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Background:Although higher blood pressures are generally recognised to be an adverse prognostic marker in risk assessment of cardiology patients, its relationship to risk in chronic heart failure (CHF) may be different.Objective:To examine systematically published reports on the relationship between blood pressure and mortality in CHF.Methods:Medline and Embase were used to identify studies that gave a hazard or relative risk ratio for systolic blood pressure in a stable population with CHF. Included studies were analysed to obtain a unified hazard ratio and quantify the degree of confidence.Results:10 studies met the inclusion criteria, giving a total population of 8088, with 29 222 person-years of follow-up. All studies showed that a higher systolic blood pressure (SBP) was a favourable prognostic marker in CHF, in contrast to the general population where it is an indicator of poorer prognosis. The decrease in mortality rates associated with a 10 mm Hg higher SBP was 13.0% (95% CI 10.6% to 15.4%) in the heart failure population. This was not related to aetiology, ACE inhibitor or β blocker use.Conclusion:SBP is an easily measured, continuous variable that has a remarkably consistent relationship with mortality within the CHF population. The potential of this simple variable in outpatient assessment of patients with CHF should not be neglected. One possible application of this information is in the optimisation of cardiac resynchronisation devices.

BackgroundAn objective of the first efficacy trial of a candidate vaccine containing recombinant human immunodeficiency virus (HIV) type 1 envelope glycoprotein 120 (rgp120) antigens was to assess correlations between antibody responses to rgp120 and the incidence of HIV-1 infection MethodsWithin the randomized trial (for vaccinees, n=3598; for placebo recipients, n=1805), binding and neutralizing antibody responses to rgp120 were quantitated. A case-cohort design was used to study correlations between antibody levels and HIV-1 incidence ResultsPeak antibody levels were significantly inversely correlated with HIV-1 incidence. The relative risk (RR) of infection was 0.63 (95% confidence interval, 0.45–0.89) per log10 higher neutralization titer against HIV-1MN, and the RRs of infection for second-, third-, and fourth-quartile responses of antibody blocking of gp120 binding to soluble CD4 versus first-quartile responses (the lowest responses) were 0.35, 0.28, and 0.22, respectively ConclusionsDespite inducing a complex, robust immune response, the vaccine was unable to reduce the incidence of HIV-1. Two interpretations of the correlative results are that the levels of antibodies (i) caused both an increased (low responders) and decreased (high responders) risk of HIV-1 acquisition or (ii) represented a correlate of susceptibility to HIV-1 but had no causal effect on susceptibility. Although the data cannot definitively discriminate between these 2 explanations, (ii) appears to be more likely

Objective To investigate whether discrepancies in trials of use of bone marrow stem cells in patients with heart disease account for the variation in reported effect size in improvement of left ventricular function.Design Identification and counting of factual discrepancies in trial reports, and sample size weighted regression against therapeutic effect size. Meta-analysis of trials that provided sufficient information.Data sources PubMed and Embase from inception to April 2013.Eligibility for selecting studies Randomised controlled trials evaluating the effect of autologous bone marrow stem cells for heart disease on mean left ventricular ejection fraction.Results There were over 600 discrepancies in 133 reports from 49 trials. There was a significant association between the number of discrepancies and the reported increment in EF with bone marrow stem cell therapy (Spearman’s r=0.4, P=0.005). Trials with no discrepancies were a small minority (five trials) and showed a mean EF effect size of −0.4%. The 24 trials with 1-10 discrepancies showed a mean effect size of 2.1%. The 12 with 11-20 discrepancies showed a mean effect of size 3.0%. The three with 21-30 discrepancies showed a mean effect size of 5.7%. The high discrepancy group, comprising five trials with over 30 discrepancies each, showed a mean effect size of 7.7%.Conclusions Avoiding discrepancies is difficult but is important because discrepancy count is related to effect size. The mechanism is unknown but should be explored in the design of future trials because in the five trials without discrepancies the effect of bone marrow stem cell therapy on ejection fraction is zero.

Objective: To assess the haemodynamic effect of simultaneously adjusting atrioventricular (AV) and interventricular (VV) delays. Method: 35 different combinations of AV and VV delay were tested by using digital photoplethysmography (Finometer) with repeated alternations to measure relative change in systolic blood pressure (SBPrel) in 15 patients with cardiac resynchronisation devices for heart failure. Results: Changing AV delay had a larger effect than changing VV delay (range of SBPrel 21 v 4.2 mm Hg, p < 0.001). Each had a curvilinear effect. The curve of response to AV delay fitted extremely closely to a parabola (average R2  =  0.99, average residual variance 0.8 mm Hg2). The response to VV delay was significantly less curved (quadratic coefficient 67 v 1194 mm Hg/s2, p  =  0.003) and therefore, although the residual variance was equally small (0.8 mm Hg2), the R2 value was 0.7. Reproducibility at two months was good, with the SD of the difference between two measurements of SBPrel being 2.5 mm Hg for AV delay (2% of mean systolic blood pressure) and 1.5 mm Hg for VV delay (1% of mean systolic blood pressure). Conclusions: Changing AV and VV delays results in a curvilinear acute blood pressure response. This shape fits very closely to a parabola, which may be valuable information in developing a streamlined clinical protocol. VV delay adjustment provides an additional, albeit smaller, haemodynamic benefit to AV optimisation.

