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This study examined whether participants’ adherence to an algorithmic aid was related to the degree of control they were provided at decision point and their attitudes toward new technologies and algorithms. It also tested the influence of control on participants’ subjective reports of task demands whilst using the aid. A total of 159 participants completed an online experiment centred on a simulated forecasting task, which required participants to predict the performance of school students on a standardized mathematics test. For each student, participants also received an algorithm-generated forecast of their score. Participants were randomly assigned to either the ‘full control’ (adjust forecast as much as they wish), ‘moderate control’ (adjust forecast by 30%) or ‘restricted control’ (adjust forecast by 2%) group. Participants then completed an assessment of subjective task load, a measure of their explicit attitudes toward new technologies, demographic and experience items (age, gender and computer literacy) and a novel version of the Go/No-Go Association Task, which tested their implicit attitudes toward algorithms. The results revealed that participants who were provided with more control over the final forecast tended to deviate from it more greatly and reported lower levels of frustration. Furthermore, participants showing more positive implicit attitudes toward algorithms were found to deviate less from the algorithm’s forecasts, irrespective of the degree of control they were given. The findings allude to the importance of users’ control and preexisting attitudes in their acceptance of, and frustration in using a novel algorithmic aid, which may ultimately contribute to their intention to use them in the workplace. These findings can guide system developers and support workplaces implementing expert system technology.

The rapid development of artificial intelligence brings with it the increasing likelihood of ubiquitous interaction between humans and robots. A significant contribution to studying human–robot interactions (HRI) comes from experimental studies, whereby humans and robots interact in controlled conditions and researchers observe and measure the reactions of humans (and robots). The use of experiments to understand human interactions has long been a central source of information in the field of experimental social psychology. These studies have yielded numerous major insights into the causes and outcomes of interaction. The methodology of experiments, however, including the demands made upon human participants to behave in predictable ways and the impact of experimenters’ expectancies upon results, has been a focus of much critical analysis. We examined a sample of 100 high impact HRI studies for evidence of potentially contaminating experimental artefacts and/or authors’ awareness of such factors. In our conclusions we highlight several methodological issues that appeared frequently in our sample, which may impede generalisations from laboratory experiments to real-world settings. Ultimately, we suggest that researchers may need to reformulate the methodologies used to study the unique features of HRI, and offer a number of recommendations for researchers designing HRI experiments. Refereed/Peer-reviewed

This article discusses the French debate of the 1580s over the status of the Salic Law and its influence upon an important text in English political thought, Robert Persons’s Conference about the n...

This article explores how, and why, Robert Persons's A conference about the next succession to the crowne of Ingland (1594) scandalized late Elizabethan England. By invoking the spectres of popular sovereignty and political resistance, Persons, as is well known, threatened to disrupt the succession of James VI of Scotland to Elizabeth I's throne. In doing so, however, he also undermined the very notion that the English crown passed by succession at all. After discussing Persons's political thought, this article examines the responses to it by such writers as John Hayward, Henry Constable, Peter Wentworth, and James VI himself. Their turn towards natural law as a basis for James's title was, it is argued, a direct consequence of the Conference’s argument. As well as shining long-overdue light on Hayward's political thought, the article thus argues that the reception of Persons's Conference was a significant influence on the development of English political thought in the early seventeenth century.

Since identification of the CFTR gene over 25 years ago, gene therapy for cystic fibrosis (CF) has been actively developed. More recently gene therapy has been joined by other forms of "genetic medicines" including mRNA delivery, as well as genome editing and mRNA repair-based strategies. Proof-of-concept that gene therapy can stabilize the progression of CF lung disease has recently been established in a Phase IIb trial. An early phase study to assess the safety and explore efficacy of CFTR mRNA repair is ongoing, while mRNA delivery and genome editing-based strategies are currently at the pre-clinical phase of development. This review has been written jointly by some of those involved in the various CF "genetic medicine" fields and will summarize the current state-of-the-art, as well as discuss future developments. Where applicable, it highlights common problems faced by each of the strategies, and also tries to highlight where a specific strategy may have an advantage on the pathway to clinical translation. We hope that this review will contribute to the ongoing discussion about the hype versus reality of genetic medicine-based treatment approaches in CF. Pediatr Pulmonol. 2016;51:S5-S17. © 2016 Wiley Periodicals, Inc.

