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Glucocorticoids are highly effective medicines in the treatment of inflammatory disorders. However they cause severe adverse reactions, particularly where taken at high doses systemically for prolonged periods. Systemic glucocorticoids are therefore given at dosage sufficient to control the disease, then withdrawn as fast as is possible to minimise dose- and time-related adverse drug reactions without losing disease control. Adverse withdrawal reactions present a major challenge in the withdrawal of long term glucocorticoids. Suppression of the hypothalamic-pituitary-adrenal (HPA) axis causes adrenal insufficiency, which is potentially life threatening and can become symptomatic as treatment is withdrawn. Adrenal insufficiency can be extremely difficult to differentiate from 'glucocorticoid withdrawal syndrome', where patients experience symptoms despite adequate adrenal function, and from psychological dependence. Long term systemic glucocorticoids should therefore be withdrawn slowly. The rate at which the dose is tapered should initially be determined by treatment requirements of the underlying disease. Once 'physiological' doses are reached, the rate of reduction is determined by rate of HPA recovery and need for exogenous glucocorticoid cover while endogenous secretion recovers. If symptoms prevent treatment withdrawal, HPA testing should be used to look for adrenal insufficiency. Patients with adrenal insufficiency require 'physiological' doses of glucocorticoids for adrenal replacement, which may be lifelong if the HPA axis fails to recover.

BackgroundThe pharmacokinetics of β-lactam antibiotics in critical illness remain poorly characterized, particularly in neonates, children and the elderly. We undertook a pharmacokinetic study of commonly used β-lactam antibiotics in critically ill patients of all ages. The aims were to produce a whole-life β-lactam pharmacokinetic model and describe the extent to which standard doses achieve pharmacokinetic/pharmacodynamic targets associated with clinical cure.Patients and methodsA total of 212 critically ill participants with an age range from 1 day (gestational age 24 weeks) to 90 years were recruited from a UK hospital, providing 1339 pharmacokinetic samples. Population pharmacokinetic analysis was undertaken using non-linear mixed-effects modelling (NONMEM) for each drug. Pooled data were used to estimate maturation and decline of β-lactam pharmacokinetics throughout life.ResultsPharmacokinetic models for eight drugs were described, including what is thought to be the first benzylpenicillin model in critically ill adults. We estimate that 50% of adult β-lactam clearance is achieved by 43 weeks post-menstrual age (chronological plus gestational age). Fifty percent of decline from peak adult clearance occurs by 71 years. Paediatric participants were significantly less likely than adults to achieve pharmacokinetic/pharmacodynamic targets with standard antibiotic doses (P ConclusionsWe believe this to be the first prospective whole-life antibiotic pharmacokinetic study in the critically ill. The study provides further evidence that standard antibiotic doses fail to achieve pharmacokinetic/pharmacodynamic targets associated with clinical success in adults, children and neonates. Maturation and decline parameters estimated from this study could be adopted as a standard for future prospective studies.

Syndrome Coronavirus 2 (SARS-CoV-2) has led to remarkable efforts by the scientific communities internationally to identify potential pharmacological treatments through the rapid initiation of clinical trials of novel and/or re-purposed regulatory authorityapproved therapies. We greatly welcome the significant global effort to safely expedite trials. However, we are concerned that many studies have not been of high quality to generate clinically meaningful data to enable effective translation to clinical practice. Identifying the “right” drug (or drug combinations) is only the first step. Applying core clinical pharmacology principles at all stages of research will help identify the right dose, the right patient, and the right treatment protocol. We hope that by setting out the principles outlined in this statement, efforts to find a safe and efficacious treatment for COVID-19 will have the best chance of success.

Aims To investigate the longitudinal exposure of English primary care patients to pharmacogenomic drugs to inform design of pre-emptive testing. Methods Sixty-three drugs were identified with dosing guidelines based on variants of 19 pharmacogenes in the Pharmacogenomics Knowledgebase on 01 September 2018. Prescribing of these pharmacogenomic drugs between 1993 and 2017 was summarised for a sample of 648 141 English patients aged 50-99 years on 01 January 2013, registered with Clinical Practice Research Datalink practices during 2011-12. Exposure of patients to pharmacogenomic drugs retrospectively (2, 10, 20 y) and prospectively (5 y) was described. Results During 2011-12, 58% of patients were prescribed at least 1 pharmacogenomic drug, increasing to 80% over the previous 20 years. Multiple exposure was common, with 47% patients prescribed ≥2 pharmacogenomic drugs and 7% prescribed ≥5 pharmacogenomic drugs over the next 5 years. The likelihood of exposure to pharmacogenomic drugs increased with age, with 89% patients ≥70 years prescribed at least 1 pharmacogenomic drug over the previous 20 years. Even among those aged 50-59 years, 71% were prescribed at least 1 pharmacogenomic drug over the previous 20 years. The pharmacogenomic drugs prescribed to the most patients were for pain relief, gastroprotection, psychiatric and cardiovascular conditions. Three pharmacogenes (CYP2D6, CYP2C19 and SLCO1B1) accounted for >95% pharmacogenomic drugs prescribed. Conclusions In primary care patients, exposure to pharmacogenomic drugs is extremely common, multiplicitous and has commenced by relatively early adulthood. A small number of pharmacogenes account for the majority of drugs prescribed. These findings could inform design of pre-emptive pharmacogenomic testing for implementation in primary care.

