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Globally, waste disposal options such as landfill, incineration, and discharge to water, are not preferred long-term solutions due to their social, environmental, political, and economic implications. However, there is potential for increasing the sustainability of industrial processes by considering land application of industrial wastes. Applying waste to land can have beneficial outcomes including reducing waste sent to landfill and providing alternative nutrient sources for agriculture and other primary production. However, there are also potential hazards, including environmental contamination. This article reviewed the literature on industrial waste applications to soils and assessed the associated hazards and benefits. The review investigated wastes in relation to soil characteristics, dynamics between soils and waste constituents, and possible impacts on plants, animals, and humans. The current body of literature demonstrates the potential for the application of industrial waste into agricultural soils. The main challenge for applying industrial wastes to land is the presence of contaminants in some wastes and managing these to enhance positive effects and reduce negative outcomes to within acceptable limits. Examination of the literature also revealed several gaps in the research and opportunities for further investigation: specifically, a lack of long-term experiments and mass balance assessments, variable waste composition, and negative public opinion. [ABSTRACT FROM AUTHOR]

Background: Sudden death (SD) and pump failure death (PFD) are leading modes of death in heart failure and preserved ejection fraction (HFpEF). Risk stratification for mode-specific death may aid in patient enrichment for new device trials in HFpEF. Methods: Models were derived in 4116 patients in the Irbesartan in Heart Failure with Preserved Ejection Fraction trial (I-Preserve), using competing risks regression analysis. A series of models were built in a stepwise manner, and were validated in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved and Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trials. Results: The clinical model for SD included older age, men, lower LVEF, higher heart rate, history of diabetes or myocardial infarction, and HF hospitalization within previous 6 months, all of which were associated with a higher SD risk. The clinical model predicting PFD included older age, men, lower LVEF or diastolic blood pressure, higher heart rate, and history of diabetes or atrial fibrillation, all for a higher PFD risk, and dyslipidaemia for a lower risk of PFD. In each model, the observed and predicted incidences were similar in each risk subgroup, suggesting good calibration. Model discrimination was good for SD and excellent for PFD with Harrell's C of 0.71 (95% CI 0.68–0.75) and 0.78 (95% CI 0.75–0.82), respectively. Both models were robust in external validation. Adding ECG and biochemical parameters, model performance improved little in the derivation cohort but decreased in validation. Including NT-proBNP substantially increased discrimination of the SD model, and simplified the PFD model with marginal increase in discrimination. Conclusions: The clinical models can predict risks for SD and PFD separately with good discrimination and calibration in HFpEF and are robust in external validation. Adding NT-proBNP further improved model performance. These models may help to identify high-risk individuals for device intervention in future trials. Clinical trial registration: I-Preserve: ClinicalTrials.gov NCT00095238; TOPCAT: ClinicalTrials.gov NCT00094302; CHARM-Preserved: ClinicalTrials.gov NCT00634712. [ABSTRACT FROM AUTHOR]

The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory (HFC) and Academic Research Consortium (ARC), comprised of leading heart failure (HF) academic research investigators, patients, United States (US) Food and Drug Administration representatives, and industry members from the US and Europe. A series of meetings were convened to establish definitions and key concepts for the evaluation of HF therapies including optimal medical and device background therapy, clinical trial design elements and statistical concepts, and study endpoints. This manuscript summarizes the expert panel discussions as consensus recommendations focused on populations and endpoint definitions; it is not exhaustive or restrictive, but designed to stimulate HF clinical trial innovation. [ABSTRACT FROM AUTHOR]

Background: The CHARM-Preserved trial suggested that the renin-angiotensin system (RAS) inhibitor candesartan might have been beneficial in heart failure with preserved ejection fraction (HFpEF); however, this hypothesis was not supported by the findings of I-Preserve with irbesartan. Aims: To re-analyse the results of I-Preserve, adjusting for imbalances in baseline variables that may have influenced the trial outcomes. Methods: Cox proportional hazards models with covariate adjustment for baseline variables, including age, sex, medical history, physiological and laboratory variables. Results: In I-Preserve, 763 (37.0%) participants in the placebo group and 742 (35.9%) in the irbesartan group experienced the primary composite outcome (death from any cause or hospitalization for heart failure, myocardial infarction, unstable angina, arrhythmia, or stroke). The prespecified analysis of this outcome, stratifying for the use of ACEi at baseline, gave a hazard ratio (HR) of 0.95 (95% confidence interval, 0.86–1.05); p = 0.35. Adjusting the effect of treatment for key prognostic baseline variables, gave a HR of 0.89 (0.80–0.99); p = 0.033. Similar findings were observed for the composite of cardiovascular death or HF hospitalization. Conclusion: Adjusting for imbalances in baseline variables that influence outcomes (or the response to therapy or both) can improve the power around the estimate of the effect of treatment and may alter its statistical significance. Along with the CHARM-Preserved results, these findings suggest that angiotensin-receptor blockers may have a modest effect in HFpEF. [ABSTRACT FROM AUTHOR]