To the Editor: The vast majority of treatments for cystic fibrosis (CF) target the downstream consequences of the disease and are incompletely effective. The success of the CF transmembrane conductance regulator (CFTR) potentiator ivacaftor has illustrated the clinical benefits arising from restoration of CFTR protein function (1). This agent is applicable as a monotherapy for a minority of patients with specific, rare mutations. CFTR gene therapy, a mutation-independent alternative, has demonstrated proof of principle for gene transfer in animal models and human trials, but only one study (using a viral vector) has unsuccessfully assessed whether clinical outcomes can be improved (2). In preparation for a phase IIb clinical trial of repeatedly administered, nonviral, liposome-mediated CFTR gene transfer assessing clinically meaningful outcomes (3), the UK CF Gene Therapy Consortium (www.cfgenetherapy.org.uk) undertook a single-application safety and dose-ranging study (NCT00789867). Some of the results of these studies have been previously reported in the form of abstracts (4, 5). The chosen plasmid DNA expresses CFTR under the control of the human cytomegalovirus enhancer/elongation factor 1α sequence (6), a modified EF1a promoter aiming for extended duration of expression (7), and was rendered CpG-free to minimize a host inflammatory response (6). The cationic lipid, GL67A, was chosen on the basis of extensive preclinical testing (8). After informed consent, adult patients with CF received a single nebulized +/− nasal dose of pGM169/GL67A. Reconstitution and preparation of pGM169/GL67A was undertaken on the day, and doses were delivered in sealed negative-pressure cubicles after pretreatment with inhaled salbutamol (albuterol). Preplanned adjunctive therapies including ibuprofen, prednisolone, or paracetamol were administered to some patients. The primary outcome of the clinical study was safety; assessment included examination, standard hematology/biochemistry, adverse events, spirometry, lung clearance index, chest computed tomography scan, gas transfer, bronchial biopsy histology, and immune markers. pGM169-specific DNA and mRNA were measured on nasal and lower airway brushings, with potential difference also measured bronchoscopically and nasally. For the latter, “responders” were defined as demonstrating chloride secretion 5 mV or more greater than their mean predose value, and greater than any of their predose responses. A total of 35 subjects (Tables 1 and ​and2)2) received a nebulized dose (5 ml, n = 8; 10 ml, n = 10; 20 ml, n = 17) via an AeroEclipse II (Trudell Medical International, London, ON, Canada) breath-actuated nebulizer (9). Three subjects undertook slow delivery (∼75 vs. 25 min for each 5 ml). Standard spray devices were used for nasal delivery (2 ml, n = 21). According to pre-/post-device weighing, a mean (SD) of 88.7% (2.9%) of expected nebulized dose and 94.5% (15.0%) of expected nasal dose was delivered. There were two serious adverse events: one occurred after the predosing bronchoscopy (swelling of the uvula related to intubation) and led to observation overnight in hospital, and the other was an episode of pancreatitis occurring around Day 10 after dosing (10 ml nebulized cohort). The subject was exocrine pancreatic sufficient and had likely experienced previous similar, but undiagnosed, episodes. Table 1. Baseline Demographics Table 2. Postdosing Responses Overall, in the trial, 94.3% of subjects experienced at least one adverse event, the majority of which were mild to moderate in severity and resolved spontaneously or with standard antipyretics. The most common occurred on the day of dosing and largely resolved within 24–48 hours (Tables 1 and ​and2):2): Typically, within the first few hours after dosing, a mild, self-limiting influenza-like systemic response was seen, most frequently in the 20-ml patients. This was not affected by slow delivery or coadministration of ibuprofen or prednisolone but was clearly dose-related and reduced by paracetamol. Symptoms of headache and/or tiredness were reported by 82, 70, and 13%, and raised serum inflammatory markers were recorded in 100, 60, and 63% of the 20-, 10-, and 5-ml groups respectively, with dose-related trends in maximal values. No patient dosed with 5 ml had a temperature higher than 38°C (Table 2). A relatively asymptomatic, dose-related, restrictive drop in spirometry was also observed, with no change in respiratory rate or oxygen saturation. No patient dosed with 5 ml showed a more than 20% relative fall in FEV1 (Table 2). The 20-ml group showed a small, significant (P

