Are beta-blockers needed in patients receiving spironolactone for severe chronic heart failure? An analysis of the COPERNICUS study

BACKGROUND: The beneficial effects of beta-blockers and aldosterone receptor antagonists are now well established in patients with severe systolic chronic heart failure (CHF). However, it is unclear whether beta-blockers are able to provide additional benefit in patients already receiving aldosterone antagonists. We therefore examined this question in the COPERNICUS study of 2289 patients with severe CHF receiving the beta1-beta2/alpha1 blocker carvedilol compared with placebo. METHODS: Patients were divided post hoc into subgroups according to whether they were receiving spironolactone (n = 445) or not (n = 1844) at baseline. Consistency of the effect of carvedilol versus placebo was examined for these subgroups with respect to the predefined end points of all-cause mortality, death or CHF-related hospitalizations, death or cardiovascular hospitalizations, and death or all-cause hospitalizations. RESULTS: The beneficial effect of carvedilol was similar among patients who were or were not receiving spironolactone for each of the 4 efficacy measures. For all-cause mortality, the Cox model hazard ratio for carvedilol compared with placebo was 0.65 (95% CI 0.36-1.15) in patients receiving spironolactone and 0.65 (0.51-0.83) in patients not receiving spironolactone. Hazard ratios for death or all-cause hospitalization were 0.76 (0.55-1.05) versus 0.76 (0.66-0.88); for death or cardiovascular hospitalization, 0.61 (0.42-0.89) versus 0.75 (0.64-0.88); and for death or CHF hospitalization, 0.63 (0.43-0.94) versus 0.70 (0.59-0.84), in patients receiving and not receiving spironolactone, respectively. The safety and tolerability of treatment with carvedilol were also similar, regardless of background spironolactone. CONCLUSION: Carvedilol remained clinically efficacious in the COPERNICUS study of patients with severe CHF when added to background spironolactone in patients who were practically all receiving angiotensin-converting enzyme inhibitor (or angiotensin II antagonist) therapy. Therefore, the use of spironolactone in patients with severe CHF does not obviate the necessity of additional treatment that interferes with the adverse effects of sympathetic activation, specifically beta-blockade.

The role of targeted viral load testing in diagnosing virological failure in children on antiretroviral therapy with immunological failure

Objectives  To determine the improvement in positive predictive value of immunological failure criteria for identifying virological failure in HIV-infected children on antiretroviral therapy (ART) when a single targeted viral load measurement is performed in children identified as having immunological failure. Methods  Analysis of data from children (<16 years at ART initiation) at South African ART sites at which CD4 count/per cent and HIV-RNA monitoring are performed 6-monthly. Immunological failure was defined according to both WHO 2010 and United States Department of Health and Human Services (DHHS) 2008 criteria. Confirmed virological failure was defined as HIV-RNA >5000 copies/ml on two consecutive occasions <365 days apart in a child on ART for ≥18 months. Results  Among 2798 children on ART for ≥18 months [median (IQR) age 50 (21-84) months at ART initiation], the cumulative probability of confirmed virological failure by 42 months on ART was 6.3%. Using targeted viral load after meeting DHHS immunological failure criteria rather than DHHS immunological failure criteria alone increased positive predictive value from 28% to 82%. Targeted viral load improved the positive predictive value of WHO 2010 criteria for identifying confirmed virological failure from 49% to 82%. Conclusion  The addition of a single viral load measurement in children identified as failing immunologically will prevent most switches to second-line treatment in virologically suppressed children.

Fulminant hepatic and multiple organ failure following acute viral tonsillitis: a case report.

