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This biophysical analysis explores the first-principles physics of movement of white blood cell sized particles, suspended in an aqueous fluid and experiencing progressive or standing waves of acoustic pressure. In many current applications the cells are gradually nudged or herded toward the nodes of the standing wave, providing a degree of acoustic focusing and concentration of the cells in layers perpendicular to the direction of sound propagation. Here the underlying biomechanics of this phenomenon are analyzed specifically for the viscous regime of water and for small diameter microscopic spheroids such as living cells. The resulting mathematical model leads to a single algebraic expression for the creep or drift velocity as a function of sound frequency, amplitude, wavelength, fluid viscosity, boundary dimensions, and boundary reflectivity. This expression can be integrated numerically by a simple and fast computer algorithm to demonstrate net movement of particles as a function of time, providing a guide to optimization in a variety of emerging applications of ultrasonic cell focusing., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Acute cardiovascular stress increases systemic wall shear stress (WSS)-a frictional force exerted by the flow of blood on vessel walls-which raises plasma nitrite concentration due to enhanced endothelial nitric oxide synthase (eNOS) activity. Upstream eNOS inhibition modulates distal perfusion, and autonomic stress increases both the consumption and vasodilatory effects of endogenous nitrite. Plasma nitrite maintains vascular homeostasis during exercise and disruption of nitrite bioavailability can lead to intermittent claudication., Hypothesis: During acute cardiovascular stress or strenuous exercise, we hypothesize enhanced production of nitric oxide (NO) by vascular endothelial cells raises nitrite concentrations in near-wall layers of flowing blood, resulting in cumulative NO concentrations in downstream arterioles sufficient for vasodilation., Confirmation and Implications: Utilizing a multiscale model of nitrite transport in bifurcating arteries, we tested the hypothesis for femoral artery flow under resting and exercised states of cardiovascular stress. Results indicate intravascular transport of nitrite from upstream endothelium could result in vasodilator-active levels of nitrite in downstream resistance vessels. The hypothesis could be confirmed utilizing artery-on-a-chip technology to measure NO production rates directly and help validate numerical model predictions. Further characterization of this mechanism may improve our understanding of symptomatic peripheral artery occlusive disease and exercise physiology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Muskat, Babbs, Goergen and Rayz.)

Wall shear stress (WSS)-a key regulator of endothelial function-is commonly estimated in vivo using simplified mathematical models based on Poiseuille's flow, assuming a quasi-steady parabolic velocity distribution, despite evidence that more rapidly time-varying, pulsatile blood flow during each cardiac cycle modulates flow-mediated dilation (FMD) in large arteries of healthy subjects. More exact and accurate models based on the well-established Womersley solution for rapidly changing blood flow have not been adopted clinically, potentially because the Womersley solution relies on the local pressure gradient, which is difficult to measure non-invasively. We have developed an open-source method for automatic reconstruction of unsteady, Womersley-derived velocity profiles, and WSS in conduit arteries. The proposed method (available online at https://doi.org/10.5281/zenodo.7576408) requires only the time-averaged diameter of the vessel and time-varying velocity data available from non-invasive imaging such as Doppler ultrasound. Validation of the method with subject-specific computational fluid dynamics and application to synthetic velocity waveforms in the common carotid, brachial, and femoral arteries reveals that the Poiseuille solution underestimates peak WSS 38.5%-55.1% during the acceleration and deceleration phases of systole and underestimates or neglects retrograde WSS. Following evidence that oscillatory shear significantly augments vasodilator production, it is plausible that mischaracterization of the shear stimulus by assuming parabolic flow leads to systematic underestimates of important biological effects of time-varying blood velocity in conduit arteries., (© 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Theoretical models of retinal hemodynamics showed the modulation of retinal pulsatile patterns (RPPs) by heart rate (HR), yet in-vivo validation and scientific merit of this biological process is lacking. Such evidence is critical for result interpretation, study design, and (patho-)physiological modeling of human biology spanning applications in various medical specialties. In retinal hemodynamic video-recordings, we characterize the morphology of RPPs and assess the impact of modulation by HR or other variables. Principal component analysis isolated two RPPs, i.e., spontaneous venous pulsation (SVP) and optic cup pulsation (OCP). Heart rate modulated SVP and OCP morphology (p FDR < 0.05); age modulated SVP morphology (p FDR < 0.05). In addition, age and HR demonstrated the effect on between-group differences. This knowledge greatly affects future study designs, analyses of between-group differences in RPPs, and biophysical models investigating relationships between RPPs, intracranial, intraocular pressures, and cardiovascular physiology., (© 2022. The Author(s).)

