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BACKGROUND: Dilated cardiomyopathy (DCM) is a final common manifestation of heterogenous etiologies. Adverse outcomes highlight the need for disease stratification beyond ejection fraction. OBJECTIVES: The purpose of this study was to identify novel, reproducible subphenotypes of DCM using multiparametric data for improved patient stratification. METHODS: Longitudinal, observational UK-derivation (n = 426; median age 54 years; 67% men) and Dutch-validation (n = 239; median age 56 years; 64% men) cohorts of DCM patients (enrolled 2009-2016) with clinical, genetic, cardiovascular magnetic resonance, and proteomic assessments. Machine learning with profile regression identified novel disease subtypes. Penalized multinomial logistic regression was used for validation. Nested Cox models compared novel groupings to conventional risk measures. Primary composite outcome was cardiovascular death, heart failure, or arrhythmia events (median follow-up 4 years). RESULTS: In total, 3 novel DCM subtypes were identified: profibrotic metabolic, mild nonfibrotic, and biventricular impairment. Prognosis differed between subtypes in both the derivation (P < 0.0001) and validation cohorts. The novel profibrotic metabolic subtype had more diabetes, universal myocardial fibrosis, preserved right ventricular function, and elevated creatinine. For clinical application, 5 variables were sufficient for classification (left and right ventricular end-systolic volumes, left atrial volume, myocardial fibrosis, and creatinine). Adding the novel DCM subtype improved the C-statistic from 0.60 to 0.76. Interleukin-4 receptor-alpha was identified as a novel prognostic biomarker in derivation (HR: 3.6; 95% CI: 1.9-6.5; P = 0.00002) and validation cohorts (HR: 1.94; 95% CI: 1.3-2.8; P = 0.00005). CONCLUSIONS: Three reproducible, mechanistically distinct DCM subtypes were identified using widely available clinical and biological data, adding prognostic value to traditional risk models. They may improve patient selection for novel interventions, thereby enabling precision medicine. ispartof: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY vol:79 issue:22 pages:2219-2232 ispartof: location:United States status: published

Background Guidelines recommend intramuscular injection of 500 μg adrenaline (epinephrine) for anaphylaxis in teenagers and adults; however, most autoinjectors deliver a maximum 300 μg dose. We evaluated plasma adrenaline levels and cardiovascular parameters (including cardiac output) following self-injection with 300 μg or 500 μg adrenaline in teenagers at risk of anaphylaxis. Methods Subjects were recruited to a randomized, single-blind two period crossover trial. Participants received all 3 injections (Emerade® 500 μg, Emerade® 300 μg, Epipen® 0.3 mg) on 2 separate visits (allocated in a randomized block design), at least 28 days apart. Intramuscular injection was confirmed by ultrasound, and heart rate/stroke volume assessed using continuous monitoring. The trial was registered at Clinicaltrials.gov (NCT03366298). Results Twelve participants (58% male, median 15.4 years) participated; all completed the study. 500 μg injection resulted in a higher and more prolonged peak concentration (p = 0.01) and greater Area-Under-Curve for plasma adrenaline (p 40 kg in the community. The contrasting effects on stroke volume between Epipen® and Emerade®, despite similar peak plasma adrenaline levels, are unexpected. There is an urgent need to better understand differences in pharmacodynamics following adrenaline administration by autoinjector. In the meantime, we recommend adrenaline injection by needle/syringe in the healthcare setting in individuals with anaphylaxis refractory to initial treatment.

Poster session 3, September 23, 2022, 12:30 PM - 1:30 PM Background The advent of COVID-19 has meant that patients with chronic diseases needed to shield, however, investigations were needed to guide continual management of their disease. Remote monitoring options were evaluated to ensure the standard of care is not compromised. Purpose and Hypothesis The aim was to validate remote (return-posted) capillary triazole blood testing and evaluate the potential role of remote TDM in chronic antifungal therapy. Materials and Methods A single-center prospective cross-sectional study of remote finger prick capillary blood testing compared with gold standard venesection was performed. Remote finger prick capillary blood testing was validated compared to local standard venesection using comparative statistical analysis Comparative statistical analysis: Paired t-test, correlation and Bland-Altman were used to determine if there was agreement or association between the sampling methods. Results A total of 66 patients receiving triazole therapy were recruited and 57 pooled pairs of remote capillary and venous triazole concentrations and metabolites were prospectively analyzed, with the rest of the blood samples not being analyzed due to insufficient sample, hemolysis, or undetectable triazole level of Conclusions Remote capillary triazole sampling does not appear interchangeable with venous sampling, but being strongly correlated and on average 2/3rd of the venous value, could be a predictor of venous triazole level, or be useful for intra-patient longitudinal monitoring. When incorporated into an outpatient clinical pathway it can improve shared decision-making and patient experience. Further research is required to determine appropriate target reference ranges if the new lower capillary levels can be used routinely, especially in the climate of COVID-19 where social distancing measures limit patient access to hospitals and clinics for routine investigations.

