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PDF file - 46K, Pyrosequencing-based DNA methylation detection in the tissue validation set

PDF file - 46K, Statistical Power Simulation for the estimating the bronchial washing study size

PDF file - 53K, Nucleotide sequences of methylation specific primers and probes for the qMSP assays utilised in the BW screening. The ACTB assay is methylation independent

PDF file - 30K, mSHOX2 positivity in LLP panel subgroups (236 common samples between two studies).

PDF file - 33K, Comparative detection efficiency of mSHOX2 and LLP methylation panel alone or in combination in the overlapping set of 236 samples

PDF file - 38K, Coefficient and classification performance of top 6 univarite and best subset logit models in the training dataset

PDF file - 57K, Nucleotide sequences of PCR and sequencing primers for Pyrosequencing Methylation Analysis of the promoter targets which qualified for the subsequent BW screening

PDF file - 37K, Comparison of internal classification and prediction accuracies and cross-validation consistency of Best multi-marker MDR models identified using the training dataset

An understanding of physical activity (PA) and related health benefits remains limited in adults with Cystic Fibrosis (CF). Raw acceleration data metrics may improve the quality of assessment and further this understanding. The study aimed to compare PA between people with CF (pwCF) and non-CF peers and examine associations between PA, vascular function and health outcome measures. PA was assessed in 62 participants (31 pwCF) using ActiGraph accelerometers. Vascular function (a marker of cardiovascular disease risk) was assessed using flow-mediated dilatation (FMD) in sub-groups of pwCF (n = 12) and matched controls. Average Euclidean norm minus one (ENMO) (total PA) was significantly lower ( more...

BACKGROUND: The objective of this study was to explore the clinical and microbiological outcomes associated with substituting inhaled aztreonam lysine for an intravenous antibiotic in the treatment of acute pulmonary exacerbations of CF.\ud \ud METHODS: An open-label randomised crossover pilot trial was conducted at a UK CF centre among 16 adults with CF and P. aeruginosa infection. Median [IQR] age was 29.5 [24.5-32.5], mean ± SD forced expiratory volume in 1 second (FEV1) was 52.4 ± 14.7 % predicted. Over the course of two exacerbations, participants were randomised to sequentially receive 14 days of inhaled aztreonam lysine plus IV colistimethate (AZLI+IV), or dual IV antibiotics (IV+IV). Primary outcome was absolute change in % predicted FEV1. Other outcomes evaluated changes in quality of life, bacterial load and the lung microbiota.\ud \ud RESULTS: The difference between mean change in lung function at day 14 between AZLI+IV and IV+IV was +4.6% (95% CI 2.1-7.2, p=0.002). The minimum clinically important difference of the Cystic Fibrosis Revised Questionnaire (CFQ-R) was achieved more frequently with AZLI+IV (10/12, 83.3%) than IV+IV (7/16, 43.8%), p=0.05. No differences were observed for modulation of serum white cell count, C-reactive protein or sputum bacterial load. Microbiome compositional changes were observed with IV+IV (Bray-Curtis r2=0.14, p=0.02), but not AZLI+IV (r2=0.03, p=0.64).\ud \ud CONCLUSION: In adults with CF and P. aeruginosa infection experiencing an acute pulmonary exacerbation, AZLI+IV improved lung function and quality of life compared to the current standard treatment. These findings support the need for larger definitive trials of inhaled antibiotics in the acute setting.\ud \ud CLINICAL TRIAL REGISTRATION: EudraCT 2016-002832-34 ClinicalTrials.org NCT02894684. more...

Cystic fibrosis-related diabetes (CFRD) is a common complication of cystic fibrosis and can be present in over 50% of adults with the disease. CFRD is associated with poorer clinical outcomes, including accelerated pulmonary function decline and excess morbidity. The management of CFRD is complex and differs from that of type 1 and type 2 diabetes mellitus such that clinicians responsible for the care of people with CFRD must work closely with colleagues across a number of different specialities and disciplines. This review aims to discuss why a multi-disciplinary approach is important and how it can be harnessed to optimize the care of people with CFRD. more...