The circle of Willis (CW) allows blood to be redistributed throughout the brain during local ischemia; however, it is unlikely that the anatomic persistence of the CW across mammalian species is driven by natural selection of individuals with resistance to cerebrovascular disease typically occurring in elderly humans. To determine the effects of communicating arteries (CoAs) in the CW on cerebral pulse wave propagation and blood flow velocity, we simulated young, active adult humans undergoing different states of cardiovascular stress (i.e., fear and aerobic exercise) using discrete transmission line segments with stress-adjusted cardiac output, peripheral resistance, and arterial compliance. Phase delays between vertebrobasilar and carotid pulses allowed bidirectional shunting through CoAs: both posteroanterior shunting before the peak of the pulse waveform and anteroposterior shunting after internal carotid pressure exceeded posterior cerebral pressure. Relative to an absent CW without intact CoAs, the complete CW blunted anterior pulse waveforms, although limited to 3% and 6% reductions in peak pressure and pulse pressure, respectively. Systolic rate of change in pressure (i.e., ∂P/∂t) was reduced 15%-24% in the anterior vasculature and increased 23%-41% in the posterior vasculature. Bidirectional shunting through posterior CoAs was amplified during cardiovascular stress and increased peak velocity by 25%, diastolic-to-systolic velocity range by 44%, and blood velocity acceleration by 134% in the vertebrobasilar arteries. This effect may facilitate stress-related increases in blood flow to the cerebellum (improving motor coordination) and reticular-activating system (enhancing attention and focus) via a nitric oxide-dependent mechanism, thereby improving survival in fight-or-flight situations. NEW & NOTEWORTHY Hemodynamic modeling reveals potential evolutionary benefits of the intact circle of Willis (CW) during fear and aerobic exercise. The CW equalizes pulse waveforms due to bidirectional shunting of blood flow through communicating arteries, which boosts vertebrobasilar blood flow velocity and acceleration. These phenomena may enhance perfusion of the brainstem and cerebellum via nitric oxide-mediated vasodilation, improving performance of the reticular-activating system and motor coordination in survival situations.

