A clinical investigation into the ability of subjects with lung disease to provide breath specimens using the EvidenzerIRL evidential breath analyser in alcohol intoxicant driving in criminal justice evidence.

The EvidenzerIRL instrument has been in use as an evidential breath analyser in the application of drink driving laws in the Republic of Ireland since 2011. The result of the analysis is used as evidence in prosecutions before the Courts in per se offences of driving under the influence of alcohol as distinct from screening results at the roadside. This study aims to assist doctors, lawyers and judges in assessing drivers' failure to provide valid evidential breath specimens. Since the introduction of the EvidenzerIRL, approximately 10% of evidential breath tests annually result in failure or refusal to provide a successful breath specimen, this is an offence under Irish road traffic laws. The presence of lung disease has been given as a reason for the driver failing to provide evidential breath specimens. The aim of this study is to assess the ability of subjects with lung disease to provide breath specimens using the EvidenzerIRL. Pulmonary function tests (PFT) were carried out on volunteers from outpatients of the pulmonary laboratory in St Vincent's University Hospital, Dublin (n = 58) and a control group with no underlying lung disease (n = 19). After the PFTs all volunteers were asked to provide breath specimens using the EvidenzerIRL. Fourteen (24%) out of 58 lung disease volunteers failed to provide a breath specimen, no one from the control group was unsuccessful. Thirteen females and one male volunteer could not successfully provide. Female volunteers were more likely to fail to provide than male volunteers. A significant difference was found between the median age of successful (62.2 years) and unsuccessful (69.2 years) lung disease volunteers. Only one PFT, percentage predicted of Forced Expiratory Volume in 1 second (FEV1), had a significant difference between the mean of successful (86.6%) and unsuccessful (66.5%) lung disease volunteers. A subject with lung disease was more likely to be successful than unsuccessful. Drivers' effort and operators' guidance through the process were found to be crucial parts to a successful outcome.

The Use of Targeted Monoclonal Antibodies in the Treatment of ABPA-A Case Series.

Allergic bronchopulmonary aspergillosis (ABPA) is a pulmonary disorder occurring in response to Aspergillus fumigatus that can complicate the course of asthma and cystic fibrosis. Here we present a case of acute ABPA without central bronchiectasis, a case of chronic active ABPA with central bronchiectasis, and a case of severe relapsing ABPA with central bronchiectasis. All three were initially treated with corticosteroids and antifungal agents but had an incomplete response. These patients were then treated with anti-IgE therapy with omalizumab before being switched to the anti-IL5R agent benralizumab. They responded well to both agents. These case reports highlight the potential role of omalizumab and benralizumab in the treatment of ABPA, but further studies are required to evaluate the effectiveness of these medications. Longer follow-up periods and objective measurements of the impact of treatment are necessary.

A clinical investigation into the ability of subjects with a lung disease to provide breath specimens using the Dräger 6510.

In the enforcement of drink driving laws failing to provide a breath specimen for alcohol analysis at the roadside when requested by a Police Officer is an offence in many countries. Some drivers claim that a lung disease prevented their ability to be successful. This study aims to investigate the relationship between the presence of a lung disease and the ability to provide a successful breath specimen using the Dräger 6510 screening device. Sixty participants with lung disease and nineteen control participants underwent pulmonary function tests and were then tested with a Dräger 6510 screening device. Only one participant was unsuccessful using the Dräger 6510, this participant suffered from interstitial lung disease. The pulmonary function test results did not indicate if someone would be successful or how many attempts would be needed to be successful. The presence of a lung disease did not indicate if a driver would be unsuccessful however all participants were free from infection and the participants with a lung disease were stable at the time of testing. Correct instruction, subject cooperation and the technique used by the driver to provide a breath specimen were found to be important factors in the success of a breath test.

What is the role of bronchial thermoplasty in the management of severe asthma?

Asthma is a common chronic inflammatory condition of the airways. Conventional therapy comprises inhaled corticosteroid and bronchodilators as well as trigger avoidance and management of comorbid conditions. A small group remain symptomatic despite these strategies and novel therapies have been developed. Bronchial thermoplasty is a nonpharmacological therapy which targets airway smooth muscle to improve asthma control. Clinical trials to date have shown the efficacy and safety of bronchial thermoplasty with a persistent effect on extended follow up. Questions remain regarding the exact mechanism of action of bronchial thermoplasty, the cost effectiveness of the procedure and the ideal criteria for patient selection.

Perspectives on the role of the speech and language therapist in palliative care: An international survey.