Objectives To investigate the population pharmacokinetics of posaconazole gastroresistant tablets in children with cystic fibrosis (CF) and perform simulations to recommend optimal doses. Patients and methods Children from a paediatric CF centre who had received posaconazole tablets and underwent therapeutic drug monitoring were identified from pharmacy records. Relevant clinical data were collated from case notes and electronic patient records and used to develop an allometrically scaled population pharmacokinetic model. A stepwise covariate model-building exercise evaluated the influence of interacting medicines and liver function. Results One hundred posaconazole serum concentrations were collected from 37 children with a median age of 14 years (range 7–17). Posaconazole pharmacokinetics were adequately described by a one-compartment model with inter-individual variability on clearance. Dose simulations demonstrated a 77%–83% probability of attaining a trough target of 1 mg/L with a dose of 300 mg every 12 h for two doses then 300 mg once daily (OD) in children aged 6–11 years; and 86%–88% with a dose of 400 mg every 12 h for two doses then 400 mg OD in adolescents aged 12–17 years. This dose scheme also yielded a 90% probability of achieving an AUC of 30 mg·h/L. AUC and trough concentration were highly correlated (r2 = 0.98). Simulations showed that trough concentrations of >0.75 mg/L would exceed an AUC of 30 mg·h/L in 90% of patients. Conclusions A starting dose of 300 mg OD in those aged 6–11 years and 400 mg OD in those aged 12–17 years (following loading doses) yields a 90% probability of attaining an AUC of 30 mg·h/L.

Background and objective The course of systemic sclerosis-associated interstitial lung disease (SSc-ILD) is highly variable, and accurate prognostic markers are needed. KL-6 is a mucin-like glycoprotein (MUC1) expressed by type II pneumocytes, while CYFRA 21-1 is expressed by alveolar and bronchiolar epithelial cells. Both are released into the blood from cell injury. Methods Serum KL-6 and CYFRA 21-1 levels were measured in a retrospective (n = 189) and a prospective (n = 118) cohort of SSc patients. Genotyping of MUC1 rs4072037 was performed. Linear mixed-effect models were used to evaluate the relationship with change in lung function parameters over time, while association with survival was evaluated with Cox proportional hazard analysis. Results In both cohorts, KL-6 and CYFRA 21-1 were highest in patients with lung involvement, and in patients with extensive rather than limited ILD. KL-6 was higher in patients carrying the MUC1 rs4072037 G allele in both cohorts. In patients with SSc-ILD, serum KL-6, but not CYFRA 21-1, was significantly associated with DLCO decline in both cohorts (P = 0.001 and P = 0.004, respectively), and with FVC decline in the retrospective cohort (P = 0.005), but not the prospective cohort. When combining the cohorts and subgrouping by severity (median CPI = 45.97), KL-6 remained predictive of decline in DLCO in both milder (P = 0.007) and more severe disease (P = 0.02) on multivariable analysis correcting for age, gender, ethnicity, smoking history and MUC1 allele carriage. Conclusion Our results suggest serum KL-6 predicts decline in lung function in SSc, suggesting its clinical utility in risk stratification for progressive SSc-ILD.

