Consequences of unlocking the cardiac myosin molecule in human myocarditis and cardiomyopathies

Myocarditis, often initiated by viral infection, may progress to autoimmune inflammatory heart disease, dilated cardiomyopathy and heart failure. Although cardiac myosin is a dominant autoantigen in animal models of myocarditis and is released from the heart during viral myocarditis, the characterization, role and significance of anti-cardiac myosin autoantibodies is poorly defined. In our study, we define the human cardiac myosin epitopes in human myocarditis and cardiomyopathies and establish a mechanism to explain how anti-cardiac myosin autoantibodies may contribute to heart disease. We show that autoantibodies to cardiac myosin in sera from myocarditis and dilated cardiomyopathies in humans targeted primarily epitopes in the S2 hinge region of cardiac myosin. In addition, anti-cardiac myosin antibodies in sera or purified IgG from myocarditis and cardiomyopathy targeted the beta-adrenergic receptor and induced antibody-mediated cAMP-dependent protein kinase A (PKA) cell signaling activity in heart cells. Antibody-mediated PKA activity in sera was abrogated by absorption with anti-human IgG. Antibody-mediated cell signaling of PKA was blocked by antigen-specific inhibition by human cardiac myosin or the beta-adrenergic receptor but not the alpha adrenergic receptor or bovine serum albumin. Propranolol, a beta blocker and inhibitor of the beta-adrenergic receptor pathway also blocked the antibody-mediated signaling of the beta-adrenergic receptor and PKA. The data suggest that IgG antibody against human cardiac myosin reacts with the beta-adrenergic receptor and triggers PKA signaling in heart cells. In summary, we have identified a new class of crossreactive autoantibodies against human cardiac myosin and the beta-adrenergic receptor in the heart. In addition, we have defined disease specific peptide epitopes in the human cardiac myosin rod S2 region in human myocarditis and cardiomyopathy as well as a mechanistic role of autoantibody in the pathogenesis of disease.

Coordinated Design of Phase Measurement Unit and Power System Stabilisers in Large Scale Power System

This paper presents a case-study of a PMU application with PSS support in a real large scale Chinese power system to suppress inter-area oscillations. The paper uses PMU measured feedback signals from a PSS input signal for dynamic torque analysis (DTA). In the paper, a mathematical model of multi-machine power system is described, followed by formation of the residue and DTA indices. Simulations of the model are used with a large-scale power system model to demonstrate the role of PSS and the equivalence of DTA residue indices.

High population prevalence of cardiac troponin I measured by a high-sensitivity assay and cardiovascular risk estimation: the MORGAM Biomarker Project Scottish Cohort

Aims
Our aim was to test the prediction and clinical applicability of high-sensitivity assayed troponin I for incident cardiovascular events in a general middle-aged European population.

Methods and results
High-sensitivity assayed troponin I was measured in the Scottish Heart Health Extended Cohort (n = 15 340) with 2171 cardiovascular events (including acute coronary heart disease and probable ischaemic strokes), 714 coronary deaths (25% of all deaths), 1980 myocardial infarctions, and 797 strokes of all kinds during an average of 20 years follow-up. Detection rate above the limit of detection (LoD) was 74.8% in the overall population and 82.6% in men and 67.0% in women. Troponin I assayed by the high-sensitivity method was associated with future cardiovascular risk after full adjustment such as that individuals in the fourth category had 2.5 times the risk compared with those without detectable troponin I (P < 0.0001). These associations remained significant even for those individuals in whom levels of contemporary-sensitivity troponin I measures were not detectable. Addition of troponin I levels to clinical variables led to significant increases in risk prediction with significant improvement of the c-statistic (P < 0.0001) and net reclassification (P < 0.0001). A threshold of 4.7 pg/mL in women and 7.0 pg/mL in men is suggested to detect individuals at high risk for future cardiovascular events.

Conclusion
Troponin I, measured with a high-sensitivity assay, is an independent predictor of cardiovascular events and might support selection of at risk individuals.

