Coinfection with Pseudomonas aeruginosa and Aspergillus fumigatus in cystic fibrosis.

OBJECTIVES: Cystic fibrosis (CF) lung disease is characterised by mucus stasis, chronic infection and inflammation, causing progressive structural lung disease and eventual respiratory failure. CF airways are inhabited by an ecologically diverse polymicrobial environment with vast potential for interspecies interactions, which may be a contributing factor to disease progression. Pseudomonas aeruginosa and Aspergillus fumigatus are the most common bacterial and fungal species present in CF airways respectively and coinfection results in a worse disease phenotype. METHODS: In this review we examine existing expert knowledge of chronic co-infection with P. aeruginosa and A. fumigatus in CF patients. We summarise the mechanisms of interaction and evaluate the clinical and inflammatory impacts of this co-infection. RESULTS: P. aeruginosa inhibits A. fumigatus through multiple mechanisms: phenazine secretion, iron competition, quorum sensing and through diffusible small molecules. A. fumigatus reciprocates inhibition through gliotoxin release and phenotypic adaptations enabling evasion of P. aeruginosa inhibition. Volatile organic compounds secreted by P. aeruginosa stimulate A. fumigatus growth, while A. fumigatus stimulates P. aeruginosa production of cytotoxic elastase. CONCLUSION: A complex bi-directional relationship exists between P. aeruginosa and A. fumigatus, exhibiting both mutually antagonistic and cooperative facets. Cross-sectional data indicate a worsened disease state in coinfected patients; however, robust longitudinal studies are required to derive causality and to determine whether interspecies interaction contributes to disease progression.

How to perform and interpret the sweat test.

Cystic fibrosis (CF) is the most common life-threatening autosomal-recessive disease affecting Caucasians in the western world. The sweat test is the main diagnostic test for CF. It is indicated as part of the clinical assessment for infants that have picked up on the national neonatal screening programme. It may also be requested where clinical suspicion of a diagnosis of CF exists despite normal screening results. This article outlines the physiological basis behind sweat testing and the technical aspects of performing the test. Indications for performing the test are also considered. The article aims to provide clinicians with a guide to interpretation of results.

Assessment of stability and fluctuations of cultured lower airway bacterial communities in people with cystic fibrosis.

BACKGROUND: Routine clinical culture detects a subset of the cystic fibrosis (CF) airways microbiota based on culture-independent (molecular) methods. This study aimed to determine how extended sputum culture of viable bacteria changes over time in relation to clinical status and predicts exacerbations. METHODS: Sputa from patients at a baseline stable and up to three subsequent time-points were analysed by extended-quantitative culture; aerobe/anaerobe densities, ecological indexes and community structure were assessed together with clinical outcomes. RESULTS: Eighty patients were prospectively recruited. Sputa were successfully collected and cultured at 199/267 (74.5%) study visits. Eighty-two sputa from 25 patients comprised a complete sample-set for longitudinal analyses. Bacterial density, ecological indexes and clinical outcomes were unchanged in 18 patients with three sequential stable visits. Conversely, in 7 patients who had an exacerbation, total bacterial and aerobe densities differed over four study visits (P < .001) with this difference particularly apparent between the baseline visit and completion of acute antibiotic treatment where a decrease in density was observed. Bacterial communities were more similar within than between patients but stable patients had the least variation in community structure over time. Using logistic regression in a further analysis, baseline features in 37 patients without compared to 15 patients with a subsequent exacerbation showed that clinical measures rather than bacterial density or ecological indexes were independent predictors of an exacerbation. CONCLUSIONS: Greater fluctuation in the viable bacterial community during treatment of an exacerbation than between stable visits was observed. Extended-quantitative culture did not provide prognostic information of a future exacerbation.

Determination of distribution factors for heavy n-alkanes (nC12-nC98) in high temperature gas chromatography.

