Practical applications of small-angle neutron scattering.

Recent improvements in beam-line accessibility and technology have led to small-angle neutron scattering (SANS) becoming more frequently applied to materials problems. SANS has been used to study the assembly, dispersion, alignment and mixing of nanoscale condensed matter, as well as to characterise the internal structure of organic thin films, porous structures and inclusions within steel. Using time-resolved SANS, growth mechanisms in materials systems and soft matter phase transitions can also be explored. This review is intended for newcomers to SANS as well as experts. Therefore, the basic knowledge required for its use is first summarised. After this introduction, various examples are given of the types of soft and hard matter that have been studied by SANS. The information that can be extracted from the data is highlighted, alongside the methods used to obtain it. In addition to presenting the findings, explanations are provided on how the SANS measurements were optimised, such as the use of contrast variation to highlight specific parts of a structure. Emphasis is placed on the use of complementary techniques to improve data quality (e.g. using other scattering methods) and the accuracy of data analysis (e.g. using microscopy to separately determine shape and size). This is done with a view to providing guidance on how best to design and analyse future SANS measurements on materials not listed below

The role of moisture profiling towards understanding pharmaceutical solid state functionality. Validation and the application of a moisture profiling analytical tool for investigation into the characterisation of and prediction of the effects of compaction and storage on different lactose physical forms

The majority of therapeutic pharmaceutical formulations are presented in the solid form. Moisture is able to play an important role in the functional performance of pharmaceutical solids. Moisture profiling is able to provide novel information with regards to the behaviour of moisture within materials using equilibrium relative humidity as a measurement. The hypothesis investigated explores the changes in equilibrium relative humidity of pharmaceutical material induced by physical, chemical or storage conditions, these are able to be monitored using the innovative moisture profiler system. The aims within this were to primarily validate the moisture profiler and secondly evaluate the effects of moisture on physical forms and with respect to effects of compaction, finally this was compared to conventional characterisation methods. Preliminary explorations were conducted in order to assess the validity of the moisture profiler, from this lactose was selected as a suitable pharmaceutical material for further work. Processing effects were then examined, firstly storage at elevated relative humidity of different forms of lactose were explored, and this was carried out with supplementary analysis. Secondly the effects of tabletting were explored, different compaction forces were investigated to observe if this had any notable effects on equilibrium relative humidity of the different lactose forms. Finally subsequent storage of the compacts were examined in order to explore if there were any changes in the equilibrium relative humidity.EPSRC and Reckitt Benckise

Identifying and targeting defective immune surveillance mechanisms in myeloma using multi-parameter single cell profiling by mass cytometry.

PhD ThesisMyeloma is a complex, incurable bone marrow malignancy of plasma cells with a diverse clinical course. Existing data suggests that abnormalities in T cell function and PD1 expression are present in myeloma and that immune subversion may be playing a role in progression of the disease. I hypothesise that characterisation of the cellular immunological landscape in myeloma will identify distinct functional populations which may offer therapeutic targets to restore immunological control of the disease. Mass cytometry is a novel, single cell analysis technique which enables simultaneous assessment of more than 30 cell surface and intracellular antigens by utilising metal tagged antibody probes. Using this technology and an algorithmic based data analysis approach alongside traditional data analysis techniques I explored the bone marrow microenvironment in 9 control, 18 NDMM and 9 RRMM samples. RRMM samples were drawn from patients receiving dual targeting of CD38 and PDL1. In NDMM I demonstrate that immune microenvironment changes include defects in antigen presenting populations, effector and helper lymphocyte populations and NK cells. These changes are present before treatment has been initiated and have prognostic significance. These functional defects are associated with upregulation of PD1 and PDL1 expression across multiple lineages. In the RRMM setting treatment targeting PDL1 and CD38 results in early functional cytotoxicity and cytokine production signals. Defective immunological responses correlate with poor clinical outcome and there is potential to restore immune function, providing a strong argument for considering multi-lineage immunological damage to represent a form of symptomatic myeloma

Role of social comparison in exposure to athletic media images on body image, mood, and desire to exercise

The purpose of this study was to examine the role of social comparison and the impact of idealized athletic images in the media on body image and mood. The participants consisted of 90 undergraduate males and 132 undergraduate females from Lakehead University. One-week prior to the experimental manipulation, the participants completed a questionnaire package with the following instruments: Multiple Affect Adjective Checklist-Revised, visual analog scales for body image, State Self-Esteem Scale, Body-Image Ideals Questionnaire, Usual Physical Activity, Leisure Time Exercise Questionnaire, Exercise Identity Scale, and Reasons for Exercise. At time 2, the participants were randomly assigned to view either idealized images of female or male models exercising. The participants then completed the mood and body image questionnaires. Female participants reported a decrease in positive body image, a decrease in positive affect, and an increase in desire to exercise following exposure to athletic female models. The findings also indicated that exercise frequency, exercise identity, body image, and exercising for motives of fitness, attractiveness, and tone all predicted change in these state measures. Female participants who viewed male athletic models reported a decrease in positive affect following exposure. Male participants who viewed male athletic models reported a decrease in positive affect following exposure. These findings provide partial support for Festinger’s (1954) theory of social comparison. It would appear that the impact of athletic media images is less aversive for males than females

Keeping prisoners out of prison: the role of higher education in keeping Aboriginal Australians out of our prison system

