Regulatory adverse drug reaction analyses support a temporal increase in psychiatric reactions after initiation of cystic fibrosis combination modulator therapies.

INTRODUCTION: Despite improved outcomes for many people with cystic fibrosis, there have been reports of adverse neuropsychiatric effects of modulator therapy. The aim of this research is to define temporal associations in adverse drug reaction (ADR) reports for available CFTR modulators. METHODS: Methods include an analysis of the UK Yellow Card Scheme data for ADRs through accessing interactive Drug Analysis Profiles (iDAPs) to define temporal trends in absolute and proportional counts. RESULTS: Since the introduction of ETI, there has been an increase in the absolute number of psychiatric ADRs reported as well as a statistically significant increase in the proportion of psychiatric ADRs in the pre-ETI and post-ETI periods. CONCLUSION: In the post-ETI period, psychiatric ADRs are the most prevalent ADR reported via the Yellow Card scheme. Despite an unclear mechanism, there is significant clinical relevance in counselling and monitoring regarding psychiatric effects of CFTR modulator therapy.

Impact of prior oral anticoagulation therapies on post-discharge outcomes after COVID-19: Results from a global federated health network analysis.

BACKGROUND: The impact of chronic oral anticoagulant (OACs) use on long-term post-discharge outcomes after coronavirus disease 2019 (COVID-19) hospitalisation remains unclear. Herein, we compared clinical outcomes up to 2-years after COVID-19 hospitalisation between patients on vitamin K antagonists (VKAs), direct-acting OACs (DOACs) and no OAC therapy. METHODS: Data from TriNetX, a global federated health research network, were used. Adult patients on VKAs, DOACs or no OAC therapy at diagnosis of COVID-19 between 20 January 2020 and 31 December 2021, who were hospitalised for COVID-19, were included. The primary outcomes were all-cause mortality, ischaemic stroke/transient ischaemic attack (TIA)/systemic embolism (SE) and the composite of intracranial haemorrhage (ICH)/gastrointestinal bleeding, at 2 years after COVID-19 hospitalisation. RESULTS: We included 110,834 patients with COVID-19. Following propensity score matching (PSM), we identified a decreased mortality risk in DOAC-treated patients compared to the no OAC cohort (RR .808, 95% CI .751-.870). A higher risk of ischaemic stroke/TIA/SE was observed in VKA users compared to DOAC users (RR 1.100, 95% CI 1.020-1.220) and in VKA users compared to patients not taking OAC (RR 1.400, 95% CI 1.140-1.720). VKA use was associated with a greater risk of ICH/gastrointestinal bleeding than DOAC users (RR 1.198, 95% CI 1.066-1.347), while DOAC users had a lower risk compared to no OAC-treated patients (RR .840, 95% CI .754-.936). CONCLUSION: COVID-19 patients taking prior DOACs were associated with lower long-term mortality risk and ICH/gastrointestinal bleeding than patients not taking OAC. Compared to patients on DOACs, VKA users were associated with higher risks of mortality, ischaemic stroke/TIA/SE and ICH/gastrointestinal bleeding.

Low-dose azithromycin prophylaxis in patients with atrial fibrillation and chronic obstructive pulmonary disease.

