failure-free survival at 10 months. The primary analysis population consisted of patients who completed 12 weeks of treatment without progression, death, or leaving the trial. We tested BRAF and NRAS status retrospectively. The trial was registered, ISRCTN38375681.

Findings: We registered 401 patients, 226 of whom were enrolled. Results for 169 with KRAS wild-type are reported here, 78 (46%) assigned to intermittent cetuximab and 91 (54%) to continuous cetuximab. 64 patients assigned to intermittent cetuximab and 66 of those assigned to continuous cetuximab were included in the primary analysis. 10-month failure-free survival was 50% (lower bound of 95% CI 39) in the intermittent group versus 52% (lower bound of 95% CI 41) in the continuous group; median failure-free survival was 12·2 months (95% CI 8·8–15·6) and 14·3 months (10·7–20·4), respectively. The most common grade 3–4 adverse events were skin rash (21 [27%] of 77 patients vs 20 [22%] of 92 patients), neutropenia (22 [29%] vs 30 [33%]), diarrhoea (14 [18%] vs 23 [25%]), and lethargy (20 [26%] vs 19 [21%]).

Interpretation: Cetuximab was safely incorporated in two first-line intermittent chemotherapy strategies. Maintenance of biological monotherapy, with less cytotoxic chemotherapy within the first 6 months, in molecularly selected patients is promising and should be validated in phase 3 trials.

Nonlocality of two- and three-mode continuous variable systems

We address the nonlocality of fully inseparable three-mode Gaussian states generated either by bilinear three-mode Hamiltonians or by a sequence of bilinear two-mode Hamiltonians. Two different tests revealing nonlocality are considered, in which the dichotomic Bell operator is represented by the displaced parity and by the pseudospin operator respectively. Three-mode states are also considered as a conditional source of two-mode non-Gaussian states, whose nonlocality properties are analysed. We found that the non-Gaussian character of the conditional states allows violation of Bell's inequalities (by parity and pseudospin tests) stronger than with a conventional twin-beam state. However, the non-Gaussian character is not sufficient to reveal nonlocality through a dichotomized quadrature measurement strategy.

Development of a novel continuous statistical modelling technique for detecting the adulteration of extra virgin olive oil with hazelnut oil by using spectroscopic data

The adulteration of extra virgin olive oil with other vegetable oils is a certain problem with economic and health consequences. Current official methods have been proved insufficient to detect such adulterations. One of the most concerning and undetectable adulterations with other vegetable oils is the addition of hazelnut oil. The main objective of this work was to develop a novel dimensionality reduction technique able to model oil mixtures as a part of an integrated pattern recognition solution. This final solution attempts to identify hazelnut oil adulterants in extra virgin olive oil at low percentages based on spectroscopic chemical fingerprints. The proposed Continuous Locality Preserving Projections (CLPP) technique allows the modelling of the continuous nature of the produced in house admixtures as data series instead of discrete points. This methodology has potential to be extended to other mixtures and adulterations of food products. The maintenance of the continuous structure of the data manifold lets the better visualization of this examined classification problem and facilitates a more accurate utilisation of the manifold for detecting the adulterants.

Perception and Automatic Recognition of Laughter from Whole-Body Motion: Continuous and Categorical Perspectives

Despite its importance in social interactions, laughter remains little studied in affective computing. Intelligent virtual agents are often blind to users’ laughter and unable to produce convincing laughter themselves. Respiratory, auditory, and facial laughter signals have been investigated but laughter-related body movements have received less attention. The aim of this study is threefold. First, to probe human laughter perception by analyzing patterns of categorisations of natural laughter animated on a minimal avatar. Results reveal that a low dimensional space can describe perception of laughter “types”. Second, to investigate observers’ perception of laughter (hilarious, social, awkward, fake, and non-laughter) based on animated avatars generated from natural and acted motion-capture data. Significant differences in torso and limb movements are found between animations perceived as laughter and those perceived as non-laughter. Hilarious laughter also differs from social laughter. Different body movement features were indicative of laughter in sitting and standing avatar postures. Third, to investigate automatic recognition of laughter to the same level of certainty as observers’ perceptions. Results show recognition rates of the Random Forest model approach human rating levels. Classification comparisons and feature importance analyses indicate an improvement in recognition of social laughter when localized features and nonlinear models are used.