Aims: Insulin causes sodium retention and hypoglycaemia and its use is associated with worse outcomes in heart failure (HF) with reduced ejection fraction. We have investigated whether this is also the case in HF with preserved ejection fraction (HFpEF).Methods and Results: We examined the association between diabetes/diabetes treatments and the risk of the primary composite of cardiovascular death or HF hospitalization, as well as other outcomes in adjusted analyses in CHARM-Preserved (left ventricular ejection fraction ≥ 45%), I-Preserve and TOPCAT (Americas) pooled. Of 8466 patients, 2653 (31%) had diabetes, including 979 (37%) receiving insulin. Patients receiving insulin were younger, had a higher body mass index, prevalence of ischaemic aetiology, N-terminal pro-B-type natriuretic peptide and use of diuretics, worse New York Heart Association class and signs and symptoms, and worse quality of life and renal function, compared to patients with diabetes not on insulin. Among the 1398 patients with echocardiographic data, insulin use was associated with higher left ventricular end-diastolic pressure and more diastolic dysfunction than in other participants. The primary outcome occurred at a rate of 6.3 per 100 patient-years in patients without diabetes, and 10.2 and 17.1 per 100 patient-years in diabetes patients without and with insulin use, respectively [fully adjusted hazard ratio (aHR) insulin-treated diabetes vs. other diabetes: 1.41, 95% confidence interval (CI) 1.23-1.63, P < 0.001]. The adjusted HR is 1.67 (95% CI 1.20-2.32, p = 0.002) for sudden death (insulin-treated diabetes vs. other diabetes).Conclusions: Insulin use is associated with poor outcomes in HFpEF. Although we cannot conclude a causal association, the safety of insulin and alternative glucose-lowering treatments in HF needs to be evaluated in clinical trials. [ABSTRACT FROM AUTHOR]

Aims: The landmark STICH trial found that surgical revascularization compared to medical therapy alone improved survival in patients with heart failure (HF) of ischaemic aetiology and an ejection fraction (EF) ≤ 35%. However, the interaction between the burden of medical co-morbidities and the benefit from surgical revascularization has not been previously described in patients with ischaemic cardiomyopathy.Methods and Results: The STICH trial (ClinicalTrials.gov Identifier: NCT00023595) enrolled patients ≥ 18 years of age with coronary artery disease amenable to coronary artery bypass grafting (CABG) and an EF ≤ 35%. Eligible participants were randomly assigned 1:1 to receive medical therapy (MED) (n = 602) or MED/CABG (n = 610). A modified Charlson co-morbidity index (CCI) based on the availability of data and study definitions was calculated by summing the weighted points for all co-morbid conditions. Patients were divided into mild/moderate (CCI 1-4) and severe (CCI ≥ 5) co-morbidity. Cox proportional hazards models were used to evaluate the association between CCI and outcomes and the interaction between severity of co-morbidity and treatment effect. The study population included 349 patients (29%) with a mild/moderate CCI score and 863 patients (71%) with a severe CCI score. Patients with a severe CCI score had greater functional limitations based on 6-min walk test and impairments in health-related quality of life as assessed by the Kansas City Cardiomyopathy Questionnaire. A total of 161 patients (Kaplan-Meier rate = 50%) with a mild/moderate CCI score and 579 patients (Kaplan-Meier rate = 69%) with a severe CCI score died over a median follow-up of 9.8 years. After adjusting for baseline confounders, patients with a severe CCI score were at higher risk for all-cause mortality (hazard ratio 1.44, 95% confidence interval 1.19-1.74; P < 0.001). There was no interaction between CCI score and treatment effect on survival (P = 0.756).Conclusions: More than 70% of patients had a severe burden of medical co-morbidities at baseline, which was independently associated with increased risk of death. There was not a differential benefit of surgical revascularization with respect to survival based on severity of co-morbidity. [ABSTRACT FROM AUTHOR]

