Robert A. Malkin

Technologies for global health

Institute for Global Health Innovation (L Conteh PhD, Prof A Darzi FRCS, P Howitt MA, K Kerr PhD, Prof S Matlin DSc, R Merrifi eld PhD, Prof G-Z Yang PhD), Centre for Environmental Policy (E Wilson MSc), Centre for Health Policy (D King MRCS, M Kulendran MRCS, Prof P C Smith BA), Department of Bioengineering (Prof A M J Bull PhD, Prof R A Malkin PhD, Prof M M Stevens PhD), Department of Civil and Environmental Engineering (M R Templeton PhD), Department of Infectious Diseases (G S Cooke PhD, N Ford PhD, S D Reid PhD), Department of Infectious Disease Epidemiology (S A J Gregson PhD), Department of Materials (Prof M M Stevens), Department of Medicine (A Blakemore PhD), Department of Primary Care & Public Health (Prof A Majeed MD), Department of Surgery and Cancer (H Ashrafi an MRCS, Prof C Vincent PhD), Faculty of Medicine (Prof R Atun FRCP), Global eHealth Unit (J Car PhD), Imperial College Business School (Prof R Atun FRCP, Prof J Barlow PhD), and Imperial Innovations (HA Penfold PhD), Imperial College London, London, UK Technologies for global health

Very-Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency in Mice

Abstract— Fatty acid oxidation (FAO) defects are inborn errors of metabolism clinically associated with cardiomyopathy and sudden infant death syndrome (SIDS). FAO disorders often present in infancy with myocardial dysfunction and arrhythmias after exposure to stresses such as fasting, exercise, or intercurrent viral illness. It is uncertain whether the heart, in the absence of stress, is normal. We generated very-long-chain acyl-coenzyme A dehydrogenase (VLCAD)-deficient mice by homologous recombination to define the onset and molecular mechanism of myocardial disease. We found that VLCAD-deficient hearts have microvesicular lipid accumulation, marked mitochondrial proliferation, and demonstrated facilitated induction of polymorphic ventricular tachycardia, without antecedent stress. The expression of acyl-CoA synthase (ACS1), adipophilin, activator protein 2, cytochrome c, and the peroxisome proliferator activated receptor &ggr; coactivator-1 were increased immediately after birth, preceding overt histological lipidosis, whereas ACS1 expression was markedly downregulated in the adult heart. We conclude that mice with VLCAD deficiency have altered expression of a variety of genes in the fatty acid metabolic pathway from birth, reflecting metabolic feedback circuits, with progression to ultrastructural and physiological correlates of the associated human disease in the absence of stress.

Cardiovascular Collapse Caused by Electrocardiographically Silent 60-Hz Intracardiac Leakage Current Implications for Electrical Safety

BACKGROUND The national standard for safe 60-Hz intracardiac leakage current under a single-fault condition is 50 microA. This standard is intended to protect patients from alternating current (AC) at levels below the threshold for sensation, but the minimum unsafe level for AC in closed-chest humans is not known. To determine this value, we studied 40 patients at testing of implantable cardioverter-defibrillators using a programmable source of 60-Hz AC. METHODS AND RESULTS We applied AC for 5-second test periods in increasing strengths until ventricular fibrillation (VF) was induced or 1 mA was reached. Two current paths were tested: bipolar, between tip and ring electrodes of a right ventricular pacing catheter, and unipolar, from tip to a remote electrode. We observed a characteristic sequence of 3 responses as AC was increased: (1) intermittent ventricular capture with QRS morphology identical to pacing through the electrodes (minimum value, 20 microA); (2) continuous capture at cycle length 282+/-88 ms (minimum value, 32 microA); and (3) VF persisting after AC termination (minimum value, 49 microA). Continuous capture caused loss of pulsatile arterial pressure and cardiovascular collapse (mean arterial pressure, 32+/-8 mm Hg) for the duration of AC with no ECG evidence of AC stimulation. Thus, the clinical picture was that of hypotensive ventricular tachycardia (VT). The continuous-capture threshold was </=50 microA in 9 patients (22%) for bipolar AC and in 5 (12%) for unipolar AC. All patients showed continuous capture over a wide range for both bipolar AC (68+/-18 to 216+/-238 microA) and unipolar AC (84+/-27 to 278+/-226 microA). CONCLUSIONS Leakage current causes cardiovascular collapse at levels below the VF threshold. Stimulation by silent AC that is neither felt nor visible on the ECG presents as hypotensive VT. In patients with intracardiac electrodes, leakage current less than or equal to the present standard of 50 microA may cause VT or VF. The safety standard for leakage current lasting >/=5 seconds should be </=20 microA. This standard should be based on the continuous-capture threshold.

