A Systematic Kernel Function Procedure for Determining Aerodynamic Forces on Oscillating or Steady Finite Wings at Subsonic Speeds

Details are given of a numerical solution of the integral equation which relates oscillatory or steady lift and downwash distributions in subsonic flow. The procedure has been programmed for the IBM 704 electronic data processing machine and yields the pressure distribution and some of its integrated properties for a given Mach number and frequency and for several modes of oscillation in from 3 to 4 minutes, results of several applications are presented

Added Value Report: University of Westminster Transformation in Students Project

One of the core aims that all Higher Education institutions share is to enhance graduate employability, and develop a workforce that is ready for the constantly changing labour market. While the concept of employability is shifting and variable (e.g. students as ‘customers’ and/or ‘partners’ (Skea, 2017), it is necessary to develop inclusive measures of employability that can extend beyond generic skills, and include values and identity-driven attributes. The literature recognises that graduate attributes are a set of desirable skills, qualities and understandings that both the University and students deem as important for employment and for shaping identities within the labour market (O’Leary, 2016; Bridgstock, 2009; Tomlinson, 2007). Thus, focus groups and interviews were carried out with undergraduates, postgraduates and alumni to explore their experiences at the University of Westminster, and to elicit the values and qualities that they consider important and personally valuable to their success in the future. This report presents qualitative findings on students’ experiences of gaining “added value” from their time at Westminster. Subsequently, we will use the results to create a robust survey that gives a scientific measurement of students’ attribute development throughout their studies at University

Ablation and transmission of thin solid targets irradiated by intense extreme ultraviolet laser radiation

The interaction of an extreme ultraviolet (EUV) laser beam with a parylene foil was studied by experiments and simulation. A single EUV laser pulse of nanosecond duration focused to an intensity of 3 × 1010 W cm−2 perforated micrometer thick targets. The same laser pulse was simultaneously used to diagnose the interaction by a transmission measurement. A combination of 2-dimensional radiation-hydrodynamic and diffraction calculations was used to model the ablation, leading to good agreement with experiment. This theoretical approach allows predictive modelling of the interaction with matter of intense EUV beams over a broad range of parameters

Mobile telephone delivered contingency management for encouraging adherence to supervised methadone consumption: feasibility study for an RCT of clinical and cost-effectiveness (TIES)

Background: Prescription methadone or buprenorphine enables people with opioid use disorder to stop heroin use safely while avoiding withdrawal. To ensure methadone is taken as prescribed and to prevent diversion onto the illicit market, people starting methadone take their daily dose under a pharmacist’s supervision. Many patients miss their daily methadone dose risking withdrawal, craving for heroin and overdose due to loss of heroin tolerance. Contingency management (CM) can improve medication adherence, but remote delivery using technology may be resource-light and cost-effective. We developed an innovative way to deliver CM by mobile telephone. Software monitors patients’ attendance and supervised methadone consumption through an internet self-login at the pharmacy and sends reinforcing text messages to patients’ mobile telephones. A linked system sends medication adherence reports to prescribers and provides early warning alerts of missed doses. A pre-paid debit card system provides financial incentives. Methods: A cluster randomised controlled trial design was used to test the feasibility of conducting a future trial of mobile telephone CM to encourage adherence to supervised methadone in community pharmacies. Each cluster (drug service/3 allied pharmacies) was randomly allocated to provide patient’s presenting for a new episode of opiate agonist treatment (OAT) with either (a) mobile telephone text message CM, (b) mobile telephone text message reminders, or (c) no text messages. We assessed acceptability of the interventions, recruitment, and follow-up procedures. Results: Four drug clinics were approached and three recruited. Thirty-three pharmacists were approached and 9 recruited. Over 3 months, 173 individuals were screened and 10 enrolled. Few patients presented for OAT and high numbers were excluded due to receiving buprenorphine or not attending participating pharmacies. There was 96% consistency in recording medication adherence by self-login vs. pharmacy records. In focus groups, CM participants were positive about using self-login, the text messages, and debit card. Prescribers found weekly reporting, time saving, and allowed closer monitoring of patients. Pharmacists reported that the tablet device was easy to host. Conclusion: Mobile telephone CM worked well, but a planned future trial will use modified eligibility criteria (existing OAT patients who regularly miss their methadone/buprenorphine doses) and increase the number of participating pharmacies. Trial registration: The trial is retrospectively registered, ISRCTN 58958179

Telephone delivered incentives for encouraging adherence to supervised methadone consumption (TIES): study protocol for a feasibility study for an RCT of clinical and cost effectiveness