BACKGROUND Pyogenic tonsillitis may often be observed in the general Western population. In severe cases, it may require antibiotic treatment or even hospitalization and often a prompt clinical response will be noted. Here we present an unusual case of progressive multiple organ failure including fulminant liver failure following acute tonsillitis initially mistaken for "classic" pyogenic (that is bacterial) tonsillitis. CASE PRESENTATION A 68-year-old previously healthy white man was referred with suspicion of pyogenic angina. After tonsillectomy, he developed acute liver failure and consecutive multiple organ failure including acute hemodynamic, pulmonary and dialysis-dependent renal failure. Immunohistopathological analysis of his tonsils and liver as well as serum polymerase chain reaction analyses revealed herpes simplex virus-2 to be the causative pathogen. Treatment included high-dose acyclovir and multiorgan supportive intensive care therapy. His final outcome was favorable. CONCLUSIONS Fulminant herpes simplex virus-2-induced multiple organ failure is rarely observed in the Western hemisphere and should be considered a potential diagnosis in patients with tonsillitis and multiple organ failure including acute liver failure. From a clinical perspective, it seems important to note that fulminant herpes simplex virus-2 infection may masquerade as "routine" bacterial severe sepsis/septic shock. This persevering condition should be diagnosed early and treated goal-oriented in order to gain control of this life-threatening condition.

Does tin pre-treatment enhance the bond strength of adhesive systems to enamel?

OBJECTIVES The study investigated the modification of composite-to-enamel bond strength by pre-treatment of enamel with a concentrated, acidic SnCl2-solution. METHODS Six groups of flat human enamel specimens (n=44 per group) were treated as follows: OB-H: H3PO4 etching, Optibond FL application (primer+adhesive; manufacturer's instructions); OB-S: SnCl2 pre-treatment, Optibond FL application (primer+adhesive); OB-HS: H3PO4 etching+SnCl2 pre-treatment, Optibond FL application (primer+adhesive); CF-N: Clearfil SE application (primer+bond; manufacturer's instructions); CF-H: H3PO4 etching, Clearfil SE application (primer+bond); CF-S: SnCl2 pre-treatment, Clearfil SE application (primer+bond). Enamel specimens were then built up with resin composite (Clearfil Majesty Esthetic) and stored (100% humidity, 37 °C, 1 week). μTBS-measurement and failure mode analysis of one-half of the specimens were performed immediately after storage, while the other half was analysed after a thermocycling procedure (8500 cycles; 5 °C and 55 °C; dwell time 30s). Additional specimens were prepared for SEM- and EDX-analysis. RESULTS Highest values were measured for OB-H before and after thermocycling, lowest values for CF-N. Compared to OB-H treatment, OB-S treatment reduced μTBS before/after thermocycling by 23%/28% and OB-HS treatment by 8%/24% (except for OB-SH before (n.s.), all p≤0.001 compared to OB-H). In the Clearfil SE treated groups pre-treatment increased μTBS significantly compared to CF-N (before/after: CF-H: +46%/+70%; CF-S: +51%/42%; all p≤0.001). CONCLUSION Pre-treatment with H3PO4 or SnCl2 markedly increased the μTBS of Clearfil SE to enamel. However, thermocycling partly reduced the gain in μTBS obtained by SnCl2 pre-treatment. CLINICAL SIGNIFICANCE The application of an acidic and highly concentrated SnCl2 solution is a good option to increase the μTBS between enamel and a resin composite mediated by an adhesive system containing the multifunctional monomer MDP.

Geomorphic coupling between hillslopes and channels in the Swiss Alps

The coupling relationships between hillslope and channel network are fundamental for the understanding of mountainous landscapes' evolution. Here, we applied dendrogeomorphic methods to identify the hillslope–channel relationship and the sediment transfer dynamics within an alpine catchment, at the highest possible resolution. The Schimbrig catchment is located in the central Swiss Alps and can be divided into two distinct geomorphic sectors. To the east, the Schimbrig earth flow is the largest sediment source of the basin, while to the west, the Rossloch channel network is affected by numerous shallow landslides responsible for the supply of sediment from hillslopes to channels. To understand the connectivity between hillslopes and channels and between sources and sink, trees were sampled along the main Rossloch stream, on the Schimbrig earth flow and on the Rossloch depositional area. Geomorphic observations and dendrogeomophic results indicate different mechanisms of sediment production, transfer and deposition between upper and lower segments of the channel network. In the source areas (upper part of the Rossloch channel system), sediment is delivered to the channel network through slow movements of the ground, typical of earth flow, shallow landslides and soil creep. Contrariwise, in the depositional area (lower part of the channel network), the mechanisms of sediment transfer are mainly due to torrential activity, floods and debris flows. Tree analysis allowed the reconstruction of periods of high activity during the last century for the entire catchment. The collected dataset presents a very high temporal resolution but we encountered some limitations in establishing the source-to-sink connectivity at the catchment-wide scale. Despite these uncertainties, for decennial timescales the results suggest a direct coupling between hillslopes and neighbouring channels in the Rossloch channel network, and a de-coupling between sediment sources and sink farther downstream, with connections possible only during extraordinary events.