Background: The burden of resistant fungal infection is rising in patients with pulmonary disease. Options for antifungal therapy are limited, and the only orally-available antifungals, the triazoles, demonstrate inter and intra-patient variability, non-linear kinetics, toxicity, drug interactions and increasing antifungal resistance. Therapeutic drug monitoring (TDM) of itraconazole, voriconazole and posaconazole has been necessary to ensure their safety and efficacy, but is considered unnecessary for the newest triazole isavuconazole, use of which is increasing. Aims: To characterise isavuconazole susceptibility of Aspergillus fumigatus isolates in a tertiary respiratory referral centre to understand prevalence of isavuconazole antimicrobial resistance. To retrospectively review experience of isavuconazole use in this setting, assessing tolerability and therapeutic drug monitoring. Methods: A retrospective observational analysis of adult patients with respiratory disease in a tertiary hospital setting between Sept 2016 and Aug 2021. Clinical cultures were collected and triazole Minimum inhibitory concentration (MIC) were recorded (based on Clinical & Laboratory Standards Institute (CLSI method)). Isavuconazole trough drug levels were carried out as part of the standard of care. Clinical outcomes of treatment were evaluated, along with drug tolerance and TDM. Results: During the study period, isavuconazole susceptibility testing was performed on 26 Aspergillus spp isolates. 80.8% of Aspergillus fumigatus isolates were non-wild type and had isavuconazole MIC > 1mg/L, and 73.0% had MIC above the EUCAST (European Committee on Antimicrobial Susceptibility Testing) epidemiological cut-off (ECOFF) of 2mg/L. There was good correlation between isavuconazole MIC and voriconazole MIC (r =0.7, p=0.0002). 54 patients had isavuconazole therapy over the study period with a median duration of 7.7 months (IQR 0.79 - 16.42). 67% of patients were able to tolerate isavuconazole, despite toxicity with prior azole treatment being the primary indication for use (in 61.8%). Increased age (r=0.29; p=0.03 (95%CI 0.02,0.52)) and gender (r for female sex=-0.31; p=0.027 (95%CI -0.52,0.036) were associated risk factors for development of adverse events (AEs). 127 Isavuconazole TDM levels were performed over the study period with 90% >1mg/L and 72% >2mg/L. Dose change from manufacturer’s dose recommendation, however, was required in 15% of patients to achieve a serum drug concentration above the EUCAST ECOFF or Area of technical uncertainty (ATU) value of 2mg/L. Conclusion: In our study, we show use of Isavuconazole as salvage therapy in chronic pulmonary fungal disease setting with high prevalence of azole resistance. Isavuconazole MICs demonstrated good correlation with voriconazole MICs suggesting the latter could be a useful surrogate marker for isavuconazole susceptibility. Although Isavuconazole achieved excellent serum drug concentrations at standard dose compared to other azole drugs, we highlight the importance of antifungal stewardship and TDM monitoring to optimise therapy in this setting.

BackgroundIn a tertiary respiratory centre, large cohorts of patients are managed in an outpatient setting and require blood tests to monitor disease activity and organ toxicity. This requires either visits to tertiary centres for phlebotomy and physician review or utilisation of primary care services.ObjectivesThis study aims to validate remote capillary blood testing in an outpatient setting and analyse impact on clinical pathways.MethodsA single-centre prospective cross-sectional validation and parallel observational study was performed. Remote finger prick capillary blood testing was validated compared to local standard venesection using comparative statistical analysis: paired t-test, correlation and Bland-Altman. Capillary was considered interchangeable with venous samples if all 3 criteria were met: non-significant paired t-test (i.e. p>0.05), Pearson’s correlation coefficient (r) >0.8 and 95% of tests within 10% difference through Bland-Altman (Limits of agreement). In parallel, current clinical pathways including phlebotomy practice was analysed over 4 weeks to review test predictability. A subsequent pilot cohort study analysed potential impact of remote capillary blood sampling on shared decision making and outpatient clinical pathways.Results117 paired capillary and venous blood samples were prospectively analysed. Interchangeability with venous blood was seen with HbA1c (%), total protein and CRP. Further tests, although not interchangeable, are likely useful to enable longitudinal remote monitoring (e.g. liver function, total IgE, and vitamin D). 65% of outpatient clinic blood tests were predictable with 16% of patients requiring further contact due to actions required. Pilot implementation of remote capillary sampling showed patient and clinician-reported improvement in shared decision-making given contemporaneous blood test results.ConclusionsRemote capillary blood sampling can be used accurately for specific tests to monitor chronic disease, and when incorporated into an outpatient clinical pathway can improve shared decision making and patient experience. Further research is required to determine health-economic impact and applicability within telemedicine-based outpatient care.