The majority of people receiving treatment for their heroin addiction, are prescribed methadone; for which there is an extensive evidence base. When treatment starts, people take their daily dose of methadone under supervision at a community pharmacy. Supervision guarantees methadone is taken as directed by the individual for whom it has been prescribed, helps to ensure individuals take their correct dose every day, and safeguards against diversion and overdose. However, individuals often fail to attend the pharmacy to take their methadone. Each missed dose is of concern. If a patient misses their daily dose of methadone, they will start to experience opiate withdrawal and cravings and are more likely to use heroin. If they miss three days dose, there are concerns that they may lose tolerance to the drug and may be at risk of overdose when the next dose is taken. Hence there is an urgent need to develop effective interventions for medication adherence. Research suggests that incentive-based medication adherence interventions may be very effective, but there are few controlled trials and the provision of incentives requires time and organisational systems which can be challenging in pharmacies. The investigators have developed the technology to deliver incentives by mobile telephone. This cluster randomised trial will test the feasibility of conducting a future trial evaluating the clinical and cost effectiveness of using telephone delivered incentives (praise and modest financial rewards via text messaging) to encourage adherence with supervised consumption of methadone in community pharmacies. Three drug services (each with two or three community pharmacies supervising methadone consumption that will enrol 20 individuals, a total of 60 participants) will be recruited and randomly allocated to deliver either i) telephone delivered incentives, ii) telephone delivered reminders or iii) no telephone system. Acceptability, recruitment, follow-up, and suitable measures of clinical and cost effectiveness will be assessed. Findings from this feasibility study will be assessed against stated progression criteria and used to inform a future confirmatory trial of the clinical and cost effectiveness of telephone delivered incentives to encourage medication adherence. ISRCTN58958179 (retrospectively registered). [Abstract copyright: © 2019 Published by Elsevier Inc.

Clinical and cost-effectiveness of a diabetes education and behavioural weight management programme versus a diabetes education programme in adults with a recent diagnosis of type 2 diabetes: study protocol for the Glucose Lowering through Weight management (GLoW) randomised controlled trial

Introduction: People with type 2 diabetes (T2D) can improve glycaemic control or even achieve remission through weight loss and reduce their use of medication and risk of cardiovascular disease. The Glucose Lowering through Weight management (GLoW) trial will evaluate whether a tailored diabetes education and behavioural weight management programme (DEW) is more effective and cost-effective than a diabetes education (DE) programme in helping people with overweight or obesity and a recent diagnosis of T2D to lower their blood glucose, lose weight and improve other markers of cardiovascular risk. Methods and analysis: This study is a pragmatic, randomised, single-blind, parallel group, two-arm, superiority trial. We will recruit 576 adults with body mass index>25 kg/m2 and diagnosis of T2D in the past 3 years and randomise them to a tailored DEW or a DE programme. Participants will attend measurement appointments at a local general practitioner practice or research centre at baseline, 6 and 12 months. The primary outcome is 12-month change in glycated haemoglobin. The effect of the intervention on the primary outcome will be estimated and tested using a linear regression model (analysis of covariance) including randomisation group and adjusted for baseline value of the outcome and the randomisation stratifiers. Participants will be included in the group to which they were randomised, under the intention-to-treat principle. Secondary outcomes include 6-month and 12-month changes in body weight, body fat percentage, systolic and diastolic blood pressure and lipid profile; probability of achieving good glycaemic control; probability of achieving remission from diabetes; probability of losing 5% and 10% body weight and modelled cardiovascular risk (UKPDS). An intention-to-treat within-trial cost-effectiveness analysis will be conducted from NHS and societal perspectives using participant-level data. Qualitative interviews will be conducted with participants to understand why and how the programme achieved its results and how participants manage their weight after the programme ends. Ethics and dissemination: Ethical approval was received from East of Scotland Research Ethics Service on 15 May 2018 (18/ES/0048). This protocol (V.3) was approved on 19 June 2019. Findings will be published in peer-reviewed scientific journals and communicated to other stakeholders as appropriate. Trial registration number: ISRCTN18399564

The prognostic and predictive power of redox rotein expression for anthracycline-based chemotherapy response in locally advanced breast cancer

Neoadjuvant chemotherapy has become the standard of care for locally advanced primary breast cancer. Anthracycline-based regimens have proven to be one of the most effective treatments in this setting. As certain cytotoxic antineoplastic agents, such as anthracyclines, generate reactive oxygen species as a by-product of their mechanism of action, we examined whether redox protein expression was involved in the response to anthracycline-based chemotherapy and with clinical outcome. Pre treatment needle core biopsy and postanthracycline treatment tumour sections were analysed from 98 cases. In all, 32 individuals had a complete clinical response and 17 had a complete pathological response. Immunohistochemical staining was performed for eight redox proteins: thioredoxin, thioredoxin reductase thioredoxin interacting protein (TxNIP), glutathione S-transferase (GST) p, h and a, catalase and manganese superoxide dismutase. GST p (P¼0.05) and catalase (P¼0.045) were associated with pathological complete response in pre-chemotherapy samples. TxNIP (P¼0.017) and thioredoxin reductase (P¼0.022) were independent prognostic factors for distant metastasis free survival and TxNIP for overall survival (P¼0.014). In oestrogen receptor negative patients that are known to have a poor overall survival, a considerably worse prognosis was seen in cases that exhibited low expression of TxNIP (P¼0.000003), stratifying patients into more defined groups. This study indicates the importance of redox regulation in determining breast cancer response to anthracycline-based chemotherapy and provides ways of further stratifying pre-chemotherapy patients to potentially allow more tailored treatments

