Findings from a pilot randomised trial of an asthma internet self-management intervention (RAISIN)

<b>Objective </b>To evaluate the feasibility of a phase 3 randomised controlled trial (RCT) of a website (Living Well with Asthma) to support self-management.<p></p> <b>Design and setting</b> Phase 2, parallel group, RCT, participants recruited from 20 general practices across Glasgow, UK. Randomisation through automated voice response, after baseline data collection, to website access for minimum 12 weeks or usual care.<p></p> <b>Participants </b>Adults (age≥16 years) with physician diagnosed, symptomatic asthma (Asthma Control Questionnaire (ACQ) score ≥1). People with unstable asthma or other lung disease were excluded.<p></p> <b>Intervention</b> Living Well with Asthma’ is a desktop/ laptop compatible interactive website designed with input from asthma/ behaviour change specialists, and adults with asthma. It aims to support optimal medication management, promote use of action plans, encourage attendance at asthma reviews and increase physical activity.<p></p> <b>Outcome measures</b> Primary outcomes were recruitment/retention, website use, ACQ and mini- Asthma Quality of Life Questionnaire (AQLQ). Secondary outcomes included patient activation, prescribing, adherence, spirometry, lung inflammation and health service contacts after 12 weeks. Blinding postrandomisation was not possible.<p></p> <b>Results </b>Recruitment target met. 51 participants randomised (25 intervention group). Age range 16–78 years; 75% female; 28% from most deprived quintile. 45/51 (88%; 20 intervention group) followed up. 19 (76% of the intervention group) used the website, for a mean of 18 min (range 0–49). 17 went beyond the 2 ‘core’ modules. Median number of logins was 1 (IQR 1–2, range 0–7). No significant difference in the prespecified primary efficacy measures of ACQ scores (−0.36; 95% CI −0.96 to 0.23; p=0.225), and mini-AQLQ scores (0.38; −0.13 to 0.89; p=0.136). No adverse events.<p></p> <b>Conclusions</b> Recruitment and retention confirmed feasibility; trends to improved outcomes suggest use of Living Well with Asthma may improve self-management in adults with asthma and merits further development followed by investigation in a phase 3 trial

Evaluation of children’s centres in England (ECCE). Strand 1: First survey of children’s centre leaders in the most deprived areas

This is the final version of the report. Available from the Department for Education via the link in this record.The evaluation of children’s centres in England (ECCE) is a 6-year study commissioned by the Department for Education (DfE) and undertaken by NatCen Social Research, the University of Oxford and Frontier Economics. The aim of this report is to profile children’s centres in the most disadvantaged areas, providing estimates on different aspects of provision and to explore different models of provision. The profile covers all main aspects of provision including management, staff, services, users and finance and involves nearly 500 children’s centres, representative of all phase 1 and 2 centres in the most disadvantaged area

An Integrated Disease/Pharmacokinetic/Pharmacodynamic Model Suggests Improved Interleukin-21 Regimens Validated Prospectively for Mouse Solid Cancers

Interleukin (IL)-21 is an attractive antitumor agent with potent immunomodulatory functions. Yet thus far, the cytokine has yielded only partial responses in solid cancer patients, and conditions for beneficial IL-21 immunotherapy remain elusive. The current work aims to identify clinically-relevant IL-21 regimens with enhanced efficacy, based on mathematical modeling of long-term antitumor responses. For this purpose, pharmacokinetic (PK) and pharmacodynamic (PD) data were acquired from a preclinical study applying systemic IL-21 therapy in murine solid cancers. We developed an integrated disease/PK/PD model for the IL-21 anticancer response, and calibrated it using selected “training” data. The accuracy of the model was verified retrospectively under diverse IL-21 treatment settings, by comparing its predictions to independent “validation” data in melanoma and renal cell carcinoma-challenged mice (R2>0.90). Simulations of the verified model surfaced important therapeutic insights: (1) Fractionating the standard daily regimen (50 µg/dose) into a twice daily schedule (25 µg/dose) is advantageous, yielding a significantly lower tumor mass (45% decrease); (2) A low-dose (12 µg/day) regimen exerts a response similar to that obtained under the 50 µg/day treatment, suggestive of an equally efficacious dose with potentially reduced toxicity. Subsequent experiments in melanoma-bearing mice corroborated both of these predictions with high precision (R2>0.89), thus validating the model also prospectively in vivo. Thus, the confirmed PK/PD model rationalizes IL-21 therapy, and pinpoints improved clinically-feasible treatment schedules. Our analysis demonstrates the value of employing mathematical modeling and in silico-guided design of solid tumor immunotherapy in the clinic