Using Pedometer Step-Count Goals to Promote Physical Activity in Cardiac Rehabilitation: A Feasibility Study of a Controlled Trial

Background: There is a need to improve the effectiveness of strategies to help cardiac rehabilitation patients achieve recommended levels of physical activity; the use of pedometers requires further research. We aimed to examine the feasibility of a randomised controlled trial, of an intervention using pedometer step-count goals, to promote physical activity for cardiac rehabilitation patients. Methods: We invited patients who completed a supervised cardiac rehabilitation programme to participate in this community-based study. Consenting participants wore a Yamax CW-701 pedometer for one week, blinded to stepcount readings, before being randomly allocated to groups. Intervention groups were told their step-counts; working with a clinical facilitator (nurse or physiotherapist) individually, they set daily step-count goals and reviewed these weekly. Baseline step-counts were hidden from controls, who were not given pedometers but received ongoing weekly facilitator support. After six weeks both groups wore ‘blinded’ pedometers for outcome assessment and participated in semi-structured interviews which explored their experiences of the study. Outcomes included rates of uptake, adherence and completion of measures, including step-counts, quality of life (EQ-5D) and stage of behaviour change. Results: Four programme groups were recruited; two received the intervention. Of 68 invitees, 45 participated (66%) (19 intervention; 26 control). Forty-two (93%) completed the outcomes. Baseline characteristics were comparable between groups. Mean steps/day increased more for intervention participants (2,742; 95%CI 1,169 to 4,315) than controls (-42; 95%CI -1,102 to 1,017) (p=0.004). The intervention and on-going clinical contact were welcomed; participants considered that step-counts, compared to time-related targets, encouraged them to become more active. Conclusion: These findings suggest that an intervention using individually tailored step-count goals may help increase and sustain physical activity following a cardiac rehabilitation programme. A definitive randomised controlled trial using blinded outcome measurements is feasible and of potential value in determining how best to translate physical activity advice into practice.

Prospective clinical audit of chloral hydrate administration practices in a neonatal unit

Aim: Chloral hydrate is generally considered a safe and effective single dosing procedural sedative for neonates in the clinical setting. However, its safety profile as a repetitive dosing maintenance sedative is largely unknown. This study aimed to document current administration practices of chloral hydrate in the Neonatal Unit, Royal Children's Hospital, Melbourne, Australia, over a 6-month period.

Methods: Patients who had been prescribed chloral hydrate during the specified audit period were recruited into the study and prospectively followed for a period of 28 days, or until they were discharged from the unit. Demographic data were collected on recruitment, and daily documentation of chloral hydrate administration was recorded.

Results: A total of 238 doses of chloral hydrate were administered to a cohort of 32 patients during the study period. The majority of the audited doses (84%) were ordered as repeating doses. Doses were more likely to be given at night than during the day, and the median dosage for repetitive dosing was found to be above the study site's recommended dosing range. Pre-dose and/or post-dose assessment of distress/agitation accompanied dosage approximately half of the time. The audit did not reveal any recognisable pattern of sedation maintenance or weaning process for patients who received multiple doses.

Conclusions: Health-care professionals caring for hospitalised infants should be made aware of the potential risks of chloral hydrate as a repetitive dosing sedative, and of the importance of systematically evaluating the appropriateness and effectiveness of utilising such pharmacological intervention for managing and treating distress.

Implementing change in the neonatal unit: Part 1 – The evidence base

Pain management in premature and sick babies has long been recognised as a vital component of neonatal care; however practices pertaining to pain assessment and administration of analgesia remain variable in Neonatal Units (NNU). Sucrose has been identified as an effective agent in reducing pain during minor painful procedures in premature babies but the uptake has been modest.This article is the first of two, and will describe the rationale for implementation of sucrose administration as a measure for pain relief for minor procedures in one neonatal unit in Northern Ireland. Current literature relating to use of sucrose willbe utilised in generating debate and discussion around the implementation of Clinical Practice Guidelines (CPG) for Sucrose use.

Detection of cardiac arrest using a simplified frequency analysis of the impedance cardiogram recorded from defibrillator pads