High nuclear MSK1 is associated with longer survival in breast cancer patients

Purpose: Mitogen- and stress- activated kinases (MSKs) are important substrates of the mitogen-activated protein kinase (MAPK)-activated protein kinase family. MSK1 and MSK2 are both nuclear serine/threonine protein kinases, with MSK1 being suggested to potentially play a role in breast cancer cell proliferation, cell cycle progression, cell migration, invasion and tumour growth. The aim of the current study was to assess MSK1 protein expression in breast cancer tumour specimens, evaluating its prognostic significance. Methods: A large cohort of 1902 early stage invasive breast cancer patients was used to explore the expression of MSK1. Protein expression was examined using standard immunohistochemistry on tissue microarrays. Results: Low MSK1 protein expression was associated with younger age (P=0.004), higher tumour grade (P<0.001), higher Nottingham Prognostic Index scores (P=0.007), negative ER (P<0.001) and PR (P<0.001) status, and with triple-negative (P<0.001) and basal-like (P<0.001) phenotypes. Low MSK1 protein expression was significantly associated with shorter time to distant metastasis (P<0.001), and recurrence (P=0.013) and early death due to breast cancer (P=0.01). This association between high MSK1 expression and improved breast cancer-specific survival was observed in the whole cohort (P=0.009) and in the HER2 negative and non-basal like tumours (P=0.006 and P=0.024, respectively). Multivariate analysis including other prognostic variables indicated that MSK1 is not an independent marker of outcome. Conclusions: High MSK1 is associated with improved breast cancer-specific survival in early stage invasive breast cancer patients, and has additional prognostic value in HER2 negative and non-basal like disease. Although not an independent marker of outcome we believe such findings, and significant associations with well-established negative prognostic factors (age, grade, Nottingham Prognostic Index, hormone receptor status, time to distant metastasi

Immunopeptidomics of colorectal cancer organoids reveals a sparse HLA class I neoantigen landscape and no increase in neoantigens with interferon or MEK-inhibitor treatment.

Patient derived organoids (PDOs) can be established from colorectal cancers (CRCs) as in vitro models to interrogate cancer biology and its clinical relevance. We applied mass spectrometry (MS) immunopeptidomics to investigate neoantigen presentation and whether this can be augmented through interferon gamma (IFNγ) or MEK-inhibitor treatment. Four microsatellite stable PDOs from chemotherapy refractory and one from a treatment naïve CRC were expanded to replicates with 100 million cells each, and HLA class I and class II peptide ligands were analyzed by MS. We identified an average of 9936 unique peptides per PDO which compares favorably against published immunopeptidomics studies, suggesting high sensitivity. Loss of heterozygosity of the HLA locus was associated with low peptide diversity in one PDO. Peptides from genes without detectable expression by RNA-sequencing were rarely identified by MS. Only 3 out of 612 non-silent mutations encoded for neoantigens that were detected by MS. In contrast, computational HLA binding prediction estimated that 304 mutations could generate neoantigens. One hundred ninety-six of these were located in expressed genes, still exceeding the number of MS-detected neoantigens 65-fold. Treatment of four PDOs with IFNγ upregulated HLA class I expression and qualitatively changed the immunopeptidome, with increased presentation of IFNγ-inducible genes. HLA class II presented peptides increased dramatically with IFNγ treatment. MEK-inhibitor treatment showed no consistent effect on HLA class I or II expression or the peptidome. Importantly, no additional HLA class I or II presented neoantigens became detectable with any treatment. Only 3 out of 612 non-silent mutations encoded for neoantigens that were detectable by MS. Although MS has sensitivity limits and biases, and likely underestimated the true neoantigen burden, this established a lower bound of the percentage of non-silent mutations that encode for presented neoantigens, which may be as low as 0.5%. This could be a reason for the poor responses of non-hypermutated CRCs to immune checkpoint inhibitors. MEK-inhibitors recently failed to improve checkpoint-inhibitor efficacy in CRC and the observed lack of HLA upregulation or improved peptide presentation may explain this

Minimum-Width Confidence Bands via Constraint Optimization

Peer reviewe