Aims The incidence and predictors of stroke in patients with heart failure and preserved ejection fraction (HF-PEF), but without atrial fibrillation (AF), are unknown. We described the incidence of stroke in HF-PEF patients with and without AF and predictors of stroke in those without AF. Methods and results We pooled data from the CHARM-Preserved and I-Preserve trials. Using Cox regression, we derived a model for stroke in patients without AF in this cohort and compared its performance with a published model in heart failure patients with reduced ejection fraction (HF-REF)--predictive variables: age, body mass index, New York Heart Association class, history of stroke, and insulin-treated diabetes. The two stroke models were compared and Kaplan- Meier curves for stroke estimated. The risk model was validated in a third HF-PEF trial. Of the 6701 patients, 4676 did not have AF. Stroke occurred in 124 (6.1%) with AF and in 171 (3.7%) without AF (rates 1.80 and 1.00 per 100 patient-years, respectively). There was no difference in performance of the stroke model derived in the HF-PEF cohort and the published HF-REF model (c-index 0.71, 95% confidence interval 0.57-0.84 vs. 0.73, 0.59-0.85, respectively) as the predictive variables overlapped. The model performed well in the validation cohort (0.86, 0.62-0.99). The rate of stroke in patients in the upper third of risk approximated to that in patients with AF (1.60 and 1.80 per 100 patient-years, respectively). Conclusions A small number of clinical variables identify a subset of patients with HF-PEF, but without AF, at elevated risk of stroke. [ABSTRACT FROM AUTHOR]

Background: The aims of this study were to describe the prevalence of QRS prolongation and abnormal QRS morphology in patients with heart failure and preserved ejection fraction (HF-PEF) and to examine the relationship between these QRS abnormalities and clinical outcomes.Methods and Results: We categorized patients in the Irbesartan in Heart Failure with Preserved Ejection Fraction trial (I-PRESERVE) according to QRS duration <120 vs. ≥120 ms and QRS morphology: normal, left bundle branch block (LBBB), and right bundle branch block (RBBB) or other non-specific intra-ventricular conduction defect (IVCD). The outcomes examined were the composite of cardiovascular death or heart failure hospitalization (and its components) and all-cause mortality. Of the 4128 patients enrolled in I-PRESERVE, 3754 were included in the present analyses. A total of 606 patients had a QRS duration ≥120 ms, 302 had LBBB and 742 had RBBB/IVCD. Patients with an abnormal QRS had evidence of more severe heart failure [lower left ventricular ejection fraction, lower estimated glomerular filtration rate, higher N-terminal pro-B-type natriuretic peptide (NT-proBNP)] and worse clinical status (higher New York Heart Association functional class and greater use of diuretics). Both abnormalities of QRS duration and QRS morphology were associated with worse outcomes. The rates of the composite outcome were: 6.0 and 9.3 per 100 patient years in the <120 ms and ≥120 ms groups, respectively [adjusted hazard ratio (HR) 1.32, 95% confidence interval (CI) 1.11-1.57; P = 0.002) and 6.0, 7.7 and 8.7 per 100 patient years in the normal, non-LBBB and LBBB groups, respectively (adjusted HR 1.19, 95% CI 1.00-1.42, P = 0.046; and HR 1.31, 95% CI 1.03-1.66, P = 0.026, respectively, compared with normal). The heightened risk related to QRS abnormalities persisted after adjustment for other prognostic variables, including NT-proBNP.Conclusion: We found that both prolongation of QRS duration and abnormal QRS morphology were associated with a high risk of fatal and non-fatal adverse outcomes in heart failure with preserved ejection fraction. [ABSTRACT FROM AUTHOR]

Aims: To compare surgical outcomes for a simple purse string method of laparoscopic hernia (LH) repair with a traditional open inguinal hernia (OH) repair in children in a single center.Materials and Methods: Following ethical approval, a retrospective review of all children undergoing LH repair from January 2010 to December 2013 versus a historic cohort of all OH repairs between January 2010 and December 2011 was conducted. LH repair was performed by a simple purse string technique using nonabsorbable braided suture. Groups were compared using the independent t test or the Mann-Whitney test as appropriate.Results: One hundred three patients (23 females, 80 males) underwent LH repair over the 4-year period compared with 151 (25 females, 126 males) OH procedures in the first 2 years. Median age in the LH group was 0.56 years (range, 0.04-14.7 years) compared with 0.52 years (range, 0.04-13.47 years) in the OH group (P = .81). In the LH group the intended operation was bilateral in 18 (17.4%); 85 were clinically unilateral, but at operation a contralateral patent processus vaginalis was repaired in 26 (30.5%). Median operative time was 50.5 minutes (range, 20-95 minutes) in the LH group and 20 minutes (range, 10-90 minutes) in the OH cohort (P < .0001). Recurrence rate was 2.9% in the LH group and 3.9% in the OH group, and overall complication rates were 7.8% and 9.9%, respectively.Conclusions: LH repair yields similar results to OH repair; however, the operation time is significantly longer. All complication rates were statistically similar on balance. Almost one-third of LH procedures resulted in concurrent detection and repair of a contralateral patent processus vaginalis at laparoscopy. [ABSTRACT FROM AUTHOR]

