A New-Age for Biologic Therapies: Long-Term Drug-Free Therapy with BiP?

Heat shock proteins (HSPs) and other members of the much broader stress protein family have been shown to play important roles in coordinating multiple phases of immunological reactions; from facilitating immunological recognition, to promoting and regulating immunological responses and finally augmenting the resolution of inflammation and return to immunological homeostasis. In this review, we consider the challenges facing the stress protein field as we enter 2012; in particular we consider the role that HSPs and stress proteins may play in the initiation and termination of immunological responses. Special attention is afforded to the resolution-associated molecular pattern, binding immunoglobulin protein (BiP, also known as glucose regulated protein-78). We review the evidence that resolution-promoting proteins such as BiP may herald a new generation of biologics for inflammatory disease and reflect on the challenges of achieving clinical remission in rheumatoid arthritis with novel therapeutics and correlating clinical remission with immunological parameters of resolution of inflammation

Protocol for the economic evaluation of metacognitive therapy for cardiac rehabilitation participants with symptoms of anxiety and/or depression

INTRODUCTION: Cardiac rehabilitation (CR) is offered to reduce the risk of further cardiac events and to improve patients' health and quality of life following a cardiac event. Psychological care is a common component of CR as symptoms of depression and/or anxiety are more prevalent in this population, however evidence for the cost-effectiveness of current interventions is limited. Metacognitive therapy (MCT), is a recent treatment development that is effective in treating anxiety and depression in mental health settings and is being evaluated in CR patients. This protocol describes the planned approach to the economic evaluation of MCT for CR patients. METHODS AND ANALYSIS: The economic evaluation work will consist of a within-trial analysis and an economic model. The PATHWAY Group MCT study has been prospectively designed to collect comprehensive self-reported resource use and health outcome data, including the EQ-5D, within a randomised controlled trial study design (UK Clinical Trials Gateway). A within-trial economic evaluation and economic model will compare the cost-effectiveness of MCT plus usual care (UC) to UC, from a health and social care perspective in the UK. The within-trial analysis will use intention-to-treat and estimate total costs and quality-adjusted life-years (QALYs) for the trial follow-up. Single imputation will be used to impute missing baseline variables. Multiple imputation will be used to impute values missing at follow-up. Items of resource use will be multiplied by published national healthcare costs. Regression analysis will be used to estimate net costs and net QALYs and these estimates will be bootstrapped to generate 10 000 net pairs of costs and QALYs to inform the probability of cost-effectiveness. A decision analytical economic model will be developed to synthesise trial data with the published literature over a longer time frame. Sensitivity analysis will explore uncertainty. Guidance of the methods for economic models will be followed and dissemination will adhere to reporting guidelines. ETHICS AND DISSEMINATION: The economic evaluation includes a within-trial analysis. The trial which included the collection of this data was reviewed and approved by Ethics. Ethics approval was obtained by the Preston Research Ethics Committee (project ID 156862). The modelling analysis is not applicable for Ethics as it will use data from the trial (secondary analysis) and the published literature. Results of the main trial and economic evaluation will be published in the peer-reviewed National Institute for Health Research (NIHR) journals library (Programme Grants for Applied Research), submitted to a peer-reviewed journal and presented at appropriate conferences. TRIAL REGISTRATION NUMBER: ISRCTN74643496; Pre-results

Dynamics of pedestrians in regions with no visibility - a lattice model without exclusion

We investigate the motion of pedestrians through obscure corridors where the lack of visibility (due to smoke, fog, darkness, etc.) hides the precise position of the exits. We focus our attention on a set of basic mechanisms, which we assume to be governing the dynamics at the individual level. Using a lattice model, we explore the effects of non-exclusion on the overall exit flux (evacuation rate). More precisely, we study the effect of the buddying threshold (of no-exclusion per site) on the dynamics of the crowd and investigate to which extent our model confirms the following pattern revealed by investigations on real emergencies: If the evacuees tend to cooperate and act altruistically, then their collective action tends to favor the occurrence of disasters.Comment: 20 page

Early neutrophil trajectory following clozapine may predict clozapine response - Results from an observational study using electronic health records