Background Brain damage and cardiovascular disease are extra-pulmonary manifestations of chronic obstructive pulmonary disease (COPD). Cardiovascular risk factors and smoking are contributors to neurodegeneration. This study investigates whether there is a specific, COPD-related deterioration in brain structure and function independent of cardiovascular risk factors and smoking. Materials and methods Neuroimaging and clinical markers of brain structure (micro- and macro-) and function (cognitive function and mood) were compared between 27 stable COPD patients (age: 63.0±9.1 years, 59.3% male, forced expiratory volume in 1 second [FEV1]: 58.1±18.0% pred.) and 23 non-COPD controls with >10 pack years smoking (age: 66.6±7.5 years, 52.2% male, FEV1: 100.6±19.1% pred.). Clinical relationships and group interactions with brain structure were also tested. All statistical analyses included correction for cardiovascular risk factors, smoking, and aortic stiffness. Results COPD patients had significantly worse cognitive function (p=0.011), lower mood (p=0.046), and greater gray matter atrophy (p=0.020). In COPD patients, lower mood was associated with markers of white matter (WM) microstructural damage (p

Background This study was designed to investigate the genetic evidence for repurposing of GLP1R (glucagon‐like peptide‐1 receptor) agonists to prevent heart failure (HF) and whether the potential benefit exceeds the benefit conferred by more general glycemic control. Methods and Results We applied 2‐sample Mendelian randomization of genetically proxied GLP1R agonism on HF as the main outcome and left ventricular ejection fraction as the secondary outcome. The associations were compared with those of general glycemic control on the same outcomes. Genetic associations were obtained from genome‐wide association study summary statistics of type 2 diabetes mellitus (228 499 cases and 1 178 783 controls), glycated hemoglobin (n=344 182), HF (47,309 cases and 930 014 controls), and left ventricular ejection fraction (n=16 923). Genetic proxies for GLP1R agonism associated with reduced risk of HF (odds ratio per 1 mmol/mol decrease in glycated hemoglobin 0.75; 95% CI, 0.64–0.87; P =1.69×10 −4 ), and higher left ventricular ejection fraction (SD change in left ventricular ejection fraction per 1 mmol/mol decrease in glycated hemoglobin 0.22%; 95% CI, 0.03–0.42; P =0.03). The magnitude of these benefits exceeded those expected from improved glycemic control more generally. The results were similar in sensitivity analyses, and we did not find evidence to suggest that these associations were mediated by reduced coronary artery disease risk. Conclusions This genetic evidence supports the repurposing of GLP1R agonists for preventing HF.

Aims Polypharmacy is widespread and associated with medication-related harms, including adverse drug reactions, medication errors and poor treatment adherence. General practitioners and pharmacists cite limited time and training to perform effective medication reviews for patients with complex polypharmacy, yet no specialist referral mechanism exists. To develop a structured framework for specialist review of primary care patients with complex polypharmacy. Methods We developed the clinical pharmacology structured review (CPSR) and stopping by indication tool (SBIT). We tested these in an age-sex stratified sample of 100 people with polypharmacy aged 65-84 years from the Clinical Practice Research Datalink, an anonymised primary care database. Simulated medication reviews based on electronic records using the CPSR and SBIT were performed. We recommended medication changes or review to optimise treatment benefits, reduce risk of harm or reduce treatment burden. Results Recommendations were made for all patients, for almost half (4.8 ± 2.4) of existing medicines (9.8 ± 3.1), most commonly stopping a drug (1.7 ± 1.3/patient) or reviewing with the patient (1.4 ± 1.2/patient). At least 1 new medicine (0.7 ± 0.9) was recommended for 51% patients. Recommendations predominantly aimed to reduce harm (44%). There was no relationship between number of recommendations made and time since last primary care medication review. We identified a core set of clinical information and investigations (polypharmacy workup) that could inform a standard screen prior to specialist review. Conclusion The CPSR, SBIT and polypharmacy workup could form the basis of a specialist review for patients with complex polypharmacy. Further research is needed to test this approach in patients in general practice.

Background: Since the COVID-19 pandemic began in December 2019 no specific therapy for managing severe complications of infection has emerged, although this is under intensive investigation. Progressive pneumonia and multi-organ complications are managed with supportive care and COVID-19 has a mortality of >50% when ventilatory support is needed.Methods: We implemented a compassionate use protocol for tocilizumab, a humanised monoclonal anti-Il-6 receptor antibody. Patients with severe COVID-19 requiring oxygen or ventilation, and complicated by hyperinflammation and the cytokine release syndrome (CRS) received tocilizumab (8 mg/kg up to a maximum of 800 mg, with the option of a second dose given after 12-24 hours). CRS was defined as having at least three of: D-dimer above the upper limit of normal (ULN), rising C-reactive protein (CRP), ferritin >1000 ng/mL and lactate dehydrogenase (LDH) greater than the ULN.Oral consent for prescription of an off-label medicine was obtained from patients, their next of kin or representative, whenever possible. The treatment protocol adhered to the Monitored Emergency Use of Unregistered and Investigational Interventions of the WHO.Findings: Of seventeen patients with severe COVID-19 seen between 3-12th April 2020, eleven patients (seven ventilated and four receiving high flow oxygen) were treated with tocilizumab. Treatment normalised temperatures within 48 hours and was associated with a significant fall in CRP from 311 (138-332) (median, IQR mg/L) to 110 (58-184) (p = 0·001). For the group, oxygen requirements fell by 60±32% (95% CI 38-81) over 1 week (p

RATIONALE: COPD exacerbations are prone to non-recovery but there are no data about the effectiveness of retreatment on these prolonged events. We examined whether further therapy with ciprofloxacin for incompletely resolved COPD exacerbations prolonged the time until the next event. METHODS: This multi-centre randomised double-blind placebo-controlled trial studied retreatment with oral ciprofloxacin 500mg or matched placebo twice daily for 7 days in patients with GOLD stage II - IV COPD with persistent symptoms and/or serum C-reactive protein (CRP) ≥8mg/L initiated 14 (+/- 3) days after an index COPD exacerbation. The primary outcome was the time to the next exacerbation within a 90-day period. RESULTS: Of 826 patients screened at 4 centres, 144 eligible participants with incomplete recovery were randomised to receive ciprofloxacin (n=72) or placebo (n=72). 57% of patients in the ciprofloxacin group had experienced 1 or more exacerbations, compared to 53% in the placebo group. The median time to the next exacerbation was 32.5 days (IQR 13-50) in the placebo arm and 34 days (IQR 17-62) in the ciprofloxacin arm, which was not significantly different (adjusted hazard ratio = 1.07, 95% CI 0.68-1.68; p=0.76). No significant differences were seen in quality of life scores or lung function between treatment groups. CONCLUSION: In patients with persistent symptoms and/or raised CRP 14 days following a COPD exacerbation, an additional course of ciprofloxacin resulted in no additional benefit compared to placebo. This suggests that non-recovered exacerbations are not driven by ongoing bacterial infection and may potentially be targeted with anti-inflammatory therapy.