Elderly age is not a negative predictive factor for virological response to therapy with pegylated interferon-α and ribavirin in chronic hepatitis C virus patients

BACKGROUND & AIMS: Age is frequently discussed as negative host factor to achieve a sustained virological response (SVR) to antiviral therapy of chronic hepatitis C. However, elderly patients often show advanced fibrosis/cirrhosis as known negative predictive factor. The aim of this study was to assess age as an independent predictive factor during antiviral therapy. METHODS: Overall, 516 hepatitis C patients were treated with pegylated interferon-α and ribavirin, thereof 66 patients ≥60 years. We analysed the impact of host factors (age, gender, fibrosis, haemoglobin, previous hepatitis C treatment) and viral factors (genotype, viral load) on SVR per therapy course by performing a generalized estimating equations (GEE) regression modelling, a matched pair analysis and a classification tree analysis. RESULTS: Overall, SVR per therapy course was 42.9 and 26.1%, respectively, in young and elderly patients with hepatitis C virus (HCV) genotypes 1/4/6. The corresponding figures for HCV genotypes 2/3 were 74.4 and 84%. In the GEE model, age had no significant influence on achieving SVR. In matched pair analysis, SVR was not different in young and elderly patients (54.2 and 55.9% respectively; P = 0.795 in binominal test). In classification tree analysis, age was not a relevant splitting variable. CONCLUSIONS: Age is not a significant predictive factor for achieving SVR, when relevant confounders are taken into account. As life expectancy in Western Europe at age 60 is more than 20 years, it is reasonable to treat chronic hepatitis C in selected elderly patients with relevant fibrosis or cirrhosis but without major concomitant diseases, as SVR improves survival and reduces carcinogenesis.

BrainCheck - a very brief tool to detect incipient cognitive decline: optimized case-finding combining patient- and informant-based data.

INTRODUCTION Optimal identification of subtle cognitive impairment in the primary care setting requires a very brief tool combining (a) patients' subjective impairments, (b) cognitive testing, and (c) information from informants. The present study developed a new, very quick and easily administered case-finding tool combining these assessments ('BrainCheck') and tested the feasibility and validity of this instrument in two independent studies. METHODS We developed a case-finding tool comprised of patient-directed (a) questions about memory and depression and (b) clock drawing, and (c) the informant-directed 7-item version of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Feasibility study: 52 general practitioners rated the feasibility and acceptance of the patient-directed tool. Validation study: An independent group of 288 Memory Clinic patients (mean ± SD age = 76.6 ± 7.9, education = 12.0 ± 2.6; 53.8% female) with diagnoses of mild cognitive impairment (n = 80), probable Alzheimer's disease (n = 185), or major depression (n = 23) and 126 demographically matched, cognitively healthy volunteer participants (age = 75.2 ± 8.8, education = 12.5 ± 2.7; 40% female) partook. All patient and healthy control participants were administered the patient-directed tool, and informants of 113 patient and 70 healthy control participants completed the very short IQCODE. RESULTS Feasibility study: General practitioners rated the patient-directed tool as highly feasible and acceptable. Validation study: A Classification and Regression Tree analysis generated an algorithm to categorize patient-directed data which resulted in a correct classification rate (CCR) of 81.2% (sensitivity = 83.0%, specificity = 79.4%). Critically, the CCR of the combined patient- and informant-directed instruments (BrainCheck) reached nearly 90% (that is 89.4%; sensitivity = 97.4%, specificity = 81.6%). CONCLUSION A new and very brief instrument for general practitioners, 'BrainCheck', combined three sources of information deemed critical for effective case-finding (that is, patients' subject impairments, cognitive testing, informant information) and resulted in a nearly 90% CCR. Thus, it provides a very efficient and valid tool to aid general practitioners in deciding whether patients with suspected cognitive impairments should be further evaluated or not ('watchful waiting').