BackgroundIdentification of CNVs through chromosomal microarray (CMA) testing is the first-line investigation in individuals with learning difficulties/congenital abnormalities. Although recognised that CMA testing may identify CNVs encompassing a cancer predisposition gene (CPG), limited information is available on the frequency and nature of such results.MethodsWe investigated CNV gains and losses affecting 39 CPGs in 3366 pilot index case individuals undergoing CMA testing, and then studied an extended cohort (n=10 454) for CNV losses at 105 CPGs and CNV gains at 9 proto-oncogenes implicated in inherited cancer susceptibility.ResultsIn the pilot cohort, 31/3366 (0.92%) individuals had a CNV involving one or more of 16/39 CPGs. 30/31 CNVs involved a tumour suppressor gene (TSG), and 1/30 a proto-oncogene (gain of MET). BMPR1A, TSC2 and TMEM127 were affected in multiple cases. In the second stage analysis, 49/10 454 (0.47%) individuals in the extended cohort had 50 CNVs involving 24/105 CPGs. 43/50 CNVs involved a TSG and 7/50 a proto-oncogene (4 gains, 3 deletions). The most frequently involved genes, FLCN (n=10) and SDHA (n=7), map to the Smith-Magenis and cri-du-chat regions, respectively.ConclusionIncidental identification of a CNV involving a CPG is not rare and poses challenges for future cancer risk estimation. Prospective data collection from CPG-CNV cohorts ascertained incidentally and through syndromic presentations is required to determine the risks posed by specific CNVs. In particular, ascertainment and investigation of adults with CPG-CNVs and adults with learning disability and cancer, could provide important information to guide clinical management and surveillance.

Mutations in the MEF2C (myocyte enhancer factor 2) gene have been established as a cause for an intellectual disability syndrome presenting with seizures, absence of speech, stereotypic movements, hypotonia, and limited ambulation. Phenotypic overlap with Rett's and Angelman's syndromes has been noted. Following the first reports of 5q14.3q15 microdeletions encompassing the MEF2C gene, further cases with point mutations and partial gene deletions of the MEF2C gene have been described. We present the clinical phenotype of our cohort of six patients with MEF2C mutations and compare our findings with previously reported patients as well as with a growing number of genetic conditions presenting with a severe neurodevelopmental, Rett-like, phenotype. We aim to add to the current knowledge of the natural history of the “MEF2C haploinsufficiency syndrome” as well as of the differential diagnosis, clinical management, and genetic counseling in this diagnostically challenging group of patients.

The ECFS-CTN Standardisation Committee has undertaken this review of lung clearance index as part of the group's work on evaluation of clinical endpoints with regard to their use in multicentre clinical trials in CF. The aims were 1) to review the literature on reliability, validity and responsiveness of LCI in patients with CF, 2) to gain consensus of the group on feasibility of LCI and 3) to gain consensus on answers to key questions regarding the promotion of LCI to surrogate endpoint status. It was concluded that LCI has an attractive feasibility and clinimetric properties profile and is particularly indicated for multicentre trials in young children with CF and patients with early or mild CF lung disease. This is the first article to collate the literature in this manner and support the use of LCI in clinical trials in CF. © 2013 European Cystic Fibrosis Society. Published by Elsevier B.V.

For gene therapy to improve lung function in cystic fibrosis (CF) subjects, repeated administration of the gene transfer agent over the lifetime of patients is likely to be necessary. This requirement limits the utility of adenoviral and adeno-associated viral vectors (both previously evaluated in CF gene therapy trials) because of induced adaptive immune responses that render repeated dosing ineffective. For CF gene therapy trials, non-viral vectors are currently the only viable option. We previously showed that the cationic lipid formulation GL67A is the most efficient of several non-viral vectors analysed for airway gene transfer. Here, we assessed the efficacy and safety of administering 12 inhaled doses of GL67A complexed with pGM169, a CpG-free plasmid encoding human CFTR complementary DNA, into mice. We show that repeated administration of pGM169/GL67A to murine lungs is feasible, safe and achieves reproducible, dose-related and persistent gene expression (>140 days after each dose) using an aerosol generated by a clinically relevant nebuliser. This study supports progression into the first non-viral multidose lung trial in CF patients. © 2014 Macmillan Publishers Limited.