BackgroundChronic Obstructive Pulmonary Disease (COPD) is associated with an increased risk of myocardial infarction and stroke but it remains unclear how to identify microvascular changes in this population.ObjectivesWe hypothesized that simple non-mydriatic retinal photography is feasible and can be used to assess microvascular damage in COPD.MethodsNovel Vascular Manifestations of COPD was a prospective study comparing smokers with and without COPD, matched for age. Non-mydriatic, retinal fundus photographs were assessed using semi-automated software.ResultsRetinal images from 24 COPD and 22 control participants were compared. Cases were of similar age to controls (65.2 vs. 63.1 years, p = 0.38), had significantly lower Forced Expiratory Volume in one second (FEV1) (53.4 vs 100.1% predicted; p < 0.001) and smoked more than controls (41.7 vs. 29.6 pack years; p = 0.04). COPD participants had wider mean arteriolar (155.6 ±15 uM vs. controls [142.2 ± 12 uM]; p = 0.002) and venular diameters (216.8 ±20.7 uM vs. [201.3± 19.1 uM]; p = 0.012). Differences in retinal vessel caliber were independent of confounders, odds ratios (OR) = 1.08 (95% confidence intervals [CI] = 1.02, 1.13; p = 0.007) and OR = 1.05 (CI = 1.01, 1.09; p = 0.011) per uM increase in arteriolar and venular diameter respectively. FEV1 remained significantly associated with retinal vessel dilatation r = -0.39 (p = 0.02).ConclusionsNon-mydriatic retinal imaging is easily facilitated. We found significant arteriole and venous dilation in COPD compared to age-matched smokers without COPD associated with lung function independent of standard cardiovascular risk factors. Retinal microvascular changes are known to be strongly associated with future vascular events and retinal photography offers potential to identify this risk.

IntroductionCigarette smoking and oxidative stress are common risk factors for the multi-morbidities associated with chronic obstructive pulmonary disease (COPD). Elevated levels of advanced glycation endproducts (AGE) increase the risk of cardiovascular disease (CVD) comorbidity and mortality. The enzyme fructosamine-3-kinase (FN3K) reduces this risk by lowering AGE levels.MethodsThe distribution and expression of FN3K protein in lung tissues from stable COPD and control subjects, as well as an animal model of COPD, was assessed by immunohistochemistry. Serum FN3K protein and AGE levels were assessed by ELISA in patients with COPD exacerbations receiving metformin. Genetic variants within the FN3K and FN3K-RP genes were evaluated for associations with cardiorespiratory function in the Subpopulations and Intermediate Outcome Measures in COPD Study cohort.ResultsThis pilot study demonstrates that FN3K expression in the blood and human lung epithelium is distributed at either high or low levels irrespective of disease status. The percentage of lung epithelial cells expressing FN3K was higher in control smokers with normal lung function, but this induction was not observed in COPD patients nor in a smoking model of COPD. The top five nominal FN3K polymorphisms with possible association to decreased cardiorespiratory function (pDiscussionThe data highlight that low and high FN3K expressors exist within our study cohort and metformin induces FN3K levels, highlighting a potential mechanism to reduce the risk of CVD comorbidity and mortality.

In health, the glucose concentration of airway surface liquid (ASL) is 0.4 mM, about 12 times lower than the blood glucose concentration. Airway glucose homeostasis comprises a set of processes that actively maintain low ASL glucose concentration against the transepithelial gradient. Tight junctions between airway epithelial cells restrict paracellular glucose movement. Epithelial cellular glucose transport and metabolism removes glucose from ASL. Low ASL glucose concentrations make an important contribution to airway defense against infection, limiting bacterial growth by restricting nutrient availability. Both airway inflammation, which increases glucose permeability of tight junctions, and hyperglycemia, which increases the transepithelial glucose gradient, increase ASL glucose concentrations, with the greatest effect seen where they coexist. Elevated ASL glucose drives proliferation of bacteria able to use glucose as a carbon source, including Staphylococcus aureus, Pseudomonas aeruginosa, and other gram-negative bacteria. Clinically, this appears to be important in driving exacerbations of chronic lung disease, especially in patients with comorbid diabetes mellitus. Drugs can restore airway glucose homeostasis by reducing the permeability of tight junctions (eg, metformin), increasing epithelial cell glucose transport (eg, β-agonists, insulin), and/or by lowering blood glucose (eg, dapagliflozin). In cell culture and animal models these reduce ASL glucose concentrations and limit bacterial growth, preventing infection. Observational studies in humans indicate that airway glucose homeostasis-modifying drugs could prevent chronic lung disease exacerbations if tested in randomized trials.

Background and Purpose Hyperglycaemia increases glucose concentrations in airway surface liquid and increases the risk of pulmonary Pseudomonas aeruginosa infection. We determined whether reduction of blood and airway glucose concentrations by the anti-diabetic drug dapagliflozin could reduce P. aeruginosa growth/survival in the lungs of diabetic mice. Experimental Approach The effect of dapagliflozin on blood and airway glucose concentration, the inflammatory response and infection were investigated in C57BL/6J (wild type, WT) or leptin receptor-deficient (db/db) mice, treated orally with dapagliflozin prior to intranasal dosing with LPS or inoculation with P. aeruginosa. Pulmonary glucose transport and fluid absorption were investigated in Wistar rats using the perfused fluid-filled lung technique. Key Results Fasting blood, airway glucose and lactate concentrations were elevated in the db/db mouse lung. LPS challenge increased inflammatory cells in bronchoalveolar lavage fluid from WT and db/db mice with and without dapagliflozin treatment. P. aeruginosa colony-forming units (CFU) were increased in db/db lungs. Pretreatment with dapagliflozin reduced blood and bronchoalveolar lavage glucose concentrations and P. aeruginosa CFU in db/db mice towards those seen in WT. Dapagliflozin had no adverse effects on the inflammatory response in the mouse or pulmonary glucose transport or fluid absorption in the rat lung. Conclusion and Implications Pharmacological lowering of blood glucose with dapagliflozin effectively reduced P. aeruginosa infection in the lungs of diabetic mice and had no adverse pulmonary effects in the rat. Dapagliflozin has potential to reduce the use, or augment the effect, of antimicrobials in the prevention or treatment of pulmonary infection.