Predicting Outcomes of Prostate Cancer Immunotherapy by Personalized Mathematical Models

Therapeutic vaccination against disseminated prostate cancer (PCa) is partially effective in some PCa patients. We hypothesized that the efficacy of treatment will be enhanced by individualized vaccination regimens tailored by simple mathematical models.We developed a general mathematical model encompassing the basic interactions of a vaccine, immune system and PCa cells, and validated it by the results of a clinical trial testing an allogeneic PCa whole-cell vaccine. For model validation in the absence of any other pertinent marker, we used the clinically measured changes in prostate-specific antigen (PSA) levels as a correlate of tumor burden. Up to 26 PSA levels measured per patient were divided into each patient's training set and his validation set. The training set, used for model personalization, contained the patient's initial sequence of PSA levels; the validation set contained his subsequent PSA data points. Personalized models were simulated to predict changes in tumor burden and PSA levels and predictions were compared to the validation set. The model accurately predicted PSA levels over the entire measured period in 12 of the 15 vaccination-responsive patients (the coefficient of determination between the predicted and observed PSA values was R(2) = 0.972). The model could not account for the inconsistent changes in PSA levels in 3 of the 15 responsive patients at the end of treatment. Each validated personalized model was simulated under many hypothetical immunotherapy protocols to suggest alternative vaccination regimens. Personalized regimens predicted to enhance the effects of therapy differed among the patients.Using a few initial measurements, we constructed robust patient-specific models of PCa immunotherapy, which were retrospectively validated by clinical trial results. Our results emphasize the potential value and feasibility of individualized model-suggested immunotherapy protocols

Theoretical and practical development of the TOPSY self-management intervention for women who use a vaginal pessary for pelvic organ prolapse

Background: Pelvic organ prolapse (POP) is a common condition in women, where the downward descent of pelvic organs into the vagina causes symptoms which impacts quality of life. Vaginal pessaries offer an effective alternative to surgery for the management of POP. However, the need for regular follow-up can be burdensome for women and requires significant healthcare resources. The TOPSY study is a randomised controlled trial which aims to determine the clinical and cost-effectiveness of self-management of vaginal pessaries. This paper describes the theoretical and practical development of the self-management intervention. Methods: The intervention was developed using the MRC complex intervention framework, normalisation process theory (NPT) and self-management theory. The intervention aims to boost perceived self-efficacy in accordance with Bandura’s social cognitive theory and is guided by the tasks and skills Lorig and Hollman describe as necessary to self-manage a health condition. Results: The TOPSY intervention was designed to support women to undertake the medical management, role management and emotional management of their pessary. The six self-management skills described by Lorig and Hollman: problem-solving, decision-making, resource utilisation, formation of a patient-provider partnership role, action planning and self-tailoring, are discussed in detail, including how women were supported to achieve each task within the context of pessary self-management. The TOPSY intervention includes a self-management support session with a pessary practitioner trained in intervention delivery, a follow-up phone call 2 weeks later and ongoing telephone or face-to-face support as required by the woman initiated by contacting a member of the research team. Conclusions: The TOPSY study intervention was developed utilising the findings from a prior service development project, intervention development and self-efficacy theory, relevant literature, clinician experience and feedback from pessary using women and members of the public. In 2022, the findings of the TOPSY study will provide further evidence to inform this important aspect of pessary management. Trial registration: ISRCTN Registry ISRCTN62510577. Registered on June 10, 2017

The TOPSY pessary self-management intervention for pelvic organ prolapse: a study protocol for the process evaluation.