This study explores the hypothesis that the sharper, high frequency Korotkoff sounds come from resonant motion of the arterial wall, which begins after the artery transitions from a buckled state to an expanding state. The motions of one mass, two nonlinear springs, and one damper, driven by transmural pressure under the cuff, are used to model and compute the Korotkoff sounds according to principles of classical Newtonian physics. The natural resonance of this spring-mass-damper system provides a concise, yet rigorous, explanation for the origin of Korotkoff sounds. Fundamentally, wall stretching in expansion requires more force than wall bending in buckling. At cuff pressures between systolic and diastolic arterial pressure, audible vibrations (> 40 Hz) occur during early expansion of the artery wall beyond its zero pressure radius after the outward moving mass of tissue experiences sudden deceleration, caused by the discontinuity in stiffness between bucked and expanded states. The idealized spring-mass-damper model faithfully reproduces the time-domain waveforms of actual Korotkoff sounds in humans. Appearance of arterial sounds occurs at or just above the level of systolic pressure. Disappearance of arterial sounds occurs at or just above the level of diastolic pressure. Muffling of the sounds is explained by increased resistance of the artery to collapse, caused by downstream venous engorgement. A simple analytical model can define the physical origin of Korotkoff sounds, suggesting improved mechanical or electronic filters for their selective detection and confirming the disappearance of the Korotkoff sounds as the optimal diastolic end point., (Copyright © 2015 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Background: Concerns about the cost-effectiveness of invasive hemodynamic monitoring in critically ill patients using pulmonary artery catheters motivate a renewed search for effective noninvasive methods to measure stroke volume. This paper explores a new approach based on noninvasively measured pulse wave velocity, pulse contour, and ultrasonically determined aortic cross sectional area., Methods: The Bramwell-Hill equation relating pulse wave velocity to aortic compliance is applied. At the time point on the noninvasively measured pulse contour, denoted th, when pulse amplitude has fallen midway between systolic and diastolic values, the portion of stroke volume remaining in the aorta, and in turn the entire stroke volume, can be estimated from the compliance and the pulse waveform. This approach is tested and refined using a numerical model of the systemic circulation including the effects of blood inertia, nonlinear compliance, aortic tapering, varying heart rate, and varying myocardial contractility, in which noninvasively estimated stroke volumes were compared with known stroke volumes in the model., Results: The Bramwell-Hill approach correctly allows accurate calculation of known, constant aortic compliance in the numerical model. When nonlinear compliance is present the proposed noninvasive technique overestimates true aortic compliance when pulse pressure is large. However, a reasonable correction for nonlinearity can be derived and applied to restore accuracy for normal and for fast heart rates (correlation coefficient > 0.98)., Conclusions: Accurate estimates of cardiac stroke volume based on pulse wave velocity are theoretically possible and feasible. The precision of the method may be less than desired, owing to the dependence of the final result on the square of measured pulse wave velocity and the first power of ultrasonically measured aortic cross sectional area. However, classical formulas for propagation of random errors suggest that the method may still have sufficient precision for clinical applications. It remains as a challenge for experimentalists to explore further the potential of noninvasive measurement of stroke volume using pulse wave velocity. The technique is non-proprietary and open access in full detail, allowing future users to modify and refine the method as guided by practical experience.

Aim: To present statistical tools to model and optimize the cost of a randomized clinical trial as a function of the stringency of patient inclusion criteria., Methods: We consider a two treatment, dichotomous outcome trial that includes a proportion of patients who are strong responders to the tested intervention. Patients are screened for inclusion using an arbitrary number of test results that are combined into an aggregate suitability score. The screening score is regarded as a diagnostic test for the responsive phenotype, having a specific cutoff value for inclusion and a particular sensitivity and specificity. The cutoff is a measure of stringency of inclusion criteria. Total cost is modeled as a function of the cutoff value, number of patients screened, the number of patients included, the case occurrence rate, response probabilities for control and experimental treatments, and the trial duration required to produce a statistically significant result with a specified power. Regression methods are developed to estimate relevant model parameters from pilot data in an adaptive trial design., Results: The patient numbers and total cost are strongly related to the choice of the cutoff for inclusion. Clear cost minimums exist between 5.6 and 6.1 on a representative 10-point scale of exclusiveness. Potential cost savings for typical trial scenarios range in millions of dollars. As the response rate for controls approaches 50%, the proper choice of inclusion criteria can mean the difference between a successful trial and a failed trial., Conclusion: Early formal estimation of optimal inclusion criteria allows planning of clinical trials to avoid high costs, excessive delays, and moral hazards of Type II errors.