BACKGROUND: Chronic obstructive pulmonary disease (COPD; including chronic bronchitis and emphysema) is a chronic respiratory condition characterised by shortness of breath, cough and recurrent exacerbations. Long‐term antibiotic use may reduce both bacterial load and inflammation in the airways. Studies have shown a reduction of exacerbations with antibiotics in comparison to placebo in people with COPD, but there are concerns about antibiotic resistance and safety. OBJECTIVES: To compare the safety and efficacy of different classes of antibiotics (continuous, intermittent or pulsed) for prophylaxis of exacerbations in patients with COPD. SEARCH METHODS: We searched the Cochrane Airways Group Trials Register and bibliographies of relevant studies. The latest literature search was conducted on 6 February 2019. SELECTION CRITERIA: Randomised controlled trials (RCTs) were selected that compared one prophylactic antibiotic with another in patients with COPD. DATA COLLECTION AND ANALYSIS: We used the standard Cochrane methods. Two independent review authors selected trials for inclusion, extracted data and assessed risk of bias. Discrepancies were resolved by involving a third review author. MAIN RESULTS: We included two RCTs, both published in 2015 involving a total of 391 participants with treatment duration of 12 to 13 weeks. One RCT compared a quinolone (moxifloxacin pulsed, for 5 days every 4 weeks), with a tetracycline (doxycycline continuous) or a macrolide (azithromycin intermittent). The second RCT compared a tetracycline (doxycycline continuous) plus a macrolide (roxithromycin continuous), with roxithromycin (continuous) alone. The trials recruited participants with a mean age of 68 years, with moderate‐severity COPD. Both trials included participants who had between two and five exacerbations in the previous one to two years. In one trial, 17% of patients had previously been using inhaled corticosteroids. In the other study, all patients were positive for Chlamydophila pneumoniae (C pneumoniae). Overall, we judged the evidence presented to be of very low‐certainty, mainly due to imprecision, but we also had concerns about indirectness and methodological quality of the included studies. The primary outcome measures for this review included exacerbations, quality of life, drug resistance and serious adverse events. Macrolide + tetracycline versus macrolide There was no clear difference between treatments in improvement in quality of life as assessed by the Chronic Respiratory Questionnaire (CRQ). The CRQ scale ranges from 0 to 10 and higher scores on the scale indicate better quality of life. CRQ sub‐scales for dyspnoea (mean difference (MD) 0.58, 95% confidence interval (CI) ‐0.84 to 2.00; 187 participants; very low‐certainty evidence), fatigue (MD 0.02, 95% CI ‐1.08 to 1.12; 187 participants; very low‐certainty evidence), emotional function (MD ‐0.37, 95% CI ‐1.74 to 1.00; 187 participants; very low‐certainty evidence), or mastery (MD ‐0.79, 95% CI ‐1.86 to 0.28; 187 participants; very low‐certainty evidence) at 12 weeks. For serious adverse events, it was uncertain if there was a difference between combined roxithromycin and doxycycline versus roxithromycin alone at 48 weeks follow‐up after active treatment of 12 weeks (odds ratio (OR) 1.00, 95% CI 0.52 to 1.93; 198 participants; very low‐certainty evidence). There were five deaths reported in the combined treatment arm, versus three in the single treatment arm at 48 weeks follow‐up after active treatment of 12 weeks (OR 1.63, 95% CI 0.38 to 7.02; 198 participants; very low‐certainty evidence). Quinolone versus tetracycline There was no clear difference between moxifloxacin and doxycycline for the number of participants experiencing one or more exacerbations (OR 0.44, 95% CI 0.14 to 1.38; 50 participants, very low‐certainty evidence) at 13 weeks. There were no serious adverse events or deaths reported in either treatment groups. We did not identify any evidence for our other primary outcomes. Quinolone versus macrolide There was no clear difference between moxifloxacin and azithromycin for the number of participants experiencing one or more exacerbations (OR 1.00, 95% CI 0.32 to 3.10; 50 participants; very low‐certainty evidence) at 13 weeks. There were no serious adverse events or deaths reported in either treatment groups. We did not identify any evidence for our other primary outcomes. Marcolide versus tetracycline There was no clear difference between azithromycin and doxycycline for the number of participants experiencing one or more exacerbations (OR 0.44, 95% CI 0.14 to 1.38; 50 participants; very low‐certainty evidence) at 13 weeks. There were no serious adverse events or deaths reported in either treatment groups. We did not identify any evidence for our other primary outcomes. We did not find head‐to‐head evidence for impact of antibiotics on drug resistance. AUTHORS' CONCLUSIONS: It is not clear from the evidence included in this review whether there is a difference in efficacy or safety between different classes or regimens of prophylactic antibiotic, given for 12 to 13 weeks to people with COPD. Whilst no head‐to‐head comparisons of antibiotic resistance were identified, concerns about this continue. The sample size in this review is small and both included studies are of short duration. Thus, there is considerable uncertainty in effects observed and the effects of different prophylactic antibiotics requires further research.

Background Brain damage and cardiovascular disease are extra-pulmonary manifestations of chronic obstructive pulmonary disease (COPD). Cardiovascular risk factors and smoking are contributors to neurodegeneration. This study investigates whether there is a specific, COPD-related deterioration in brain structure and function independent of cardiovascular risk factors and smoking. Materials and methods Neuroimaging and clinical markers of brain structure (micro- and macro-) and function (cognitive function and mood) were compared between 27 stable COPD patients (age: 63.0±9.1 years, 59.3% male, forced expiratory volume in 1 second [FEV1]: 58.1±18.0% pred.) and 23 non-COPD controls with >10 pack years smoking (age: 66.6±7.5 years, 52.2% male, FEV1: 100.6±19.1% pred.). Clinical relationships and group interactions with brain structure were also tested. All statistical analyses included correction for cardiovascular risk factors, smoking, and aortic stiffness. Results COPD patients had significantly worse cognitive function (p=0.011), lower mood (p=0.046), and greater gray matter atrophy (p=0.020). In COPD patients, lower mood was associated with markers of white matter (WM) microstructural damage (p