The ultimate purpose of this research work is to get an insight into the incomplete elution of heavy n-alkanes which along with thermal cracking, is one of the two main factors questioning the reliability of High Temperature Gas Chromatography (HTGC) analysis of heavy oils. For this purpose, knowledge of how the Distribution Factors vary with temperature is an essential requirement in the GC modelling. This study provides an extension of the data set of distribution factors for n-alkanes up to nC98H198 in a HT5 GC column over the temperature range 10 °C-430 °C, and introduces a method to determine the distribution coefficient of heavy n-alkanes by using two complimentary HTGC modes: i.) High-Efficiency mode, for efficient resolution with a long column operated at low flow rate with n-alkanes elution rate up to nC64, and ii.) true SimDist mode, with a short column operated at high flow rate for inefficient resolution with n-alkanes elution rate up to nC100. Furthermore, this study demonstrates the use of the in-house obtained distribution factors as the main input in the in-house GC model for the prediction of the retention times. Its validation has been carried out using distribution factors obtained at both constant flow rate and constant inlet pressure operating conditions, with an average relative error in the GC modelling at the same operating conditions of 4.4% for the former and 1.5% for the latter. This new extension of the data set of heavy n-alkanes distribution factors provides the basis for studying the partitioning and incomplete elution of heavy n-alkanes in HTGC analysis. Also, these new distribution factors can be used as input in GC modelling, to determine the optimum analytical conditions to improve the separation process and thus the HTGC practices.

Oral Vitamin B12 Supplementation After Roux-en-Y Gastric Bypass: a Systematic Review.

BACKGROUND: Many respectable guidelines recommend lifelong vitamin B12 injections for Roux-en-Y gastric bypass (RYGB) patients in the absence of lack of consensus on the efficacy of oral route of prophylaxis and the appropriate doses needed for this purpose. The purpose of this review was to examine the published English language scientific literature in accordance with PRISMA principles to find out if orally given vitamin B12 is adequate for prophylactic purposes in RYGB patients and the appropriate dosages needed for this purpose if it is. METHODS: We examined the PubMed database for all English language articles examining various doses of oral vitamin B12 supplementation after proximal RYGB in adult patients. The search revealed 19 such articles. RESULTS: The data suggest that oral vitamin B12 supplementation doses of ≤ 15 µg daily are insufficient to prevent deficiency in RYGB patients. Higher supplementation doses show better results and it appears that a dose of 600.0 µg vitamin B12 daily is superior to 350.0 µg daily suggesting an incremental dose-response curve. It further appears that supplementation doses of 1000.0 µg vitamin B12 daily lead to an increase in B12 levels and are sufficient for the prevention of its deficiency in most RYGB patients. CONCLUSION: The review finds that oral supplementation doses of ≤ 15 µg vitamin B12 daily are inadequate for prophylaxis of vitamin B12 deficiency in adult RYGB patients but doses of 1000 µg vitamin B12 daily might be adequate. Future studies need to examine this and even higher oral doses for vitamin B12 supplementation for patients undergoing RYGB.

Lung function and disease severity in cystic fibrosis patients heterozygous for p.Arg117His.

Expression of p.Arg117His cystic fibrosis (CF) transmembrane conductance regulator is influenced by a polythymidine (poly-T) tract and a thymidine-guanine (TG) repeat on intron 9, which vary in length and affect exon 10 skipping. We compared clinical characteristics and the rate of progression of lung disease of CF patients carrying the p.Arg117His mutation with different intron 9 varying sequences (poly-T) and mutation classes in trans. Data were collected from patients in Northern Ireland, UK, including diagnostic features, sweat chloride, nutritional status, sputum microbiology, CF-related complications and lung function. Poly-T and TG repeats were determined by PCR. Forced expiratory volume in 1 s (FEV1) decline was determined from linear regression of FEV1 measurements of patients over time. We identified 62 patients with p.Arg117His, 55 with a class I/II mutation in trans and six with p.Arg117His/p.Gly551Asp. 42 patients had 5T and 13 had 7T. All patients had 12 TG repeats. Patients with p.Arg117His-5T had greater lung function decline, sweat chloride concentrations, pancreatic insufficiency and prevalence of Pseudomonas aeruginosa infection compared with patients with p.Arg117His-7T. Lung function decline and disease severity in p.Arg117His is determined by the poly-T tract length and identity of the mutation in trans. Patients with p.Arg117His-5T and a second class I/II mutation have a severity similar to p.Phe508del homozygous patients, although lung function decline is delayed to an older age. There may be linkage disequilibrium between p.Arg117His and 12 TG repeats.

