Comparing post-operative resource consumption following transcatheter aortic valve implantation (TAVI) and conventional aortic valve replacement in the UK.

OBJECTIVE: To define the in-hospital and 6-month post-discharge resource use, following Transcatheter Aortic Valve Implantation (TAVI) and conventional Aortic Valve Replacement (AVR) surgery within a single UK hospital. METHODS: A local service evaluation of patients undergoing TAVI or AVR between January 2011 and May 2012 captured data until 6-months post-procedure, collected from hospital records and via a General Practitioner questionnaire. The main end-points were mortality, time in ITU/HDU, hospital length of stay (LoS), discharge destination, re-admission, and post-discharge primary/secondary care resource use. Sub-group analyses were performed for AVR patients aged ≥80 (AVR ≥ 80) and with EuroSCORE of ≥10 (AVR ES ≥ 10) to allow more direct comparison with 'TAVI type' patients. RESULTS: Results are given as means (standard deviation) for TAVI (n = 51), AVR (n = 188), AVR ≥ 80 (n = 48), and AVR ES ≥ 10 (n = 47), respectively, unless otherwise stated. Age in years was 83.0 (8.1), 71.2 (13.1), 84.1 (2.7), 79.4 (7.1); EuroSCORE was 24.7 (11.9), 8.1 (6.4), 12.0 (6.0), and 16.5 (6.6); post-operative LoS (days) was 11.5 (11.2), 10.9 (10.8), 14.3 (16.7), and 15.2 (17.7). For discharged patients, 0%, 7%, 13%, and 9% had unplanned cardiac-related re-admissions within 30-days of discharge. Time to first readmission was 74.6 (34.0), 35.0 (34.2), 20.8 (9.7), and 22.6 (14.3) days. LIMITATIONS: This was a single-center retrospective evaluation, not prospectively powered to confirm differences in outcomes. CONCLUSIONS: Despite TAVI being performed in an older, higher risk population, LoS was similar to AVR. Most strikingly there were no cardiac-related re-admissions within 30-days for TAVI and time to first re-admission was significantly longer. This evaluation suggests that TAVI is clinically appropriate and provides economic advantages in both the hospital and post-discharge setting in this high risk group. Many patients undergoing TAVI are considered unfit for surgery and, hence, TAVI offers a treatment that delivers similar results to traditional AVR without the high risk associated with surgery.

Measurement of microchannel fluidic resistance with a standard voltage meter.

A simplified method for measuring the fluidic resistance (R(fluidic)) of microfluidic channels is presented, in which the electrical resistance (R(elec)) of a channel filled with a conductivity standard solution can be measured and directly correlated to R(fluidic) using a simple equation. Although a slight correction factor could be applied in this system to improve accuracy, results showed that a standard voltage meter could be used without calibration to determine R(fluidic) to within 12% error. Results accurate to within 2% were obtained when a geometric correction factor was applied using these particular channels. When compared to standard flow rate measurements, such as meniscus tracking in outlet tubing, this approach provided a more straightforward alternative and resulted in lower measurement error. The method was validated using 9 different fluidic resistance values (from ∼40 to 600kPa smm(-3)) and over 30 separately fabricated microfluidic devices. Furthermore, since the method is analogous to resistance measurements with a voltage meter in electrical circuits, dynamic R(fluidic) measurements were possible in more complex microfluidic designs. Microchannel R(elec) was shown to dynamically mimic pressure waveforms applied to a membrane in a variable microfluidic resistor. The variable resistor was then used to dynamically control aqueous-in-oil droplet sizes and spacing, providing a unique and convenient control system for droplet-generating devices. This conductivity-based method for fluidic resistance measurement is thus a useful tool for static or real-time characterization of microfluidic systems.

Self-regulated, droplet-based sample chopper for microfluidic absorbance detection.