OBJECTIVE: To assess the impact of home telemonitoring on health service use and quality of life in patients with severe chronic lung disease. DESIGN: Randomised crossover trial with 6 months of standard best practice clinical care (control group) and 6 months with the addition of telemonitoring. PARTICIPANTS: 68 patients with chronic lung disease (38 with COPD; 30 with chronic respiratory failure due to other causes), who had a hospital admission for an exacerbation within 6 months of randomisation and either used long-term oxygen therapy or had an arterial oxygen saturation (SpO2) of

Background Severe exacerbations of COPD are commonly associated with hyperglycaemia, which predicts adverse outcomes. Metformin is a well-established anti-hyperglycaemic agent in diabetes mellitus, possibly augmented with anti-inflammatory effects, but its effects in COPD are unknown. We investigated accelerated metformin therapy in severe COPD exacerbations, primarily to confirm or refute an anti-hyperglycaemic effect, and secondarily to explore its effects on inflammation and clinical outcome. Methods This was a multicentre, randomised, double-blind, placebo-controlled trial testing accelerated metformin therapy in non-diabetic patients, aged ≥35 years, hospitalised for COPD exacerbations. Participants were assigned in a 2:1 ratio to 1 month of metformin therapy, escalated rapidly to 2 g/day, or matched placebo. The primary end point was mean in-hospital blood glucose concentration. Secondary end points included the concentrations of fructosamine and C reactive protein (CRP), and scores on the COPD Assessment Test and Exacerbations of Chronic Pulmonary Disease Tool. Results 52 participants (mean (±SD) age 67±9 years) were randomised (34 to metformin, 18 to placebo). All were included in the primary end point analysis. The mean blood glucose concentrations in the metformin and placebo groups were 7.1±0.9 and 8.0±3.3 mmol/L, respectively (difference −0.9 mmol/L, 95% CI −2.1 to +0.3; p=0.273). No significant between-group differences were observed on any of the secondary end points. Adverse reactions, particularly gastrointestinal effects, were more common in metformin-treated participants. Conclusion Metformin did not ameliorate elevations in blood glucose concentration among non-diabetic patients admitted to hospital for COPD exacerbations, and had no detectable effect on CRP or clinical outcomes. Trial registration number ISRCTN66148745 and NCT01247870.

BackgroundOver 30% of adult patients with pleural infection either die and/or require surgery. There is no robust means of predicting at baseline presentation which patients will suffer a poor clinical outcome. A validated risk prediction score would allow early identification of high-risk patients, potentially directing more aggressive treatment thereafter.ObjectivesTo prospectively assess a previously described risk score (the RAPID (Renal (urea), Age, fluid Purulence, Infection source, Dietary (albumin)) score) in adults with pleural infection.MethodsProspective observational cohort study that recruited patients undergoing treatment for pleural infection. RAPID score and risk category were calculated at baseline presentation. The primary outcome was mortality at 3 months; secondary outcomes were mortality at 12 months, length of hospital stay, need for thoracic surgery, failure of medical treatment and lung function at 3 months.ResultsMortality data were available in 542 out of 546 patients recruited (99.3%). Overall mortality was 10% at 3 months (54 out of 542) and 19% at 12 months (102 out of 542). The RAPID risk category predicted mortality at 3 months. Low-risk mortality (RAPID score 0–2): five out of 222 (2.3%, 95% CI 0.9 to 5.7%); medium-risk mortality (RAPID score 3–4): 21 out of 228 (9.2%, 95% CI 6.0 to 13.7%); and high-risk mortality (RAPID score 5–7): 27 out of 92 (29.3%, 95% CI 21.0 to 39.2%). C-statistics for the scores at 3 months and 12 months were 0.78 (95% CI 0.71–0.83) and 0.77 (95% CI 0.72–0.82), respectively.ConclusionsThe RAPID score stratifies adults with pleural infection according to increasing risk of mortality and should inform future research directed at improving outcomes in this patient population.

As clinical pharmacologists representing a truly generalist specialty, spanning all ages and organs, we welcome the call for rebalancing of specialist and generalist skills to improve care for patients with multimorbidity.1 Clinical pharmacology and therapeutics (CPT) arose in the last century in response to the explosive development of new drugs and parallel evolution of medicines regulation. In the 1970s, the …

Mohani-Preet K Bajaj,1 Daniel R Burrage,2 Andrew Tappouni,3 James W Dodd,4 Paul W Jones,2 Emma H Baker2 1Neurosciences Research Centre, Molecular and Clinical Sciences Research Institute, St George’s University of London, London, UK; 2Clinical Pharmacology, Institute of Infection and Immunity, St George’s University of London, London, UK; 3St George’s University of London, London, UK; 4Academic Respiratory Unit, University of Bristol, Bristol, UK Purpose: People with COPD have cognitive dysfunction, which is greater in those hospitalized for exacerbations than in stable outpatients. We tested the hypothesis that cognitive dysfunction at exacerbation is a disease-specific feature of COPD, rather than a nonspecific feature of hospitalization for acute illness, by comparing cognition between patients hospitalized for acute COPD exacerbations and those with worsening heart failure (HF). Patients and methods: A total of 40 hospital inpatients were recruited, 20 patients with COPD exacerbations and 20 patients with congestive or left-sided HF. Exclusion criteria included previous stroke, known neurological disease, and marked alcohol excess. Participants completed the Montreal cognitive assessment (MoCA) and Hospital Anxiety and Depression Scale (HADS) and underwent spirometry and review of clinical records. Results: Age (mean±SD, COPD 73±10; HF 76±11years), acute illness severity (Acute Physiology and Chronic Health Evaluation [APACHE]-II, COPD 15.4±3.5; HF 15.9±3.0), comorbidities (Charlson index, COPD 1.3±1.9; HF 1.6±1.5), and educational background were similar between COPD and HF groups. MoCA total was significantly lower in COPD than in HF (COPD 20.6±5.6; HF 24.8±3.5, P=0.007); however, significance was lost after correction for age, sex, and pack year smoking history. When compared with HF patients, the COPD cohort performed worse on the following domains of the MoCA: visuospatial function (median [IQR], COPD 0 [1]; HF 2 [1], P=0.003), executive function (COPD 2 [1]; HF 3 [1], P=0.035), and attention (COPD 4 [3]; HF 6 [2], P=0.020). Age (P=0.012) and random glucose concentration (P=0.041) were associated with cognitive function in whole group analysis, with pack year smoking history reaching borderline significance (P=0.050). Conclusion: Total MoCA score for COPD and HF indicated that both groups had mild cognitive impairment, although this was greater in people with COPD. Mechanisms underlying the observed cognitive dysfunction in COPD remain unclear but appear related to blood glucose concentrations and greater lifetime smoking load. Keywords: Montreal cognitive assessment, cognition, comorbidities, systemic, smoking, hyperglycemia