An effective way to keep people out of prison is to stop prisoners from reoffending. In Australia, 77% of Aboriginal prisoners have been under sentence previously, as compared to around 50% for non-Aboriginal Australians. Many who end up in prison have had little opportunity to engage with education or have had negative schooling experiences. This is particularly true of Aboriginal prisoners who are half as likely to finish year 12 as non-Aboriginal Australians. With encouragement and support, these people may take the opportunity to engage with education during incarceration. This paper reports on an Australian-government-funded project, Making the Connection which facilitates participation in digital higher education in prisons with a view to reducing recidivism, particularly for Aboriginal Australians. Participation in education can help those incarcerated to develop critical thinking skills, digital literacies and the capacity for self-reflection. In addition, it promotes the prospects for employment on release and promotes positive connection to community and families. This helps reduce the risk of reoffending upon release, by equipping people with the cognitive tools to engage constructively with families, communities and an increasingly digital society. Most correctional jurisdictions prohibit the use of the internet by prisoners, yet most universities are increasingly reliant on the online provision of programs. This often results in the further marginalisation of those who are already marginalised, including prisoners. The Making the Connection project is developing internet-independent digital technologies and a suite of higher education programs that will enable Aboriginal and non-Aboriginal prisoners to engage with higher education

Mean Dynamic Topography of the Arctic Ocean

ICESat and Envisat altimetry data provide measurements of the instantaneous sea surface height (SSH) across the Arctic Ocean, using lead and open water elevation within the sea ice pack. First, these data were used to derive two independent mean sea surface (MSS) models by stacking and averaging along-track SSH profiles gathered between 2003 and 2009. The ICESat and Envisat MSS data were combined to construct the high-resolution ICEn MSS. Second, we estimate the 5.5-year mean dynamic topography (MDT) of the Arctic Ocean by differencing the ICEn MSS with the new GOCO02S geoid model, derived from GRACE and GOCE gravity. Using these satellite-only data we map the major features of Arctic Ocean dynamical height that are consistent with in situ observations, including the topographical highs and lows of the Beaufort and Greenland Gyres, respectively. Smaller-scale MDT structures remain largely unresolved due to uncertainties in the geoid at short wavelengths

Concert 6: A Triumphant Conclusion. Carl Vine: Cafe Concertino

Concert 6 at Stradbroke Chamber Music Festival

Molecular selection of therapy in metastatic colorectal cancer: the FOCUS4 molecularly stratified RCT

Complex trials with innovative designs are becoming increasingly common and offer the potential to improve patient outcomes in a shorter time frame. There is evidence that patients with colorectal cancer fall into different subgroups with varying responsiveness to therapy, and that this variation is linked to genetic biomarkers. To the best of our knowledge, FOCUS4 was the first molecularly stratified trial in metastatic colorectal cancer and remains one of the first umbrella trial designs to be launched globally. Objectives To identify novel therapies that improve disease control within the molecular subgroup of metastatic colorectal cancer in which the novel therapies were expected to be most effective. Design This was a Phase II/III molecularly stratified umbrella trial that used adaptive statistical methodology to decide which subtrial should close early; new subtrials were added as protocol amendments. Setting The maintenance setting following 16 weeks of first-line combination chemotherapy. Participants Patients with newly diagnosed metastatic colorectal cancer were registered, and central laboratory testing was used to stratify their tumour into molecular subtypes. Following 16 weeks of first-line therapy, patients with stable or responding disease were eligible for randomisation into either a molecularly stratified subtrial or the non-stratified FOCUS4-N trial. Interventions Of the 20 drug combinations that were explored for inclusion in the platform trial, three molecularly targeted subtrials were activated: FOCUS4-B (PIK3CA mutation or PTEN overexpression) – aspirin versus placebo; FOCUS4-C (TP53 and RAS mutation) – adavosertib (AstraZeneca Ltd, Cambridge, UK) versus active monitoring; and FOCUS4-D (BRAF-PIK3CA-RAS wild type) – AZD8931 versus placebo. A non-stratified subtrial was also carried out: FOCUS4-N – capecitabine versus active monitoring. Main outcome measures The main outcome measure was progression-free survival from the time of randomisation to progression, comparing the intervention with active monitoring/placebo. Toxicity and overall survival data were collected in all randomised patients, and quality of life (using EuroQol-5 Dimensions) data were collected in FOCUS4-N only. Results Between January 2014 and October 2020, 1434 patients were registered from 88 hospitals in the UK. Successful biomarker testing was completed in 1291 out of 1382 samples (93%), and 908 out of 1315 patients (69%) completing 16 weeks of first-line therapy were eligible for randomisation, with 361 randomly allocated to a subtrial. FOCUS4-B evaluated aspirin versus placebo in the PIK3CA-mutant/ PTEN -loss subgroup, but recruited only six patients, so was closed for futility. FOCUS4-C evaluated adavosertib versus active monitoring in 67 patients in the RAS + TP53 double-mutant subgroup and met its primary end point, showing an improvement in progression-free survival (median 3.61 vs. 1.87 months; hazard ratio 0.35, 95% confidence interval 0.18 to 0.68; p = 0022). FOCUS4-D evaluated AZD8931 in 32 patients in the BRAF-PIK3CA-RAS wild-type subgroup and showed no benefit, so was discontinued after the first interim analysis. FOCUS4-N evaluated capecitabine monotherapy versus active monitoring in 254 patients and met its primary end point, showing improvement in progression-free survival (hazard ratio 0.40, 95% confidence interval 0.21 to 0.75; p < 0.0001). Limitations FOCUS4-C and FOCUS4-N were closed early owing to COVID-19, so did not accrue their planned recruitment numbers. Conclusions Adaptive stratified medicine studies are feasible in common cancers but present challenges. Capecitabine monotherapy is an effective maintenance therapy. Wee1 inhibition using adavosertib shows significant clinical activity, notably in left-sided colorectal cancer. Trial registration This trial was registered as ISRCTN90061546. Funding This project was jointly funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and National Institute for Health and Care Research (NIHR) partnership, and Cancer Research UK. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 9, No. 9. See the NIHR Journals Library website for further project information