Summary Background The advent of the COVID-19 pandemic in 2020 required an alteration in the routine care of people with CF (pwCF), deemed to be extremely vulnerable. Aim We wished to report the alterations in clinical practice, including the introduction of remote video-assisted clinics, made to manage the adult pwCF attending our large centre. Methods We studied clinical records over a period of 2 years (March 2019 to February 2021) by comparing 19th March to 20th February (Y1) with 20th March to 21st February (Y2). Results We have shown out of hospital Multi Disciplinary Team (MDT) support increased and a greater proportion of IV therapy was administered at home. The VAC model of care increased clinical activity while reducing clinic non-attendance rates, suggesting more individuals engage with their carers. Conclusions This new model of care has allowed greater engagement with pwCF. more...

Neurological complications are well described in SARS-CoV-2, but for the first time we report a case of unilateral diaphragm paralysis occurring early in mechanical ventilation for respiratory failure due to such an infection. The patient subsequently required tracheostomy and ventilator support for 37 days, and had increased breathlessness and an elevated diaphragm at clinic review 9 months later. Dynamic chest radiography demonstrated persistent diaphragm paralysis with an accompanying postural change in lung volumes, and he subsequently underwent surgical plication. This case demonstrates that although persistent dyspnoea is a common feature following SARS-CoV-2 infection and is usually due to deconditioning or persistent parenchymal involvement, it can be due to other causes and needs to be investigated appropriately. more...

The Liverpool epidemic strain (LES) is an important transmissible clonal lineage ofPseudomonas aeruginosathat chronically infects the lungs of people with cystic fibrosis (CF). Previous studies have focused on the genomics of the LES in a limited number of isolates, mostly from one CF centre in the UK, and from studies highlighting identification of the LES in Canada. Here we significantly extend the current LES genome database by genome sequencing 91 isolates from multiple CF centres across the UK, and we describe the comparative genomics of this large collection of LES isolates from the UK and Canada. Phylogenetic analysis revealed that the 145 LES genomes analysed formed a distinct clonal lineage when compared with the widerP. aeruginosapopulation. Notably, the isolates formed two clades: one associated with isolates from Canada, and the other associated with UK isolates. Further analysis of the UK LES isolates revealed clustering by clinic geography. Where isolates clustered closely together, the association was often supported by clinical data linking isolates or patients. When compared with the earliest known isolate, LESB58 (from 1988), many UK LES isolates shared common loss-of-function mutations, such as in genesgltRandfleR. Other loss-of-function mutations identified in previous studies as common adaptations during CF chronic lung infections were also identified in multiple LES isolates. Analysis of the LES accessory genome (including genomic islands and prophages) revealed variations in the carriage of large genomic regions, with some evidence for shared genomic island/prophage complement according to clinic location. Our study reveals divergence and adaptation during the spread of the LES, within the UK and between continents. more...

Although non-tuberculous mycobacteria can be found in the airways of people with cystic fibrosis (pwCF), their role as pathogens may be uncertain, and treatment is problematic. We report the first case of Mycobacterium simiae (M. simiae), often associated with asymptomatic disease or colonisation, which caused pulmonary infection requiring treatment in a pwCF. This report shows that M. simiae, rare in pwCF in the United Kingdom, can cause significant illness and highlights the diagnostic difficulty in individuals with positive smear mycobacteria that can be mistaken initially for pulmonary tuberculosis (TB). more...

Introduction: Lung volume reduction (LVR) using endobronchial valves (EBV) can improve lung function in patients with emphysema, but detailed assessment can be difficult soon after EBV. Dynamic chest radiography (DCR) is a novel, real time X-ray imaging system (Konica Minolta, Inc.) with a low radiation dose compared to CT. It is performed rapidly in a standard radiology room with minimal training. Aims and Objectives: We used DCR to assess changes in lung capacity and diaphragm motion after EBV. Methods: A 76 year old woman (heterogeneous emphysema, complete fissures, previous left lower lobe EBV) (BMI 16kg/m2; FEV1 45, FVC 64, RV 270, TLCO 38 [% predicted]) was referred for right lower lobe EBV. DCR was performed immediately prior to and 48 hours post EBV: sequential PA and lateral images were recorded at 15fps over 13s during tidal and forced breathing. Lung field area per frame was recorded to calculate TLC. Diaphragm motion was tracked by software. Results: 8 EBVs were placed in the right lower lobe: volume loss was seen on CXR and DCR. Results are shown in Table 1. TLC pre-EBV calculated by DCR (7.55L) correlated with PFT TLC (7.42L). Conclusions: DCR demonstrated improvement in TLC, diaphragm motion, speed, and tidal breathing pattern 48 hours post EBV. DCR is a useful imaging modality to study diaphragm kinetics in lung volume reduction alongside PFTs and CT. more...