Virtual Electrode Effects in Transvenous Defibrillation-Modulation by Structure and Interface: Evidence from Bidomain Simulations and Optical Mapping

Virtual Electrodes, Bidomain Model, and Defibrillation. Introduction: Our goal in this combined modeling and experimental study was to gain insight into the transmembrane potential changes in defibrillation conditions, namely, when shocks are delivered by an implantable cardioverter defibrillator (ICD). Two hypotheses concerning the presence and characteristics of virtual electrode effects (VEE) during an ICD shock were tested numerically and experimentally: (H1) anisotropy‐dependent VEE are induced over a considerable portion of the “bulk” myocardium; and (H2) surface (epicardial and endocardial) VEE are generated under special tissue bath conditions and are not fully anisotropy determined.

Effect of Rapid Pacing and T-Wave Scanning on the Relation Between the Defibrillation and Upper-Limit-of-Vulnerability Dose-Response Curves

BACKGROUND The critical-point and upper-limit-of-vulnerability (ULV) hypotheses predict that the ULV dose-response curve should be steeper and to the right of the defibrillation (DF) curve. Yet, some recent experimental data contradict this prediction. Two studies are presented that test two explanations for the contradiction: (1) Testing at a single point in the T wave underestimates the ULV dose-response curve and (2) ULV testing at normal heart rates does not mimic the mechanical or electrical state of the heart in ventricular fibrillation (VF). METHODS AND RESULTS A nonthoracotomy lead system with a biphasic waveform was used throughout. In eight dogs, the dose-response curve widths (a measure of steepness) were compared between DF data and ULV data gathered at the peak (ULVPK), middownslope (ULVDWN), midupslope (ULVUP), and all times (scanning or ULVSCN) in the T wave. In another eight dogs, ULV data (ULVRAP) were gathered by scanning the T wave after 15 rapidly paced beats (166- to 198-ms pacing interval). The rapid pacing interval was chosen to more closely mimic the hemodynamics and activation rate of early VF. ULV data (ULVSTD) at normal heart rates were gathered for all animals. In the first study, scanning significantly reduced the ULV curve width (ULVSCN, 63.5 +/- 29.7 V; ULVPK, 81.9 +/- 45.2 V; ULVDWN, 116 +/- 36.5 V; DF, 105 +/- 22.0 V; P < .03) and significantly shifted the ULV curve to the right (ULV80 SCN, 410 +/- 62.6 V; ULV80 PK, 266 +/- 35.3 V; ULV80 DWN, 355 +/- 80.4 V; DF80, 427 +/- 60.9 V; P < .001). The subscript 80 signifies that the subject was left in normal sinus rhythm 80% of the time after that stimulus strength was delivered. In the second study, the ULVRAP curve was shifted dramatically to the right, the average ULV50 RAP being greater than the average DF90. Furthermore, 92% of the ULVRAP VF inductions occurred between 10 ms before and 50 ms after the peak of the T wave, suggesting that scanning of the entire T wave may not be necessary. CONCLUSIONS With a single rapidly paced ULV sequence with limited T-wave scanning, it may be possible to estimate highly effective defibrillation doses with few VF episodes and high-voltage stimuli.

Effectiveness of medical equipment donations to improve health systems: how much medical equipment is broken in the developing world?

It is often said that most of the medical equipment in the developing world is broken with estimates ranging up to 96% out of service. But there is little documented evidence to support these statements. We wanted to quantify the amount of medical equipment that was out of service in resource poor health settings and identify possible causes. Inventory reports were analyzed from 1986 to 2010, from hospitals in sixteen countries across four continents. The UN Human Development Index was used to determine which countries should be considered developing nations. Non-medical hospital equipment was excluded. This study examined 112,040 pieces of equipment. An average of 38.3% (42,925, range across countries: 0.83–47%) in developing countries was out of service. The three main causes were lack of training, health technology management, and infrastructure. We hope that the findings will help biomedical engineers with their efforts toward effective designs for the developing world and NGO’s with efforts to design effective healthcare interventions.

THE NATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND HEALTH INDOOR ENVIRONMENTAL EVALUATION EXPERIENCE. PART THREE : ASSOCIATIONS BETWEEN ENVIRONMENTAL FACTORS AND SELF-REPORTED HEALTH CONDITIONS

Abstract Associations between environmental factors and work-related health conditions were assessed using regression techniques with environmental and health data for 2435 respondents in 80 office buildings included in the National Institute for Occupational Safety and Health Health Hazard Evaluation program. The health conditions analyzed included two symptom groupings—multiple lower respiratory symptoms and multiple atopic symptoms—and the presence of asthma diagnosed after beginning work in the building. Four categories of environmental variables were included: heating, ventilation, and air conditioning (HVAC) system design; HVAC maintenance; building design; and building maintenance. Female gender and age over 40 years showed increased relative risks (RRs) for each health condition. In regression models adjusted for age and gender, RRs of multiple lower respiratory symptoms were increased for variables in the HVAC design and maintenance categories, with the highest RR for presence of debris inside th...