Background: A compact theory that predicts quantitatively when and where magnetic neurostimulation will occur is needed as a guide to therapy, ideally providing a single equation that defines the target volume of tissue excited by single or dual coils., Methods: A first-principles analysis of magnetic stimulation incorporating a simplified description of electromagnetic fields and a simplified cable theory of the axon yields a mathematical synthesis predicting how to aim., Results: Nerve stimulation produced by a single circular coil having one or more closely packed turns occurs in donut shaped volume of tissue beneath the coil. Axons spanning several millimeters are the sites of magnetic stimulation. The sites of maximal transmembrane depolarization in nerve fibers correspond to points where the axons enter or exit this volume of magnetically induced voltage and current. The axonal membrane at one end is depolarized locally during the rising phase of current in the coil. The axonal membrane at the opposite end is depolarized locally during the falling phase of current in the coil. Penetration depths of several centimeters from the skin surface or approximately one to two coil radii are practical. With two coils placed in a figure-of-eight configuration the separate clockwise and counterclockwise currents generate magnetic fields that add, producing maximal stimulation of a spindle shaped volume, centered at a depth of one-third to one-half coil radius from the body surface., Conclusions: This condensed synthesis of electromagnetic theory and cable theories of axon physiology provides a partial solution to the targeting problem in peripheral and in transcranial magnetic stimulation.

This study explores in detail the functional consequences of subtle retraction and detachment of myelin around the nodes of Ranvier following mild-to-moderate crush or stretch mediated injury. An equivalent electrical circuit model for a series of equally spaced nodes of Ranvier was created incorporating extracellular and axonal resistances, paranodal resistances, nodal capacitances, time varying sodium and potassium currents, and realistic resting and threshold membrane potentials in a myelinated axon segment of 21 successive nodes. Differential equations describing membrane potentials at each nodal region were solved numerically. Subtle injury was simulated by increasing the width of exposed nodal membrane in nodes 8 through 20 of the model. Such injury diminishes action potential amplitude and slows conduction velocity from 19.1 m/sec in the normal region to 7.8 m/sec in the crushed region. Detachment of paranodal myelin, exposing juxtaparanodal potassium channels, decreases conduction velocity further to 6.6 m/sec, an effect that is partially reversible with potassium ion channel blockade. Conduction velocity decreases as node width increases or as paranodal resistance falls. The calculated changes in conduction velocity with subtle paranodal injury agree with experimental observations. Nodes of Ranvier are highly effective but somewhat fragile devices for increasing nerve conduction velocity and decreasing reaction time in vertebrate animals. Their fundamental design limitation is that even small mechanical retractions of myelin from very narrow nodes or slight loosening of paranodal myelin, which are difficult to notice at the light microscopic level of observation, can cause large changes in myelinated nerve conduction velocity.

Background: Research is needed to explore the relative benefits of alternative electrode placements in biventricular and left ventricular (LV) pacing for heart failure with left bundle branch block (LBBB)., Methods: A fast computational model of the left ventricle, running on an ordinary laptop computer, was created to simulate the spread of electrical activation over the myocardial surface, together with the resulting electrocardiogram, segmental wall motion, stroke volume, and ejection fraction in the presence of varying degrees of mitral regurgitation. Arbitrary zones of scar and blocked electrical conduction could be modeled., Results: Simulations showed there are both sweet spots and poor spots for LV electrode placement, sometimes separated by only a few centimeters. In heart failure with LBBB, pacing at poor spots can produce little benefit or even reduce pumping effectiveness. Pacing at sweet spots can produce up to 35% improvement in ejection fraction. Relatively larger benefit occurs in dilated hearts, in keeping with the greater disparity between early and late activated muscle. Sweet spots are typically located on the basal to midlevel, inferolateral wall. Poor spots are located on or near the interventricular septum. Anteroapical scar with conduction block causes little shift in locations for optimal pacing. Hearts with increased passive ventricular compliance and absence of preejection mitral regurgitation exhibit greater therapeutic gain. The durations and wave shapes of QRS complexes in the electrocardiogram can help predict optimum electrode placement in real time., Conclusions: Differences between poor responders and hyperresponders to cardiac resynchronization therapy can be understood in terms of basic anatomy, physiology, and pathophysiology. Computational modeling suggests general strategies for optimal electrode placement. In a given patient heart size, regional pathology and regional dynamics allow individual pretreatment planning to target optimal electrode placement., (©2012, The Author. Journal compilation ©2012 Wiley Periodicals, Inc.)