An algorithm based only on the impedance cardiogram (ICG) recorded through two defibrillation pads, using the strongest frequency component and amplitude, incorporated into a defibrillator could determine circulatory arrest and reduce delays in starting cardiopulmonary resuscitation (CPR). Frequency analysis of the ICG signal is carried out by integer filters on a sample by sample basis. They are simpler, lighter and more versatile when compared to the FFT. This alternative approach, although less accurate, is preferred due to the limited processing capacity of devices that could compromise real time usability of the FFT. These two techniques were compared across a data set comprising 13 cases of cardiac arrest and 6 normal controls. The best filters were refined on this training set and an algorithm for the detection of cardiac arrest was trained on a wider data set. The algorithm was finally tested on a validation set. The ICG was recorded in 132 cardiac arrest patients (53 training, 79 validation) and 97 controls (47 training, 50 validation): the diagnostic algorithm indicated cardiac arrest with a sensitivity of 81.1% (77.6-84.3) and specificity of 97.1% (96.7-97.4) for the validation set (95% confidence intervals). Automated defibrillators with integrated ICG analysis have the potential to improve emergency care by lay persons enabling more rapid and appropriate initiation of CPR and when combined with ECG analysis they could improve on the detection of cardiac arrest.

Loss-of-Mains Protection System by Application of Phasor Measurement Unit Technology with Experimentally Assessed Threshold Settings

Loss-of-mains protection is an important component of the protection systems of embedded generation. The role of loss-of-mains is to disconnect the embedded generator from the utility grid in the event that connection to utility dispatched generation is lost. This is necessary for a number of reasons, including the safety of personnel during fault restoration and the protection of plant against out-of-synchronism reclosure to the mains supply. The incumbent methods of loss-of-mains protection were designed when the installed capacity of embedded generation was low, and known problems with nuisance tripping of the devices were considered acceptable because of the insignificant consequence to system operation. With the dramatic increase in the installed capacity of embedded generation over the last decade, the limitations of current islanding detection methods are no longer acceptable. This study describes a new method of loss-of-mains protection based on phasor measurement unit (PMU) technology, specifically using a low cost PMU device of the authors' design which has been developed for distribution network applications. The proposed method addresses the limitations of the incumbent methods, providing a solution that is free of nuisance tripping and has a zero non-detection zone. This system has been tested experimentally and is shown to be practical, feasible and effective. Threshold settings for the new method are recommended based on data acquired from both the Great Britain and Ireland power systems.

Synergy Between an Improved Covariate Unit Root Test and Cross-sectionally Dependent Panel Data Unit Root Tests, with two Applications

This paper proposes the use of an improved covariate unit root test which exploits the cross-sectional dependence information when the panel data null hypothesis of a unit root is rejected. More explicitly, to increase the power of the test, we suggest the utilization of more than one covariate and offer several ways to select the ‘best’ covariates from the set of potential covariates represented by the individuals in the panel. Employing our methods, we investigate the Prebish-Singer hypothesis for nine commodity prices. Our results show that this hypothesis holds for all but the price of petroleum.

Streptococcus bovis bacteraemia: an evaluation of the long-term effect on cardiac outcomes

Introduction: Streptococcus bovis can lead to bacteraemia, septicaemia, and ultimately endocarditis. The objective of this study was to evaluate the long-term implications of S. bovis endocarditis on cardiac morbidity and mortality. 

Methods: A retrospective cohort study was performed between January 2000 and March 2009 to assess all patients diagnosed with S. bovis bacteraemia from the Belfast Health and Social Care Trust. The primary end-point for cardiac investigations was the presence of endocarditis. Secondary end-points included referral for cardiac surgery and overall mortality. 

Results: Sixty-one positive S. bovis blood cultures from 43 patients were included. Following echocardiography, seven patients were diagnosed with infective endocarditis (16.3 % of total patients); four patients (9.3 %) had native valve involvement while three (7.0 %) had prosthetic valve infection. Five of these seven patients had more than one positive S. bovis culture (71.4 %). Three had significant valve dysfunction that warranted surgical repair/replacement, one of whom was unfit for surgery. There was a 100 % recurrence rate amongst the valve replacement patients (n = 2) and six patients with endocarditis had colorectal pathology. Patients with endocarditis had similar long-term survival as those with non-endocarditic bacteraemia (57.1 % alive vs. 50 % of non-endocarditis patients, p = 0.73). 

Conclusion: Streptococcus bovis endocarditis patients tended to have pre-existing valvular heart disease and those with prosthetic heart valves had higher surgical intervention and relapse rates. These patients experienced a higher rate of co-existing colorectal pathology but currently have reasonable long-term outcomes. This may suggest that they represent a patient population that merits consideration for an early surgical strategy to maximise long-term results, however, further evaluation is warranted. © 2013 The Japanese Association for Thoracic Surgery.