Background: Patients with heart failure and preserved ejection fraction (HFpEF) have a poor prognosis, and no therapies have been proven to improve outcomes. It has been proposed that heart failure, including HFpEF, represents overlapping syndromes that may have different prognoses. We present an exploratory study of patients enrolled in the Irbesartan in Heart Failure with Preserved Ejection Fraction Study (I-PRESERVE) using latent class analysis (LCA) with validation using the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved study to identify HFpEF subgroups.Methods and Results: In total, 4113 HFpEF patients randomized to irbesartan or placebo were characterized according to 11 clinical features. The HFpEF subgroups were identified using LCA. Event-free survival and effect of irbesartan on the composite of all-cause mortality and cardiovascular hospitalization were determined for each subgroup. Subgroup definitions were applied to 3203 patients enrolled in CHARM-Preserved to validate observations regarding prognosis and treatment response. Six subgroups were identified with significant differences in event-free survival (P < 0.001). Clinical profiles and prognoses of the six subgroups were similar in CHARM-Preserved. The two subgroups with the worst event-free survival in both studies were characterized by a high prevalence of obesity, hyperlipidaemia, diabetes mellitus, anaemia, and renal insufficiency (Subgroup C) and by female predominance, advanced age, lower body mass index, and high rates of atrial fibrillation, valvular disease, renal insufficiency, and anaemia (Subgroup F).Conclusion: Using a data-driven approach, we identified HFpEF subgroups with significantly different prognoses. Further development of this approach for characterizing HFpEF subgroups is warranted. [ABSTRACT FROM AUTHOR]

Aims In patients with heart failure ( HF) and reduced ejection fraction, decreases or increases in NT-proBNP levels are associated with better and worse outcomes, respectively. The association in HF and preserved ejection fraction ( HF-PEF) is unknown. We examined the association between change in level of NT-proBNP and prognosis in patients with HF-PEF. Methods and results We examined the association between change in NT-proBNP from baseline to 6 months and cardiovascular ( CV) death or HF hospitalization in 2612 participants in the Irbesartan in Patients with Heart Failure and Preserved Systolic Function Study (I-Preserve). Change in NT-proBNP was modelled as a restricted cubic spline in a Cox model after adjusting for baseline NT-proBNP and known prognostic variables. Median change in NT-proBNP from baseline was −7 pg/ mL (interquartile range −143 to +108). After adjustment, a 1000 pg/ mL decrease in NT-proBNP from baseline was associated with a reduction in the risk of CV death or HF hospitalization [hazard ratio ( HR) 0.73, 95% confidence interval ( CI) 0.53-1.02]; a 1000 pg/ mL increase was associated with an increase in risk ( HR 2.01, 95% CI 1.50-2.69). Beyond a 1000 pg/ mL rise or fall, there was little additional change in risk. Addition of change in NT-proBNP at 6 months to a model with only baseline NT-proBNP improved the C-statistic from 0.752 to 0.769 ( P = 0.013). Conclusion In HF-PEF, a rise in NT-proBNP was associated with an increase in risk of CV death or HF hospitalization and a fall was associated with a trend towards a decrease in risk. NT-proBNP may be a useful marker to monitor prognosis in this condition. [ABSTRACT FROM AUTHOR]

Aims To investigate the prognostic significance of hospitalization for worsening heart failure ( WHF), myocardial infarction ( MI), and stroke in patients with chronic heart failure ( HF). Methods and results We studied 5011 patients with HF and reduced EF ( HF-REF) in the CORONA trial and 4128 patients with HF and preserved EF ( HF-PEF) in the I-Preserve trial. Adjusted hazard ratios ( HRs) for death were estimated for 0-30 days and ≥31 days after first post-randomization WHF, MI, or stroke used as a time-dependent variable, compared with patients with none of these events. In CORONA, 1616 patients (32%) had post-randomization first events (1223 WHF, 216 MI, 177 stroke), and the adjusted HR for mortality ≤30 days after an event was: WHF 7.21 [95% confidence interval ( CI) 2.05-25.40], MI 23.08 (95% CI 6.44-82.71), and stroke 32.15 (95% CI 8.93-115.83). The HR for mortality at >30 days was: WHF 3.62 (95% CI 3.11-4.21), MI 4.41 (95% CI 3.23-6.02), and stroke 3.19 (95% CI 2.21-4.61). In I-Preserve, 896 patients (22%) experienced a post-randomization event (638 WHF, 111 MI, 147 stroke). The HR for mortality ≤30 days was WHF 31.77 (95% CI 7.60-132.81), MI 154.77 (95% CI 34.21-700.17), and stroke 223.30 (95% CI 51.42-969.78); for >30 days it was WHF 3.36 (95% CI 2.79-4.05), MI 3.29 (95% CI 2.14-5.06), and stroke 5.13 (95% CI 3.61-7.29). Conclusions In patients with both HF-REF and HF-PEF, hospitalization for WHF was associated with high early and late mortality. The early relative risk of death was not as great as following MI or stroke, but the longer term relative risk of death was similar following all three types of event. Numerically, more deaths occurred following WHF because it was a much more common event. [ABSTRACT FROM AUTHOR]