Akin to optical beam chopping, we demonstrate that formation and routing of aqueous droplets in oil can chop a fluidic sample to permit phase sensitive detection. This hand-operated microfluidic sample chopper (µChopper) greatly reduces the detection limit of molecular absorbance in a 27 µm optical path. With direct dependence on path length, absorbance is fundamentally incompatible with microfluidics. While other microfluidic absorbance approaches use complex additions to fabrication, such as fiber coupling and increased optical paths, this self-regulated µChopper uses opposing droplet generators to passively alternate sample and reference droplets at ~10 Hz each. Each droplet's identity is automatically locked-in to its generator, allowing downstream lock-in analysis to nearly eliminate large signal drift or 1/f noise. With a lock-in time constant of 1.9 s and total interrogated volume of 59 nL (122 droplets), a detection limit of 3.0 × 10(-4) absorbance units or 500 nM bromophenol blue (BPB) (29 fmol) was achieved using only an optical microscope and a standard, single-depth (27 µm) microfluidic device. The system was further applied to nanoliter pH sensing and validated with a spectrophotometer. The µChopper represents a fluidic analog to an optical beam chopper, and the self-regulated sample/reference droplet alternation promotes ease of use.

Passively operated microfluidic device for stimulation and secretion sampling of single pancreatic islets.

A passively operated polydimethylsiloxane (PDMS) microfluidic device was designed for sampling of hormone secretions from eight individual murine pancreatic islets in parallel. Flow control was achieved using a single hand-held syringe and by exploiting inherent fluidic resistances of the microchannels (R(sampling) = 700 ± 20 kPa s mm(-3) at 37 °C). Basal (3 mM) or stimulatory (11 mM) glucose levels were applied to islets, with stimulation timing (t(stim)) minimized to 15 ± 2 s using modified reservoirs. Using enzyme-linked immunosorbent assays (ELISA) for postsampling analyses, we measured statistically equal levels of 1 h insulin secretion (1.26 ± 0.26 and 6.55 ± 1.00 pg islet(-1) min(-1), basal and stimulated; 62 islets) compared to standard, bulk sampling methods (1.01 ± 0.224 and 6.04 ± 1.53 pg islet(-1) min(-1), basal and stimulated; 200 islets). Importantly, the microfluidic platform revealed novel information on single-islet variability. Islet volume measurements with confocal reflectance microscopy revealed that insulin secretion had only limited correlation to islet volume, suggesting a more significant role for cellular architecture and paracrine signaling within the tissue. Compared to other methods using syringe pumps or electroosmotic flow control, this approach provides significant advantages in ease-of-use and device disposability, easing the burden on nonexperts.

The oral mucosa graft: a systematic review.

PURPOSE: We provide the reader with a critical, nonbiased, systematic review of current and precedent literature regarding the use of oral mucosa in the reconstruction of urethral defects associated with stricture and hypospadias/epispadias. MATERIALS AND METHODS: We reviewed pertinent English literature from January 1966 through August 1, 2006 via the databases MEDLINE/PubMed, the Cochrane Library, and EMBASE Drugs and Pharmacology regarding the use of oral mucosa graft urethroplasty in the reconstruction of urethral defects associated with stricture and hypospadias/epispadias. Bibliographies of pertinent articles were explored for additional important literature. RESULTS: Data were stratified among studies that only used oral mucosa graft urethroplasty in the reconstruction of urethral defects associated with stricture, and those that used oral mucosa graft urethroplasty in the reconstruction of urethral defects associated with hypospadias/epispadias. Recipient site success in the reconstruction of defects associated with stricture was significantly associated with the location of graft placement (ventral vs dorsal, p <0.001) when an onlay graft was used. Hypospadias/epispadias recipient site success was significantly associated with the type of graft used (tube vs onlay, p <0.001), and by the site of oral mucosa harvest (labial vs buccal, p <0.001). Other perioperative and patient oriented variables were not significantly associated with success at the recipient site. CONCLUSIONS: The oral mucosa is a viable source of donor tissue displaying many characteristics of the ideal urethral graft. There are numerous variations of the oral mucosa graft urethroplasty technique. Herein comparisons are made.

Urethroplasty in patients older than 65 years: indications, results, outcomes and suggested treatment modifications.