A web-based clinical decision tool to support treatment decision-making in psychiatry: a pilot focus group study with clinicians, patients and carers.

BACKGROUND: Treatment decision tools have been developed in many fields of medicine, including psychiatry, however benefits for patients have not been sustained once the support is withdrawn. We have developed a web-based computerised clinical decision support tool (CDST), which can provide patients and clinicians with continuous, up-to-date, personalised information about the efficacy and tolerability of competing interventions. To test the feasibility and acceptability of the CDST we conducted a focus group study, aimed to explore the views of clinicians, patients and carers. METHODS: The CDST was developed in Oxford. To tailor treatments at an individual level, the CDST combines the best available evidence from the scientific literature with patient preferences and values, and with patient medical profile to generate personalised clinical recommendations. We conducted three focus groups comprising of three different participant types: consultant psychiatrists, participants with a mental health diagnosis and/or experience of caring for someone with a mental health diagnosis, and primary care practitioners and nurses. Each 1-h focus group started with a short visual demonstration of the CDST. To standardise the discussion during the focus groups, we used the same topic guide that covered themes relating to the acceptability and usability of the CDST. Focus groups were recorded and any identifying participant details were anonymised. Data were analysed thematically and managed using the Framework method and the constant comparative method. RESULTS: The focus groups took place in Oxford between October 2016 and January 2017. Overall 31 participants attended (12 consultants, 11 primary care practitioners and 8 patients or carers). The main themes that emerged related to CDST applications in clinical practice, communication, conflicting priorities, record keeping and data management. CDST was considered a useful clinical decision support, with recognised value in promoting clinician-patient collaboration and contributing to the development of personalised medicine. One major benefit of the CDST was perceived to be the open discussion about the possible side-effects of medications. Participants from all the three groups, however, universally commented that the terminology and language presented on the CDST were too medicalised, potentially leading to ethical issues around consent to treatment. CONCLUSIONS: The CDST can improve communication pathways between patients, carers and clinicians, identifying care priorities and providing an up-to-date platform for implementing evidence-based practice, with regard to prescribing practices.

Lung Clearance Index in Adults and Children With Cystic Fibrosis.

BACKGROUND: Lung clearance index (LCI) has good clinimetric properties and an acceptable feasibility profile as a surrogate end point in cystic fibrosis (CF). Although most studies to date have been in children, increasing numbers of adults with CF also have normal spirometric findings. Further study of LCI as an end point in adults with CF is required. Therefore, the purpose of this study was to determine the clinimetric properties of LCI across the age range of people with CF. METHODS: Clinically stable adults and children with CF and age-matched healthy control subjects were recruited. RESULTS: LCI and spirometry data for 110 subjects with CF and 61 control subjects were collected at a stable visit. The CF Questionnaire-Revised (CFQ-R) was completed by 80 of 110 subjects with CF. Fifty-six subjects with CF completed a second stable visit. The LCI coefficient of variation percent was 4.1% in adults and 6.3% in children with CF. The coefficient of repeatability of LCI was 1.2 in adults and 1.3 in children. In both adults and children, LCI (area under the receiving operator characteristic curve [AUCROC] = 0.93 and 0.84, respectively) had greater combined sensitivity and specificity to discriminate between people with CF and control subjects when compared with FEV1 (AUCROC = 0.88 and 0.60, respectively) and forced expiratory flow at 25% to 75% of the curve (AUCROC = 0.87 and 0.68, respectively). LCI correlated significantly with the CFQ-R treatment burden in adults (r = -0.37; P < .01) and children (r = -0.50; P < .01). Washout tests were successful in 90% of subjects with CF and were perceived as comfortable and easy to perform in both adults and children. CONCLUSIONS: These data support the use of LCI as a surrogate outcome measure in CF clinical trials in adults as well as in children.

Using [(11)C]Ro15 4513 PET to characterise GABA-benzodiazepine receptors in opiate addiction: Similarities and differences with alcoholism.