Context There is little room in clerkship curricula for students to express emotions, particularly those associated with the development of a caring identity. Yet it is recognised that competence, alone, does not make a good doctor. We therefore set out to explore the relationship between emotions and identity in clerkship education. Our exploration was conceptually oriented towards Figured Worlds theory, which is linked to Bakhtin's theory of dialogism. Methods Nine female and one male member of a mixed student cohort kept audio-diaries and participated in both semi-structured and cognitive individual interviews. The researchers identified 43 emotionally salient utterances in the dataset and subjected them to critical discourse analysis. They applied Figured Worlds constructs to within-case and cross-case analyses, supporting one another's reflexivity and openness to different interpretations, and constantly comparing their evolving interpretation against the complete set of transcripts. Results Students' emotions were closely related to their identity development in the world of medicine. Patients were disempowered by their illnesses. Doctors were powerful because they could treat those illnesses. Students expressed positive emotions when they were granted positions in the world of medicine and were able to identify with the figures of doctors or other health professionals. They identified with doctors who behaved in caring and professionally appropriate ways towards patients and supportively towards students. Students expressed negative emotions when they were unable to develop their identities. Conclusions Critical discourse analysis has uncovered a link between students' emotions and their identity development in the powerful world of becoming and being a doctor. At present, identity development, emotions and power are mostly tacit in undergraduate clinical curricula. We speculate that helping students to express emotions and exercise power in the most effective ways might help them to develop caring identities. [ABSTRACT FROM AUTHOR]

Aims Sudden cardiac death ( SCD) accounts for ∼ 25% of all deaths in heart failure with preserved ejection fraction ( HFpEF). However, strategies to identify HFpEF patients at a higher risk of SCD have not been developed. Methods and results We studied 4128 patients with HFpEF enrolled in the Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction (I- PRESERVE) trial. All SCDs were adjudicated by a clinical endpoint committee. Cumulative incidences of SCD were estimated counting other deaths as competing risks. Cox regression analysis was used to generate a risk model for SCD. During a mean follow-up of 4.1 years, 231 (5.6%) patients died suddenly and 650 (15.7%) died non-suddenly. A multivariable model in 3480 patients including age, gender, history of diabetes and myocardial infarction, LBBB on ECG, and the natural logarithm of NT-proBNP identified a subgroup of 837 (24%) patients with ≥10% cumulative incidence of SCD over 5 years, accounting for other deaths as competing risk (Harrell's C index 0.75). The 5-year cumulative incidences of SCD in the higher and lower risk groups were 11% and 4%, respectively. In the higher risk group, 32% of deaths were SCD compared with 26% in the entire I- PRESERVE cohort. Conclusions A multivariable prediction model identified patients with HFpEF who have a ≥10% risk of SCD over 5 years, similar to the risk of SCD in the Sudden Cardiac Death in Heart Failure ( SCD-Heft) trial. This model may be useful for selecting patients with HFpEF for SCD prevention trials. [ABSTRACT FROM AUTHOR]

The green peach aphid, Myzus persicae (Sulzer), is a serious pest throughout the world, attacking a broad range of crop plants across numerous agricultural industries. This species has a high propensity to develop chemical resistance, and has the unenviable title of having resistance to more insecticides than any other insect species. An extensive survey of field populations was undertaken across Australia, and showed widespread and high levels of resistance to carbamates and synthetic Pyrethroids in M. persicae. Moderate levels of resistance to organophosphates were also observed in many populations, while there is new evidence of resistance developing to neonicotinoids. Isofemale (clonal) lines of M. persicae were generated and subsequently tested across a range of insecticides; individual genetic clones were found to contain resistance to multiple chemical classes. Resistance genotyping of these aphids were consistent with published literature of known resistant mechanisms. The high and widespread levels of resistance identified within Australia are concerning. Resistance in M. persicae has spread quickly across Australia, and thus farmers are likely to have fewer chemical control options in the future. There is a need to develop resistance management strategies that rotate insecticides, spray insecticides only when economically necessary, and incorporate nonchemical control options. [ABSTRACT FROM AUTHOR]