Objectives Although gastric emptying rate (GER) influences incretin response and nutrient absorption, both defective in people with cystic fibrosis (CF), there are few studies in this group, and the circadian rhythm is unknown. We employed an ultrasonographic technique to assess GER in people with CF following liquid and mixed meals and also evaluated the circadian rhythm, compared to normal controls. Methods Thirteen pancreatic-insufficient adults with CF and 10 healthy controls underwent a fasting oral glucose tolerance test (OGTT; liquid meal) and on a second visit underwent a fasting mixed meal test (MMT) thrice on the same day. GER was measured during the OGTT and each MMT using a 3.5-MHz abdominal transducer probe at baseline and 30, 60, 90, and 120 minutes. Results Controls had normal GER for both OGTT and MMT. Compared to controls, people with CF had delayed GER60 for OGTT (mean 46%), which increased with time (P = .001), and also delayed GER90 for MMT in the morning (mean 56%), afternoon (58%), and evening (59%). The GER in the control group was better at all time points throughout the day compared to patients with CF. Conclusions This is the first study to use ultrasonography, an inexpensive bedside technique, to assess GER in adults with CF. For the first time, we have shown that adults with CF have delayed GER for both liquid and mixed meals, and this delay continues throughout the day. more...

Introduction Stenotrophomonas maltophilia is common in the sputum of people with cystic fibrosis related diabetes (CFRD), raising the question as to whether this is a risk factor for its acquisition. We investigated this at a population level. Methods We analysed national Cystic Fibrosis Registry data 2011–2015 for 8047 people with CF > age 6 years, looking at demographics, diagnosis of CFRD, lung function and sputum microbiology; using descriptive and multivariate strategies to establish independent predictors for S. maltophilia culture and associated outcomes. Results S. maltophilia was present in 1148 (14.1%). Although univariate analysis confirmed it was more prevalent in those with CFRD, when adjusted for other clinical parameters there was no longer a relationship. Markers of more severe lung disease were independent risk-factors for S. maltophilia . Conclusion Although S. maltophilia is more common in people with CFRD, it is not an independent risk-factor for S. maltophilia acquisition. more...

BackgroundFosfomycin, effective in Cystic Fibrosis (CF), competes with aminoglycosides at renal binding sites and may therefore afford a renoprotective effect when used in combination therapy. We explored this by using markers of acute renal tubular damage [N-acetyl-β-d-glucose-aminidase (NAG), alanine amino-peptidase (AAP) and β2-microglobulin].MethodsUsing a prospective randomized crossover trial design, at an acute pulmonary exacerbation, 18 adult CF patients received either 14 days of intravenous (IV) tobramycin or IV tobramycin and IV fosfomycin, both in combination with a second IV antibiotic (colomycin).ResultsUrinary NAG (P = 0.003) and AAP (P = 0.03) following treatment with concomitant fosfomycin were lower than those after treatment with tobramycin and colomycin alone. Fosfomycin attenuated the total 24-h urinary protein leak (P = 0.0001). The 14-day improvements in all surrogate markers of exacerbation resolution (FEV1% predicted, FVC, white cell count and C-reactive protein) were similar for both treatment regimens.ConclusionThe addition of fosfomycin reduces acute renal injury caused by IV aminoglycoside therapy in CF pulmonary exacerbations. more...