Low-dose azithromycin prophylaxis is associated with improved outcomes in people suffering frequent exacerbations of chronic obstructive pulmonary disease (COPD), but the use of macrolides in patients with cardiovascular disease has been debated. To investigate the risk of adverse events after COPD exacerbations in patients with atrial fibrillation (AF) treated with azithromycin prophylaxis. Retrospective cohort study within the TriNetX Platform, including AF patients with COPD exacerbations. Risks of primary and secondary outcomes were recorded up to 30 days post-COPD exacerbations and compared between azithromycin users and azithromycin non-users. The primary outcomes were the risks for a composite of (1) cardiovascular (all-cause death, heart failure, ventricular arrhythmias, ischemic stroke, myocardial infarction, and cardiac arrest), and (2) hemorrhagic events (intracranial hemorrhage (ICH), and gastro-intestinal bleeding). Cox-regression analyses compared outcomes between groups after propensity score matching (PSM). After PSM, azithromycin users (n = 2434, 71 ± 10 years, 49% females) were associated with a lower 30-day risk of post-exacerbation cardiovascular (HR 0.67, 95% CI 0.61-0.73) and hemorrhagic composite outcome (HR 0.45, 95% CI 0.32-0.64) compared to azithromycin non-users (n = 2434, 72 ± 11 years, 51% females). The beneficial effect was consistent for each secondary outcomes, except ICH. On sensitivity analyses, the reduced risk of adverse events in azithromycin users was irrespective of smoking status, exacerbation severity, and type of oral anticoagulation. Azithromycin prophylaxis is associated with a lower risk of all-cause death, thrombotic and hemorrhagic events in AF patients with COPD. The possible role of azithromycin prophylaxis as part of the integrated care management of AF patients with COPD needs further study.

Prevalence, risk factors and outcomes of cardiac disease in cystic fibrosis: a multinational retrospective cohort study.

BACKGROUND: Although people living with cystic fibrosis (PwCF) often have some risk factors for cardiovascular disease, including diabetes and chronic inflammation, little is known about the long-term cardiac risk in this condition. We aimed to determine the characteristics, rates and outcomes for cardiac disease in CF. METHODS: We looked at rates and outcomes for cardiac disease in 5649 adult PwCF in the UK CF Registry and 6265 adult PwCF in TriNetX (a global federated database of electronic healthcare record data). We used propensity matching to compare risk of major adverse cardiac events (MACE) (myocardial infarction, left-sided heart failure and atrial fibrillation) in PwCF against matched non-CF comparators in the general population and other inflammatory diseases. RESULTS: PwCF had a high prevalence of diabetes but low rates of hypertension and obesity. Some cardiac risk factors (age, diabetes and hypertension) were associated with MACE, but relationships between disease-specific risk factors (lung function and intravenous antibiotic days) were also observed. In propensity score-matched analyses, PwCF had higher risk of MACE than matched general population comparators (hazard ratio (HR) 1.65, 95% CI 1.40-1.95; p<0.001) and an equivalent or higher relative risk compared with other inflammatory conditions considered "high risk" for cardiovascular disease, including systemic lupus erythematosus (HR 0.95, 95% CI 0.82-1.09; p=0.44), rheumatoid arthritis (HR 1.21, 95% CI 1.00-1.48; p<0.001) and HIV (HR 0.93, 95% CI 0.82-1.06; p=0.29). CONCLUSIONS: PwCF are at increased risk of adverse cardiac disease events. Future work should focus on defining determinants of cardiovascular risk such that appropriate risk stratification can be employed.

HEART Score Recalibration Using Higher Sensitivity Troponin T.

STUDY OBJECTIVE: We examined the diagnostic performance of a recalibrated History, Electrocardiogram, Age, Risk factors, Troponin (HEART), and Thrombolysis in Myocardial Infarction (TIMI) score in patients with suspected acute cardiac syndrome (ACS). Recalibration of troponin thresholds was performed, including shifting from the 99th percentile to the limit of detection (LOD) or to the limit of quantification (LOQ) We compared the discharge potential and safety of the recalibrated composite scores using a single presentation high-sensitivity cardiac troponin (hs-cTn) T to the conventional scores and with a LOD/LOQ troponin strategy alone. METHODS: We undertook a 2-center prospective cohort study in the United Kingdom (UK) (2018) (Clinicaltrials.gov NCT03619733) to specifically assess recalibrated risk scores (shifting the troponin subset scoring from 99th percentile to LOD [UK]) and combined the results of this with secondary analyses of 2 prospective cohort studies in the UK (2011) and the United States (2018, using LOQ rather than LOD). The primary outcome was major adverse cardiovascular events (MACE), defined as adjudicated type 1 myocardial infarction (MI), urgent coronary revascularization, and all-cause death, at 30 days. We evaluated the original scores using hs-cTn below the 99th percentile and recalibrated scores using hs-cTn

The long-term effects of insulin use in incident cystic fibrosis-related diabetes: a target trial emulated using longitudinal national registry data.

