Clinical characteristics of Pseudomonas and Aspergillus co-infected cystic fibrosis patients: A UK registry study.

BACKGROUND: Pseudomonas aeruginosa (Pa) and Aspergillus species (Asp) are the most common bacterial and fungal organisms respectively in CF airways. Our aim was to examine impacts of Asp infection and Pa/Asp co-infection. METHODS: Patients on the UK CF Registry in 2016 were grouped into: absent (Pa-), intermittent (Pai) or chronic Pa (Pac), each with Asp positive (Asp+) or negative (Asp-). Primary outcome was best percentage predicted FEV1 (ppFEV1) that year. Secondary outcomes were intravenous (IV) antibiotic courses, growth (height, weight, BMI) and additional disease complications. Associations between outcomes and infection-status were assessed using regression models adjusting for significant confounders (age, sex, Phe508del homozygosity and CF-related diabetes (CFRD)). RESULTS: 9,270 patients were included (median age 19 [IQR 9-30] years, 54% male, 50% Phe508del/F508del). 4,142 patients (45%) isolated Pa, 1,460 (16%) Asp. Pa-/Asp+ subjects had an adjusted ppFEV1 that was 5.9% lower than Pa-/Asp- (p < 0.0001). In patients with Pai or Pac, there was no additional impact of Asp on ppFEV1. However, there was a higher probability that Pac/Asp+ patients had required IV antibiotics than Pac/Asp- group (OR 1.23 [1.03-1.48]). Low BMI, ABPA, CF-liver disease and CFRD were all more frequent with Asp alone than Pa-/Asp-, though not more common in Pac/Asp+ than Pac/Asp-. CONCLUSIONS: Co-infection with Pa and Asp was not associated with reduced lung function compared with Pa alone, but was associated with additional use of IV antibiotics. Asp infection itself is associated with several important indicators of disease severity. Longitudinal analyses should explore the impact of co-infection on disease progression.

Incidence and risk factors of cancer in individuals with cystic fibrosis in the UK; a case-control study.

To assess cancer incidence in the UK cystic fibrosis (CF) population and determine the associated risk factors, we undertook a nested case-control study of patients with CF, registered with the UK CF Registry. Each case with a first reported cancer between 1999 and 2017 was matched with up to 4 controls: by age (±2-years) and year of cancer diagnosis. Conditional logistic regressions were adjusted for sex, lung function (FEV1%), CF related diabetes (CFRD), F508del status, transplant status, DIOS, gastro-oesophageal reflux disease, meconium ileus, Pseudomonas aeruginosa infection, pancreatic insufficiency, proton pump inhibitor (PPI) use, IV antibiotic days and BMI. Results: From 12,886 registered patients, 146 (1.1%) cases of malignancy were identified with 14.3% of cases occurring post solid organ transplant. Site of primary cancer was available for 98 patients: 22% were gastro-intestinal in origin (77% lower, 23% upper GI), 13% skin, 13% breast and 11% lymphomas/leukaemia. In univariable analysis, transplantation increased the odds of reporting any cancer by 2.46 times (95%CI: 1.3-4.6). CFRD also increased the odds of reporting any cancer (OR 2.35; CI: 1.37-4.0) and PPI use (OR 2.0; CI 1.28-3.19). In the multivariable models significant associations with CFRD and transplant remained, while PA infection, PPI use and being overweight showed increased, but statistically insignificant risks. The incidence of GI cancer was strongly associated with CFRD (OR=4.04; 1.47-11.1). Conclusions: We observed a high incidence of lower GI cancers in our cohort which was significantly affected by the presence of CFRD. Screening for gastrointestinal cancers could benefit patients at higher risk.

Health State Utility Data in Cystic Fibrosis: A Systematic Review.