Introduction Continuous glucose monitoring (CGM) allows assessment of day to day glycaemic excursions and detects early glucose handling abnormalities that may not be apparent on oral glucose tolerance testing (OGTT). However, there is little published evidence as to whether these early dysglycaemic changes are amenable to treatment. We present outcomes following CGM guided insulin initiation at our centre. Methods Adults without a prior diagnosis of cystic fibrosis related diabetes (CFRD) whom underwent >72 h CGM at our adult CF centre were included in the study. Clinical outcomes including weight and pulmonary function changes over the next 12 months were compared between groups based on CGM results and subsequent management. Results CGM profiles for 59 patients were analysed. Insulin was commenced in 37 patients who had evidence of hyperglycaemia on CGM. Significant improvements in mean [95% confidence intervals] forced expiratory volume in 1 s (FEV1) (+4.3% predicted [1.06–7.48], p = 0.01) and weight (+1.2 kg [0.32–2.15], p = 0.01) were observed at 3 months in the insulin group. Annual rate of pulmonary function decline was also improved following insulin initiation. Conclusion Insulin treatment targeted towards glycaemic excursions seen on CGM is associated with improvements in lung function and weight with subsequent reduced pulmonary function decline. more...

Renal disease is a well-recognized manifestation of cystic fibrosis (CF) and people with CF are at increased risk of nephrolithiasis. Lithotripsy is the preferred treatment but has occasionally been associated with pulmonary complications. Here we report the case of a person with CF who developed a pneumothorax soon after lithotripsy and discuss the potential mechanism of injury. We hope this case highlights some of the additional considerations clinicians should take into account when managing patients with advanced pulmonary disease in CF. more...

Aim To investigate the incretin axis in people with cystic fibrosis. Methods Adults with cystic fibrosis-related diabetes, cystic fibrosis without diabetes, and controls (adults without cystic fibrosis and without diabetes) underwent an oral glucose tolerance test and then a closely matched isoglycaemic i.v. glucose infusion. On each occasion, glucose, insulin, C-peptide, total and active glucagon-like peptide-1 and gastric inhibitory polypeptide responses were recorded and incremental areas under curves were calculated for 60 and 240 min. Results Five adults with cystic fibrosis-related diabetes, six with cystic fibrosis without diabetes and six controls, matched for age and BMI, completed the study. Glucose during oral glucose tolerance test closely matched those during isoglycaemic i.v. glucose infusion. The calculated incretin effect was similar in the control group and the cystic fibrosis without diabetes group (28% and 29%, respectively), but was lost in the cystic fibrosis-related diabetes group (cystic fibrosis-related diabetes vs control group: -6% vs 28%; p=0.03). No hyposecretion of glucagon-like peptide-1 or gastric inhibitory polypeptide was observed; conversely, 60-min incremental area under the curve for total glucagon-like peptide-1 was significantly higher in the cystic fibrosis-related diabetes group than in the control group [1070.4 (254.7) vs 694.97 (308.1); p=0.03] CONCLUSIONS: The incretin effect was lost in cystic fibrosis-related diabetes despite adequate secretion of the incretin hormones. These data support the concept that reduced incretin hormone insulinotropic activity contributes significantly to postprandial hyperglycaemia in cystic fibrosis-related diabetes. more...

Introduction: Lung function tests are important but technically challenging diagnostic investigations. ATS/ERS guidelines exist to inform quality standards for testing procedures, there have been very few published studies of compliance. We wished to assess the performance of our large regional pulmonary function laboratory, which performs 24,365 such tests every year, against these standards. Methods: We audited the results of 293 consecutive patients (mean age [SD] 67 [11] years, 149 male) where spirometry and singe breath diffusion (SB) had been attempted. Thirteen were unable to perform SB due to a reduced VC. Results: Table 1. The within-manoeuvre criterion was achieved for spirometry in 248 (84.6%) and the between-manoeuvre in 253 (86.3%). For SB, 248 (88.6%) performed within the acceptability criterion, repeatability was met in 262 (93.6%). Conclusions: The compliance of our service to ATS/ERS criteria matches previously published studies. We suggest that such audits should be carried out routinely in pulmonary function laboratories to ensure that accurate results are provided to clinicians to assist the diagnostic process. Robust national/international quality assurance measures may further enhance the quality of diagnostic testing. more...

Rationale: Ivacaftor can greatly improve clinical outcomes in people with cystic fibrosis (CF) and has been shown to have in vitro antibacterial properties, yet the long-term microbiological outcom... more...