Introduction: Cystic fibrosis-related diabetes (CFRD) is a common complication of cystic fibrosis and is associated with deleterious clinical outcomes. Insulin is recommended as a treatment by international guidelines. However, there are scarce clinical trial data to support the use of insulin, and little is known about the long-term outcomes of treatment. The aim of this study was to compare the long-term impacts of insulin use versus non-use in CFRD. Methods: We used data from the national UK Cystic Fibrosis Registry and adopted a target trial framework. Eligible individuals included those 12 years and older with a new diagnosis of CFRD. Outcomes were change in % predicted forced expiratory volume in 1 s (FEV1 %) and body mass index z-scores (BMI) over a 5-year follow-up period. Treatment strategies were to receive insulin or not for the duration of follow-up. Treatment effect estimates were obtained using two methods to control for confounding: inverse-probability-of-treatment weighted estimation of marginal structural models and the G-formula. Results: We identified 1613 individuals diagnosed with CFRD between 2008 and 2016 and included 1196 and 1192 in the FEV1 % and BMI outcome analyses respectively. We found no evidence of an effect of insulin on FEV1 % over the 5-year study period. Similarly, we found no overall effect of insulin on BMI; however, there was some evidence for a positive treatment effect in patients with lower baseline BMI. Conclusion: Using well-established national registry data, we found no evidence of long-term treatment effects for insulin on FEV1 % or BMI in people with incident CFRD.

Physical activity assessment and vascular function in adults with cystic fibrosis and their non-CF peers.

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 (p = 0.005) in pwCF (35.09 ± 10.60 mg), than their non-CF peers (44.62 ± 13.78 mg). PwCF had PA profiles (intensity gradient) indicative of more time in lower intensity activity (-2.62 ± 0.20, -2.37 ± 0.23). Vigorous activity was positively associated with lung function (rs = 0.359) and Quality of Life (r = 0.412). There were no significant differences (p = 0.313) in FMD% between pwCF (5.29 ± 2.76%) and non-CF peers (4.34 ± 1.58%) and no associations with PA. PwCF engaged in less moderate-to-vigorous PA and demonstrated a steeper PA profile than their non-CF peers.

Developing an ecological approach to physical activity promotion in adults with Cystic fibrosis.

BACKGROUND: There are few examples of interventions designed to promote physical activity (PA) in adults with Cystic fibrosis (CF). Increasing levels of habitual PA may be more feasible and result in greater compliance than conventional exercise training inventions which give little or no attention to long-term PA behaviour. Despite this there is limited research exploring perceptions of PA among adults with CF. The study aimed to understand the ecological correlates of PA in adults with CF and to involve individuals with CF, their families (where applicable) and clinicians in a formative process to inform the development of an ecological approach to PA promotion in this population. METHODS: An iterative approach was utilised, whereby findings from earlier phases of the research informed subsequent phases. Semi-structured interviews were conducted to explore patients' perceptions of PA, devised using the PRECEDE component of the PRECEDE-PROCEED model. Followed by, focus groups to discuss the perceived barriers, facilitators and opportunities for PA participation and how this information could inform the development and delivery of a PA intervention. Separate focus groups were conducted with individuals with CF (n = 11) and their families and CF MDT members. Thematic analysis was used to construct themes. RESULTS: Physical and mental wellbeing manifested as both barriers and facilitators of PA. CF is characterised by a progressive decline in physical function, which presents as a number of challenging symptoms and set-backs for an individual with CF. PA represents an opportunity for participants to slow the rate of this decline and manage the symptoms associated with the condition. Enjoyment was an important facilitator of PA. Exercise professionals and family reinforce PA behaviour, particularly during adolescence. CONCLUSIONS: PA promotion should form part of routine CF care with additional exercise professional support during adolescence.