Synthesis by extrusion: continuous, large-scale preparation of MOFs using little or no solvent

Grinding solid reagents under solvent-free or low-solvent conditions (mechanochemistry) is emerging as a general synthetic technique which is an alternative to conventional solvent-intensive methods. However, it is essential to find ways to scale-up this type of synthesis if its promise of cleaner manufacturing is to be realised. Here, we demonstrate the use of twin screw and single screw extruders for the continuous synthesis of various metal complexes, including Ni(salen), Ni(NCS)(2)(PPh3)(2) as well as the commercially important metal organic frameworks (MOFs) Cu-3(BTC)(2) (HKUST-1), Zn(2-methylimidazolate)(2) (ZIF-8, MAF-4) and Al(fumarate)(OH). Notably, Al(fumarate)(OH) has not previously been synthesised mechanochemically. Quantitative conversions occur to give products at kg h(-1) rates which, after activation, exhibit surface areas and pore volumes equivalent to those of materials produced by conventional solvent-based methods. Some reactions can be performed either under completely solvent-free conditions whereas others require the addition of small amounts of solvent (typically 3-4 mol equivalents). Continuous neat melt phase synthesis is also successfully demonstrated by both twin screw and single screw extrusion for ZIF-8. The latter technique provided ZIF-8 at 4 kg h(-1). The space time yields (STYs) for these methods of up to 144 x 10(3) kg per m(3) per day are orders of magnitude greater than STYs for other methods of making MOFs. Extrusion methods clearly enable scaling of mechanochemical and melt phase synthesis under solvent-free or low-solvent conditions, and may also be applied in synthesis more generally.

Development of a slurry continuous flow reactor for photocatalytic treatment of industrial waste water

The water treatment capability of a novel photocatalytic slurry reactor was investigated using methylene blue (MB) as a model pollutant in an aqueous suspension. A pellet TiO ₂ catalyst was employed and this freed the system from the need of filtration of catalyst following photocatalysis. This configuration combines the high surface area contact of catalyst with pollutant of the slurry reactor and also offers a high illumination of catalyst by its unique array of weir-like baffles. In this work, the batch adsorption of MB from aqueous solution (10μM) onto the TiO ₂ catalyst was studied, adsorption isotherms and kinetics were determined from the experimental data. Complete degradation of MB was achieved within 60 min illumination with various loadings of catalyst (30-200 g L ^-1). A modest catalyst loading (30 g L ^-1) achieved 98% degradation within 60 min of irradiation. Experimental results indicate that this novel reactor configuration has a high effective mass transfer rate and UV light penetration characteristics. 

A continuous flow packed bed photocatalytic reactor for the destruction of 2-methylisoborneol and geosmin utilising pelletised TiO2

Taste and odour compounds, especially geosmin (GSM) and 2-methylisoborneol (2-MIB), cause major problems in both drinking water and aquaculture industries world-wide. Aquaculture in particular has experienced significant financial losses due to the accumulation of taint compounds prior to harvest resulting in consumer rejection. UV-TiO2 photocatalysis has been demonstrated to remove GSM and 2-MIB at laboratory scale but the development of a continuous flow reactor suitable for use in water treatment has not been investigated. In this study, a pilot packed bed photocatalytic reactor was developed and evaluated for water treatment with both laboratory and naturally tainted samples. A significant reduction of both 2-MIB and GSM was achieved in both trials using the packed bed reactor unit. With the laboratory spiked water (100ngL-1 of each compound added prior to treatment), detectable levels were reduced by up to 97% after a single pass through the unit. When the reactor was used to treat water in a fish farm where both compounds were being produced in situ (2-MIB: 19ngL-1 and GSM: 14ngL-1) a reduction of almost 90% in taint compounds was achieved. These very encouraging promising results demonstrate the potential of this UV-TiO2 photocatalytic reactor for water treatment in fish rearing systems and other applications.