Study protocol for the development and internal validation of Schizophrenia Prediction of Resistance to Treatment (SPIRIT): a clinical tool for predicting risk of treatment resistance to antipsychotics in first-episode schizophrenia.

INTRODUCTION: Treatment-resistant schizophrenia (TRS) is associated with significant impairment of functioning and high treatment costs. Identification of patients at high risk of TRS at the time of their initial diagnosis may significantly improve clinical outcomes and minimise social and functional disability. We aim to develop a prognostic model for predicting the risk of developing TRS in patients with first-episode schizophrenia and to examine its potential utility and acceptability as a clinical decision tool. METHODS AND ANALYSIS: We will use two well-characterised longitudinal UK-based first-episode psychosis cohorts: Aetiology and Ethnicity in Schizophrenia and Other Psychoses and Genetics and Psychosis for which data have been collected on sociodemographic and clinical characteristics. We will identify candidate predictors for the model based on current literature and stakeholder consultation. Model development will use all data, with the number of candidate predictors restricted according to available sample size and event rate. A model for predicting risk of TRS will be developed based on penalised regression, with missing data handled using multiple imputation. Internal validation will be undertaken via bootstrapping, obtaining optimism-adjusted estimates of the model's performance. The clinical utility of the model in terms of clinically relevant risk thresholds will be evaluated using net benefit and decision curves (comparative to competing strategies). Consultation with patients and clinical stakeholders will determine potential thresholds of risk for treatment decision-making. The acceptability of embedding the model as a clinical tool will be explored using qualitative focus groups with up to 20 clinicians in total from early intervention services. Clinicians will be recruited from services in Stafford and London with the focus groups being held via an online platform. ETHICS AND DISSEMINATION: The development of the prognostic model will be based on anonymised data from existing cohorts, for which ethical approval is in place. Ethical approval has been obtained from Keele University for the qualitative focus groups within early intervention in psychosis services (ref: MH-210174). Suitable processes are in place to obtain informed consent for National Health Service staff taking part in interviews or focus groups. A study information sheet with cover letter and consent form have been prepared and approved by the local Research Ethics Committee. Findings will be shared through peer-reviewed publications, conference presentations and social media. A lay summary will be published on collaborator websites

Cysteinyl leukotrienes: multi-functional mediators in allergic rhinitis

Cysteinyl leukotrienes (CysLTs) are a family of inflammatory lipid mediators synthesized from arachidonic acid by a variety of cells, including mast cells, eosinophils, basophils, and macrophages. This article reviews the data for the role of CysLTs as multi-functional mediators in allergic rhinitis (AR). We review the evidence that: (1) CysLTs are released from inflammatory cells that participate in AR, (2) receptors for CysLTs are located in nasal tissue, (3) CysLTs are increased in patients with AR and are released following allergen exposure, (4) administration of CysLTs reproduces the symptoms of AR, (5) CysLTs play roles in the maturation, as well as tissue recruitment, of inflammatory cells, and (6) a complex inter-regulation between CysLTs and a variety of other inflammatory mediators exists.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75432/1/j.1365-2222.2006.02498.x.pd

Sublingual immunotherapy for asthma.

BACKGROUND: Asthma is a common long-term respiratory disease affecting approximately 300 million people worldwide. Approximately half of people with asthma have an important allergic component to their disease, which may provide an opportunity for targeted treatment. Sublingual immunotherapy (SLIT) aims to reduce asthma symptoms by delivering increasing doses of an allergen (e.g. house dust mite, pollen extract) under the tongue to induce immune tolerance. However, it is not clear whether the sublingual delivery route is safe and effective in asthma. OBJECTIVES: To assess the efficacy and safety of sublingual immunotherapy compared with placebo or standard care for adults and children with asthma. SEARCH METHODS: We identified trials from the Cochrane Airways Group Specialised Register (CAGR), ClinicalTrials.gov (www.ClinicalTrials.gov), the World Health Organization (WHO) trials portal (www.who.int/ictrp/en/) and reference lists of all primary studies and review articles. The search is up to date as of 25 March 2015. SELECTION CRITERIA: We included parallel randomised controlled trials (RCTs), irrespective of blinding or duration, that evaluated sublingual immunotherapy versus placebo or as an add-on to standard asthma management. We included both adults and children with asthma of any severity and with any allergen-sensitisation pattern. We included studies that recruited participants with asthma, rhinitis, or both, providing at least 80% of trial participants had a diagnosis of asthma. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results for included trials, extracted numerical data and assessed risk of bias, all of which were cross-checked for accuracy. We resolved disagreements by discussion.We analysed dichotomous data as odds ratios (ORs) or risk differences (RDs) using study participants as the unit of analysis; we analysed continuous data as mean differences (MDs) or standardised mean differences (SMDs) using random-effects models. We rated all outcomes using GRADE (Grades of Recommendation, Assessment, Development and Evaluation) and presented results in the 'Summary of findings' table. MAIN RESULTS: Fifty-two studies met our inclusion criteria, randomly assigning 5077 participants to comparisons of interest. Most studies were double-blind and placebo-controlled, but studies varied in duration from one day to three years. Most participants had mild or intermittent asthma, often with co-morbid allergic rhinitis. Eighteen studies recruited only adults, 25 recruited only children and several recruited both or did not specify (n = 9).With the exception of adverse events, reporting of outcomes of interest to this review was infrequent, and selective reporting may have had a serious effect on the completeness of the evidence. Allocation procedures generally were not well described, about a quarter of the studies were at high risk of bias for performance or detection bias or both and participant attrition was high or unknown in around half of the studies.One short study reported exacerbations requiring a hospital visit and observed no adverse events. Five studies reported quality of life, but the data were not suitable for meta-analysis. Serious adverse events were infrequent, and analysis using risk differences suggests that no more than 1 in 100 are likely to suffer a serious adverse event as a result of treatment with SLIT (RD 0.0012, 95% confidence interval (CI) -0.0077 to 0.0102; participants = 2560; studies = 22; moderate-quality evidence).Within secondary outcomes, wide but varied reporting of largely unvalidated asthma symptom and medication scores precluded meaningful meta-analysis; a general trend suggested SLIT benefit over placebo, but variation in scales meant that results were difficult to interpret.Changes in inhaled corticosteroid use in micrograms per day (MD 35.10 mcg/d, 95% CI -50.21 to 120.42; low-quality evidence), exacerbations requiring oral steroids (studies = 2; no events) and bronchial provocation (SMD 0.69, 95% CI -0.04 to 1.43; very low-quality evidence) were not often reported. This led to many imprecise estimates with wide confidence intervals that included the possibility of both benefit and harm from SLIT.More people taking SLIT had adverse events of any kind compared with control (OR 1.70, 95% CI 1.21 to 2.38; low-quality evidence; participants = 1755; studies = 19), but events were usually reported to be transient and mild.Lack of data prevented most of the planned subgroup and sensitivity analyses. AUTHORS' CONCLUSIONS: Lack of data for important outcomes such as exacerbations and quality of life and use of different unvalidated symptom and medication scores have limited our ability to draw a clinically useful conclusion. Further research using validated scales and important outcomes for patients and decision makers is needed so that SLIT can be properly assessed as clinical treatment for asthma. Very few serious adverse events have been reported, but most studies have included patients with intermittent or mild asthma, so we cannot comment on the safety of SLIT for those with moderate or severe asthma. SLIT is associated with increased risk of all adverse events