INTRODUCTION: Cystic fibrosis (CF) is a life-limiting, hereditable condition, with the highest prevalence in Europe. CF treatments have led to improvements in clinical symptoms, disease management and decelerated disease progression. However, little is known about the health state utility (HSU) associated with CF disease states, adverse events, and changes in disease severity. Although HSU data have contributed to existing health economic modelling studies, a lack of such data have been highlighted. This systematic review aims to provide a summary of HSU-related research in CF and highlight related research gaps. METHODS: Online searches were performed in six databases and studies in any of the following categories were included: (1) estimation of HSUs in CF; (2) mapping studies between patient-reported outcome measures (PROMs) and HSUs; (3) economic evaluations on the management of CF that report primary HSU data; and (4) any CF clinical trial that reported HSU as an outcome. RESULTS: A total of 17 studies were reviewed, of which 12 provided HSU values for specific CF populations. The remaining five articles provided HSU data that were broken down by CF relevant health states, including lung transplantations, pulmonary exacerbation (PEx) events and forced expiratory volume in 1 s (FEV1). CONCLUSION: Current HSU data in CF are limited and there is considerable scope for further research, both in providing HSU values for CF and in investigating methods for HSU elicitation/evaluation in CF populations.

Health economic modelling in Cystic Fibrosis: A systematic review.

INTRODUCTION: Cystic Fibrosis (CF) is a heritable chronic condition. Due to the genetic and progressive nature of CF, a number of interventions are available for the condition. In the United Kingdom (U.K.) average annual cost of CF treatment is between €49,000 to €76,000 (2012) per patient [1]. A review of health economic modelling studies is warranted to provide decision makers and researchers with an in depth understanding of modelling practices in CF and guidance for future research. METHODS: Online searches were performed in the 5 databases, studies were included if they were: a) Model based economic evaluation for management of Cystic Fibrosis. Articles were restricted to English language only, but no restriction was applied on publication year. RESULTS: Nine studies were reviewed, most were Markov cohort models. Models evaluated pharmaceutical interventions and drug adherence. Modelling structure was consistent across most articles and a range of sources were used to populate the models. Cost and utility data were based on different sources and elicitation methods respectively. The majority of models failed to incorporate significant health events which impact both cost and disease progression. CONCLUSION: In our review we observed a lack of, application of European Medicines Agency (EMA) guidelines for clinical trial endpoints, model structure justifications and lastly, health-related quality of life derived utility information around important clinical events. Future work around conceptual modelling of CF progression, utility valuation of significant health events and meeting EMA guidelines for trial reporting is encouraged.

Non-invasive ventilation and clinical outcomes in cystic fibrosis: Findings from the UK CF registry.

BACKGROUND: Non-invasive ventilation (NIV) for respiratory failure and airway clearance is an established intervention in cystic fibrosis (CF), but its therapeutic benefit on lung function and survival remains under-investigated. METHODS: Using data from the UK CF Registry between 2007 and 2015, we explored the patterns of NIV use, and assessed changes in mean percent predicted FEV1 (ppFEV1) prior to and after NIV use, and the survival of patients on NIV. RESULTS: Among 11,079 patients, 1107 had at least one record of NIV treatment. Incidence and prevalence of NIV was lower in children and followed non-linear temporal patterns. Adjusting for other risk factors, ppFEV1 rose by 0.70 (95%CI: -0.83, 2.24) after first NIV use in children. In adults with a low ppFEV1 (<40%) at initiation of treatment, NIV increased mean ppFEV1 by 2.60 (95% CI: 0.93, 4.27). Our analysis showed that NIV initiation is associated with an increased risk of death/transplant in both children (HR = 2.47; 95%CI: 1.20-5.08) and adults (HR = 1.96; 95% CI: 1.63-2.36) but effect was attenuated in children with low ppFEV1 (<40%). CONCLUSIONS: NIV usage in CF improves spirometric values but does not benefit survival. Further studies are required to better understand survival outcomes and ultimately improve NIV outcomes in CF.

Clinically recorded heart rate and incidence of 12 coronary, cardiac, cerebrovascular and peripheral arterial diseases in 233,970 men and women: A linked electronic health record study.