Background Higher heart rate is associated with poorer outcomes in patients with heart failure and reduced ejection fraction ( HF-REF). Less is known about the association between heart rate and outcomes in patients with heart failure and preserved ejection fraction ( HF-PEF). Therefore, we examined the relationship between heart rate and outcomes in the irbesartan in patients with heart failure and preserved systolic function trial (I-Preserve) in patients with an ejection fraction >45% aged >60 years. Methods and results Heart rate was analysed as both a categorical (tertiles) and continuous variable. Patients in sinus rhythm ( n = 3271) and atrial fibrillation ( n = 696) were analysed separately. The outcomes examined were the primary endpoint of the trial (all-cause death or cardiovascular hospitalization), the composite of cardiovascular death or heart failure hospitalization (and its components) and all-cause death alone. Higher heart rate was associated with a significantly higher risk of all outcomes studied for patients in sinus rhythm, even after adjustment for other prognostic variables, including N-terminal pro-B-type natriuretic peptide. Each standard deviation (12.4 bpm) increase in heart rate was associated with an increase in risk of 13% for cardiovascular death or heart failure hospitalization ( P = 0.002). No relationship between heart rate and outcomes was observed for patients in atrial fibrillation. Beta-blocker treatment did not reduce the heart rate-risk relationship. Conclusions In patients with heart failure and preserved ejection fraction, heart rate is in sinus rhythm an independent predictor of adverse clinical outcomes and might be a therapeutic target in this syndrome. Clinical Trial Registration - URL . Unique identifier: NCT 0095238 [ABSTRACT FROM AUTHOR]

Aims There is little evidence of beta-blocker treatment benefit in patients with heart failure and reduced left ventricular ejection fraction (HFREF) and atrial fibrillation (AF). We investigated the effects of bucindolol in HFREF patients with AF enrolled in the Beta-blocker Evaluation of Survival Trial (BEST). Methods and results A post-hoc analysis of patients in BEST with and without AF was performed to estimate the effect of bucindolol on mortality and hospitalization. Patients were also evaluated for treatment effects on heart rate and the influence of beta1-adrenergic receptor position 389 (β1389) arginine (Arg) vs. glycine (Gly) genotypes. In the 303/2708 patients in AF, patients receiving bucindolol were more likely to achieve a resting heart rate ≤80 b.p.m. at 3 months (P < 0.005) in the absence of treatment-limiting bradycardia. In AF patients and sinus rhythm (SR) patients who achieved a resting heart rate ≤80 b.p.m., there were beneficial treatment effects on cardiovascular mortality/cardiovascular hospitalization [hazard ratio (HR) 0.61, P = 0.025, and 0.79, P = 0.002]. Without achieving a resting heart rate ≤80 b.p.m., there were no treatment effects on events in either group. β1389-Arg/Arg AF patients had nominally significant reductions in all-cause mortality/HF hospitalization and cardiovascular mortality/hospitalization with bucindolol (HR 0.23, P = 0.037 and 0.28, P = 0.039), whereas Gly carriers did not. There was no evidence of diminished heart rate response in β1389-Arg homozygotes. Conclusion In HFREF patients with AF, bucindolol was associated with reductions in composite HF endpoints in those who achieved a resting heart rate ≤80 b.p.m. and nominally in those with the β1389-Arg homozygous genotype. [ABSTRACT FROM AUTHOR]

Background: Pharmacogenetics involves complex interactions of gene products affecting pharmacodynamics and pharmacokinetics, but there is little information on the interaction of multiple genetic modifiers of drug response. Bucindolol is a β-blocker/sympatholytic agent whose efficacy is modulated by polymorphisms in the primary target (β1 adrenergic receptor [AR] Arg389 Gly on cardiac myocytes) and a secondary target modifier (α2C AR Ins [wild-type (Wt)] 322-325 deletion [Del] on cardiac adrenergic neurons). The major allele homozygotes and minor allele carriers of each polymorphism are respectively associated with efficacy enhancement and loss, creating the possibility for genotype combination interactions that can be measured by clinical trial methodology. Methodology: In a 1,040 patient substudy of a bucindolol vs. placebo heart failure clinical trial, we tested the hypothesis that combinations of β1389 and α2C322-325 polymorphisms are additive for both efficacy enhancement and loss. Additionally, norepinephrine (NE) affinity for β1389 AR variants was measured in human explanted left ventricles. Principal Findings: The combination of β1389 Arg+α2C322-325 Wt major allele homozygotes (47% of the trial population) was non-additive for efficacy enhancement across six clinical endpoints, with an average efficacy increase of 1.70-fold vs. 2.32-fold in b1389 Arg homozygotes+α2C322-325 Del minor allele carriers. In contrast, the minor allele carrier combination (13% subset) exhibited additive efficacy loss. These disparate effects are likely due to the higher proportion (42% vs. 8.7%, P = 0.009) of high-affinity NE binding sites in b1389 Arg vs. Gly ARs, which converts α2CDel minor allele-associated NE lowering from a therapeutic liability to a benefit. Conclusions: On combination, the two sets of AR polymorphisms 1) influenced bucindolol efficacy seemingly unpredictably but consistent with their pharmacologic interactions, and 2) identified subpopulations with enhanced (β1389 Arg homozygotes), intermediate (β1389 Gly carriers+α2C322-325 Wt homozygotes), and no (β1389 Gly carriers+α2C322-325 Del carriers) efficacy. [ABSTRACT FROM AUTHOR]