PURPOSE: Despite an aging population, the results of urethroplasty in elderly patients have not been extensively reported. We performed a multi-institutional review of urethroplasty results in 70 elderly males to determine outcomes. MATERIALS AND METHODS: We reviewed all urethroplasties performed on males older than 64 years with at least 6 months of followup at 4 medical centers. Stricture type varied and included anastomotic urethroplasty (44%), penile fasciocutaneous onlay flap (31%), Johanson urethroplasty (stage 1, 6%, stages 1 and 2, 4%), buccal mucosa grafts (7%), foreskin grafts (6%) and meatoplasty (1%). RESULTS: Stricture recurred in 11 (16%) patients, but was managed with a single direct visual internal urethrotomy or dilation in 5 of 11 patients, yielding a final success rate of 91%. Recurrent strictures were more common after fasciocutaneous flaps (7 of 22 cases, 32%) than end-to-end urethroplasty (2 of 31 cases, 6%, p <0.05). Compared to patients younger than 65 years there were more treatment failures, but this was not statistically significant. Perioperative complications were uncommon. Moderate bladder outlet obstructive symptoms developed in 3 patients due to benign prostatic hyperplasia. Notably 6 patients treated previously for post-radiation strictures did well without complications. CONCLUSIONS: Older men tolerate urethroplasty and these data indicate that therapy should not be withheld solely on the basis of age. The potential for impaired flap blood supply in this population is suggested but has not been proven. Benign prostatic hyperplasia must be considered in those patients who have decreased stream after stricture repair.

C reactive protein for risk stratification in acute coronary syndromes? Verdict: unproven.

Although C reactive protein is intimately involved with the pathogenic mechanisms that drive acute coronary syndromes, there is no evidence that it is helpful for identifying patient groups who might benefit from particular treatment strategies

Cumulative risk assessment in unstable angina: clinical, electrocardiographic, autonomic, and biochemical markers.

OBJECTIVES: To determine the incremental value of clinical data, troponin T, ST segment monitoring, and heart rate variability for predicting outcome in patients with non-ST elevation acute coronary syndromes. METHODS: Prospective cohort study of 304 consecutive patients. Baseline clinical and electrocardiographic data were recorded, serial blood samples were obtained for troponin T assay, and 48 hour Holter monitoring was performed for ST segment and heart rate variability analysis. End points were cardiac death and non-fatal myocardial infarction during 12 months' follow up. RESULTS: After 12 months, 7 patients had died and 21 had had non-fatal myocardial infarction. The risk of an event was increased by troponin T > 0.1 microg/l, T wave inversion on the presenting ECG, Holter ST shift, and a decrease in the standard deviation of 5 minute mean RR intervals. Positive predictive values of individual multivariate risk were low; however, analysis of all multivariate risk markers permitted calculation of a cumulative risk score, which increased the positive predictive value to 46.9% while retaining a negative predictive value of 96.9%. CONCLUSION: A cumulative approach to risk stratification in non-ST elevation coronary syndromes successfully identifies a group in whom the risk of cardiac death or non-fatal myocardial infarction approaches 50%.

Interaction between smoking and the glycoprotein IIIa P1(A2) polymorphism in non-ST-elevation acute coronary syndromes.

OBJECTIVES: The goal of this study was to determine the interaction between smoking and the glycoprotein IIIa P1(A2) polymorphism in patients admitted with non-ST-elevation acute coronary syndromes (ACS). BACKGROUND: An increased incidence of the P1(A2) polymorphism in smokers presenting with ST-elevation acute myocardial infarction (AMI) has recently been reported. We, therefore, postulated that, as a consequence of this interaction, fewer smokers with the P1(A2) polymorphism would present with non-ST-elevation ACS. METHODS: We performed a prospective cohort analysis of 220 white Caucasoid patients admitted with non-ST-elevation ACS fulfilling Braunwald class IIIb criteria for unstable angina who were stratified by smoking status. RESULTS: There were twice as many nonsmokers as smokers. Nonsmokers compared with smokers were older (mean [SD]; 63.9 [11.2] vs. 57.6 [10.3]; p < 0.0001), more likely to have had a previous admission with unstable angina (24.3% vs. 13.2%; p = 0.051) and AMI (45.8% vs. 30.3%; p < 0.026), more likely to have undergone revascularization (24.3% vs. 1.8%; p = 0.028) and were more likely to be on aspirin on admission (60.4% vs. 44.7%; p = 0.026). The proportion of nonsmokers positive for the P1(A2) polymorphism was equivalent to that expected for this population but was significantly reduced in smokers (28.7% vs. 10%; Pearson chi-square = 9.09, p = 0.0026). In a logistic regression model, the odds ratio (OR) for being positive for the P1(A2) polymorphism was significantly reduced by smoking (OR [interquartile range]: 0.26 [0.11 to 0.62]; p = 0.0026). CONCLUSIONS: There is a significant reduction in the P1(A2) polymorphism in smokers admitted with non-ST-elevation ACS compared with nonsmokers, which suggests an interaction between smoking and this polymorphism.