Background: The oscillometric method of measuring blood pressure with an automated cuff yields valid estimates of mean pressure but questionable estimates of systolic and diastolic pressures. Existing algorithms are sensitive to differences in pulse pressure and artery stiffness. Some are closely guarded trade secrets. Accurate extraction of systolic and diastolic pressures from the envelope of cuff pressure oscillations remains an open problem in biomedical engineering., Methods: A new analysis of relevant anatomy, physiology and physics reveals the mechanisms underlying the production of cuff pressure oscillations as well as a way to extract systolic and diastolic pressures from the envelope of oscillations in any individual subject. Stiffness characteristics of the compressed artery segment can be extracted from the envelope shape to create an individualized mathematical model. The model is tested with a matrix of possible systolic and diastolic pressure values, and the minimum least squares difference between observed and predicted envelope functions indicates the best fit choices of systolic and diastolic pressure within the test matrix., Results: The model reproduces realistic cuff pressure oscillations. The regression procedure extracts systolic and diastolic pressures accurately in the face of varying pulse pressure and arterial stiffness. The root mean squared error in extracted systolic and diastolic pressures over a range of challenging test scenarios is 0.3 mmHg., Conclusions: A new algorithm based on physics and physiology allows accurate extraction of systolic and diastolic pressures from cuff pressure oscillations in a way that can be validated, criticized, and updated in the public domain.

The objective of this study was to create a clinically applicable mathematical model of immunotherapy for cancer and use it to explore differences between successful and unsuccessful treatment scenarios. The simplified predator-prey model includes four lumped parameters: tumor growth rate, g; immune cell killing efficiency, k; immune cell signaling factor, λ; and immune cell half-life decay, μ. The predator-prey equations as functions of time, t, for normalized tumor cell numbers, y, (the prey) and immunocyte numbers, ×, (the predators) are: dy/dt = gy - kx and dx/dt = λxy - μx. A parameter estimation procedure that capitalizes on available clinical data and the timing of clinically observable phenomena gives mid-range benchmarks for parameters representing the unstable equilibrium case in which the tumor neither grows nor shrinks. Departure from this equilibrium results in oscillations in tumor cell numbers and in many cases complete elimination of the tumor. Several paradoxical phenomena are predicted, including increasing tumor cell numbers prior to a population crash, apparent cure with late recurrence, one or more cycles of tumor growth prior to eventual tumor elimination, and improved tumor killing with initially weaker immune parameters or smaller initial populations of immune cells. The model and the parameter estimation techniques are easily adapted to various human cancers that evoke an immune response. They may help clinicians understand and predict certain strange and unexpected effects in the world of tumor immunity and lead to the design of clinical trials to test improved treatment protocols for patients.

To explore the fundamental biomechanics of sound frequency transduction in the cochlea, a two-dimensional analytical model of the basilar membrane was constructed from first principles. Quantitative analysis showed that axial forces along the membrane are negligible, condensing the problem to a set of ordered one-dimensional models in the radial dimension, for which all parameters can be specified from experimental data. Solutions of the radial models for asymmetrical boundary conditions produce realistic deformation patterns. The resulting second-order differential equations, based on the original concepts of Helmholtz and Guyton, and including viscoelastic restoring forces, predict a frequency map and amplitudes of deflections that are consistent with classical observations. They also predict the effects of an observation hole drilled in the surrounding bone, the effects of curvature of the cochlear spiral, as well as apparent traveling waves under a variety of experimental conditions. A quantitative rendition of the classical Helmholtz-Guyton model captures the essence of cochlear mechanics and unifies the competing resonance and traveling wave theories.