Alpha-1 antitrypsin deficiency (AATD) is a cause of bronchiectasis. Guidelines for bronchiectasis from the British Thoracic Society do not recommend to routinely test patients for AATD. In contrast, guidelines for AATD recommend routine screening. This contradiction, in part, results from the lack of data from large studies performing comprehensive screening. We screened 1600 patients with bronchiectasis at two centres in the UK from 2012 to 2016. In total, only eight individuals with AATD were identified representing 0.5% of the overall population. We conclude that routine screening for AATD in bronchiectasis in the UK has a low rate of detection. Further studies are required in different geographical regions, which may have a higher prevalence of AATD. info:eu-repo/semantics/publishedVersion

Background In a tertiary respiratory centre, large cohorts of patients are managed in the outpatient setting and require monitoring of inflammatory or disease activity markers and organ toxicity from medications. This either requires utilisation of primary care services for phlebotomy and subsequent physician review of results or frequent visits to tertiary centres. Although remote monitoring, such as telemedicine and wearable technology (e.g. remote spirometry), is being increasingly utilised in the outpatient setting, there is little data analysing the possibility of remote blood test monitoring. Purpose To identify the potential healthcare utilisation of remote capillary blood testing in a tertiary level chronic lung disease cohort. Methods A retrospective analysis of blood testing in outpatient cystic fibrosis clinics, assessing frequency, indication and delayed impact upon clinical plans. This was followed by a prospective single centre validation study of finger prick capillary blood testing using a novel capillary blood collection system compared to local standard venesection. Results were analysed using paired T test and Bland-Altman statistical analysis. Results 18 outpatient clinics with 181 patients were retrospectively analysed. 63 patients underwent blood testing, of which 41 (65%) patients’ blood tests were predictable prior to the clinic visit. 16% of patients who underwent blood tests were consequently contacted after the clinic due to actions required from results. A number of tests (including CPR, IgE, ALT and HbA1c) showed no significant differences (paired T test p≤0.05) between the capillary sample and control (standard venesection), and good method comparison through Bland Altman analysis, suggesting accuracy of remote finger prick monitoring. (see Figure 1) Other tests, including FBC and renal function, showed significant statistical differences between the capillary and venous samples. Following validation it was evident that 23 patients (56%) who underwent venesection for predictable reasons could have provided accurate blood samples by exclusively using remote finger prick monitoring rather than standard venesection. Conclusions Remote capillary blood testing could potentially be utilised in over half of patients requiring blood monitoring in the outpatient setting to either prevent a hospital visit or be provided in advance of clinic visits to provide contemporaneous clinical data to aid shared management planning.

AS: A 74-year-old male was transferred to the Royal Brompton hospital from a local hospital with respiratory failure and expectoration of bronchial casts (see figure 1A). The patient recalls recurrent chest infections with occasional haemoptysis in his teens with no prior history of asthma, TB or pertussis. Despite investigation and antibiotic treatment, his symptoms of intermittent, chronic recurrent bronchial cast expectoration continued. A fibreoptic bronchoscopy on the patient, aged 41, revealed erythematous bronchial mucosa in the right middle lobe, with a ventilation/perfusion scan revealing concomitant decreased ventilation. Bronchial washings were unremarkable, and given concern of a pathology originating from the right middle lobe, a right middle lobectomy was performed. Histology showed non-specific inflammatory fibrosis around the lobar bronchus. Figure 1 (A) Representative image of an expectorated bronchial cast by the patient. (B and C) CT image demonstrating marked diffuse bronchial wall thickening with mild bilateral patchy ground glass opacities with extensive consolidation in the right upper lobe. Minimal interlobular septal thickening in the lower lobes is also noted. (D) Image following centrifugation of a liquefied bronchial cast expectorated by the patient revealing a turbid fatty layer confirming its chylous nature. (E) Images of lymphangioscintogram (anterior thorax with and without right shoulder and costal margin markers) showing abnormal tracer activity in the right lung (indicated by red arrow) confirming chylous leak. Tracer activity is also seen in the abdominal lymphatic channels and in the liver (indicated by red star) due to systemic circulation of radiotracer on delayed images. His symptoms, however, did not resolve. Microbiological examination of his casts revealed no growth, and histological examination showed fibrin and mucus with some lymphocytes. Further trials of corticosteroids, nebulised N-acetylcysteine, hypertonic saline, prophylactic azithromycin, systemic antifungals and oral cyclophosphamide were unsuccessful. Extensive immunological and allergic tests were normal. His symptoms remained stable till age …