Angiotensin-converting enzyme inhibition is associated with reduced troponin release in non-ST-elevation acute coronary syndromes.

OBJECTIVES: This study was done to determine the effects of angiotensin-converting enzyme (ACE) inhibition and other clinical factors on troponin release in non-ST-elevation acute coronary syndrome (ACS). BACKGROUND: Troponin is now widely used as a marker of risk in ACS, but determinants of its release have not been defined. METHODS: This was a prospective cohort study of 301 consecutive patients admitted with non-ST-elevation ACS. Baseline clinical data were recorded, ACE gene polymorphism was determined and serial blood samples were obtained for troponin-I assay. RESULTS: Significant troponin-I release (>0.1 microg/l) was detected in 93 (31%) patients. Pretreatment with ACE inhibitors, recorded in 53 patients (17.6%), independently reduced the odds of troponin-I release (odds ratio 0.25; 95% confidence intervals 0.10 to 0.64) and was associated with lower maximum troponin-I concentrations (median [interquartile range]) compared with patients not pretreated with ACE inhibitors (0.44 microg/l [0.19 to 2.65 microg/l] vs. 4.18 microg/l [0.91 to 12.41 microg/l], p = 0.01). Pretreatment with aspirin, recorded in 173 patients (57.5%), did not significantly reduce the odds of troponin-I release after adjustment but was associated with lower maximum troponin-I concentrations compared with patients not pretreated with aspirin (2.31 microg/l [0.72 to 8.02 microg/l] vs. 5.85 microg/l [1.19 to 12.79 microg/l], p = 0.05). The ACE genotyping (n = 268) showed 81 patients (30%) DD homozygous and 77 (29%) II homozygous. There was no association between ACE genotype and troponin release. CONCLUSIONS: We conclude that ACE inhibition reduces troponin release in non-ST-elevation ACS. This is likely to be mediated by the beneficial effects of treatment on vascular reactivity and the coagulation system.

The effect of aspirin on C-reactive protein as a marker of risk in unstable angina.

OBJECTIVES: This study was designed to assess the interaction between aspirin and C-reactive protein (CRP) release in unstable angina. BACKGROUND: C-reactive protein release in acute coronary syndromes may be a response to myocardial necrosis or may reflect the inflammatory process that drives atherogenesis. Aspirin has the potential to influence CRP release, either by its anti-inflammatory activity or by reducing myocardial necrosis. The clinical significance of this potential interaction has not previously been tested. METHODS: We conducted a prospective cohort study of 304 consecutive patients admitted with non-ST-elevation acute coronary syndromes. Serial blood samples were obtained for CRP and troponin I assay. End points were cardiac death and nonfatal myocardial infarction during follow-up for 12 months. RESULTS: A total of 174 patients (57%) were taking aspirin before admission. Patients taking aspirin had lower troponin I concentrations throughout the sampling period, only 45 (26.0%) having concentrations >0.1 mg/l compared with 48 (37.8%) patients not taking aspirin (p = 0.03). Maximum CRP concentrations were also lower in patients taking aspirin (8.16 mg/l [3.24 to 24.5]) than in patients not taking aspirin (11.3 mg/l [4.15 to 26.1]), although the difference was not significant. However, there was significant interaction (p = 0.04) between prior aspirin therapy and the predictive value of CRP concentrations for death and myocardial infarction at 12 months. Thus, odds ratios (95% confidence intervals) for events associated with an increase of 1 standard deviation in maximum CRP concentration were 2.64 (1.22-5.72) in patients not pretreated with aspirin compared with 0.98 (0.60-1.62) in patients pretreated with aspirin. CONCLUSIONS: The association between CRP and cardiac events in patients with unstable angina is influenced by pretreatment with aspirin. Modification of the acute-phase inflammatory responses to myocardial injury is the major mechanism of this interaction.

Beta-cell dysfunction in 48-hour glucose-infused rats is not a consequence of elevated plasma lipid or islet triglyceride levels.