Background: A valveless pump generates a unidirectional net flow of fluid around a closed loop of soft viscoelastic tubing that is rhythmically compressed at one point. The tubing must have at least two sections with two different stiffnesses. When a short segment of the tube is squeezed asymmetrically at certain frequencies, net flow of fluid around the loop can occur without valves., Methods: Partial differential equations for the pressures, volumes, and flows define a simple one-dimensional model of such a pump, based upon elementary physical principles. Numerical computations on a personal computer can predict measured net flows., Results: Net flow varies with the frequency and waveform of compression used to excite the pump, as well as with the site of compression and the stiffness and viscosity of the tubing. Net flows on the order of 1 ml/sec are obtained in a water-filled loop including 46 cm of stiffer plastic (Tygon) laboratory tubing and 70 cm of softer latex rubber tubing., Conclusions: The heretofore mysterious phenomenon of valveless pumping can be described in terms of classical Newtonian physics, in which viscous damping in the walls of the pump is included. Studying valveless pumps in the laboratory and modeling their behavior numerically provides a low-cost, engaging, and instructive exercise for research and teaching in biomedical engineering.

The conventional impedance cardiogram is a record of pulsatile changes in the electrical impedance of the chest with each heartbeat. The signal seems intuitively related to cardiac stroke volume. However doubts persist about the validity of stroke volume measurements based on electrical impedance. This paper presents a new electrical axis for impedance cardiography that is perpendicular to the conventional head-to-foot axis in an anterior-posterior direction. Dual chest and back electrodes are concentric, permitting tetrapolar technique. A relatively simple analytical model is developed, and this model is validated in a three-dimensional finite element model of current flow through the human chest. Three-dimensional simulations show predictable relationships between the fractional increase in anterior-posterior chest impedance and the ventricular ejection fraction (cardiac stroke volume/ventricular end-diastolic volume). Ejection fraction can be computed accurately with a roughly 30-fold increase in signal level compared to the conventional impedance cardiogram. Breathing causes only modest changes in the signal. When the axis of current flow is optimized, one can interpret the impedance changes during the cardiac cycle with greater confidence as noninvasive, beat-by-beat indicators of ventricular ejection fraction in a wide variety of clinical settings.

Coronary perfusion pressure (CPP) is a major indicator of the effectiveness of cardiopulmonary resuscitation in human and animal research studies, however, methods for calculating CPP differ among research groups. Here we compare the 6 published methods for calculating CPP using the same data set of aortic (Ao) and right atrial (RA) blood pressures. CPP was computed using each of the 6 calculation methods in an anesthetized pig model, instrumented with catheters with Cobe pressure transducers. Aortic and right atrial pressures were recorded continuously during electrically induced ventricular fibrillation and standard AHA CPR. CPP calculated from the same raw data set by the 6 calculation methods ranged from -1 (signifying retrograde blood flow) to 26 mmHg (mean +/- SD of 15 +/- 11 mmHg). The CPP achieved by standard closed chest CPR is typically reported as 10-20 mmHg. Within a single study the CPP values may be comparable; however, the CPP values for different studies may not be a reliable indicator of the efficacy of a given CPR method. Electronically derived true mean coronary perfusion pressure is arguably the gold standard method for representing coronary perfusion pressure.

This paper demonstrates quantitatively, using streamlined mathematics, how the transmembrane ionic currents in individual cardiac muscle cells act to produce the body surface potentials of the electrocardiogram (ECG). From fundamental principles of electrostatics, anatomy, and physiology, one can characterize the strength of apparent dipoles along a wavefront of depolarization in a local volume of myocardium. Net transmembrane flow of ionic current in actively depolarizing or repolarizing tissue induces extracellular current flow, which sets up a field of electrical potential that resembles that of a dipole. The local dipole strength depends upon the tissue cross section, the tissue resistivity, the resting membrane potential, the membrane capacitance, the volume fraction of intracellular fluid, the time rate of change of the action potential, and the cell radius. There are no unknown, "free" parameters. There are no arbitrary scale factors. Body surface potentials are a function of the summed local dipole strengths, directions, and distances from the measuring points. Calculations of body surface potentials can be made for the scenarios of depolarization (QRS complex), repolarization (T wave) and localized acute injury (ST segment shifts) and agree well with experimentally measured potentials. This simplified predictive dipole theory provides a solution to the forward problem of electrocardiography that explains from a physiological perspective how the collective depolarization and repolarization of individual cardiac muscle cells create body surface potentials in health and disease.