Background In healthy population cohorts, resting heart rate above 90 bpm is associated with mortality from coronary heart disease, but it is not clear whether associations are present at lower heart rates or whether these associations differ between women. Methods The CALIBER resource of linked electronic health records from primary care, hospitalisations, myocardial infarction registry and cause-specific mortality in the UK was used to assess associations between resting heart rate and 12 fatal and non-fatal coronary, cardiac, cerebral and peripheral vascular cardiovascular diseases and death using Cox proportional hazard models. Results Among 233,970 patients, 29,690 fatal and non-fatal events occurred. Fully adjusted models showed that resting heart rate was not associated in men or women with cerebrovascular events. In men a resting heart rate of 70-79 bpm (29.1% of all men) versus less than 60 bpm was associated with an increased risk of heart failure (hazard ratio (HR) 1.65, 95% confidence interval (CI) 1.26-2.16), unheralded coronary death (HR 1.65, 95% CI 1.13-2.41), total cardiovascular events (HR 1.22, 95% CI 1.15-1.28) and all-cause mortality (HR 1.39, 95% CI 1.22-1.58). Women with a higher resting heart rate level of 80-89 bpm versus 60 bpm had a higher risk of total cardiovascular disease events (HR 1.17, 95% CI 1.07-1.24) and all-cause mortality (HR 1.21, 95% CI 1.07-1.35) compared to a resting heart rate less than 60 bpm. The risk was also present at higher heart rates (>90 bpm) for heart failure and sudden cardiac death. Conclusions A resting heart rate that clinicians currently consider as 'normal' in the general population is specifically associated with the incidence of certain major cardiovascular diseases and death, with the risk starting at lower resting heart rate levels in men compared to women. Further research is required to evaluate whether interventions to lower resting heart rate are warranted to prevent disease. The study is registered at: clinicaltrials.gov (ID: NCT01947361).

Body-weight and psychological well-being in the UK general population.

Background: While the consequences of body weight for physical health are well explored, the evidence for psychological well-being is less straightforward. An instrumental variable approach is used to address the endogenous relationship between body weight and well-being in the UK general population. Methods: Data from the Health Survey for England (2003, 2004 and 2006) are used to fit linear and ordered probit instrument variable models for a sample of 13 862 individuals, with frequent white meat consumption instrumenting for body-weight. Non-linearities in the relationship, robustness to weak instruments and relaxation of strict exogeneity assumption are further examined. Results: Accounting for endogeneity and conditional on health a protective effect on well-being is observed. A unit increase in body mass index (BMI) improves General Health Questionnaire (GHQ) by 0.17 (95% CI: 0.02-0.31) points and reduces the probability of reporting very low GHQ by 2.5% (95% CI: 0.01-0.05). Empirical testing showed that the instrument performs well, with increased meat consumption adding 0.58 points (95% CI: 0.42-0.74) to ones' BMI. Conclusions: We present support for the jolly-fat hypothesis, however, caution is recommended in drawing inferences. Further research needs to resolve the mixed findings in the literature.

The Economic Costs of Type 2 Diabetes: A Global Systematic Review.