The abnormal insulin secretion found in human diabetics and animal models of diabetes has been attributed to the deleterious effects of chronic hyperglycemia and/or elevated circulating levels of nonesterified fatty acids (NEFAs). In this study, abnormal glucose-induced insulin secretion (GIIS) was generated by a 48-hour infusion of glucose and assessed by the isolated perfused pancreas technique. In these hyperglycemic animals, abnormal GIIS is accompanied by a decrease in plasma NEFAs, while plasma and, more importantly, islet triglycerides remain at levels comparable to those in the controls. It is concluded that the abnormal insulin secretion in this glucose infusion model was likely caused by 48 hours of hyperglycemia and not by changes in circulating or islet lipids.

Influence of previous aspirin treatment and smoking on the electrocardiographic manifestations of injury in acute myocardial infarction.

OBJECTIVE: To examine demographic and clinical characteristics of patients with acute myocardial infarction in order to identify factors affecting the electrocardiographic evolution of injury. METHODS: Prospective cohort study of 1399 consecutive patients with a first myocardial infarction. Baseline clinical data associated with ST elevation and Q wave development were identified and 12 month survival was estimated. RESULTS: Smoking had complex effects on the evolution of injury, increasing the odds of ST elevation (odds ratio (OR) 1.61; 95% confidence interval (CI) 1.08 to 2.36), but reducing the odds of Q wave development (OR 0.69, 95% CI 0.49 to 0.96). The effects of previous aspirin treatment were more consistent with reductions in the odds of ST elevation (OR 0.57, 95% CI 0.35 to 0.94) and Q wave development (OR 0.53, 95% CI 0.34 to 0. 84). ST elevation and Q wave development were both associated with an adverse prognosis, with estimated 12 month survival rates of 80. 6% (95% CI 78.2% to 83.1%) and 80.0% (95% CI 77.5% to 82.5%), respectively, compared with 86.5% (95% CI 81.2% to 91.9%) and 89.9% (95% CI 86.2% to 93.7%) for patients without these ECG changes. CONCLUSIONS: The thrombogenicity of the blood may be a major determinant of infarct severity. Smoking increases thrombogenicity and the likelihood of ST elevation, but because coronary occlusion is relatively more thrombotic in smokers, responses to both endogenous and exogenous thrombolysis are better, reducing the risk of Q wave development. Previous aspirin treatment reduces thrombogenicity, protecting against ST elevation and Q wave development.

Selection bias in the management of unstable angina.

OBJECTIVES: To examine the criteria for selecting patients presenting with unstable angina for cardiac catheterisation and to assess the extent to which these criteria successfully incorporate high risk groups. METHODS AND RESULTS: This was a prospective cohort study of 517 patients admitted with unstable angina with 12 months follow-up; 139 patients (26.9%) had cardiac catheterisation 32 days or longer after presentation. The odds of early catheterisation were increased by regional ST segment depression on the presenting ECG (odds ratio (OR) 1.70, 95% confidence intervals (CI) 1.01-2.87) and ongoing ischaemic chest pain more than 12 hours after admission (OR 9.72, CI 6.10-15.49), and reduced by age over 65 years (OR 0.56, 95% CI 0.35-0.90) and heart failure (OR 0.26, CI 0.11-0.64). The 12-month rates of myocardial infarction (MI) or death were 8.6% and 17.7% (p = 0.01) in patients who were and were not referred for early cardiac catheterisation, respectively. Survival analysis showed that the odds of MI and death in the first 12 months were increased substantially by heart failure (OR 2.82, 95% CI 1.53-5.20) and age over 65 (OR 1.91, 95% CI 1.13-3.23). CONCLUSION: Selection for early cardiac catheterisation in this unstable angina population was largely ischaemia-driven, based on ongoing chest pain and ST segment depression. This policy was associated with a low event rate in the ischaemic group, but it failed to target elderly patients and those with heart failure who were at greatest risk of MI and death during the first year.

Evaluation of a new troponin I method on the Bayer Immuno 1 immunoassay analyser.