Introduction and objectives COPD patients are more likely to die from cardiovascular disease than from their lung disease. However, under diagnosis of vascular risk factors is common. The aim of this study was to evaluate prevalence and control of cardiovascular risk factors in COPD patients. Methods This was a cross-sectional study of stable COPD outpatients (no exacerbation for >6 weeks). Prior diagnosis and treatment of hypertension, dyslipidaemia and diabetes was recorded. Participants underwent spirometry and measurement of blood pressure, fasting blood lipid profile, plasma glucose and glycated haemoglobin (HbA1c). Hypertension was defined as a blood pressure ≥140/90 mmHg; type 2 diabetes was defined as HbA1c≥48 mmol/mol or fasting plasma glucose ≥7.0 mmol/L, and need for lipid-lowering therapy was based on QRISK2 score ≥10%. Blood pressure was considered controlled if Results 56 participants were recruited (age 69±8 years, 36 (64%) male, 47±25 pack years, FEV1% predicted 55±24 [means ±SD]). 45 (80%) participants had hypertension, 53 (95%) participants had a diagnosis of hyperlipidaemia or met the threshold for lipid-lowering therapy, and 6 (11%) participants had type 2 diabetes. The table 1 shows the proportion of participants with hypertension, hyperlipidaemia and type 2 diabetes who had an existing diagnosis (controlled), an existing diagnosis (uncontrolled) or a new diagnosis. Conclusions In this study around a third of patients had undiagnosed hypertension, and a third met the threshold for requiring lipid lowering therapy. Even in patients who had existing diagnoses, the majority were uncontrolled. In view of the high burden of cardiovascular disease in COPD patients, more attention needs to be given to assessment, treatment and monitoring of cardiovascular risk.

Background: COPD, cardiovascular disease and structural brain disease commonly coexist, but the relative contributions of COPD and cardiovascular disease to structural brain disease is unclear. Aim: The aim of this study was to determine the association between two different COPD phenotypes and structural brain disease. Methods: COPD patients were recruited from two populations. Group 1 were recruited from people attending for elective coronary angiography who had no exacerbations in the preceding year. Group 2 were recruited from people attending the respiratory outpatient department who had had at least 1 exacerbation in the preceding year. Participants underwent measurement of Framingham score (10-year risk of cardiovascular event), spirometry, arterial stiffness, skin capillary density, cardiac biomarkers, systemic inflammatory markers and structural brain MRI. Results: Group 1 had mild/moderate COPD with significantly higher cardiovascular risk whereas group 2 had moderate/severe COPD with lower cardiovascular risk (FEV1 % predicted 78±19 v 54±24 p Conclusion: Cardiovascular risk, rather than respiratory health, appears more strongly associated with white matter brain disease in these two groups of patients with COPD.

Background: People with COPD have reduced physical activity and increased cardiometabolic disease. Understanding the relationship between different types of inactivity and cardiometabolic impairment is important to design appropriate interventions Aim: To determine the effects of physical inactivity and sedentary behaviour on cardiometabolic profiles in COPD patients Methods: Stable COPD patients underwent actigraphy over 8 days. Physical inactivity was defined as Results: Metabolic syndrome was more common in high (SE 71%, CP 66%) than low sedentary groups (BB 20%, LM 0%, p=0.01). High sedentary patients had greater insulin resistance (HOMA2IR) (SE 2.2±1.0, CP 3.1±2.2, BB 1.5±0.7, LM 0.9±0.4, p=0.028) and lower HDL cholesterol (SE 1.7±0.5, CP 1.5±0.5, BB 2.2±1.0, LM 2.4±0.6, p=0.015). On univariate analysis, after adjustment for age and gender, sedentary behaviour determined HOMA2IR and HDL, independent of physical activity Conclusions: Sedentary behaviour was associated with worse cardiometabolic profile, independent of physical activity. Interventions to promote non-sedentary behaviour could improve cardiometabolic profiles, even in COPD patients unable to achieve moderate intensity activity

Background: Cardiovascular disease is common in chronic obstructive pulmonary disease but little is known about its effect on capillary rarefaction, a marker of microvascular function. Both inhaled salbutamol and ipratropium can induce systemic haemodynamic changes acutely potentially confounding measurements of capillary rarefaction. Aim: To investigate the acute effect of inhaled salbutamol and ipratropium on changes in skin capillary density, a marker of capillary rarefaction and microvascular function. Methods: 27 healthy normotensive adults 19-24 years were recruited into a crossover study receiving inhaled salbutamol 400 micrograms or ipratropium 160 micrograms via a spacer in random order at least 24 hours apart. Spirometry and functional skin capillary density were assessed before and after drug administration. A subgroup of participants also had capillary density measured after venous congestion to assess maximal (structural) capillary density. Results: There was no significant difference in functional capillary density after salbutamol or ipratropium (mean±SD, 57±13 to 60±11 per field; p=0.205, n=23, and 57±13 to 54±12 per field; p=0.138, n=23, respectively). However, salbutamol significantly increased maximal skin capillary density compared to baseline (58±12 to 71±15 per field; p=0.009, n=10) whereas ipratropium had no effect (58±12 to 61±12 per field; p=0.663, n=9). Conclusions: Inhaled salbutamol has a significant effect on capillary rarefaction. This may be attributable to vasodilatation of resistance arterioles. When performing capillaroscopy in conjunction with post-bronchodilator spirometry, ipratropium may be the bronchodilator of choice due to its lack of acute effect on vascular tone.