Clinically effective gene therapy for Cystic Fibrosis has been a goal for over 20 years. A plasmid vector (pGM169) that generates persistent expression and reduced host inflammatory responses in mice has raised prospects for translation to the clinic. The UK CF Gene Therapy Consortium is currently evaluating long-term repeated delivery of pGM169 complexed with the cationic lipid GL67A in a large Multidose Trial. This regulatory-compliant evaluation of aerosol administration of nine doses of pGM169/GL67A at monthly intervals, to the sheep lung, was performed in preparation for the Multidose Trial. All sheep tolerated treatment well with no adverse effects on haematology, serum chemistry, lung function or histopathology. Acute responses were observed in relation to bronchoalveolar cellularity comprising increased neutrophils and macrophage numbers 1 day post-delivery but these increases were transient and returned to baseline. Importantly there was no cumulative inflammatory effect or lung remodelling with successive doses. Molecular analysis confirmed delivery of pGM169 DNA to the airways and pGM169-specific mRNA was detected in bronchial brushing samples at day 1 following doses 1, 5 and 9. In conclusion, nine doses of pGM169/GL67A were well tolerated with no significant evidence of toxicity that would preclude adoption of a similar strategy in CF patients. © 2013 Elsevier Ltd.

Background: Induced sputum cytology and protein biomarkers can be used to assess airways infl ammation. Increases in sputum iron have been described in infl ammatory lung disease. We hypothesized that other sputum metals may be affected by airways infl ammation and investigated their potential value as biomarkers. Methods: Sputum was obtained from 20 healthy control subjects and from patients with infl ammatory pulmonary diseases (23 with cystic fi brosis [CF], 16 with bronchiectasis, 17 with asthma, and 23 with COPD), and iron, zinc, manganese, and copper were measured. Fourteen patients with CF were also studied through an exacerbation cycle. Results: Sputum zinc and iron were elevated in CF and non-CF bronchiectasis vs controls ( P , .001, zinc; P , .01 iron). Manganese was elevated in asthma ( P , .01) and bronchiectasis ( P , .05) vs controls. Copper was elevated in CF vs controls ( P , .05). Zinc decreased ( P , .01) following treatment of CF exacerbation. In subjects with CF zinc levels correlated with other biomarkers. Conclusions: These results suggest a relationship of high concentrations of total zinc and iron with airways infl ammation in CF and non-CF bronchiectasis, with longitudinal changes being observed in CF. Further work is required to elucidate potential infl ammatory mechanisms related to these observations. CHEST 2010; 137(3):635–641

Plantar pressure measurement is an important tool in gait analysis. Manual placement of small masks (masking) is increasingly used to calculate plantar pressure characteristics. Little is known concerning the reliability of manual masking. The aim of this study was to determine the reliability of masking on 2D plantar pressure footprints, in a population with forefoot deformity (i.e. hallux valgus). Using a random repeated-measure design, four observers identified the third metatarsal head on a peak-pressure barefoot footprint, using a small mask. Subsequently, the location of all five metatarsal heads was identified, using the same size of masks and the same protocol. The 2D positional variation of the masks and the peak pressure (PP) and pressure time integral (PTI) values of each mask were calculated. For single-masking the lowest inter-observer reliability was found for the distal-proximal direction, causing a clear, adverse impact on the reliability of the pressure characteristics (PP and PTI). In the medial-lateral direction the inter-observer reliability could be scored as high. Intra-observer reliability was better and could be scored as high or good for both directions, with a correlated improved reliability of the pressure characteristics. Reliability of multi-masking showed a similar pattern, but overall values tended to be lower. Therefore, small sized masking in order to define pressure characteristics in the forefoot should be done with care. ispartof: Gait & Posture vol:30 issue:3 pages:379-382 ispartof: location:England status: published

Background: In adults with asthma, ventilation heterogeneity, independent of inflammation, has been hypothesised to be associated with airway remodelling. Bronchial biopsy in preschool children with wheeze demonstrates early structural changes. Ventilation heterogeneity is sensitive to airway disease in other paediatric respiratory conditions such as cystic fibrosis, so may be sensitive to early airway disease in asthma. An observational study was performed in which it was hypothesised that ventilation heterogeneity (lung clearance index (LCI) and phase III slope indices (S cond and S acin )) were more sensitive than conventional measurements (forced expiratory volume in 1 s (FEV 1 ) and exhaled nitric oxide (Feno)) for detecting residual airways disease in children with well controlled asthma. Methods: In 31 children with asthma of mean age 10.6 years (range 5–15), FEV 1 , LCI, S cond and S acin were measured at two separate visits, before and after blinded salbutamol or placebo, with Feno measured once. 29 healthy volunteers of mean age 11.2 years (range 5–16) completed measurements at one visit only. Results: Baseline mean (SD) LCI was significantly higher in children with asthma than in controls (6.69 (0.91) vs 6.24 (0.47), p = 0.02). There were no significant differences in FEV 1 or median Feno. Following salbutamol there was a small significant change in mean (SD) FEV 1 (from −1.26 (1.25) to −0.93 (0.23), p = 0.03) but not in LCI, S cond or S acin . Importantly, LCI remained significantly higher after bronchodilator in children with asthma than in controls (6.64 (0.69), p = 0.01). Conclusion: This study identifies the presence of residual ventilation heterogeneity in children with well controlled asthma and normal FEV 1 . The role of LCI in measuring early airway disease in children with asthma requires further exploration, possibly as a surrogate of structural remodelling.