Antibiotic therapy for chronic infection with Burkholderia cepacia complex in people with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) a life-limiting inherited disease affecting a number of organs, but classically associated with chronic lung infection and progressive loss of lung function. Chronic infection by Burkholderia cepacia complex (BCC) is associated with increased morbidity and mortality and therefore represents a significant challenge to clinicians treating people with CF. This review examines the current evidence for long-term antibiotic therapy in people with CF and chronic BCC infection. OBJECTIVES: The objective of this review is to assess the effects of long-term oral and inhaled antibiotic therapy targeted against chronic BCC lung infections in people with CF. The primary objective is to assess the efficacy of treatments in terms of improvements in lung function and reductions in exacerbation rate. Secondary objectives include quantifying adverse events, mortality and changes in quality of life associated with treatment. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched online trial registries and the reference lists of relevant articles and reviews. Date of last search: 12 April 2021. SELECTION CRITERIA: Randomised controlled trials (RCTs) of long-term antibiotic therapy in people with CF and chronic BCC infection. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed risk of bias and assessed the quality of the evidence using GRADE. MAIN RESULTS: We included one RCT (100 participants) which lasted 52 weeks comparing continuous inhaled aztreonam lysine (AZLI) and placebo in a double-blind RCT for 24 weeks, followed by a 24-week open-label extension and a four-week follow-up period. The average participant age was 26.3 years, 61% were male and average lung function was 56.5% predicted. Treatment with AZLI for 24 weeks was not associated with improvement in forced expiratory volume in one second (FEV1), mean difference 0.91% (95% confidence interval (CI) -3.15 to 4.97) (moderate-quality evidence). The median time to the next exacerbation was 75 days in the AZLI group compared to 51 days in the placebo group, but the difference was not significant (P = 0.27) (moderate-quality evidence). Similarly, the number of participants hospitalised for respiratory exacerbations showed no difference between groups, risk ratio (RR) 0.88 (95% CI 0.53 to 1.45) (moderate-quality evidence). Overall adverse events were similar between groups, RR 1.08 (95% CI 0.98 to 1.19) (moderate-quality evidence). There were no significant differences between treatment groups in relation to mortality (moderate-quality evidence), quality of life or sputum density. In relation to methodological quality, the overall risk of bias in the study was assessed to be unclear to low risk. AUTHORS' CONCLUSIONS: We found insufficient evidence from the literature to determine an effective strategy for antibiotic therapy for treating chronic BCC infection.

Continuous glucose monitoring systems for monitoring cystic fibrosis-related diabetes.

BACKGROUND: Cystic fibrosis (CF) is one of the most common life-shortening autosomal-recessive genetic conditions with around 100,000 people affected globally. CF mainly affects the respiratory system, but cystic fibrosis-related diabetes (CFRD) is a common extrapulmonary co-morbidity and causes excess morbidity and mortality in this population. Continuous glucose monitoring systems (CGMS) are a relatively new technology and, as yet, the impact of these on the monitoring and subsequent management of CFRD remains undetermined. OBJECTIVES: To establish the impact of insulin therapy guided by continuous glucose monitoring compared to insulin therapy guided by other forms of glucose data collection on the lives of people with CFRD. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. Date of latest search: 23 September 2021. We also searched the reference lists of relevant articles and reviews and online trials registries. Date of last search: 23 September 2021. SELECTION CRITERIA: Randomised controlled studies comparing insulin regimens led by data from CGMS (including real-time or retrospective data, or both) with insulin regimens guided by abnormal blood glucose measurements collected through other means of glycaemic data collection in people with CFRD. Studies with a cross-over design, even with a washout period between intervention arms, are not eligible for inclusion due to the potential long-term impact of each of the interventions and the potential to compromise the outcomes of the second intervention. DATA COLLECTION AND ANALYSIS: No studies were included in the review, meaning that no data were available to be collected for analysis. MAIN RESULTS: Review authors screened 14 studies at the full-text stage against the review's inclusion criteria. Consequently, seven were excluded due to the study type being ineligible (not randomised), two studies were excluded due to their cross-over design, and two studies was excluded since the intervention used was not eligible and one was a literature review. One study in participants hospitalised for a pulmonary exacerbation is ongoing. Investigators are comparing insulin dosing via insulin pump with blood sugar monitoring by a CGMS to conventional diabetes management with daily insulin injections (or on an insulin pump if already on an insulin pump in the outpatient setting) and capillary blood glucose monitoring. The participants in the control arm will wear a blinded continuous glucose monitoring system for outcome assessment. In addition to this, one further study is still awaiting classification, and will be screened to determine whether it is eligible for inclusion, or is to be excluded, in an update of this review. AUTHORS' CONCLUSIONS: No studies were included in the review, indicating that there is currently insufficient evidence to determine the impact of insulin therapy guided by CGMS compared to insulin therapy guided by other forms of glucose data collection on the lives of people with CFRD, nor on potential adverse effects of continuous glucose monitoring in this context. Randomised controlled studies are needed to generate evidence on the efficacy and safety of continuous glucose monitoring in people with CFRD. There is one relevant ongoing study that may be eligible for inclusion in a future update of this Cochrane Review, and whose results may help answer the review question.