Background: Accurate evaluation of aortic stiffness and pressure wave reflection may improve cardiovascular risk stratification in chronic obstructive pulmonary disease. However, it is not clear whether systemic haemodynamic changes induced acutely by inhaled salbutamol and ipratropium confound these measurements. Aim: To investigate the acute effect of inhaled salbutamol and ipratropium on measures of aortic stiffness (aortic pulse wave velocity/aPWV) and pressure wave reflection (central augmentation index/cAIx). Methods: 27 healthy normotensive adults aged 19-24 years were recruited into a crossover study receiving inhaled salbutamol 400 micrograms or ipratropium 160 micrograms via a spacer in random order at least 24 hours apart. Spirometry, blood pressure, aPWV (carotid-femoral) and cAIx were measured at baseline, 15 mins after salbutamol and 45 mins after ipratropium administrations. aPWV and cAIx were measured using a validated system (Vicorder®). Results: Salbutamol reduced cAIx from 12±5% to 8±6% (mean±SD; p Conclusions: Inhaled salbutamol has a significant effect on cAIx in healthy volunteers. This may be due to its actions on resistance arterioles and pressure wave reflection. If performing pulse wave analysis/pulse wave velocity with post-bronchodilator spirometry, ipratropium may be the bronchodilator of choice due to its lack of acute effect on central haemodynamics.

Elevation of blood glucose results in increased glucose in the fluid that lines the surface of the airways and this is associated with an increased susceptibility to infection with respiratory pathogens. Infection induces an inflammatory response in the lung, but how this is altered by hyperglycemia and how this affects glucose, lactate and cytokine concentrations in the airway surface liquid is not understood. We used Wild Type (WT) and glucokinase heterozygote (GK+/-) mice to investigate the effect of hyperglycemia, with and without LPS-induced inflammatory responses, on airway glucose, lactate, inflammatory cells and cytokines measured in Bronchoalveolar Lavage Fluid (BALF).

Airway epithelial tight junction (TJ) proteins form a resistive barrier to the external environment, however, during respiratory bacterial infection TJs become disrupted compromising barrier function. This promotes glucose flux/accumulation into the lumen which acts as a nutrient source for bacterial growth. Metformin used for the treatment of diabetes increases transepithelial resistance (TEER) and partially prevents the effect of bacteria but the mechanisms of action are unclear. We investigated the effect of metformin and Staphylococcus aureus on TJ proteins, zonula occludins (ZO)‐1 and occludin in human airway epithelial cells (H441). We also explored the role of AMP‐activated protein kinase (AMPK) and PKCζ in metformin‐induced effects. Pretreatment with metformin prevented the S. aureus‐induced changes in ZO‐1 and occludin. Metformin also promoted increased abundance of full length over smaller cleaved occludin proteins. The nonspecific PKC inhibitor staurosporine reduced TEER but did not prevent the effect of metformin indicating that the pathway may involve atypical PKC isoforms. Investigation of TJ reassembly after calcium depletion showed that metformin increased TEER more rapidly and promoted the abundance and localization of occludin at the TJ. These effects were inhibited by the AMPK inhibitor, compound C and the PKCζ pseudosubstrate inhibitor (PSI). Metformin increased phosphorylation of occludin and acetyl‐coA‐carboxylase but only the former was prevented by PSI. This study demonstrates that metformin improves TJ barrier function by promoting the abundance and assembly of full length occludin at the TJ and that this process involves phosphorylation of the protein via an AMPK‐PKCζ pathway.

AIMS: Prescribing is a complex skill required of doctors and, increasingly, other healthcare professionals. Use of a personal formulary can help to develop this skill. In 2006–9, we developed a core list of the 100 most commonly prescribed drugs. Our aim in the present study was to update this ‘starter formulary’ to ensure its continued relevance for prescriber training. METHODS: We analysed large contemporary primary and secondary care datasets to identify the most frequently prescribed medicinal products. Items were classified into natural groups, broadly following their British National Formulary classification. The resulting drug groups were included in the core list if they comprised ≥0.1% prescriptions in both settings or ≥0.2–0.3% prescriptions in one setting. Drugs from emergency guidelines that did not qualify by prescribing frequency completed the list. RESULTS: Over 1 billion primary care items and approximately 1.8 million secondary care prescriptions were analysed. The updated list comprises 81 drug groups commonly prescribed in both settings; six from primary care; seven from secondary care; and six from emergency guidelines. Eighty‐eight per cent of the formulary was unchanged. Notable changes include entry of newer anti‐epileptics and dipeptidyl peptidase‐4 inhibitors and exit of phenytoin and thiazolidinediones. CONCLUSIONS: The relative stability of the core drug list over 9 years and the current update ensure that learning based on this list remains relevant to practice. Trainee prescribers may be encouraged to use this ‘starter formulary’ to develop a sound basis of prescribing knowledge and skills that they can subsequently apply more widely.

Background Loss of muscle mass is a co-morbidity common to a range of chronic diseases including chronic obstructive pulmonary disease (COPD). Several systemic features of COPD including increased inflammatory signalling, oxidative stress, and hypoxia are known to increase the expression of growth differentiation factor-15 (GDF-15), a protein associated with muscle wasting in other diseases. We therefore hypothesized that GDF-15 may contribute to muscle wasting in COPD. Methods We determined the expression of GDF-15 in the serum and muscle of patients with COPD and analysed the association of GDF-15 expression with muscle mass and exercise performance. To determine whether GDF-15 had a direct effect on muscle, we also determined the effect of increased GDF-15 expression on the tibialis anterior of mice by electroporation. Results Growth differentiation factor-15 was increased in the circulation and muscle of COPD patients compared with controls. Circulating GDF-15 was inversely correlated with rectus femoris cross-sectional area (P

BACKGROUND AND OBJECTIVE: Quadriceps weakness is seen across all GOLD stages of COPD and is associated with increased morbidity and mortality. As quadriceps weakness is only weakly associated with FEV1 , mechanisms other than airflow obstruction are implicated. We tested the hypothesis that insulin resistance contributes to skeletal muscle weakness in people with stable COPD. METHODS: Fifty-one COPD patients (no exacerbations preceding 6 weeks, no rehabilitation preceding 3 months) without known diabetes mellitus underwent assessment of skeletal muscle, including measurement of quadriceps maximal voluntary contraction (QMVC). Physical activity was measured for 7 days using a multisensory biaxial accelerometer armband. Insulin resistance (HOMA2 IR) was calculated from fasting blood glucose and insulin concentrations. RESULTS: QMVC was 30 ± 13 kg (74 ± 25% predicted) and 16 (31%) participants had quadriceps weakness. There was a negative univariate correlation between HOMA2 IR and QMVC (r = -0.446, P = 0.002). HOMA2 IR was greater in people with quadriceps weakness (1.59 ± 0.99) than in those without (1.11 ± 0.55, P = 0.032). On multivariate analysis, with age, sex, weight, BODE index and step count per day included in the model, a one-unit increase in insulin resistance was associated with a 5.9 (2.0-9.8)-kg decrease in QMVC (P = 0.004) and a 4.2 (1.3-14.3)-fold increased risk of quadriceps weakness (P = 0.02). CONCLUSION: Insulin resistance is associated with skeletal muscle weakness in COPD, independent of potential confounders. Further studies are required to explore underlying mechanisms and determine whether insulin-sensitizing drugs could augment pulmonary rehabilitation in building skeletal muscle strength in COPD.