Interstitial lung disease (ILD) is the main cause of death in systemic sclerosis (SSc). The progression of SSc associated ILD (SSc-ILD) is highly variable. Markers predictive of progressive ILD are needed early in the disease course, to appropriately target patients at risk of developing progressive pulmonary fibrosis. CYFRA 21–1 (CYFRA) is a tumour marker expressed by type I/type II pneumocytes and respiratory bronchiolar epithelial cells, released into the blood following cell lysis. Serum levels of CYFRA were measured in both a retrospective (n=180) and a prospective (n=118) cohort of SSc patients. Retrospective cohort mean age: 49.1 (range 47.08–51.05), 77.25% female, prospective cohort age: 56.4 (54.10–58.73), 76.23% female. Median FVC% predicted and DLCO% predicted: retrospective cohort: 80.1% (IQR:67.2–95.5) and 55.5% (44.3–68.35), respectively – prospective cohort: 73.8% (57.2–87) and 39.9% (29.2–48.8), respectively. ILD was defined as the presence of fibrosis on chest imaging (chest x-ray or HRCT) and/or a forced vital capacity (FVC)

Interstitial lung disease (ILD) is the main cause of death in systemic sclerosis (SSc). The progression of SSc associated ILD (SSc-ILD) is highly variable, and markers predictive of progressive ILD are needed early in the disease course, to aim treatment towards patients likely to develop irreversible fibrosis. KL-6 is a mucin-like glycoprotein expressed on type II pneumocytes, prominently expressed/solubilised when epithelial cell injury occurs. Serum levels of KL-6 were measured in both a retrospective (n=180) and a prospective (n=118) cohort of SSc patients. Genotyping of rs4072037 in MUC1 was carried out using a TaqMan assay. Statistical analysis was performed using STATA12. In both cohorts, KL-6 was lowest in patients without ILD (median:374 (IQR:226-666) U/ml), and highest in patients with extensive (1371 (446-1245) U/ml), rather than limited ILD (729 (872-2816) U/ml, p= 0.0001), according to our staging system based on CT extent, integrated as necessary by FVC. Serum KL-6 was higher in patients carrying the C allele of rs4072037 in both cohorts (981 (U/ml vs 491U/ml p=0.0001 and 932 (568-1310) U/ml vs 1419 (905-2254) U/ml p=0.0015). In the retrospective cohort, on both univariate and multivariate analyses (adjusting for severity, allele carriage, gender, age, ethnicity, and smoking), serum KL-6 was an independent marker of survival and time to decline in FVC ≥5%, FVC ≥10%, and DLCO ≥15%. The association with decline in DLCO15% was replicated in the prospective cohort. Our results suggest that serum KL-6 may be an effective biomarker for predicting decline in lung function, and mortality, in SSc-ILD. This suggests that epithelial cell damage plays an important role in pathogenesis.

Background In patients with acquired heart failure, hypoalbuminaemia is associated with increased risk of death. The prevalence of hypoproteinaemia and hypoalbuminaemia and their relation to outcome in adult patients with congenital heart disease (ACHD) remains, however, unknown. Methods Data on patients with ACHD who underwent blood testing in our centre within the last 14 years were collected. The relation between laboratory, clinical or demographic parameters at baseline and mortality was assessed using Cox proportional hazards regression analysis. Results A total of 2886 patients with ACHD were included. Mean age was 33.3 years (23.6–44.7) and 50.1% patients were men. Median plasma albumin concentration was 41.0 g/L (38.0–44.0), whereas hypoalbuminaemia (