The rapid development and deployment of a new multidisciplinary CPAP service outside of a critical care environment during the early stages of the COVID-19 pandemic.

The COVID-19 pandemic has led to a dramatic increase in patients presenting with type 1 respiratory failure. In order to protect our limited critical care capacity, we rapidly developed a new ward-based inpatient continuous positive airway pressure (CPAP) service with direct input from the respiratory, infectious diseases and critical care teams. Close collaboration between these specialties and new innovative solutions were required to facilitate this. CPAP equipment (normally reserved for domiciliary care) was adapted to reduce the pressure on our strained oxygen infrastructure. Side rooms on the infectious diseases ward were swiftly converted into new negative pressure areas using temporary installed ventilatory equipment, reducing the viral aerosol risk for staff. Novel patient monitoring solutions were used to protect staff while also ensuring patient safety. Staff training and specialist oversight was organised within days. The resulting service was successful, with over half (17/26 (65%)) of patients avoiding invasive ventilation.

Assessing the validity and applicability of the French 3-year prognostic score in the UK cystic fibrosis population - a national cohort study.

Models that predict outcomes, aid prognostication and inform the assessment of urgency for lung transplantation (LT) in CF are in demand. A prognostic score derived from the French adult CF registry to predict death or LT over 3-year follow-up was described in 2017 and validated using Canadian CF registry data. We assessed its performance in the UK CF population. The French prognostic score was applied to untransplanted adults with CF. The index year (2014) and outcomes (Death or LT) were evaluated to 2017. Receiver operator characteristics plots and area under curve (AUC) was computed. 4407 adults with CF met the inclusion criteria. After 3 years, 7.1% (P < 0.001) were dead or had received LT compared to the French (12.8%) and Canadian (9.4%) cohorts. The French score deemed 592 (26.2%) 'High-risk' - death/LT occurred in 189/592 (30.2%), less than previously reported in France and Canada (P < 0.0001). The discriminatory power of the French score was lower (AUC 0.830) than reported. Recalibration yielded only marginal improvement in model performance (AUC 0.833). The French prognostic score does not perform as well in the UK as reported elsewhere. Bespoke UK scores are needed to aid prognostication and inform LT decision-making.

The clinical and microbiological utility of inhaled aztreonam lysine for the treatment of acute pulmonary exacerbations of cystic fibrosis: An open-label randomised crossover study (AZTEC-CF).

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. 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. 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). 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. CLINICAL TRIAL REGISTRATION: EudraCT 2016-002832-34 ClinicalTrials.org NCT02894684.

Utility of established prognostic scores in COVID-19 hospital admissions: multicentre prospective evaluation of CURB-65, NEWS2 and qSOFA.