Type 2 diabetes mellitus (T2DM) is commonly associated with chronic obstructive pulmonary disease (COPD). Metformin is a valuable treatment for T2DM, and may offer additional benefits in COPD. However, due to its rare association with lactic acidosis, its safety in COPD is uncertain. We retrospectively identified patients with T2DM who had been admitted to hospital for COPD exacerbations. We compared those who were taking metformin with those who were not, with respect to their lactate concentration (primary endpoint) and survival (secondary endpoint). The study cohort (n = 130) had a mean (±standard deviation) age of 73.0 ± 9.8 years and 47 (36%) were female. Arterial blood gases were recorded in 120 cases: 88 (73%) were hypoxemic, 45 (38%) were in respiratory failure and 33 (28%) had respiratory acidosis. The 51 patients (39%) in the metformin group had a median (interquartile range) lactate concentration of 1.45 mmol/L (1.10-2.05) versus 1.10 mmol/L (0.80-1.50) in the non-metformin group (p = 0.012). Median survival was 5.2 years (95% CI 4.5-5.8) versus 1.9 years (1.1-2.6), respectively (hazard ratio 0.57; 95% CI 0.35-0.94). This remained significant in a multivariate model adjusted for measurable confounders. In conclusion, among patients with COPD at high risk for lactate accumulation, metformin therapy was associated with a minor elevation of lactate concentration of doubtful clinical significance. Metformin was associated with a survival benefit, but this must be interpreted cautiously due to possible effects from unmeasured confounders. Viewed collectively, the results suggest that COPD should not present a barrier to the investigational or clinical use of metformin.

Within certain limits, missing items in the EXACT instrument can be imputed from the remaining answered items http://ow.ly/4mJQzP

Background COPD is linked to risk of MI, stroke and white matter brain lesions, but there is no recognised method of identifying those who go on to have acute vascular events. It also remains unclear if vascular risk in COPD is truly independent of smoking. The Novel Vascular Manifestations of COPD (NoVasC) study was designed to address this limitation through direct comparison of COPD patients and smoking controls using multimodal brain MRI, retinal photography, cardiac MRI (CMR) and aortic stiffness in addition to cognitive and disease severity measures. Methods MR brain volumes, diffusion, blood flow and white matter lesions were acquired for 27 COPD patients (age 67±8, 41% male, pack years 39±21, FEV158%±18% predicted) and 23 controls (age 63±9, 48% male, pack years 30±14, FEV1101%±19% predicted). CMR of LV and RV function, volumes and aortic distensibility were captured using a 3-Telsa MR scanner. Pulse wave velocity and augmentation index were acquired using Vicorder. Retinal fundus photographs were analysed using validated automated software (SIVA). Analyses adjusted for differences in age, gender, blood pressure and pack years smoked. Results Significant differences in grey matter volume (p=0.004), retinal vessels (p=0.005) and CMR (p=0.01) were identified in COPD (Table 1). There was significant correlation between grey matter volume and BMI (r=−0.42 p=0.005) only. White matter lesion volume was associated with FEV1/FVC and creatinine (r=0.29 p=0.048 and r=−0.33 p=0.027). Cerebral blood flow was associated with arterial pH in COPD (r=−0.49 p=0.019).There were no significant associations identified between other MR brain, cognition, disease severity or retinal measures. Significant correlations were identified between CMR and white matter damage (DTI r=0.50 p=0.001) and FEV1/FVC (r=0.447 p=0.003) and retinal measures with FEV1% pred (r=−0.43 p=0.006). Conclusions Grey matter atrophy, retinal vessel dilatation, and aortic distensibility are present in COPD. White matter lesions volume is associated with lung function but there was no relationship between other MRI brain measures, cognition or disease severity. Non-invasive vascular measures of retinal vessels and cardiac MR appear to relate to lung function and white matter damage and warrant further investigation in larger longitudinal studies of vascular events in COPD.

In health, the glucose concentration of airway surface liquid (ASL) is 0.4 mM, about 12 times lower than the blood glucose concentration. Airway glucose homeostasis comprises a set of processes that actively maintain low ASL glucose concentration against the transepithelial gradient. Tight junctions between airway epithelial cells restrict paracellular glucose movement. Epithelial cellular glucose transport and metabolism removes glucose from ASL. Low ASL glucose concentrations make an important contribution to airway defense against infection, limiting bacterial growth by restricting nutrient availability. Both airway inflammation, which increases glucose permeability of tight junctions, and hyperglycemia, which increases the transepithelial glucose gradient, increase ASL glucose concentrations, with the greatest effect seen where they coexist. Elevated ASL glucose drives proliferation of bacteria able to use glucose as a carbon source, including Staphylococcus aureus, Pseudomonas aeruginosa, and other gram-negative bacteria. Clinically, this appears to be important in driving exacerbations of chronic lung disease, especially in patients with comorbid diabetes mellitus. Drugs can restore airway glucose homeostasis by reducing the permeability of tight junctions (eg, metformin), increasing epithelial cell glucose transport (eg, β-agonists, insulin), and/or by lowering blood glucose (eg, dapagliflozin). In cell culture and animal models these reduce ASL glucose concentrations and limit bacterial growth, preventing infection. Observational studies in humans indicate that airway glucose homeostasis-modifying drugs could prevent chronic lung disease exacerbations if tested in randomized trials.