Spores of Clostridium difficile Clinical Isolates Display a Diverse Germination Response to Bile Salts

Clostridium difficile spores play a pivotal role in the transmission of infectious diarrhoea, but in order to cause disease spores must complete germination and return to vegetative cell growth. While the mechanisms of spore germination are well understood in Bacillus, knowledge of C. difficile germination remains limited. Previous studies have shown that bile salts and amino acids play an important role in regulating the germination response of C. difficile spores. Taurocholate, in combination with glycine, can stimulate germination, whereas chenodeoxycholate has been shown to inhibit spore germination in a C. difficile clinical isolate. Our recent studies of C. difficile sporulation characteristics have since pointed to substantial diversity among different clinical isolates. Consequently, in this study we investigated how the germination characteristics of different C. difficile isolates vary in response to bile salts. By analysing 29 isolates, including 16 belonging to the BI/NAP1/027 type, we show that considerable diversity exists in both the rate and extent of C. difficile germination in response to rich medium containing both taurocholate and glycine. Strikingly, we also show that although a potent inhibitor of germination for some isolates, chenodeoxycholate does not inhibit the germination, or outgrowth, of all C. difficile strains. Finally, we provide evidence that components of rich media may induce the germination of C. difficile spores, even in the absence of taurocholate. Taken together, these data suggest that the mechanisms of C. difficile spore germination in response to bile salts are complex and require further study. Furthermore, we stress the importance of studying multiple isolates in the future when analysing the nutrients or chemicals that either stimulate or inhibit C. difficile spore germination

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

A Formulary Analysis of Angiotensin II Antagonists in a UK Teaching Hospital

Objective: To develop a method of value analysis which would facilitate an objective comparison of available angiotensin II antagonists as antihypertensive agents, in order to provide an adaptable framework which would allow for future developments in new product introduction and changes in evidence base. Methods: Six angiotensin II antagonists were available for review at the time of the study: candesartan, eprosartan, irbesartan, losartan, telmisartan and valsartan. A team comprised of a cardiologist, a physician and a pharmacist conducted the evaluation. A nine-point selection criteria set was developed as a comparison framework. Each criterion was assigned a relative weighted value by the panel. Each drug product was systematically evaluated against each criterion to generate a series of product-criterion scores. Results: A total score for each product was derived by combining product-criterion scores and the respective weighted values. The results obtained were presented to the hospital's Drug and Therapeutics committee. Analysis of these scores ranked losartan highest (707), followed by valsartan (611) and candesartan (610). The agents most recently introduced on to the UK market scored the lowest. Conclusion: The formulary analysis was accepted by the therapeutics committee as a viable method of comparison and consequently the previous formulary selections of candesartan and losartan was deemed to be justified.Angiotensin II 1 receptor antagonists, Antihypertensives, Hypertension, Pharmacoeconomics

Left atrial size and function:Assessment using echocardiographic automatic boundary detection

OBJECTIVE--To evaluate the waveforms of left atrial area changes obtained by automated boundary detection with newly developed acoustic quantification technology. DESIGN--All subjects had measurements of left atrial areas taken in the apical four chamber, parasternal long axis, and parasternal short axis views using both conventional echocardiographic methods and automatic boundary detection on two occasions separated by at least a week. On the second visit measurements were also repeated in healthy volunteers after acute intravenous volume loading with 1 litre of saline over 2-5 minutes. SETTING--A university medical school echocardiographic laboratory. SUBJECTS--12 healthy male volunteers and 8 patients with cardiac disease (5 with congestive heart failure, 1 with mitral stenosis, and 2 with hypertensive left ventricular hypertrophy, and dilated left atria). RESULTS--There was close correlation between conventionally derived left atrial areas and those obtained by automatic boundary detection, particularly in the apical four chamber view (r = 0.98). Both inter and intra observer variabilities (coefficient of variation) for left atrial areas measured by automatic boundary detection were good (4.7-14.2% and 8.1-18.6% respectively). The reproducibility (coefficient of variation) for derived indices of left atrial function, however, was much poorer (10.4-104.8% and 12.5-88% respectively). After acute volume loading significant increases in left atrial area were observed at all stages in the cardiac cycle. CONCLUSIONS--These data demonstrate that although the reproducibility of left atrial functional indices is poor, instantaneous left atrial cavity measurements with automatic boundary detection are reproducible. This suggests that automatic boundary detection may assist in serial non-invasive measurement of left atrial size to assess disease states and treatments