INTRODUCTION: The COVID-19 pandemic is ongoing, yet, due to the lack of a COVID-19-specific tool, clinicians must use pre-existing illness severity scores for initial prognostication. However, the validity of such scores in COVID-19 is unknown. METHODS: The North West Collaborative Organisation for Respiratory Research performed a multicentre prospective evaluation of adult patients admitted to the hospital with confirmed COVID-19 during a 2-week period in April 2020. Clinical variables measured as part of usual care at presentation to the hospital were recorded, including the Confusion, Urea, Respiratory Rate, Blood Pressure and Age Above or Below 65 Years (CURB-65), National Early Warning Score 2 (NEWS2) and Quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) scores. The primary outcome of interest was 30-day mortality. RESULTS: Data were collected for 830 people with COVID-19 admitted across seven hospitals. By 30 days, a total of 300 (36.1%) had died and 142 (17.1%) had been in the intensive care unit. All scores underestimated mortality compared with pre-COVID-19 cohorts, and overall prognostic performance was generally poor. Among the 'low-risk' categories (CURB-65 score<2, NEWS2<5 and qSOFA score<2), 30-day mortality was 16.7%, 32.9% and 21.4%, respectively. NEWS2≥5 had a negative predictive value of 98% for early mortality. Multivariable logistic regression identified features of respiratory compromise rather than circulatory collapse as most relevant prognostic variables. CONCLUSION: In the setting of COVID-19, existing prognostic scores underestimated risk. The design of new prognostic tools should focus on features of respiratory compromise rather than circulatory collapse. We provide a baseline set of variables which are relevant to COVID-19 outcomes and may be used as a basis for developing a bespoke COVID-19 prognostication tool.

Identification of high-risk non-ST elevation myocardial infarction at presentation to emergency department. A prospective observational cohort study in North West England.

OBJECTIVES: Early access to invasive coronary angiography and revascularisation for high-risk non-ST elevation myocardial infarction (NSTEMI) improves outcomes and is supported by current guidelines. We sought to determine the most effective criteria at presentation to emergency department (ED) to identify high-risk NSTEMI. SETTING: Secondary care centre northwest England with national follow-up. PARTICIPANTS: 1642 consecutive patients (median age 59, 52% male) presenting to ED with a primary symptom of chest pain in whom there is suspicion of NSTEMI. PRIMARY AND SECONDARY MEASURES: Multivariate logistic regression analysis for the prediction of all-cause death (primary) and major adverse cardiac event (MACE defined as all-cause death, unplanned coronary revascularisation and adjudicated NSTEMI (third universal definition)) (secondary measure) at 1 year. RESULTS: The incidence of adjudicated NSTEMI was 10.7%, and 1-year mortality was 6.3%. Independent predictors for all-cause death at 1 year were Global Registry of Acute Coronary Events (GRACE) >140, age (per decade increase) and high-sensitive cardiac troponin T (hs-cTnT) >50 ng/L. hs-cTnT >50 ng/L was associated with adjudicated index presentation NSTEMI in the greatest proportion of patients (61.7%). When using MACE at 12 months, as opposed to all-cause death, as an end point History, ECG, Age, Risk factors and Troponin (HEART) score ≥7 was included in the multivariate model and had better prediction of index NSTEMI than GRACE>140. Combining hs-cTnT >50 ng/L and a second independent predictor identified both a high proportion of index NSTEMI and elevated risk of all-cause death at 1 year. CONCLUSIONS: hs-cTnT >50 ng/L or HEART score ≥7 appear effective strategies to identify high-risk NSTEMI at presentation to emergency room with chest pain. Multicentre prospective studies enriched with early presenters, and with competitor high-sensitive and point-of-care troponins, are required to validate and extend these findings. TRIAL REGISTRATION NUMBER: NCT02581540.

Ivacaftor Is Associated with Reduced Lung Infection by Key Cystic Fibrosis Pathogens. A Cohort Study Using National Registry Data.