We have evaluated the analytical and clinical performance of an automated immunoassay for serum cardiac troponin I (Bayer Immuno 1TM, Bayer Diagnostics, Tarrytown, NY). The between batch imprecision was found to be between 1.2 and 3.2% over the concentration range 2.5 - 34.0 microg/L. The analytical range obtained from duplicate analysis of patient samples and defined as a coefficient of variation of 10% or less was 0.3 - 200 microg/L. The detection limit was found to be less than 0.1 microg/L. A method comparison with the Dade Stratus method (Dade Behring, Wilmington, DE) yielded regression statistics with a slope of 0.705 and an intercept of -0.260. An analysis of samples from 40 patients with renal failure demonstrated six with detectable levels of troponin I (0.2 - 1.9 microg/L). Samples from patients with paraproteinaemia did not demonstrate detectable troponin I (from n = 30); however, two patients with elevated rheumatoid factor titers (from n = 20) demonstrated a detectable amount of troponin I (0.1 and 0.2 microg/L). In a study of 100 patients admitted with acute chest pain and a diagnosis of unstable angina, 6 were subsequently diagnosed as having suffered a myocardial infarction. On admission the sensitivity and specificity of the troponin I results were 26.7% and 94.7%, respectively, moving to 100% and 83% 12 hours after admission.

Clinical characteristics determining the mode of presentation in patients with acute coronary syndromes.

OBJECTIVES: The purpose of this study was to examine clinical characteristics of patients with acute coronary syndromes to identify factors that influence the mode of presentation. BACKGROUND: In acute coronary syndromes, presentation with myocardial infarction or unstable angina has major prognostic implications, yet clinical factors affecting the mode of presentation are not well defined. METHODS: A prospective cohort study was made of 1,111 patients with acute coronary syndromes. Baseline demographic, clinical and biochemical data were compared in groups with myocardial infarction (n = 633) and unstable angina (n = 478). RESULTS: The risk of myocardial infarction relative to unstable angina was increased by age >70 years (odds ratio [OR] 2.21; 95% confidence interval [CI] 1.33 to 3.66), male gender (OR 1.56; CI 1.13 to 2.16) and cigarette smoking (OR 1.49; CI 1.09 to 2.03). A rise in admission creatinine from the 10th to the 90th centile of the distribution also increased the odds of myocardial infarction (OR 1.30; CI 1.05 to 1.94). Conversely, the risk of myocardial infarction relative to unstable angina was reduced by previous treatment with aspirin (OR 0.37; CI 0.27 to 0.52), hypertension (OR 0.64; CI 0.47 to 0.86) and previous acute coronary syndromes (OR 0.36; CI 0.26 to 0.51) and revascularization procedures (OR 0.36; CI 0.21 to 0.62). CONCLUSIONS: The clinical presentation of acute coronary syndromes may be influenced by various factors that have the potential to influence the coagulability of the blood, the collateralization of the coronary circulation and myocardial mass. Myocardial infarction is favored by cigarette smoking, advanced age and renal impairment, while unstable angina is favored by treatment with aspirin, hypertension, previous revascularization and previous coronary syndromes.

Expression, purification, and characterization of the human squalene synthase: use of yeast and baculoviral systems.

We have cloned and utilized a cDNA corresponding to the human squalene synthase gene to generate active enzyme from yeast and baculoviral expression systems. Expression of human squalene synthase in yeast resulted in production of active enzyme in cellular lysates. The presence of the active human enzyme, however, was insufficient to rescue growth of spores defective in yeast squalene synthase function, suggesting that structural differences in the yeast and human enzymes may affect localization or folding of the protein. Expression of the human enzyme in Sf-9 insect cells after infection with recombinant baculovirus encoding the human squalene synthase gene resulted in detection of substantial enzymatic activity in cell lysate preparations. Following extraction from the Sf-9 cells, the human enzyme was purified to near homogeneity utilizing a series of ion-exchange chromatography steps with an overall yield of purified protein of approximately 5 mg per liter of Sf-9 cell culture. The purified enzyme was characterized through steady-state kinetic and physical measurements and the kinetic constants are consistent with values observed for other squalene synthases. Zaragozic acid C was found to be a competitive inhibitor with respect to farnesyl pyrophosphate and has a Kis value of 250 pM (@ [NADPH] = 5 mM). Inhibition experiments with zaragozic acid C at low (approximately 0.5 x Km) and high (approximately 10 x Km) concentrations of NADPH indicated that the inhibitor does not bind in the enzyme's NADPH binding domain. These studies demonstrate that the human enzyme can be prepared from baculovirus-infected Sf-9 cells in a catalytically active configuration and in sufficient quantities to allow for further biochemical, kinetic, and structural characterization.