This report highlights the case of a patient with X-linked agammaglobulinaemia (XLA) and resultant bronchiectasis who was discharged from hospital after recovering from real-time reverse transcriptase-PCR positive COVID-19 infection having had a subsequent negative swab and resolution of symptoms, but was readmitted 3 weeks later with recrudescent symptoms and a further positive swab. Although there are reports of COVID-19 infection in XLA, for the first time we report a case of possible reinfection. Lessons learnt from this case include the potential for reinfection of COVID-19 in a patient with a weakened immune system and the importance of repeating COVID-19 swabs in inpatients. Extra caution needs to be taken when providing care in groups of patients who have a weakened or absent immune system. more...

NICE produced a guideline for the diagnosis and management of CF (NG78) in October 2017. This paper describes the process of producing the guideline and highlights some of the areas covered by it, including ideas for further research and tools that can be used by purchasers to help improve CF care. more...

Introduction: Glycaemic variability (GV), a measure of short-term fluctuations in blood glucose levels, has been associated with increased oxidative stress and subsequently implicated in the pathogenesis of microvascular disease. We investigated whether GV was associated with pulmonopathy in people with cystic fibrosis. Methods: Retrospective analysis of patients undergoing continuous glucose monitoring (CGM) at our regional adult CF centre was undertaken. To avoid a confounding treatment effect those with a previous diagnosis of CFRD were excluded. Contemporaneous baseline characteristics at time of CGM and annual pulmonary function change in the year preceding were recorded. Raw CGM data were then analysed using the EasyGV (Oxford, UK) software. Associations were tested for clinical characteristics and measures of GV (SD = standard deviation, CONGA=Continuous Overall Net Glycaemic Action, MAGE=Mean amplitude of Glycaemic Excursions). Results: CGMs for 56 patients were analysed (58% female, mean [SD] age 28 [9] years, % predicted FEV1 64.9 [22.0]). All measures of GV showed inverse correlations with baseline FEV1 (SD: r=-0.35, p=0.004, CONGA: r= -0.267, p=0.02, MAGE: -0.318, p=0.009). SD (r=-0.33, p=0.007) and CONGA (r=-2.6, p=0.02) were inversely correlated with baseline weight. Furthermore, CONGA was inversely associated with pulmonary function change in the preceding 12 months (r=-0.28, p=0.017). Conclusion: In the first study to assess GV and outcomes in CF we found that increased GV appears to be associated with more severe pulmonary function and also accelerated pulmonary decline in the preceding 12 months. Further evaluation of these indices is warranted. more...

Spirometry is safe as part of pre-operative work-up in patients with thoracic aortic aneurysmshttp://ow.ly/uwSe30lJ6Qn

Drug-induced Immune Haemolytic Anaemia (DIIHA) is a rare but serious complication of cephalosporin use. Ceftazidime is recognized to be a rare cause of DIIHA. We report and discuss a case of DIIHA in a person with cystic fibrosis who developed severe haemolytic anaemia following use of ceftazidime in the management of an acute pseudomonal pulmonary exacerbation. more...

Global spread of aggressive mycobacteria Many mycobacteria, in addition to those causing leprosy and tuberculosis, are capable of infecting humans. Some can be particularly dangerous in patients suffering from immunosuppression or chronic disease, such as cystic fibrosis (CF). Bryant et al. observed clusters of near-identical isolates of drug-resistant Mycobacterium abscessus in patients reporting to CF clinics. The similarity of the isolates suggests transmission between patients, rather than environmental acquisition. Although this bacterium is renowned for its environmental resilience, the mechanism for its long-distance transmission among the global CF patient community remains a puzzle. Science , this issue p. 751 more...

Rationale: Pseudomonas aeruginosa, the predominant cause of chronic airway infections of patients with cystic fibrosis, exhibits extensive phenotypic diversity among isolates within and between sputum samples, but little is known about the underlying genetic diversity. Objectives: To characterize the population genetic structure of transmissible P. aeruginosa Liverpool Epidemic Strain in chronic infections of nine patients with cystic fibrosis, and infer evolutionary processes associated with adaptation to the cystic fibrosis lung. Methods: We performed whole-genome sequencing of P. aeruginosa isolates and pooled populations and used comparative analyses of genome sequences including phylogenetic reconstructions and resolution of population structure from genome-wide allele frequencies. Measurements and Main Results: Genome sequences were obtained for 360 isolates from nine patients. Phylogenetic reconstruction of the ancestry of 40 individually sequenced isolates from one patient sputum sample revealed the coexistence of two genetically diverged, recombining lineages exchanging potentially adaptive mutations. Analysis of population samples for eight additional patients indicated coexisting lineages in six cases. Reconstruction of the ancestry of individually sequenced isolates from all patients indicated smaller genetic distances between than within patients in most cases. Conclusions: Our population-level analysis demonstrates that coexistence of distinct lineages of P. aeruginosa Liverpool Epidemic Strain within individuals is common. In several cases, coexisting lineages may have been present in the infecting inoculum or assembled through multiple transmissions. Divergent lineages can share mutations via homologous recombination, potentially aiding adaptation to the airway during chronic infection. The genetic diversity of this transmissible strain within infections, revealed by high-resolution genomics, has implications for patient segregation and therapeutic strategies. more...