New approaches to the definition and treatment of hypertension have increased emphasis on reducing overall cardiovascular risk and on targeting the underlying mechanisms of cardiovascular disease. During the past several decades, renin–angiotensin–aldosterone system (RAAS) activation has emerged as an important factor in the pathophysiology of endothelial dysfunction and cardiovascular disease (CVD). Angiotensin-converting enzyme inhibitors (ACEIs) have well-established efficacy for treating CVD, but their use may be limited by intolerable side effects, such as cough and angioedema. Angiotensin II receptor blockers (ARBs), a different class of RAAS inhibitors, are considered a viable alternative to ACEIs. Clinical trials have further elucidated the role of ARBs in CVD. This article reviews the mechanism of action of ARBs and selected clinical trials of ARBs in CVD. [ABSTRACT FROM PUBLISHER]

Several retrospective studies have raised concerns regarding digoxin therapy in select subgroups of heart failure patients. To assess the impact of digoxin therapy on outcomes in the current era of heart failure therapy, the authors analyzed data representing 5010 patients enrolled in the Valsartan Heart Failure Trial (Val-HeFT) to examine the relationship of baseline digoxin use and all-cause mortality, first morbid event, and heart failure hospitalizations. At baseline, 3374 patients (67%) were receiving digoxin therapy and 1636 (33%) were not. Patients receiving digoxin had features of worse heart failure with higher New York Heart Association class and lower blood pressure, ejection fraction, and b-blocker use (32.1% vs 40.8%). Digoxin use was associated with worse mortality (21.1 vs 15.0%, P<.001), first morbid event (34.6 vs 21.7, P<.001), and HF hospitalization rate (19.1 vs 10.1%, P<.001). After adjustment for baseline group differences including medical therapy and baseline rhythm, patients receiving digoxin remained at a higher risk for all-cause mortality (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.05-1.57), first morbid event (HR, 1.35; 95% CI, 1.15-1.59), and heart failure hospitalization (HR, 1.41; 95% CI, 1.12-1.78). These results remained materially unchanged with propensity matched analysis. No benefit with digoxin use was observed in this study, underscoring the need to reassess the role of digoxin in the contemporary management of heart failure. [ABSTRACT FROM AUTHOR]

It is unknown whether statin use improves survival in patients with advanced chronic heart failure (HF) receiving cardiac resynchronization therapy (CRT). The authors retrospectively assessed the effect of statin use on survival in patients with advanced chronic HF receiving CRT alone (CRT-P) or CRT with implantable cardioverter-defibrillator therapy (CRT-D) in 1520 patients with advanced chronic HF from the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial database. Six hundred three patients (40%) were taking statins at baseline. All-cause mortality was 18% in the statin group and 22% in the no statin group (hazard ratio [HR] 0.85; confidence interval (CI), 0.67–1.07; P=.15). In a multivariable analysis controlling for significant baseline characteristics and use of CRT-P/CRT-D, statin use was associated with a 23% relative risk reduction in mortality (HR, 0.77; CI, 0.61–0.97; P=.03). Statin use is associated with improved survival in patients with advanced chronic HF receiving CRT. No survival benefit was seen in patients receiving statins and optimal pharmacologic therapy without CRT. [ABSTRACT FROM AUTHOR]