Background: Clozapine has unique effectiveness in treatment-resistant schizophrenia and is known to cause immunological side-effects. A transient spike in neutrophils commonly occurs in the first weeks of clozapine therapy. There is contradictory evidence in the literature as to whether neutrophil changes with clozapine are linked to treatment response. Aims: The current study aims to further examine the neutrophil changes in response to clozapine and explore any association between neutrophil trajectory and treatment response. Methods: A retrospective cohort study of patients undergoing their first treatment with clozapine and continuing for at least 2 years identified 425 patients (69% male/31% female). Neutrophil counts at baseline, 3 weeks and 1 month were obtained predominantly by linkage with data from the clozapine monitoring service. Clinical Global Impression- Severity (CGI-S) was rated from case notes at the time of clozapine initiation and at 2 years. Latent class growth analysis (LCGA) was performed to define distinct trajectories of neutrophil changes during the first month of treatment. Logistic regression was then conducted to investigate for association between the trajectory of neutrophil count changes in month 1 and clinical response at 2 years as well as between baseline neutrophil count and response. Results: Of the original cohort, 397 (93%) patients had useable neutrophil data during the first 6 weeks of clozapine treatment. LCGA revealed significant differences in neutrophil trajectories with a three-class model being the most parsimonious. The classes had similar trajectory profiles but differed primarily on overall neutrophil count: with low, high-normal and high neutrophil classes, comprising 52%, 40% and 8% of the sample respectively. Membership of the high-normal group was associated with significantly increased odds of a positive response to clozapine, as compared to the low neutrophil group [Odds ratio (OR) = 2.10, p-value = 0.002; 95% confidence interval (95% CI) = 1.31–3.36]. Baseline neutrophil count was a predictor of response to clozapine at 2 years, with counts of ≥5 × 109/l significantly associated with positive response (OR = 1.60, p-value = 0.03; 95% CI = 1.03–2.49). Conclusions: Our data are consistent with the hypothesis that patients with low-level inflammation, reflected in a high-normal neutrophil count, are more likely to respond to clozapine, raising the possibility that clozapine exerts its superior efficacy via immune mechanisms.</p

Utilising Patient and Public Involvement in Stated Preference Research in Health: Learning from the Existing Literature and a Case Study

From Springer Nature via Jisc Publications RouterHistory: registration 2020-07-17, online 2020-08-04, pub-electronic 2020-08-04, pub-print 2021-07Publication status: PublishedFunder: Programme Grants for Applied Research; doi: http://dx.doi.org/10.13039/501100007602; Grant(s): RP-PG-1211-20011Abstract: Publications reporting discrete choice experiments of healthcare interventions rarely discuss whether patient and public involvement (PPI) activities have been conducted. This paper presents examples from the existing literature and a detailed case study from the National Institute for Health Research-funded PATHWAY programme that comprehensively included PPI activities at multiple stages of preference research. Reflecting on these examples, as well as the wider PPI literature, we describe the different stages at which it is possible to effectively incorporate PPI across preference research, including the design, recruitment and dissemination of projects. Benefits of PPI activities include gaining practical insights from a wider perspective, which can positively impact experiment design as well as survey materials. Further benefits included advice around recruitment and reaching a greater audience with dissemination activities, amongst others. There are challenges associated with PPI activities; examples include time, cost and outlining expectations. Overall, although we acknowledge practical difficulties associated with PPI, this work highlights that it is possible for preference researchers to implement PPI across preference research. Further research systematically comparing methods related to PPI in preference research and their associated impact on the methods and results of studies would strengthen the literature

Additional weekend therapy may reduce length of rehabilitation stay after stroke: a meta-analysis of individual patient data