Objectives: To develop new methods for studying correlations between the performance and outcome of resuscitation efforts in real-world clinical settings using data recorded by automatic devices, such as automatic external defibrillators (AEDs), and to explore effects of shock timing and chest compression depth in the field., Methods: In 695 records of AED use in the pre-hospital setting, continuous compression data were recorded using AEDs capable of measuring sternal motion during compressions, together with timing of delivered shocks and the electrocardiogram. In patients who received at least one shock, putative return of spontaneous circulation (P-ROSC) was defined as a regular, narrow complex electrical rhythm > 40 beats/min with no evidence of chest compressions at the end of the recorded data stream. Transient return of spontaneous circulation (t-ROSC) was defined as the presence of a post-shock organized rhythm > 40 beats/min within 60s, and sustained > or = 30 s. 2x2 contingency tables were constructed to examine the association between these outcomes and dichotomized time of shock delivery or chest compression depth, using the Mood median test for statistical significance., Results: The probability of P-ROSC for first shocks delivered < 50 s (the median time) after the start of resuscitation was 23%, versus 11% for first shocks > 50 s (p=0.028, one tailed). Similarly, the probability of t-ROSC for shorter times to shock was 29%, compared to the 15% for delayed first shocks (p=0.016). For shocks occurring > 3 min after initiation of rescue attempts, the probability of t-ROSC with pre-shock average compression depth > 5 cm was more than double that with compression depth < 5 cm (17.7% vs. 8.3%, p=0.028). For shocks > 5 min, the effect of deeper compressions increased (23.4% versus 8.2%, p=0.008)., Conclusions: Much can be learned from analysis of performance data automatically recorded by modern resuscitation devices. Use of the Mood median test of association proved to be sensitive, valid, distribution independent, noise-resistant and also resistant to biases introduced by the inclusion of hopeless cases. Efforts to shorten the time to delivery of the first shock and to encourage deeper chest compressions after the first shock are likely to improve resuscitation success. Such refinements can be effective even after an unknown period of preceding downtime.

SH2-containing 5'-inositol phosphatase (SHIP2) is a known regulator of insulin function. Genetic knockout of SHIP2 in mice causes mild insulin hypersensitivity and prevents high-fat-diet-induced obesity. SHIP2 also regulates actin remodeling and epidermal growth factor receptor (EGFR) turnover and supports breast cancer; and metastatic growth. To determine the clinical significance of SHIP2 expression in breast cancer and its relationship to relevant oncogenic molecules, SHIP2 expression was determined immunohistochemically in 285 primary breast cancers; 140 ductal carcinomas in situ (DCIS) and 145 invasive carcinomas. Forty-five percent of the specimens showed high SHIP2 levels in cancer cells while only 15% of adjacent normal cells expressed high SHIP2 levels (p < 0.0001). In cancer cells, the risk of SHIP2 overexpression is elevated (a) in women aged < or =50 years (relative risk, RR = 4.13; 95% confidence interval, CI, 2.5-6.9) compared to women aged >50 years (RR = 2.37; 95% CI 1.6-3.5; p = 0.0003), and (b) in invasive carcinomas (RR = 3.52; 95% CI 2.3-5.5) compared with DCIS (RR = 2.22; 95% CI 1.5-3.5; p = 0.0009). Patients with higher SHIP2 levels in invasive carcinomas had significantly reduced disease-free (p = 0.0025) and overall survival periods (p = 0.0228). In invasive carcinomas, SHIP2 correlated with estrogen receptor absence (p = 0.003) and EGFR presence (p = 0.0147). In conclusion, SHIP2 is an important biomarker for breast cancer., (Copyright 2008 S. Karger AG, Basel.)