The importance of the GABA-benzodiazepine receptor complex and its subtypes are increasingly recognised in addiction. Using the α1/α5 benzodiazepine receptor PET radioligand [(11)C]Ro15 4513, we previously showed reduced binding in the nucleus accumbens and hippocampus in abstinent alcohol dependence. We proposed that reduced [(11)C]Ro15 4513 binding in the nucleus accumbens was a marker of addiction whilst the reduction in hippocampus and positive relationship with memory was a consequence of chronic alcohol abuse. To examine this further we assessed [(11)C]Ro15 4513 binding in another addiction, opiate dependence, and used spectral analysis to estimate contributions of α1 and α5 subtypes to [(11)C]Ro15 4513 binding in opiate and previously acquired alcohol-dependent groups. Opiate substitute maintained opiate-dependent men (n=12) underwent an [(11)C]Ro15 4513 PET scan and compared with matched healthy controls (n=13). We found a significant reduction in [(11)C]Ro15 4513 binding in the nucleus accumbens in the opiate-dependent compared with the healthy control group. There was no relationship between [(11)C]Ro15 4513 binding in the hippocampus with memory. We found that reduced [(11)C]Ro15 4513 binding was associated with reduced α5 but not α1 subtypes in the opiate-dependent group. This was also seen in an alcohol-dependent group where an association between memory performance and [(11)C]Ro15 4513 binding was primarily driven by α5 and not α1 subtype. We suggest that reduced α5 levels in the nucleus accumbens are associated with addiction since we have now shown this in dependence to two pharmacologically different substances, alcohol and opiates.

Adherence to treatment in children and adolescents with cystic fibrosis: a cross-sectional, multi-method study investigating the influence of beliefs about treatment and parental depressive symptoms.

BACKGROUND: Adherence to treatment is often reported to be low in children with cystic fibrosis. Adherence in cystic fibrosis is an important research area and more research is needed to better understand family barriers to adherence in order for clinicians to provide appropriate intervention. The aim of this study was to evaluate adherence to enzyme supplements, vitamins and chest physiotherapy in children with cystic fibrosis and to determine if any modifiable risk factors are associated with adherence. METHODS: A sample of 100 children (≤18 years) with cystic fibrosis (44 male; median [range] 10.1 [0.2-18.6] years) and their parents were recruited to the study from the Northern Ireland Paediatric Cystic Fibrosis Centre. Adherence to enzyme supplements, vitamins and chest physiotherapy was assessed using a multi-method approach including; Medication Adherence Report Scale, pharmacy prescription refill data and general practitioner prescription issue data. Beliefs about treatments were assessed using refined versions of the Beliefs about Medicines Questionnaire-specific. Parental depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale. RESULTS: Using the multi-method approach 72% of children were classified as low-adherers to enzyme supplements, 59% low-adherers to vitamins and 49% low-adherers to chest physiotherapy. Variations in adherence were observed between measurement methods, treatments and respondents. Parental necessity beliefs and child age were significant independent predictors of child adherence to enzyme supplements and chest physiotherapy, but parental depressive symptoms were not found to be predictive of adherence. CONCLUSIONS: Child age and parental beliefs about treatments should be taken into account by clinicians when addressing adherence at routine clinic appointments. Low adherence is more likely to occur in older children, whereas, better adherence to cystic fibrosis therapies is more likely in children whose parents strongly believe the treatments are necessary. The necessity of treatments should be reinforced regularly to both parents and children.

Reduced bacterial colony count of anaerobic bacteria is associated with a worsening in lung clearance index and inflammation in cystic fibrosis.

Anaerobic bacteria have been identified in abundance in the airways of cystic fibrosis (CF) subjects. The impact their presence and abundance has on lung function and inflammation is unclear. The aim of this study was to investigate the relationship between the colony count of aerobic and anaerobic bacteria, lung clearance index (LCI), spirometry and C-Reactive Protein (CRP) in patients with CF. Sputum and blood were collected from CF patients at a single cross-sectional visit when clinically stable. Community composition and bacterial colony counts were analysed using extended aerobic and anaerobic culture. Patients completed spirometry and a multiple breath washout (MBW) test to obtain LCI. An inverse correlation between colony count of aerobic bacteria (n = 41, r = -0.35; p = 0.02), anaerobic bacteria (n = 41, r = -0.44, p = 0.004) and LCI was observed. There was an inverse correlation between colony count of anaerobic bacteria and CRP (n = 25, r = -0.44, p = 0.03) only. The results of this study demonstrate that a lower colony count of aerobic and anaerobic bacteria correlated with a worse LCI. A lower colony count of anaerobic bacteria also correlated with higher CRP levels. These results indicate that lower abundance of aerobic and anaerobic bacteria may reflect microbiota disruption and disease progression in the CF lung.