Introduction: Patients with PCD typically suffer from rhinosinusitis. Despite the negative impact of nasal symptoms on quality of life there has been no nasal cavity inflammation research in this cohort. We aimed to identify whether PCD patients have increased levels of inflammatory cytokines in the nasal cavity compared to patients with cystic fibrosis (CF) and controls. Methods: Nasal mucosal lining fluid was collected (n= 50 PCD, 7 CF, 22 control) using nasosorption (NS) and analysed for inflammatory cytokines. Nasal swabs were performed for bacterial culture (n= 43 PCD). To assess ex vivo inflammatory response to controlled bacterial challenge, nasal brushings (n= 10 PCD, 10 CF, 18 control) were infected for 1 hour with Haemophilus influenzae, Pseudomonas aeruginosa or Staphylococcus aureus, the supernatant analysed for IL-8 at 1 and 24 hours post infection and compared with uninfected controls. Results: PCD patients had significantly higher NS levels of IL- 1β, IL-2, IL-6, IL-10, TNFα and IFNγ than patients with CF and significantly higher levels of IL-6, IL-8, IL- 1β and TNFα than controls. 50% of PCD patients had a positive bacterial culture. This was associated with significantly higher levels of IL-6, IL- 1β and TNFα, compared to patients with no growth who had similar levels to controls. Ex vivo PCD nasal cells produced higher baseline levels of IL-8 compared to control and CF cells but had a blunted response to infection at 24 hours. Conclusions: PCD patients have elevated levels of inflammatory cytokines in the nasal cavity, which are associated with bacterial infection. Further investigation is needed to determine the cause of a blunted IL-8 response ex vivo.

BackgroundAortic stenosis is the most common age-related valvular pathology. Patients with aortic stenosis and myocardial fibrosis have worse outcome but the underlying mechanism is unclear. Lipoprotein(a) is associated with adverse cardiovascular risk and is elevated in patients with aortic stenosis. Although mechanistic pathways could link Lipoprotein(a) with myocardial fibrosis, whether the two are related has not been previously explored. In this study, we investigated whether elevated Lipoprotein(a) was associated with the presence of myocardial replacement fibrosis.MethodsA total of 110 patients with mild, moderate and severe aortic stenosis were assessed by late gadolinium enhancement (LGE) cardiovascular magnetic resonance to identify fibrosis. Mann Whitney U tests were used to assess for evidence of an association between Lp(a) and the presence or absence of myocardial fibrosis and aortic stenosis severity and compared to controls. Univariable and multivariable linear regression analysis were undertaken to identify possible predictors of Lp(a).ResultsThirty-six patients (32.7%) had no LGE enhancement, 38 (34.6%) had midwall enhancement suggestive of midwall fibrosis and 36 (32.7%) patients had subendocardial myocardial fibrosis, typical of infarction. The aortic stenosis patients had higher Lp(a) values than controls, however, there was no significant difference between the Lp(a) level in mild, moderate or severe aortic stenosis. No association was observed between midwall or infarction pattern fibrosis and Lipoprotein(a), in the mild/moderate stenosis (p = 0.91) or severe stenosis patients (p = 0.42).ConclusionThere is no evidence to suggest that higher Lipoprotein(a) leads to increased myocardial midwall or infarction pattern fibrosis in patients with aortic stenosis.

Apelin is a novel endogenous peptide with inotropic and vasodilatory properties that is the ligand for the APJ receptor. Apelin and APJ are widely distributed in the vasculature of a number of organs and peripheral venous apelin is reduced in heart failure (HF). The location of apelin production in humans with and without HF was investigated.Plasma apelin and brain natriuretic peptide (BNP) concentrations in coronary sinus (CS), aorta (Ao), and renal vein (RV) of individuals with HF (n = 9) were compared to subjects with normal structural hearts (n = 8). In HF the concentration of CS apelin was reduced compared with controls (310 pg/mL [interquartile range 290-390] vs. 470 pg/mL [340-570], P.035) but Ao apelin (330 pg/mL [275-375] vs. 340 pg/mL [230-455], P = .76) and RV apelin (290 pg/mL [280-360] vs. 370 pg/mL [273-410], P = .56) were unchanged. Plasma BNP was increased at all sampling sites in patients with HF as compared with controls. A step down from CS to Ao to RV in all subjects was observed. The step down in apelin from CS to Ao (470 pg/mL [310-595] vs. 320 pg/mL [225-482], P.04) in control subjects was not apparent in patients with HF.These novel data show that apelin is produced in the human heart and that production is reduced in individuals with HF. In contrast to BNP, apelin production is not exclusive to the heart.

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.