Comparison of Upper Limit of Vulnerability and Defibrillation Probability of Success Curves Using a Nonthoracotomy Lead System

BACKGROUND An upper limit to the strength of shocks that induce fibrillation during the vulnerable period, the upper limit of vulnerability (ULV), has been shown to exist in both humans and animals. The purpose of this study was to compare ULV and defibrillation (DF) probability of success curves for a clinically useful nonthoracotomy lead system. METHODS AND RESULTS Sixteen pentobarbital-anesthetized pigs were studied. Single-capacitor biphasic waveforms with both phases 5.5 ms in duration were used for ULV and DF testing. A right ventricular catheter electrode served as first-phase cathode and a superior vena cava catheter electrode coupled with a cutaneous R2 patch electrode served as common first-phase anodes. A pacing catheter was placed in the right ventricle to deliver a train of 15 S1 stimuli at a pacing interval of 250 to 300 ms. A ULV shock was delivered on the peak of the T wave as measured from the surface ECG; if ventricular fibrillation was induced, a DF shock was delivered after 10 seconds of fibrillation. Shock voltages were determined by an up-down protocol. Ventricular fibrillation was induced an average of 53 times in each animal. The composite data indicate that below V97, that is, the voltage that leaves the animal in normal sinus rhythm 97% of the time when delivered on the peak of the T wave or the voltage that defibrillates 97% of the time, ULV is lower than DF. ULV and DF became significantly correlated at V80 and maximally correlated at V97. Even at V97, however, ULV and DF differed by more than 100 V in 2 of the 16 animals. CONCLUSIONS ULV approximately equaled DF at V97. This is fortunate because it is clinically important to set the device voltage at the uppermost portion of the probability of success curve. Estimating DF V97 from ULV V97 would reduce the number of fibrillation inductions needed to establish defibrillation shock strength requirements. However, the large difference between ULV V97 and DF in a few animals indicates that further improvement and testing of algorithms for determining ULV V97 must be developed before the technique is used clinically.

Estimating the 95% effective defibrillation dose

Minimum-squared-error (MinSE) testing protocols and a MinSE estimator that accurately estimate the voltage that defibrillates 95% of the time (the ED95) are presented. The MinSE experimental procedures, presented in the form of lookup tables, detail the response to successful and unsuccessful trials. The lookup tables also show the ED95 estimates calculated from the observed results using the MinSE estimator. The MinSE estimator and experimental procedure were evaluated in a study of five dogs (19-25 kg, heart weights 139.3-236.9 gm) using nonthoracotomy implantable defibrillator electrodes and a biphasic defibrillation waveform (3.5 ms first phase, 2.0 ms second phase). For ED95 between 0.0 and 800.0 V, the measured RMS error was 15% of the mean measured ED95 for the MinSE, four-test-shock, ED95 estimates. If the protocols are designed with an ED95 population distribution assumption for animals of the same species and size, and defibrillation is constrained to one electrode configuration and waveform, the estimates improve by 3.8%. The MinSE approach can be extended to a variety of defibrillation parameter estimation problems.<<ETX>>

AN UP-DOWN BAYESIAN, DEFIBRILLATION EFFICACY ESTIMATOR

In both the clinic and the laboratory, efficacy estimators are used to estimate the shock strength required to achieve a given defibrillation success rate. In the clinic, efficacy estimators are used to estimate highly effective doses (i.e., the shock strength that defibrillates 95% of the time), in order to choose the setting for an ICD. Efficacy estimators are used in the laboratory to compare defibrillation techniques and configurations. Current efficacy estimators are inadequate because they are either difficult to use, can only estimate the shock strength that defibrillates 50% of the time, or do not yield desirable accuracy (low RMS error). This article presents a Bayesian estimation technique that forces the difference between successive test shock strengths (step‐size) to be a fixed value after each measurement. Constraining the difference dramatically reduces the computational complexity of the up‐down Bayesian method. This new, up‐down Bayesian protocol can be used with up to 15 measurements to estimate the shock strength for any given success rate. Simulations show that the added constraint (fixed step‐size) only slightly increases the rms error, as compared to the optimum Bayesian protocol. Our simulations also show that protocols can be generated for shock strengths rounded to the nearest 1, 10, or 50 V, without a great increase in RMS error. Experimental results from a subset of all the simulations are reported from six animals, showing a < ‐2.4% difference between the simulated and measured errors. (PACE 1997; 20[Pt. I]:1292‐1300)