A NATO guide for assessing deployability for military personnel with chronic medical conditions: medical fitness for expeditionary missions, Task Group 174, Human Factors, and Medicine Panel.

BACKGROUND: Each time a deployed military member has an exacerbation of a pre-existing chronic disease there is a potential risk to mission success, individual health, and the safety of the unit. Currently, North Atlantic Treaty Organization (NATO) member nations employ different approaches to assessing an individual's medical fitness for deployment. OBJECTIVE: To set the minimum medical standards for NATO deployments. METHODS: A seven nation task group met periodically from 2008 to 2012 to develop guidelines for frontline military physicians to assess medical fitness for deployment. RESULTS: A medical deployment guide for 31 specific diseases/conditions using a rational, standardized and algorithmic approach based on a red-yellow-green risk stratification. CONCLUSIONS: If adopted as a NATO policy, this guide could then be kept up-to-date through a process that allows nations to track individuals with known chronic disease who were deployed into a theater of operations, allowing the guide to become increasingly evidence-based, and also more accurate in quantifying the risk of exacerbation based on individual and disease characteristics, as well as the nature and length of the deployment.

Adrenal incidentalomas: management in British district general hospitals.

INTRODUCTION: Adrenal incidentalomas have become a common clinical dilemma with the increasing use and resolution of cross sectional imaging modalities. OBJECTIVES: This retrospective observational study examined the management of adrenal incidentalomas in district general hospitals in Northumbria and adherence to current guidelines. MATERIALS AND METHODS: We searched 4028 abdominal CT scans performed in Northumbria between 1 January and 31 December 2010. All patients with an incidental adrenal lesion were identified and their clinical records reviewed. RESULTS: 75 patients with adrenal incidentalomas were identified. Of these, only 13 (17%) were referred for specialist review with a further two patients undergoing additional evaluation by the primary medical team; 80% received no biochemical investigation or follow-up. Comorbidity may have affected the decision in a proportion, but 36 of 62 patients (58%) had no comorbidities precluding additional evaluation. In contrast, all patients reviewed by an endocrine specialist were appropriately investigated and managed, the majority conservatively, with three requiring adrenalectomy for phaeochromocytoma or cortisol secreting adenomas. In the patients with an incidentaloma, comorbidities which may be attributable to autonomous adrenal cortisol or aldosterone release were higher than regional averages, suggesting possible undiagnosed functional tumours. CONCLUSIONS: The management of adrenal incidentalomas in British district general hospitals in Northumbria shows poor adherence to guidelines. Adherence was significantly better in those patients managed by an endocrine specialist. We suggest a pathway for the management and referral process.

Investigating expectation and reward in human opioid addiction with [(11) C]raclopride PET.

The rewarding properties of some abused drugs are thought to reside in their ability to increase striatal dopamine levels. Similar increases have been shown in response to expectation of a positive drug effect. The actions of opioid drugs on striatal dopamine release are less well characterized. We examined whether heroin and the expectation of heroin reward increases striatal dopamine levels in human opioid addiction. Ten opioid-dependent participants maintained on either methadone or buprenorphine underwent [(11) C]raclopride positron emission tomography imaging. Opioid-dependent participants were scanned three times, receiving reward from 50-mg intravenous heroin (diamorphine; pharmaceutical heroin) during the first scan to generate expectation of the same reward at the second scan, during which they only received 0.1-mg intravenous heroin. There was no heroin injection during the third scan. Intravenous 50-mg heroin during the first scan induced pronounced effects leading to high levels of expectation at the second scan. There was no detectable increase in striatal dopamine levels to either heroin reward or expectation of reward. We believe this is the first human study to examine whether expectation of heroin reward increases striatal dopamine levels in opioid addiction. The absence of detectable increased dopamine levels to both the expectation and delivery of a heroin-related reward may have been due to the impact of substitute medication. It does however contrast with the changes seen in abstinent stimulant users, suggesting that striatal dopamine release alone may not play such a pivotal role in opioid-maintained individuals.