Treatment failure in pneumonia: Impact of antibiotic treatment and cost analysis

The aim of this study was to investigate treatment failure (TF) in hospitalised community-acquired pneumonia (CAP) patients with regard to initial antibiotic treatment and economic impact. CAP patients were included in two open, prospective multicentre studies assessing the direct costs for in-patient treatment. Patients received treatment either with moxifloxacin (MFX) or a nonstandardised antibiotic therapy. Any change in antibiotic therapy after >72 h of treatment to a broadened antibiotic spectrum was considered as TF. Overall, 1,236 patients (mean ± SD age 69.6 ± 16.8 yrs, 691 (55.9%) male) were included. TF occurred in 197 (15.9%) subjects and led to longer hospital stay (15.4 ± 7.3 days versus 9.8 ± 4.2 days; p < 0.001) and increased median treatment costs (€2,206 versus €1,284; p<0.001). 596 (48.2%) patients received MFX and witnessed less TF (10.9% versus 20.6%; p < 0.001). After controlling for confounders in multivariate analysis, adjusted risk of TF was clearly reduced in MFX as compared with β-lactam monotherapy (adjusted OR for MFX 0.43, 95% CI 0.27-0.68) and was more comparable with a β-lactam plus macrolide combination (BLM) (OR 0.68, 95% CI 0.38-1.21). In hospitalised CAP, TF is frequent and leads to prolonged hospital stay and increased treatment costs. Initial treatment with MFX or BLM is a possible strategy to prevent TF, and may thus reduce treatment costs.

Proposal on How To Conduct a Biopharmaceutical Process Failure Mode and Effect Analysis (FMEA) as a Risk Assessment Tool

With the publication of the quality guideline ICH Q9 "Quality Risk Management" by the International Conference on Harmonization, risk management has already become a standard requirement during the life cycle of a pharmaceutical product. Failure mode and effect analysis (FMEA) is a powerful risk analysis tool that has been used for decades in mechanical and electrical industries. However, the adaptation of the FMEA methodology to biopharmaceutical processes brings about some difficulties. The proposal presented here is intended to serve as a brief but nevertheless comprehensive and detailed guideline on how to conduct a biopharmaceutical process FMEA. It includes a detailed 1-to-10-scale FMEA rating table for occurrence, severity, and detectability of failures that has been especially designed for typical biopharmaceutical processes. The application for such a biopharmaceutical process FMEA is widespread. It can be useful whenever a biopharmaceutical manufacturing process is developed or scaled-up, or when it is transferred to a different manufacturing site. It may also be conducted during substantial optimization of an existing process or the development of a second-generation process. According to their resulting risk ratings, process parameters can be ranked for importance and important variables for process development, characterization, or validation can be identified. LAY ABSTRACT: Health authorities around the world ask pharmaceutical companies to manage risk during development and manufacturing of pharmaceuticals. The so-called failure mode and effect analysis (FMEA) is an established risk analysis tool that has been used for decades in mechanical and electrical industries. However, the adaptation of the FMEA methodology to pharmaceutical processes that use modern biotechnology (biopharmaceutical processes) brings about some difficulties, because those biopharmaceutical processes differ from processes in mechanical and electrical industries. The proposal presented here explains how a biopharmaceutical process FMEA can be conducted. It includes a detailed 1-to-10-scale FMEA rating table for occurrence, severity, and detectability of failures that has been especially designed for typical biopharmaceutical processes. With the help of this guideline, different details of the manufacturing process can be ranked according to their potential risks, and this can help pharmaceutical companies to identify aspects with high potential risks and to react accordingly to improve the safety of medicines.

Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts

American College of Cardiology/American Heart Association guidelines for the diagnosis and management of heart failure recommend investigating exacerbating conditions such as thyroid dysfunction, but without specifying the impact of different thyroid-stimulation hormone (TSH) levels. Limited prospective data exist on the association between subclinical thyroid dysfunction and heart failure events.