Lung clearance index (LCI) is a more sensitive measure of lung function than spirometry in cystic fibrosis (CF) and correlates well with abnormalities in high-resolution computed tomography (HRCT) scanning. We hypothesized LCI would be equally sensitive to lung disease in primary ciliary dyskinesia (PCD).To test the relationships between LCI, spirometry, and HRCT in PCD and to compare them to the established relationships in CF.Cross-sectional study of 127 patients with CF and 33 patients with PCD, all of whom had spirometry and LCI, of which a subset of 21 of each had HRCT performed. HRCT was scored for individual features and these features compared with physiological parameters.Unlike in CF, and contrary to our hypothesis, there was no correlation between spirometry and LCI in PCD and no correlation between HRCT features and LCI or spirometry in PCD.We show for the first time that HRCT, spirometry, and LCI have different relationships in different airway diseases and that LCI does not appear to be a sensitive test of airway disease in advanced PCD. We hypothesize that this results from dissimilarities between the components of large and small airway disease in CF and PCD. These differences may in part lead to the different prognosis in these two neutrophilic airway diseases.

BACKGROUND: Clinical trials in cystic fibrosis (CF) have been hindered by the paucity of well characterised and clinically relevant outcome measures. AIM: To evaluate a range of conventional and novel biomarkers of CF lung disease in a multicentre setting as a contributing study in selecting outcome assays for a clinical trial of CFTR gene therapy. METHODS: A multicentre observational study of adult and paediatric patients with CF (>10 years) treated for a physician-defined exacerbation of CF pulmonary symptoms. Measurements were performed at commencement and immediately after a course of intravenous antibiotics. Disease activity was assessed using 46 assays across five key domains: symptoms, lung physiology, structural changes on CT, pulmonary and systemic inflammatory markers. RESULTS: Statistically significant improvements were seen in forced expiratory volume in 1 s (p

Introduction Elevated NT-pro BNP is associated with worse outcome in patients with cardiomyopathy. Hypothesis We hypothesized that a mild elevation in NT-pro BNP may be associated with a worse outcome in patients with Aortic Stenosis (AS). Methods Between 2011 and 2015, consecutive consenting patients with moderate (1.0–1.5 cm 2 ) or severe ( 2 ) AS considered for aortic valve intervention (either for severe AS or moderate AS with coronary disease) who had a cardiovascular magnetic resonance (CMR) scan undertaken for anatomy and function and also had blood stored for biomarker analysis were included. NT-pro BNP was measured using one-step immunoassay sandwich method with a final fluorescent detection (ELFA). Survival was obtained from hospital notes, electronic records and the National Strategic Office. Results 112 patients (76 ± 10 years, 78 male) were included. The group was dichotomised according to NT-pro BNP value, into normal NT-pro BNP value group (values from 0–300 pg/ml, 23 patients) and high group (>300 pg/ml, 89 patients). End point was all cause mortality. At a median of 12 months follow-up, 21 patients had died, all from the high NT-pro BNP group. The high NT-pro BNP group had significantly worse prognosis hazard ratio=3.6 (95% CI=1.24–10.44, p = 0.00184). Although the NT-pro BNP correlated with LVEF its association with outcome was independent of this. Conclusions In a prospective mixed cohort of patients with AS undergoing investigations for consideration of aortic valve intervention, even a mild elevation in NT-pro BNP is associated with worse short term outcome. This can be taken into consideration regarding timing of intervention especially in the asymptomatic population.

Inflammatory markers in sputum and serum have been used with variable success as outcome measures in interventional studies. Limited data are available on reproducibility of such assays in cystic fibrosis (CF) particularly over a long time period. This study was designed to address this; stable patients (FEV1>40, >10 years age) were recruited into the study which ran over an 18-month period with up to four hospital visits. Patients provided a 24 h sputum collection, for weighing at each visit. Spontaneous sputum was collected at the beginning of each visit; if insufficient sample was obtained, sputum was induced with hypertonic saline. Inflammatory markers were measured in dithiothreitol-processed sputum (total and differential cell counts, IL8 (and other cytokines), calprotectin, neutrophil elastase, myeloperoxidase and extracellular DNA). Blood was collected at each visit for cytokines (IL1β, IL6, IL8, IL10, IL12 (p40) and TNFα) and calprotectin. Data are available from 189 patients at 655 visits. Adequate sputum for analysis was obtained at only 60% of visits. Sputum induction accounted for only 16% of adequate samples. Median and range for each detectable assay are shown below. Serum cytokines IL1β, IL10, IL12 (p40) and TNFα were undetectable at each visit, and IL6 was only detectable in 17% of samples. To assess intra-individual variability the coefficient of variation of results across each visit for each patient is presented. Both sputum and serum assays showed a large range of results at each visit, but the variation for each individual was much higher than the ideal 10%. Serum assays were not able to discriminate between CF and non-CF, apart from calprotectin (CF 10.1(0.8–72.5) vs non-CF 0.40 (0.2–1.12) p