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 outcomes of treatment are unknown.Objectives: To investigate changes in respiratory microbiology associated with long-term ivacaftor use.Methods: This was a retrospective cohort study using data from the UK CF Registry 2011-2016. Primary outcome was the annual prevalence ratios for key CF pathogens between ivacaftor users and their contemporaneous comparators. Multivariable log-binomial regression models were designed to adjust for confounders. Changes in Pseudomonas aeruginosa status were compared between groups using nonparametric maximum likelihood estimate for the purposes of Kaplan-Meier approximation.Results: Ivacaftor use was associated with early and sustained reduction in P. aeruginosa rates (2016 adjusted prevalence ratio, 0.68; 95% confidence interval, 0.58-0.79; P < 0.001) via a combination of increased clearance in those with infection (ivacaftor: 33/87 [37.9%] vs. nonivacaftor: 432/1,872 [22.8%]; P < 0.001) and reduced acquisition in those without infection (49/134 [36.6%] vs. 1,157/2,382 [48.6%]; P = 0.01). The improved prevalence of P. aeruginosa infection was independent of reduced sampling in the ivacaftor cohort. Ivacaftor was also associated with reduced prevalence of Staphylococcus aureus and Aspergillus spp. but not Burkholderia cepacia complex.Conclusions: In this study, long-term ivacaftor use was associated with reduced infection with important CF pathogens including P. aeruginosa. These findings have implications for antibiotic stewardship and the need for ongoing chronic antimicrobial therapy in this cohort.

Antibiotic therapy for chronic infection with Burkholderia cepacia complex in people with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) a life-limiting inherited disease affecting a number of organs, but classically associated with chronic lung infection and progressive loss of lung function. Chronic infection by Burkholderia cepacia complex (BCC) is associated with increased morbidity and mortality and therefore represents a significant challenge to clinicians treating people with CF. This review examines the current evidence for long-term antibiotic therapy in people with CF and chronic BCC infection. OBJECTIVES: The objective of this review is to assess the effects of long-term oral and inhaled antibiotic therapy targeted against chronic BCC lung infections in people with CF. The primary objective is to assess the efficacy of treatments in terms of improvements in lung function and reductions in exacerbation rate. Secondary objectives include quantifying adverse events, mortality and changes in quality of life associated with treatment. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched online trial registries and the reference lists of relevant articles and reviews.Date of last search: 29 May 2019. SELECTION CRITERIA: Randomised controlled trials (RCTs) of long-term antibiotic therapy in people with CF and chronic BCC infection. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed risk of bias and assessed the quality of the evidence using GRADE. MAIN RESULTS: We included one RCT (100 participants) which lasted 52 weeks comparing continuous inhaled aztreonam lysine (AZLI) and placebo in a double-blind RCT for 24 weeks, followed by a 24-week open-label extension and a four-week follow-up period. The average participant age was 26.3 years, 61% were male and average lung function was 56.5% predicted.Treatment with AZLI for 24 weeks was not associated with improvement in forced expiratory volume in one second (FEV1), mean difference 0.91% (95% confidence interval (CI) -3.15 to 4.97) (moderate-quality evidence). The median time to the next exacerbation was 75 days in the AZLI group compared to 51 days in the placebo group, but the difference was not significant (P = 0.27) (moderate-quality evidence). Similarly, the number of participants hospitalised for respiratory exacerbations showed no difference between groups, risk ratio (RR) 0.88 (95% CI 0.53 to 1.45) (moderate-quality evidence). Overall adverse events were similar between groups, RR 1.08 (95% CI 0.98 to 1.19) (moderate-quality evidence). There were no significant differences between treatment groups in relation to mortality (moderate-quality evidence), quality of life or sputum density.In relation to methodological quality, the overall risk of bias in the study was assessed to be unclear to low risk. AUTHORS' CONCLUSIONS: We found insufficient evidence from the literature to determine an effective strategy for antibiotic therapy for treating chronic BCC infection.

Cystic fibrosis-related diabetes: optimizing care with a multidisciplinary approach.

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.