Pseudomonas aeruginosa chronic infections of cystic fibrosis (CF) airways are a paradigm for within-host evolution with abundant evidence for rapid evolutionary adaptation and diversification. Recently emerged transmissible strains have spread globally, with the Liverpool Epidemic Strain (LES) the most common strain infecting the UK CF population. Previously we have shown that highly divergent lineages of LES can be found within a single infection, consistent with super-infection among a cross-sectional cohort of patients. However, despite its clinical importance, little is known about the impact of transmission on the genetic structure of these infections over time. To characterize this, we longitudinally sampled a meta-population of 15 genetic lineages within the LES over 13 months among seven chronically infected CF patients by genome sequencing. Comparative genome analyses of P. aeruginosa populations revealed that the presence of coexisting lineages contributed more to genetic diversity within an infection than diversification in situ. We observed rapid and substantial shifts in the relative abundance of lineages and replacement of dominant lineages, likely to represent super-infection by repeated transmissions. Lineage dynamics within patients led to rapid changes in the frequencies of mutations across suites of linked loci carried by each lineage. Many loci were associated with important infection phenotypes such as antibiotic resistance, mucoidy and quorum sensing, and were repeatedly mutated in different lineages. These findings suggest that transmission leads to rapid shifts in the genetic structure of CF infections, including in clinically important phenotypes such as antimicrobial resistance, and is likely to impede accurate diagnosis and treatment. more...

A 20-year-old woman with recurrent left-sided pneumothoraces underwent video-assisted thoracoscopic pleurectomy and wedge resection of a left apical bulla. Medical history included ABCA3 pulmonary surfactant dysfunction and subsequent interstitial lung disease with diffuse ground glass changes suggestive of a desquamative interstitial pneumonitis (DIP). She was a lifelong non-smoker. Spirometry revealed forced vital capacity 0.97 L, 32% predicted and carbon monoxide transfer factor (TLCO) 27% predicted. The operation was uneventful but there was a persistent postoperative air leak requiring prolonged pleural drainage but no other intervention. … more...

Introduction: Endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) is increasingly used both in the diagnosis and staging of lung cancer and in the diagnosis of unexplained mediastinal lymphadenopathy. It is minimally invasive, safe and complications are rare. Methods: We report three cases of pneumomediastinum without pneumothorax post EBUS-TBNA in patients with interstitial lung disease (one chronic pulmonary sarcoidosis, one non-specific interstitial pneumonia [NSIP] and one idiopathic pulmonary fibrosis and lung cancer) at our tertiary centre (450 EBUS-TBNA procedures each year). Results: Two were performed under local anaesthesia and sedation with midazolam and one under general anaesthesia. A 21G needle was used to sample 2, 3 and 5 lymph node stations in each respective case. Patients presented with chest pain and neck surgical emphysema 2, 3 and 9 hours post procedure. The diagnosis of pneumomediastinum was confirmed on CT scan and none had a pneumothorax or respiratory or haemodynamic compromise. All cases resolved with conservative management. Conclusion: To our knowledge, this is the first case series of pneumomediastinum in patients with pulmonary fibrosis following EBUS-TBNA. We believe the radial traction placed on the airways (splinting) by the fibrotic lung disease and the increased airway pressure may have allowed air in to the mediastinum through the needle puncture sites. Both physicians and patients should be aware of this complication and we suggest a smaller 22 G EBUS-TBNA needle be used in patients with pulmonary fibrosis. more...