BackgroundFor cystic fibrosis (CF) patients there is a lack of good assays of disease activity and response to new therapeutic interventions, including gene therapy. Current measures of airways inflammation severity are insensitive or non-specific.MethodsBronchoalveolar lavage fluid from 39 CF children and 38 respiratory disease controls was obtained at bronchoscopy and analysed by surface enhanced laser desorption ionisation time of flight (SELDI-TOF) mass spectrometry. Recognized proteins were assessed for CF disease specificity. Individual protein identification of specific peaks was performed.Results1277 proteins/peptides, > 4 kDa, were detected using 12 different surfaces and binding conditions. 202 proteins/peptides were differentially expressed in the CF samples (p < 0.001), 167 up-regulated and 35 down-regulated. The most discriminatory biomarker had a mass of 5.163 kDa. The most abundant, with a mass of 10.6 kDa, was identified as s100 A8 (calgranulin A).ConclusionsThe application of SELDI-TOF mass spectrometry allows evaluation of proteins in BAL fluid avoiding the limitations of only analysing predetermined proteins and potentially identifying proteins not previously appreciated as biomarkers. Its application to cystic fibrosis should enable appropriate evaluation of evolving illness, of gene therapy and other new therapies.

Summary Background Treatment of acute asthma is based on rapid reversal of bronchospasm and airway inflammation. Magnesium sulphate (MgSO 4 ) is known to have a bronchodilator effect on smooth muscle but studies have shown conflicting results on its efficacy in acute asthma, although its use is recommended in national and international guidelines. Aims To determine if intravenous MgSO 4 , when used as an adjunct to standard therapy, improves the outcome in acute asthma. Methods A double blind, randomised placebo controlled trial comparing 1.2g MgSO 4 with standard therapy in adult patients with acute asthma. Patients had a PEF ⩽75% predicted and all were treated with oxygen, nebulised salbutamol and ipratropium, and IV hydrocortisone. They then received 1.2g IV MgSO 4 or placebo. Outcome measures were % predicted PEF at 60min and hospital admission rates. Results One hundred and twenty nine patients were studied. Placebo and active treatment groups were well matched at baseline. MgSO 4 had no benefit with regards hospital admission rates or % predicted PEF at 60min ( p =0.48) for the whole group, or for subgroups of life-threatening ( p =0.85), severe ( p =0.63) and moderate ( p =0.67) acute asthma. Conclusion This study did not show additional benefit from 1.2g IV MgSO 4 when given as an adjunct to standard therapy for acute asthma.

Lung clearance index (LCI) is a sensitive marker of early lung disease in children but has not been assessed in adults. Measurement is hindered by the complexity of the equipment required. The aims of this study were to assess performance of a novel gas analyser (Innocor) and to use it as a clinical tool for the measurement of LCI in cystic fibrosis (CF).LCI was measured in 48 healthy adults, 12 healthy school-age children and 33 adults with CF by performing an inert gas washout from 0.2% sulfur hexafluoride (SF6). SF6 signal:noise ratio and 10-90% rise time of Innocor were compared with a mass spectrometer used in similar studies in children.Compared with the mass spectrometer, Innocor had a superior signal:noise ratio but a slower rise time (150 ms vs 60 ms) which may limit its use in very young children. Mean (SD) LCI in healthy adults was significantly different from that in patients with CF: 6.7 (0.4) vs 13.1 (3.8), p0.001. Ten of the patients with CF had forced expiratory volume in 1 sor = 80% predicted but only one had a normal LCI. LCI repeats were reproducible in all three groups of subjects (mean intra-visit coefficient of variation ranged from 3.6% to 5.4%).Innocor can be adapted to measure LCI and affords a simpler alternative to a mass spectrometer. LCI is raised in adults with CF with normal spirometry, and may prove to be a more sensitive marker of the effects of treatment in this group.