BACKGROUND: There has been a widely documented and recognized increase in diabetes prevalence, not only in high-income countries (HICs) but also in low- and middle-income countries (LMICs), over recent decades. The economic burden associated with diabetes, especially in LMICs, is less clear. OBJECTIVE: We provide a systematic review of the global evidence on the costs of type 2 diabetes. Our review seeks to update and considerably expand the previous major review of the costs of diabetes by capturing the evidence on overall, direct and indirect costs of type 2 diabetes worldwide that has been published since 2001. In addition, we include a body of economic evidence that has hitherto been distinct from the cost-of-illness (COI) work, i.e. studies on the labour market impact of diabetes. METHODS: We searched PubMed, EMBASE, EconLit and IBSS (without language restrictions) for studies assessing the economic burden of type 2 diabetes published from January 2001 to October 2014. Costs reported in the included studies were converted to international dollars ($) adjusted for 2011 values. Alongside the narrative synthesis and methodological review of the studies, we conduct an exploratory linear regression analysis, examining the factors behind the considerable heterogeneity in existing cost estimates between and within countries. RESULTS: We identified 86 COI and 23 labour market studies. COI studies varied considerably both in methods and in cost estimates, with most studies not using a control group, though the use of either regression analysis or matching has increased. Direct costs were generally found to be higher than indirect costs. Direct costs ranged from $242 for a study on out-of-pocket expenditures in Mexico to $11,917 for a study on the cost of diabetes in the USA, while indirect costs ranged from $45 for Pakistan to $16,914 for the Bahamas. In LMICs-in stark contrast to HICs-a substantial part of the cost burden was attributed to patients via out-of-pocket treatment costs. Our regression analysis revealed that direct diabetes costs are closely and positively associated with a country's gross domestic product (GDP) per capita, and that the USA stood out as having particularly high costs, even after controlling for GDP per capita. Studies on the labour market impact of diabetes were almost exclusively confined to HICs and found strong adverse effects, particularly for male employment chances. Many of these studies also took into account the possible endogeneity of diabetes, which was not the case for COI studies. CONCLUSIONS: The reviewed studies indicate a large economic burden of diabetes, most directly affecting patients in LMICs. The magnitude of the cost estimates differs considerably between and within countries, calling for the contextualization of the study results. Scope remains large for adding to the evidence base on labour market effects of diabetes in LMICs. Further, there is a need for future COI studies to incorporate more advanced statistical methods in their analysis to account for possible biases in the estimated costs.

Drug eluting balloons for de novo coronary lesions - a systematic review and meta-analysis.

BACKGROUND: The role of drug-eluting balloons (DEB) is unclear. Increasing evidence has shown a benefit for the treatment of in-stent restenosis. Its effect on de novo coronary lesions is more controversial. Several smaller randomized trials found conflicting results. METHODS: This is a systematic review and meta-analysis of randomized controlled trials (RCT) evaluating the effect of local Paclitaxel delivery/drug eluting balloons (DEB) (+/- bare metal stent) compared to current standard therapy (stenting) to treat de novo coronary lesions. Data sources for RCT were identified through a literature search from 2005 through 28 December 2012. The main endpoints of interest were target lesion revascularization (TLR), major adverse cardiac events (MACE), binary in-segment restenosis, stent thrombosis (ST), myocardial infarction (MI), late lumen loss (LLL) and mortality. A random effects model was used to calculate the pooled relative risks (RR) with 95% confidence intervals. RESULTS: Eight studies (11 subgroups) and a total of 1,706 patients were included in this analysis. Follow-up duration ranged from 6 to 12 months. Overall, DEB showed similar results to the comparator treatment. The relative risk (RR) for MACE was 0.95 (0.64 to 1.39); P = 0.776, for mortality it was 0.79 (0.30 to 2.11), P = 0.644, for stent thrombosis it was 1.45 (0.42 to 5.01), P = 0.560, for MI it was 1.26 (0.49 to 3.21), P = 0.629, for TLR it was 1.09 (0.71 to 1.68); P = 0.700 and for binary in-stent restenosis it was 0.96 (0.48 to 1.93), P = 0.918. Compared to bare metal stents (BMS), DEB showed a lower LLL (- 0.26 mm (-0.51 to 0.01)) and a trend towards a lower MACE risk (RR 0.66 (0.43 to 1.02)). CONCLUSION: Overall, drug-eluting balloons (+/- bare metal stent) are not superior to current standard therapies (BMS or drug eluting stent (DES)) in treating de novo coronary lesions. However, the performance of DEB seems to lie in between DES and BMS with a trend towards superiority over BMS alone. Therefore, DEB may be considered in patients with contraindications for DES. The heterogeneity between the included studies is a limitation of this meta-analysis; different drug-eluting balloons have been used.