Questions: Among people receiving inpatient rehabilitation after stroke, does additional weekend physiotherapy and/or occupational therapy reduce the length of rehabilitation hospital stay compared to those who receive a weekday-only service, and does this change after controlling for individual factors? Does additional weekend therapy improve the ability to walk and perform activities of daily living, measured at discharge? Does additional weekend therapy improve health-related quality of life, measured 6 months after discharge from rehabilitation? Which individual, clinical and hospital characteristics are associated with shorter length of rehabilitation hospital stay? Design: This study pooled individual data from two randomised, controlled trials (n = 350) using an individual patient data meta-analysis and multivariate regression. Participants: People with stroke admitted to inpatient rehabilitation facilities. Intervention: Additional weekend therapy (physiotherapy and/or occupational therapy) compared to usual care (5 days/week therapy). Outcome measures: Length of rehabilitation hospital stay, independence in activities of daily living measured with the Functional Independence Measure, walking speed and health-related quality of life. Results: Participants who received weekend therapy had a shorter length of rehabilitation hospital stay. In the un-adjusted analysis, this was not statistically significant (MD -5.7 days, 95% CI -13.0 to 1.5). Controlling for hospital site, age, walking speed and Functional Independence Measure score on admission, receiving weekend therapy was significantly associated with a shorter length of rehabilitation hospital stay (beta = 7.5, 95% CI 1.7 to 13.4, p = 0.001). There were no significant between-group differences in Functional Independence Measure scores (MD 1.9 points, 95% CI -2.8 to 6.6), walking speed (MD 0.06 m/second, 95% CI -0.15 to 0.04) or health-related quality of life (SMD -0.04, 95% CI -0.26 to 0.19) at discharge. Discussion: Modest evidence indicates that additional weekend therapy might reduce rehabilitation hospital length of stay

Delivery preferences for psychological intervention in cardiac rehabilitation : a pilot discrete choice experiment

BACKGROUND: Cardiac rehabilitation (CR) is a programme of care offered to people who recently experienced a cardiac event. There is a growing focus on home-based formats of CR and a lack of evidence on preferences for psychological care in CR. This pilot study aimed to investigate preferences for delivery attributes of a psychological therapy intervention in CR patients with symptoms of anxiety and/or depression. METHODS: A discrete choice experiment (DCE) was conducted and recruited participants from a feasibility trial. Participants were asked to choose between two hypothetical interventions, described using five attributes; intervention type (home or centre-based), information provided, therapy manual format, cost to the National Health Service (NHS) and waiting time. A separate opt-out was included. A conditional logit using maximum likelihood estimation was used to analyse preferences. The NHS cost was used to estimate willingness to pay for aspects of the intervention delivery. RESULTS: 35 responses were received (39% response rate). Results indicated that participants would prefer to receive any form of therapy compared with no therapy. Statistically significant results were limited, but included participants being keen to avoid not receiving information prior to therapy (β=-0.270; p=0.03) and preferring a lower cost to the NHS (β=-0.001; p=0.00). No significant results were identified for the type of psychological intervention, format of therapy/exercises and programme start time. Coefficients indicated preferences were stronger for home-based therapy compared with centre-based, but this was not significant. CONCLUSIONS: The pilot study demonstrates the feasibility of a DCE in this group, it identifies potential attributes and levels, and estimates the sample sizes needed for a full study. Preliminary evidence indicated that sampled participants tended to prefer home-based psychological therapy in CR and wanted to receive information before initiating therapy. Results are limited due to the pilot design and further research is needed

Raman Spectroscopy of Lymphocytes for the Identification of Prostate Cancer Patients with Late Radiation Toxicity Following Radiotherapy

The success of radiotherapy in tumour control depends on the total dose given. However, the tolerance of the normal tissues surrounding the tumour limits this dose. It is not known why some patients develop radiation toxicity and, currently, it is not possible to predict before treatment which patients will experience adverse effects. Thus, there is an unmet clinical need for a new test to identify patients at risk of radiation toxicity. Here, we report a new approach based on Raman spectroscopy.Blood samples were collected from 42 patients who had undergone radiotherapy for prostate cancer and had shown either severe or no/minimal late radiation toxicity in follow up. Radiation response was assessed following in vitro irradiation using Raman spectroscopy in addition to the G2 chromosomal radiosensitivity assay and the H2AX DNA damage assay.A Partial Least Squares Discriminant Analysis model was developed to classify patients using known radiation toxicity scores. A sensitivity of 95%, specificity of 92% and overall accuracy of 93% was achieved. In the future, this technology may have potential to lead to individualised patient radiotherapy by identifying which patients are at risk of radiation toxicity