Increased mucosal vascularity is a hallmark of airway inflammation in asthma. It was hypothesised that this would lead to a detectable increase in respiratory heat and moisture loss (RHML), which would reflect the degree of airway inflammation present. A total of 23 subjects with asthma and 18 healthy controls had RHML measured in a cross-sectional study. The measurements were made using a device that combines temperature and humidity measurement during inspiration and expiration and allows precise control over inspirate conditions and ventilatory pattern. The subjects with asthma underwent parallel measurements of exhaled nitric oxide, sputum eosinophil percentage and exhaled breath condensate pH. Mean+/-SD RHML was elevated in patients with asthma (98.1+/-7.3 J.L(-1)) compared with control subjects (91.9+/-4.5 J.L(-1)). RHML measurement in asthma correlated with sputum eosinophil percentage. This novel correlation between thermal and cellular measurements in asthma suggests that both of these noninvasive indices are sensitive to the degree of underlying chronic airway inflammation.

The improved survival in people with cystic fibrosis has led to an increasing number of patients reaching adulthood. This trend is likely to be maintained over the next decades, suggesting a need to increase the number of centres with expertise in the management of adult patients with cystic fibrosis. These centres should be capable of delivering multidisciplinary care addressing the complexity of the disease, in addition to addressing the psychological burden on patients and their families. Further issues that require attention are organ transplantation and end of life management.Lung disease in adults with cystic fibrosis drives most of the clinical care requirements, and major life-threatening complications, such as respiratory infection, respiratory failure, pneumothorax and haemoptysis, and the management of lung transplantation require expertise from trained respiratory physicians. The taskforce therefore strongly reccommends that medical leadership in multidisciplinary adult teams should be attributed to a respiratory physician adequately trained in cystic fibrosis management.The task force suggests the implementation of a core curriculum for trainees in adult respiratory medicine and the selection and accreditation of training centres that deliver postgraduate training to the standards of the HERMES programme.

BACKGROUND: Lung delivery of plasmid DNA encoding the CFTR gene complexed with a cationic liposome is a potential treatment option for patients with cystic fibrosis. We aimed to assess the efficacy of non-viral CFTR gene therapy in patients with cystic fibrosis.METHODS: We did this randomised, double-blind, placebo-controlled, phase 2b trial in two cystic fibrosis centres with patients recruited from 18 sites in the UK. Patients (aged ≥12 years) with a forced expiratory volume in 1 s (FEV1) of 50-90% predicted and any combination of CFTR mutations, were randomly assigned, via a computer-based randomisation system, to receive 5 mL of either nebulised pGM169/GL67A gene-liposome complex or 0·9% saline (placebo) every 28 days (plus or minus 5 days) for 1 year. Randomisation was stratified by % predicted FEV1 (FINDINGS: Between June 12, 2012, and June 24, 2013, we randomly assigned 140 patients to receive placebo (n=62) or pGM169/GL67A (n=78), of whom 116 (83%) patients comprised the per-protocol population. We noted a significant, albeit modest, treatment effect in the pGM169/GL67A group versus placebo at 12 months' follow-up (3·7%, 95% CI 0·1-7·3; p=0·046). This outcome was associated with a stabilisation of lung function in the pGM169/GL67A group compared with a decline in the placebo group. We recorded no significant difference in treatment-attributable adverse events between groups.INTERPRETATION: Monthly application of the pGM169/GL67A gene therapy formulation was associated with a significant, albeit modest, benefit in FEV1 compared with placebo at 1 year, indicating a stabilisation of lung function in the treatment group. Further improvements in efficacy and consistency of response to the current formulation are needed before gene therapy is suitable for clinical care; however, our findings should also encourage the rapid introduction of more potent gene transfer vectors into early phase trials.FUNDING: Medical Research Council/National Institute for Health Research Efficacy and Mechanism Evaluation Programme.

This chapter covers the most common medical complications of severe CF lung disease, excluding the treatment of infection exacerbation. The section on haemoptysis covers severity assessment, medical and interventional radiological approaches to managing this problem. The particular risks of pneumothorax in CF are then discussed, including the factors guiding referral to surgery. The management of acute and chronic respiratory failure in CF is covered. This includes the indications for home oxygen and for non-invasive ventilation, and guidance on how these should be used in CF. Finally, there is a section on terminal care in cystic fibrosis, covering the management of the transition to palliative management at the end of life, and appropriate strategies to support patient and family in advanced disease.