Vitamin D (vD) levels have been reported to correlate with (a) lung function in healthy populations and (b) disease severity in pulmonary TB, COPD and asthma. The proposed mechanism, supported by in vitro studies, relates to vD response elements in the promoter regions of genes encoding molecules involved in innate immunity such as defensins and cathelicidin (LL-37). As patients with CF are at risk of fat and fat-soluble vitamin malabsorption, we sought to explore this relationship in a cohort of CF children. Frozen serum and bronchoalveolar (BAL) fluid samples, which had been donated for research at the time of a clinically-indicated bronchoscopy were available from 49 children with CF. Mean age at the time of the procedure was 6.8 years (range 0.03–15.99). 44 (90%) were biochemically pancreatic insufficient and were prescribed pancreatic enzyme supplementation and fat-soluble mulitvitamins. Serum 25OH vD3 was measured using HPLC and mass spectrometry. BALF human beta defensin-2 (hbD2) and LL-37 were quantified using ELISA. vD deficiency was defined as

Objectives:We studied whether an increase in adenosine dose overcomes caffeine antagonism on adenosine-mediated coronary vasodilation.Background:Caffeine is a competitive antagonist at the adenosine receptors, but it is unclear whether caffeine in coffee alters the actions of exogenous adenosine, and whether the antagonism can be surmounted by increasing the adenosine dose.Methods:Myocardial perfusion scintigraphy (MPS) was used to assess adenosine-induced hyperemia in 30 patients before (baseline) and after coffee ingestion (caffeine). At baseline, patients received 140 µg/kg/min of adenosine combined with low-level exercise. For the caffeine study, 12 patients received 140 µg/kg/min of adenosine (standard) and 18 patients received 210 µg/kg/min (high dose) after caffeine intake (200 mg). Myocardial perfusion was assessed semiquantitatively and quantitatively, and perfusion defect was characterized according to the presence of reversibility.Results:Caffeine reduced the magnitude of perfusion abnormality induced by standard adenosine as measured by the summed difference score (SDS) (12.0 ± 4.4 at baseline vs. 4.1 ± 2.1 after caffeine, p < 0.001) as well as defect size (18% [3% to 38%] vs. 8% [0% to 22%], p < 0.01), whereas it had no effect on the abnormalities caused by high-dose adenosine (SDS, 7.7 ± 4.0 at baseline vs. 7.8 ± 4.2 after caffeine, p = 0.7). There was good agreement between baseline and caffeine studies for segmental defect category (kappa = 0.72, 95% confidence interval: 0.65 to 0.79) in the high-dose group. An increase in adenosine after caffeine intake was well tolerated.Conclusions:Caffeine in coffee attenuates adenosine-induced coronary hyperemia and, consequently, the detection of perfusion abnormality by adenosine MPS. This can be overcome by increasing the adenosine dose without compromising test tolerability.

Background Quantification of interstitial (diffuse) myocardial fibrosis by T1 mapping may prove useful in a range of conditions. Both native T1 maps and extracellular volume fraction (ECV) are being increasingly used clinically and have been shown to be sensitive to a wide range of conditions and associate with worse prognosis. However, quality control by T1 phantoms is essential [1,2] and their long-term stability has not been demonstrated. Phantoms with long term stability could assure the stability of methods applied to patients against scanner alternations and across multiple centers. We sought to investigate the long-term stability of phantoms prepared to model T1 and T2 of blood and myocardium over a period of 52 weeks.

Background Quantification of interstitial fibrosis by T1-mapping continues to gather momentum clinically with the recognition that extracellular volume fraction (ECV) measurements are pathologically elevated in a range of conditions. Well-known dependence of ECV estimation on imaging parameters requires quality-control by T1 phantoms[1-3]. These typically comprise agarose with NiCl[2] doping,[4] and are often used short-term, but with limited long-term data[5]. Such phantoms might assure long-term stability (over years) of methods applied in patients eg against scanner alterations. We therefore sought to assess their long-term T1 and T2 stability.