Introduction - This paper is the second of four reviews exploring the relationships between oral health and general medical conditions, in order to support teams within Public Health England, health practitioners and policymakers.Aim - This review aimed to explore the most contemporary evidence on whether poor oral health and pulmonary disease occurs in the same individuals or populations, to outline the nature of the relationship between these two health outcomes, and discuss the implication of any findings for health services and future research.Methods - The work was undertaken by a group comprising consultant clinicians from medicine and dentistry, trainees, public health, and academics. The methodology involved a streamlined rapid review process and synthesis of the data.Results - The results identified a number of systematic reviews of medium to high quality which provide evidence that oral health and oral hygiene habits have an impact on incidence and outcomes of lung diseases, such as pneumonia and chronic obstructive pulmonary disease in people living in the community and in long-term care facilities. The findings are discussed in relation to the implications for service and future research.Conclusion - The cumulative evidence of this review suggests an association between oral and pulmonary disease, specifically COPD and pneumonia, and incidence of the latter can be reduced by oral hygiene measures such as chlorhexidine and povidone iodine in all patients, while toothbrushing reduces the incidence, duration, and mortality from pneumonia in community and hospital patients. more...

Cystic fibrosis is primarily considered a respiratory disease with superadded pancreatic dysfunction; however the underlying genetic mutation results in the abnormal function of cells throughout the body - including tissues involved in reproduction. Practically all males and up to 50% of females with CF will suffer fertility issues - the causes of which are multifactorial and could be improved by treatments that target the underlying physiological deficit, such as ivacaftor. We consider the mechanisms by which the rapidly developing field of systemic treatments for CF could impact on the fertility of this group and review the available real world evidence. more...

BACKGROUND: Although the evolution and adaptation of Pseudomonas aeruginosa (PA) populations during chronic lung infections of cystic fibrosis (CF) patients has been well studied, much less is known in non-CF bronchiectasis (BE). AIMS: Using isolates from 93 BE patients known to have chronic PA infection (enrolled in a trial of nebulised antibiotic therapy), we used whole genome sequencing to (i) assess the diversity of PA strains causing infections, (ii) assess the prevalence of multi-lineage (strain) infections, (iii) look for evidence for cross-infection or common source acquisition and (iv) characterise both adaptive mutations and within-population heterogeneity. METHODS: Using the Illumina platform, 189 isolates were genome sequenced, obtained from 93 patients attending 16 adult UK BE centres. Genomic data were used for typing by multilocus sequence type (MLST) and core genome SNP phylogeny, and to analyse genetic variations. RESULTS: The BE isolates were widely distributed within the global PA population structure. Of 23 patients from whose samples multiple isolates were examined, there were 6 examples of multi-lineage infections. SNP phylogeny revealed examples of more than one patient attending the same centre being infected with a common lineage. CONCLUSIONS: During infections of BE patients, PA populations adapt by accumulating loss of function mutations, leading to switches in phenotypes such as mode of iron acquisition and the production of biofilm-associated polysaccharides. As in CF, infecting PA populations exhibit considerable within-patient heterogeneity Supported by UK MRC as part of the BRONCH-UK network. more...

Cystic fibrosis related diabetes (CFRD) is a common co-morbidity of cystic fibrosis. It is associated with diminishing lung function, poorer nutritional state, and a worse prognosis and its early diagnosis and treatment is important. In addition, the adverse pulmonary effects of CFRD may be present for up to 10 years prior to diagnosis. Prevalence increases with age from 1 to 2% below 10 years of age, 20% of adolescents and 40-50% by adulthood, and up to 90% of adults with CF will have some degree of glucose intolerance by 40 years of age. Although its pathophysiology is not well understood, the primary cause is thought to be the fatty infiltration of the pancreas leading to fibrosis and destruction of the pancreatic cells resulting in beta cell destruction and progressive insulin deficiency. Oral glucose tolerance testing (OGTT) remains the method of choice for a diagnosis of type I, type II and gestational diabetes; it is less discriminating in CFRD where early glucose trends are important, and continuous glucose monitoring may prove a more useful diagnostic and management tool. Diabetic complications occur in CFRD and annual screening for these is necessary. As life expectancy rises, diabetic complications may become more prevalent. This chapter discusses the diagnosis and treatment of CFRD and touches on devel‐ opments in research which will enhance the future management of this increasingly common and important manifestation of the CF condition. more...