Abstract: Background: We describe the baseline characteristics of subjects randomised in the largest placebo-controlled, morbidity-mortality trial to date in patients with heart failure and preserved ejection fraction — the irbesartan in heart failure with preserved systolic function trial (I-PRESERVE). Methods and results: 4133 patients with a mean age of 72 years (a third were 75 years or older) were randomised and 60% were women. The mean (SD) LVEF was 59 (9)% and almost 80% of patients were in NYHA Class III or IV. Approximately 80% of patients were also overweight or obese. Heart failure was reported by investigators to have a hypertensive aetiology in 64% of patients. Prior myocardial infarction was relatively uncommon (24%), as was coronary revascularisation (13%). Atrial fibrillation and diabetes each occurred in between a quarter and a third of patients. The following treatments were used at baseline: diuretic 83%, beta-blocker 59%, calcium channel blocker 40%, ACE inhibitor 25%, spironolactone 15% and digoxin 14%. Conclusions: Patients in I-PRESERVE are broadly representative of those seen in epidemiological studies and, because of this, the results of this trial should be generally applicable to “real world” patients with heart failure and preserved ejection fraction. [Copyright &y& Elsevier]

The magnitude of benefit on mortality of combined angiotensin-converting enzyme inhibitor (ACEI) and β-blocker (BB) therapy for heart failure cannot be reliably assessed from prospective randomized trials of individual drugs with intent-to-treat analysis. The placebo arm of the Valsartan Heart Failure Trial (Val-HeFT) included patients who remained on background therapy with ACEIs, BBs, neither, or both. The outcomes in these four subgroups should provide a better guide to mortality benefit. Overall mortality (mean follow-up, 23 months) was 31.6% in those receiving neither neurohormonal blocker, 29% and 39% lower in those on ACEIs or BBs, respectively, and 62% lower (11.9% mortality) in those receiving both drugs. In the neither neurohormonal inhibitor group, 48% of the heart failure-related deaths were adjudicated as sudden, whereas in the group receiving ACEIs and BBs, 79% of the deaths were sudden, and pump failure mortality was only 1% per year. The combination of ACEIs and BBs exerts a greater mortality reduction than suggested from clinical trials and reduces pump failure mortality to 1% per year. [ABSTRACT FROM AUTHOR]

Abstract: Aims: To investigate the effect of valsartan in the Valsartan-Heart Failure Trial (Val-HeFT) when added to angiotensin-converting enzyme inhibitor (ACEi) alone in patients with heart failure (HF). Methods: Subjects in Val-HeFT receiving ACEi but not beta-blocker at baseline were analysed; 1532 were assigned to valsartan and 1502 assigned to placebo. Primary outcome events (all-cause mortality, hospitalisation for adjudicated heart failure, sudden death with resuscitation and need for >4 h of parenteral therapy for worsening heart failure) were monitored. Results: Mortality was not affected by valsartan but morbidity endpoints were significantly reduced (36.3% in placebo, 31.0% in valsartan, p=0.002) in patients receiving an ACEi but no beta-blocker. Quality of life (QOL) was significantly improved, ejection fraction (EF) significantly increased, left ventricular (LV) diameter significantly reduced and plasma B-type natriuretic peptide, norepinephrine and aldosterone levels significantly reduced with valsartan compared to placebo. The morbidity benefit was significant in patients on ACEi doses below the median (22% reduction, p=0.003) and not statistically significant in those receiving ACEi doses above the median (14% reduction, p=0.143). Conclusion: Valsartan reduces heart failure hospitalisations and slows LV remodelling in patients treated with an ACEi in the absence of beta-blockade, particularly in those on lower doses of ACEi. [Copyright &y& Elsevier]

Presents several letters to the editor published in the 'British Medical Journal' as of August 1989. Inquiries related to selection of surgeon as leader for the trauma team; Interrelations between the death at Lake Nyos and carbon dioxide emission; Scrutiny on the ethical practices involved in clinical research.

Focuses on medical-related issues in Great Britain. Agreement on HIV testing within the British Medical Association; Incidence of coronary disease in people taking strenuous exercise; Management of patients undergoing gastrointestinal operations.

Electrocardiograms were recorded from human patients using a bipolar chest lead together with simultaneous His-bundle electrograms. These were then subjected to the technique of signal averaging in an attempt to extract His-bundle activity from the surface record. This was successful in three out of 10 cases subjected to the truly non-invasive surface technique. Methods are discussed by which the technique could be improved. [ABSTRACT FROM PUBLISHER]

Presents a comparison on the effectiveness between hospital and home care for patients with coronary thrombosis in Great Britain. Information on mortality rates in home-treated cases; Indications for hospital treatment; Role of general practitioners in providing efficient care during the first two hours after infarction.

Presents several correspondents on medicine. Reduction in the incidence of clinical staphylococcal infection in the newborn; Comment on the 'critical' blood concentrations of hexachlorophene; Benefits of the computer system at Stoke-on-Trent to medical experiments.