A 5-year review of atrial fibrillation in military aircrew.

INTRODUCTION: Atrial fibrillation (AF) is a common cause of disqualification from flying in both civilian and military aircrew. We reviewed 5 yr of atrial fibrillation management in the Royal Air Force (RAF) from both a clinical and occupational perspective. METHODS: Patients were identified from the RAF Medical Boards (RAFMB) electronic database using search terms "atrial," "fibrillation," and "arrhythmia." Management was compared to current RAF and national clinical guidelines and current civilian and military aviation medicine policy. RESULTS: Over the 5-yr period assessed, 23 aircrew were identified with AF. Paroxysmal AF (PAF) was the most common diagnosis. Five aircrew remained fit to fly with no limitations, 12 fit to fly with restrictions, and 6 were graded permanently unfit for flying, with one of these being medically discharged. DISCUSSION: The incidence and demographics of aircrew identified with AF in this paper is comparable to previous studies. All aircrew in our study were treated in accordance with current RAF/national guidelines. Emerging treatments such as radiofrequency ablation and the new anticoagulants remain to be assessed for suitability in a military context. CONCLUSION: Management of AF in RAF aircrew requires a holistic approach, with an awareness of the arrhythmogenic aviation environment in which RAF aircrew operate. Most RAF aircrew with AF will retain a restricted flying status, but this should be considered on a case-by-case basis.

Cycle ergometer tests in children with cystic fibrosis: reliability and feasibility.

The aim of this study was to assess the reliability and feasibility of cycle ergometer tests in young children with cystic fibrosis (CF). Children with CF aged 6-11 years and with stable lung disease performed two cycle ergometry tests (intermittent sprint and continuous incremental) on two occasions 1 week apart. Reliability was assessed using repeated-measures ANOVA. Bias was considered to be significant at P < 0.05 level and a coefficient of variation (CV) below 10% was considered acceptable. Feasibility and acceptability data were also collected. Sixteen children with CF completed the study: (9M:7F), 8.7(1.8) years, FEV(1) %predicted: 88.1(17.4). Power measurements recorded during the intermittent sprint test demonstrated significant bias over days (P < 0.05) and CVs were between 10% and 15%. Peak work capacity recorded during the continuous incremental test was reliable (bias P < 0.05, CV < 10%), as was heart rate and SpO(2) recorded during both tests (bias P < 0.05, CV < 10%). No problems were experienced in administering the tests and all children completed both tests on two separate occasions. There was a mixed response to questions on acceptability of tests. This is the first study to provide information on the reliability of performance measures recorded during an intermittent sprint protocol (peak power) and a continuous incremental cycle ergometry (peak work capacity) in children with CF.

A [11C]Ro15 4513 PET study suggests that alcohol dependence in man is associated with reduced α5 benzodiazepine receptors in limbic regions.

Preclinical evidence suggests the α5 subtype of the GABA-benzodiazepine receptor is involved in some of the actions of alcohol and in memory. The positron emission tomography (PET) tracer, [(11)C]Ro15 4513 shows relative selectivity in labelling the α5 subtype over the other GABA-benzodiazepine receptor subtypes in limbic regions of the brain. We used this tracer to investigate the distribution of α5 subtype availability in human alcohol dependence and its relationship to clinical variables. Abstinent (>6 weeks) alcohol-dependent men and healthy male controls underwent an [(11)C]Ro15 4513 PET scan. We report [(11)C]Ro15 4513 brain uptake for 8 alcohol-dependent men and 11 healthy controls. We found a significant reduction in [(11)C]Ro15 4513 binding in the nucleus accumbens, parahippocampal gyri, right hippocampus and amygdala in the alcohol-dependent compared with the healthy control group. Levels of [(11)C]Ro15 4513 binding in both hippocampi were significantly and positively associated with performance on a delayed verbal memory task in the alcohol-dependent but not the control group. We speculate that the reduced limbic [(11)C]Ro15 4513 binding seen here results from the effects of alcohol, though we cannot currently distinguish whether they are compensatory in nature or evidence of brain toxicity.