► Dengue is a serious disease and progress is being achieved in vaccine development. ► A vaccine's price affects its uptake and is influenced by the cost of production. ► We estimate production cost of a tetravalent live attenuated dengue vaccine. ► At 60 million doses produced annually, cost would be ∼$0.20 in 10-dose vials and ∼$0.70 in single-dose vials. ► The vaccine can be made available at a price that most ministries of health could afford. A vaccine to prevent dengue disease is urgently needed. Fortunately, a few tetravalent candidate vaccines are in the later stages of development and show promise. But, if the cost of these candidates is too high, their beneficial potential will not be realized. The price of a vaccine is one of the most important factors affecting its ultimate application in developing countries. In recent years, new vaccines such as those for human papilloma virus and pneumococcal disease (conjugate vaccine) have been introduced with prices in developed countries exceeding $50 per dose. These prices are above the level affordable by developing countries. In contrast, other vaccines such as those against Japanese encephalitis (SA14-14-2 strain vaccine) and meningitis type A have prices in developing countries below one dollar per dose, and it is expected that their introduction and use will proceed more rapidly. Because dengue disease is caused by four related viruses, vaccines must be able to protect against all four. Although there are several live attenuated dengue vaccine candidates under clinical evaluation, there remains uncertainty about the cost of production of these tetravalent vaccines, and this uncertainty is an impediment to rapid progress in planning for the introduction and distribution of dengue vaccines once they are licensed. We have undertaken a detailed economic analysis, using standard industrial methodologies and applying generally accepted accounting practices, of the cost of production of a live attenuated vaccine, originally developed at the US National Institutes of Health (National Institute of Allergy and Infectious Diseases), to be produced at the Instituto Butantan in Sao Paulo, Brazil. We determined direct costs of materials, direct costs of personnel and labor, indirect costs, and depreciation. These were analyzed assuming a steady-state production of 60 million doses per year. Although this study does not seek to compute the price of the final licensed vaccine, the cost of production estimate produced here leads to the conclusion that the vaccine can be made available at a price that most ministries of health in developing countries could afford. This conclusion provides strong encouragement for supporting the development of the vaccine so that, if it proves to be safe and effective, licensure can be achieved soon and the burden of dengue disease can be reduced.

Aims/hypothesis A high prevalence of diabetes contributes to excess CHD in Indian Asians, but the underlying mechanisms are unclear. Heart rate, heart rate variability (HRV) and baroreflex sensitivity (BRS) are measures of cardiac autonomic function that are disturbed by hyperglycaemia and predict CHD. We compared these measures in Indian Asians and Europeans, and sought explanations for the observed differences. Methods A representative sample of 149 Europeans and 151 Indian Asians was recruited from primary care, 66% of them men (aged 35-75 years), 34% women (aged 55-75 years). Heart rate, HRV, BRS and cardio-metabolic profiles were measured over four successive 5 min periods with continuous ECG and blood pressure monitoring. Results Indian Asians were hyperglycaemic compared with Europeans (HbA₁c (mean ± SD) 6.5 ± 1.2% vs 5.9 ± 1.0%, p = 0.001). They had shorter mean RR intervals ((mean ± SE) 969 ± 13 vs 1,022 ± 12 ms, p = 0.002), lower total RR interval power ((geometric mean, 95% CI) 925 [796-1075] vs 1,224 [1,064-1,422] ms², p = 0.008) and lower BRS ((mean ± SE) 5.7 ± 1.0 vs 6.6 ± 1.0 ms/mmHg, p = 0.01). All measures of cardiac autonomic dysfunction were significantly associated with hyperglycaemia (mean RR interval vs HbA₁c r = −0.22; p < 0.001). Ethnic differences in cardiac autonomic function persisted after adjustment for age, blood pressure and medication (mean RR interval 973 vs 1,021 ms, p = 0.004), but were attenuated or abolished by adjusting for HbA₁c (979 vs 1,014 ms, p = 0.06) or other markers of hyperglycaemia. Conclusions/interpretation Indian Asians from the general population have impaired cardiovascular autonomic function compared with Europeans. This is due to greater hyperglycaemia in Indian Asians and may determine their increased CHD risk.