BACKGROUND: Process evaluations have become a valued component, alongside clinical trials, of the wider evaluation of complex health interventions. They support understanding of implementation, and fidelity, related to the intervention and provide valuable insights into what is effective in a practical setting by examining the context in which interventions are implemented. The TOPSY study consists of a large multi-centre randomised controlled trial comparing the effectiveness of pessary self-management with clinic-based care in improving women's condition-specific quality of life, and a nested process evaluation. The process evaluation aims to examine and maximise recruitment to the trial, describe intervention fidelity and explore participants' and healthcare professionals' experiences. METHODS: The trial will recruit 330 women from approximately 17 UK centres. The process evaluation uses a mixed-methods approach. Semi-structured interviews will be conducted with randomised women (18 per randomised group/n = 36), women who declined trial participation but agreed to interview (non-randomised women) (n = 20) and healthcare professionals recruiting to the trial (n ~ 17) and delivering self-management and clinic-based care (n ~ 17). The six internal pilot centres will be asked to record two to three recruitment discussions each (total n = 12-18). All participating centres will be asked to record one or two self-management teaching appointments (n = 30) and self-management 2-week follow-up telephone calls (n = 30). Process data (quantitative and qualitative) will be gathered in participant completed trial questionnaires. Interviews will be analysed thematically and recordings using an analytic grid to identify fidelity to the intervention. Quantitative analysis will be predefined within the process evaluation analysis plan. DISCUSSION: The wide variety of pessary care delivered across the UK for women with pelvic organ prolapse presents specific localised contexts in which the TOPSY interventions will be implemented. Understanding this contextual variance is central to understanding how and in what circumstances pessary self-management can be implemented (should it be effective). The inclusion of non-randomised women provides an innovative way of collecting indispensable information about eligible women who decline trial participation, allowing broader contextualisation and considerations of generalisability of trial findings. Methodological insights from examination of recruitment processes and mechanisms have the potential to inform recruitment mechanisms and future recruitment strategies and study designs. TRIAL REGISTRATION: ISRCTN62510577 . Registered on 6 October 2017

The Local Optima Level in Chemotherapy Schedule Optimisation

In this paper a multi-drug Chemotherapy Schedule Optimisation Problem (CSOP) is subject to Local Optima Network (LON) analysis. LONs capture global patterns in fitness landscapes. CSOPs have not previously been subject to fitness landscape analysis. We fill this gap: LONs are constructed and studied for meaningful structure. The CSOP formulation presents novel challenges and questions for the LON model because there are infeasible regions in the fitness landscape and an unknown global optimum; it also brings a topic from healthcare to LON analysis. Two LON Construction algorithms are proposed for sampling CSOP fitness landscapes: a Markov-Chain Construction Algorithm and a Hybrid Construction Algorithm. The results provide new insight into LONs of highly-constrained spaces, and into the proficiency of search operators on the CSOP. Iterated Local Search and Memetic Search, which are the foundations for the LON algorithms, are found to markedly out-perform a Genetic Algorithm from the literature

The effects of symmetry on the dynamics of antigenic variation

In the studies of dynamics of pathogens and their interactions with a host immune system, an important role is played by the structure of antigenic variants associated with a pathogen. Using the example of a model of antigenic variation in malaria, we show how many of the observed dynamical regimes can be explained in terms of the symmetry of interactions between different antigenic variants. The results of this analysis are quite generic, and have wider implications for understanding the dynamics of immune escape of other parasites, as well as for the dynamics of multi-strain diseases.Comment: 21 pages, 4 figures; J. Math. Biol. (2012), Online Firs

Dickkopf1 Regulates Fate Decision and Drives Breast Cancer Stem Cells to Differentiation: An Experimentally Supported Mathematical Model

BACKGROUND: Modulation of cellular signaling pathways can change the replication/differentiation balance in cancer stem cells (CSCs), thus affecting tumor growth and recurrence. Analysis of a simple, experimentally verified, mathematical model suggests that this balance is maintained by quorum sensing (QS). METHODOLOGY/PRINCIPAL FINDINGS: To explore the mechanism by which putative QS cellular signals in mammary stem cells (SCs) may regulate SC fate decisions, we developed a multi-scale mathematical model, integrating extra-cellular and intra-cellular signal transduction within the mammary tissue dynamics. Preliminary model analysis of the single cell dynamics indicated that Dickkopf1 (Dkk1), a protein known to negatively regulate the Wnt pathway, can serve as anti-proliferation and pro-maturation signal to the cell. Simulations of the multi-scale tissue model suggested that Dkk1 may be a QS factor, regulating SC density on the level of the whole tissue: relatively low levels of exogenously applied Dkk1 have little effect on SC numbers, whereas high levels drive SCs into differentiation. To verify these model predictions, we treated the MCF-7 cell line and primary breast cancer (BC) cells from 3 patient samples with different concentrations and dosing regimens of Dkk1, and evaluated subsequent formation of mammospheres (MS) and the mammary SC marker CD44(+)CD24(lo). As predicted by the model, low concentrations of Dkk1 had no effect on primary BC cells, or even increased MS formation among MCF-7 cells, whereas high Dkk1 concentrations decreased MS formation among both primary BC cells and MCF-7 cells. CONCLUSIONS/SIGNIFICANCE: Our study suggests that Dkk1 treatment may be more robust than other methods for eliminating CSCs, as it challenges a general cellular homeostasis mechanism, namely, fate decision by QS. The study also suggests that low dose Dkk1 administration may be counterproductive; we showed experimentally that in some cases it can stimulate CSC proliferation, although this needs validating in vivo