BACKGROUND: Speech and language therapists can improve the quality of life of people receiving palliative care through the management of communication and swallowing difficulties (dysphagia). However, their role in this domain is poorly defined and little is understood about the current international professional practice in this field. AIMS: To examine how speech and language therapists perceive their role in the delivery of palliative care to clients, to discover current international speech and language therapist practices and to explore the similarities and differences in speech and language therapists' practice in palliative care internationally. This will inform professional clinical guidelines and practice in this area. DESIGN: Anonymous, non-experimental, cross-sectional survey design. PARTICIPANTS: Speech and language therapists working with adult and paediatric palliative care populations in Republic of Ireland, United Kingdom, United States, Canada, Australia and New Zealand where the speech and language therapist profession is well established. METHOD: Purposive and snowball sampling were used to recruit participants internationally using gatekeepers. An online survey was disseminated using Survey Monkey (http://www.surveymonkey.com). RESULTS: A total of 322 speech and language therapists responded to the survey. Speech and language therapist practices in palliative care were similar across continents. Current speech and language therapist practices along with barriers and facilitators to practice were identified. The need for a speech and language therapist professional position paper on this topic was emphasised by respondents. CONCLUSION: Internationally, speech and language therapists believe they have a role in palliative care. The speech and language therapist respondents highlighted that this area of practice is under-resourced, under-acknowledged and poorly developed. They highlighted the need for additional research as well as specialist training and education for speech and language therapists and other multidisciplinary team members in the area of palliative care.

Targeting AML through DR4 with a novel variant of rhTRAIL.

Despite progress in the treatment of acute myelogenous leukaemia (AML) the outcome often remains poor. Tumour necrosis factor related apoptosis-inducing ligand (TRAIL) is a promising therapeutic agent in many different types of tumours, but AML cells are relatively insensitive to TRAIL-induced apoptosis. Here we show that TRAIL-induced apoptosis in AML cells is predominantly mediated by death receptor 4 (DR4) and not DR5. Therefore, we constructed a variant of TRAIL (rhTRAIL-C3) that is a strong inducer of DR4-mediated apoptosis. TRAIL-C3 demonstrated much stronger pro-apoptotic activity than wild-type (WT) TRAIL in a panel of AML cell lines as well as in primary AML blasts. The higher pro-apoptotic potential was further enhanced when the TRAIL mutant was used in combination with BMS-345541, a selective inhibitor of inhibitor-κB kinases. It illustrates that combination of this TRAIL variant with chemotherapeutics or other targeted agents can kill AML with high efficacy. This may represent a major advantage over the currently used therapies that have serious toxic side effects. The high efficacy of rhTRAIL-C3 containing therapies may enable the use of lower drug doses to reduce the toxic side effects and improve patient outcome. Our findings suggest that the rational design of TRAIL variants that target DR4 potentiate the death-inducing activity of TRAIL and offer a novel therapeutic strategy for the treatment of AML.

Stem cells are resistant to TRAIL receptor-mediated apoptosis.

New therapeutic approaches aim to eradicate tumours by expression of tumouricidal proteins in the tumour stroma. One such anti-neoplastic protein is tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) because it induces apoptosis in cancerous cells, but not in non-transformed cells. Stem cells can migrate to, survive and proliferate in tumours. We examined the suitability of bone marrow-derived adult mesenchymal stem cells (bmMSC), foetal-MSC and umbilical cord matrix stem cells (Wharton's Jelly MSCs) as TRAIL-delivery vehicles. Although all MSC types expressed DR4 and/or DR5, none of them were sensitive to TRAIL-induced apoptosis. Selective activation of DR4 or DR5 with agonistic antibodies or DR5-selective TRAIL-mutant (D269H/E195R) revealed that the TRAIL receptors are inactive in MSCs. In fMSC DR5 was not fully inactivated, its activity however was minimal in comparison to the colon carcinoma cell, Colo205. The intracellular components of the TRAIL-apoptotic pathway, such as pro-caspase-8 and -9 were also expressed at very low; almost undetectable levels in all three MSC types. In conclusion, the MSC species examined are resistant to TRAIL and thus can be suitable tools for TRAIL delivery to tumours.

Development of a high-affinity anti-domoic acid sheep scFv and its use in detection of the toxin in shellfish.

The potential of immunoassays as high-throughput screening tools for the detection of harmful substances in foods will only be realized when convenient methods are available for production of the high affinity antibodies needed for sensitive assay development. Recombinant antibodies offer advantages over traditional monoclonal antibodies in terms of ease of production, much greater antibody repertoire for selection, and versatility. We describe here the development of recombinant antibodies against the common shellfish toxin, domoic acid (DA), utilizing the sheep immunoglobulin system as an effective method for generating high affinity anti-hapten recombinant antibody fragments. A single-chain antibody fragment (scFv) library was generated from a sheep immunized with DA-bovine serum albumin conjugate, and anti-DA scFvs were isolated by phage-display. Three selected scFvs gave I50s of 2.6 to 58 ng/mL (8.3-186 nM) in competitive enzyme-linked immunosorbent assay (ELISA). Assay optimization with one of these scFvs gave a very reproducible standard curve with a range of 0.3 to 5.6 ng/mL (1.0 to 17.9 nM), a mean limit of quantification (LOQ, defined as the I20) of 0.5 ng/mL (1.6 nM), and a mean I50 of 1.2 ng/mL (3.9 nM). When the assay was used for the analysis of crude methanolic extracts of scallop tissues, results obtained correlated well with standard HPLC assay results (R2, 0.90, n = 40; R2, 0.81, n = 34), although ELISA results were lower than HPLC results. Adjusting the cutoff point for DA concentration accordingly from the regulatory 20 mg/kg, the potential of the sheep scFv-based ELISA for use as a screening assay for DA in shellfish extracts was demonstrated.