Abstract Objective To determine the effect of exercise training on survival in patients with heart failure due to left ventricular systolic dysfunction. Design Collaborative meta-analysis. Inclusion criteria Randomised parallel group controlled trials of exercise training for at least eight weeks with individual patient data on survival for at least three months. Studies reviewed Nine datasets, totalling 801 patients: 395 received exercise training and 406 were controls. Main outcome measure Death from all causes. Results During a mean (SD) follow up of 705 (729) days there were 88 (22%) deaths in the exercise arm and 105 (26%) in the control arm. Exercise training significantly reduced mortality (hazard ratio 0.65, 95% confidence interval, 0.46 to 0.92; log rank χ2 = 5.9; P = 0.015). The secondary end point of death or admission to hospital was also reduced (0.72, 0.56 to 0.93; log rank χ2 = 6.4; P = 0.011). No statistically significant subgroup specific treatment effect was observed. Conclusion Meta-analysis of randomised trials to date gives no evidence that properly supervised medical training programmes for patients with heart failure might be dangerous, and indeed there is clear evidence of an overall reduction in mortality. Further research should focus on optimising exercise programmes and identifying appropriate patient groups to target.

The first trial of the efficacy of a human immunodeficiency virus (HIV)–1 vaccine was conducted in North America and The Netherlands between 1998 and 2003. This multicenter, randomized, placebo-controlled trial of a recombinant glycoprotein 120 vaccine included 5403 initially HIV-negative volunteers who were monitored for 3 years. The 368 subjects who acquired HIV-1 infection were monitored for 2 years by use of the following postinfection end points: plasma HIV-1 RNA level (viral load), CD4+ lymphocyte count, initiation of antiretroviral therapy (ART), and HIV-1–related clinical outcomes. This article reports the study results that pertain to the effect of vaccination on the postinfection end points. The time until initiation of ART and the time until virologic failure or initiation of ART were similar in the vaccine arm and the placebo arm. The pre-ART viral load and CD4+ lymphocyte count trajectories were also comparable between the groups. Evidently, the vaccine did not affect HIV-1 disease progression

Background:Cardiac resynchronisation therapy improves peak oxygen uptake (peak VO2) 3–9 months after device implantation. In chronic heart failure, total isovolumic time (t-IVT) is a major determinant of peak VO2 and of cardiac output at peak dobutamine stress. In selected patients, resynchronisation can instantaneously shorten t-IVT. We sought to determine the acute effect of resynchronisation on exercise performance and determine, with pharmacological stress echocardiography, the mechanism underlying this effect.Methods and results:Twenty-two patients with resynchronisation were studied within 3 months after device implantation. On a single study day, sequential cardiopulmonary exercise tests were performed during native activation (left bundle branch block) and resynchronisation (atrio-biventricular pacing) in random order. Total-IVT and cardiac output (at rest and peak dobutamine stress) were then measured in each activation mode.Resynchronisation acutely increased peak VO2 by 1.6 (SD 1.5) ml/kg/min (p<0.001) and shortened peak stress t-IVT by 10 (SD 7) s/min (p<0.001), with the effects in individual patients showing a correlation (r = –0.46, p<0.05). Amongst all measurements during native activation, the best predictor of gain in peak VO2 from resynchronisation was peak stress t-IVT (r = 0.71, p<0.001) with every increment of 5 s/min of peak stress t-IVT during native activation predicting an 8% gain in peak VO2. No conventional measures during native activation at rest or on stress (including QRS duration, Tei index, tissue Doppler intraventricular delay, and resting t-IVT) added significant additional information.Conclusions:In eligible patients, resynchronisation can acutely augment peak VO2, possibly through a mechanism of t-IVT shortening. Under native activation, long t-IVT during peak stress is the single best predictor of acute resynchronisation-mediated increment in peak VO2.

Objective:To determine the effects of interventricular pacing interval and left ventricular (LV) pacing site on ventricular dyssynchrony and function at baseline and during biventricular pacing, using tissue Doppler imaging.Methods:Using an angioplasty wire to pace the left ventricle, 20 patients with heart failure and left bundle branch block underwent temporary biventricular pacing from lateral (n = 20) and inferior (n = 10) LV sites at five interventricular pacing intervals: +80, +40, synchronous, −40, and −80 ms.Results:LV ejection fraction (EF) increased (mean (SD) from 18 (8)% to 26 (10)% (p = 0.016) and global mechanical dyssynchrony decreased from 187 (91) ms to 97 (63) ms (p = 0.0004) with synchronous biventricular pacing compared to unpaced baseline. Sequential pacing with LV preactivation produced incremental improvements in EF and global mechanical dyssynchrony (p<0.0001 and p = 0.0026, respectively), primarily as a result of reductions in inter-LV–RV dyssynchrony (p = 0.0001) rather than intra-LV dyssynchrony (NS). Results of biventricular pacing from an inferior or lateral LV site were comparable (for example, synchronous biventricular pacing, global mechanical dyssynchrony: lateral LV site, 97 (63) ms; inferior LV site, 104 (41) ms (NS); EF: lateral LV site, 26 (10)%; inferior LV site, 27 (10)% (NS)). ECG morphology was identical during biventricular pacing through an angioplasty wire and a permanent lead.Conclusions:Sequential biventricular pacing with LV preactivation most often optimises LV synchrony and EF. An inferior LV site offers a good alternative to a lateral site. Pacing through an angioplasty wire may be useful in assessing the acute effects of pacing.