Selective recall deficits for heterogeneous associations in detoxified individuals with alcohol use disorder

Aim: Alcohol use disorder (AUD) has been associated with recognition memory deficits. However, it remains unclear whether these deficits occur at the general recognition memory level or whether they selectively affect its subcomponents. Evidence suggests that recognition memory deficits may vary according to the heterogeneity of memory stimuli. Our aim was to investigate stimuli pair-dependent recognition memory deficits in AUD, using a cued recall task including homogeneous and heterogeneous stimuli pairs. Methods: Twenty-three patients with AUD (days since last alcohol consumption: 11.70 ± 10.20) and 23 healthy controls (HC) underwent a neuropsychological examination tapping attention, verbal fluency, logical, working and long-term memory, and a recognition and recall task involving both homogeneous (tool-tool) and heterogeneous (tool-scene, tool-animal) stimuli pairs. Group (AUD-HC) by condition (tool-tool, tool-scene, tool-animal) ANOVAs were performed on all neuropsychological indices. Results: In the neuropsychological examination, AUD individuals showed deficits in delayed recall and faster reaction times compared with HC. The administration of the recognition and recall task revealed specific performance decreases in cued recall occurring in the whole sample (AUD + HC) for heterogeneous (tool-scene, tool-animal) pairs compared with homogeneous pairs. Within this pattern, AUD patients showed a lower cued recall rate than HC only for tool-animal pairs. Conclusions: Our results support the existence of specific recall/recollection deficits in AUD which occurred for heterogeneous, but not for homogeneous stimuli pairs. This finding calls for further neuroimaging investigations aimed at investigating the neurobiological substrate of (i) different recognition memory subcomponents, and (ii) the processing of stimuli with different degree or type of heterogeneity

Pharmacoeconomics of subcutaneous allergen immunotherapy.

The current burden of allergic diseases, estimated by both direct and indirect costs, is very relevant. In fact the cost estimation for rhinitis amount globally to 4-10 billion dollars/year in the U.S. and to an average annual cost of 1089 euros per child/adolescent and 1543 euros per adult in Europe. The estimated annual costs in Northern America for asthma amounted to 14 billion dollars. Consequently, preventive strategies aimed at reducing the clinical severity of allergy are potentially able to reduce its costs. Among them, specific immunotherapy (SIT) joins to the preventive capacity the carryover effect once treatment is discontinued. A number of studies, mainly conducted in the US and Germany demonstrated a favourable cost-benefit balance. In the nineties, most surveys on patients with allergic rhinitis and asthma reported significant reductions of the direct and indirect costs in subjects treated with SIT compared to those treated with symptomatic drugs. This is fully confirmed in recent studies conducted in European countries: in Denmark the direct cost per patient/year of the standard care was more than halved following SIT; in Italy a study on Parietaria allergic patients demonstrated a significant difference in favor of SIT plus drug treatment for three years versus drug treatment alone, with a cost reduction starting from the 2nd year and increasing to 48% at the 3rd year, with a highly statistical significance which was maintained up to the 6th year, i.e. 3 years after stopping immunotherapy, corresponding to a net saving for each patient at the final evaluation of 623 euros per year; in France a cost/efficacy analysis comparing SIT and current symptomatic treatment in adults and children with dust mite and pollen allergy showed remarkable savings with SIT for both allergies in adults and children