Objectives: This study investigated sustained abdominal compression as a means to improve coronary perfusion pressure (CPP) during cardiopulmonary resuscitation (CPR) and compared the resulting CPP augmentation with that achieved using vasopressor drugs., Method: During electrically induced ventricular fibrillation in anesthetized, 30kg juvenile pigs, Thumper CPR was supplemented at intervals either by constant abdominal compression at 100-500mmHg using an inflated contoured cuff or by the administration of vasopressor drugs (epinephrine, vasopressin, or glibenclamide). CPP before and after cuff inflation or drug administration was the end point., Results: Sustained abdominal compression at >200mmHg increases CPP during VF and otherwise standard CPR by 8-18mmHg. The effect persists over practical ranges of chest compression force and duty cycle and is similar to that achieved with vasopressor drugs. Constant abdominal compression also augments CPP after prior administration of epinephrine or vasopressin., Conclusions: During CPR noninvasive abdominal compression with the inflatable contoured cuff rapidly elevates the CPP, sustains the elevated CPP as long as the device is inflated, and is immediately and controllably reversible upon device deflation. Physical control of peripheral vascular resistance during CPR by abdominal compression has some advantages over pharmacological manipulation and deserves serious reconsideration, now that the limitations of pressor drugs during CPR have become better understood, including post-resuscitation myocardial depression and the need for intravenous access.

Objective: To develop statistical tools that use combined initial survival data and post-resuscitation survival data to test the null hypothesis that true, population-wide outcomes following experimental CPR interventions are not different from control., Method: A new test statistic, d(2), for evaluating Type 1 error is derived from a bivariate, two-dimensional analysis of categorical initial resuscitation and post-resuscitation survival data, which are statistically independent because they are obtained during non-overlapping periods of time. The d(2) test statistic, which is distributed as a chi-squared distribution, is derived from first principles and validated using Monte Carlo methods of computer simulation for thousands of clinical trials., Results: Under the null hypothesis, the normalized difference in the proportions of patients surviving the initial resuscitation period and the normalized difference in the proportions of such short-term survivors that also survive the post-resuscitation period are jointly distributed in a two-dimensional space as a bivariate standard normal distribution, against which observed intervention and control outcomes can be compared in a test of statistical significance. Typically this two-dimensional approach has greater statistical power to detect true differences, compared to conventional one-dimensional tests. Smaller group sizes (Ns) are usually required to reach statistical significance when both initial survival and post-resuscitation survival are considered together. Such two-dimensional analysis is easily extended to meta-analysis of multiple trials., Conclusions: A straightforward, easy-to-use bivariate test for Type I errors in statistical inference can be done for resuscitation studies reporting both short-term and long-term survival data. Acceptance of such two-dimensional tests of the null hypothesis, as proposed by Hallstrom, can save time, money, effort, and disappointment in the difficult and sometimes frustrating field of resuscitation research.

An intrathoracic pressure regulator (ITPR) is a device that can be added to the external end of a tracheal tube to create controlled negative airway pressure between positive pressure ventilations. The resulting downward bias of the airway pressure baseline promotes increased venous return and enhanced circulation during CPR and also during hypovolemic shock. In the present study, we exercised a mathematical model of the human cardiopulmonary system, including airways, lungs, a four chambered heart, great vessels, peripheral vascular beds, and the biomechanics of chest compression and recoil, to determine the relationship between systemic perfusion pressure during CPR and the value of baseline negative airway pressure in an ITPR. Perfusion pressure increases approximately 50% as baseline airway pressure falls from zero to -10 cm H2O. Thereafter perfusion pressure plateaus. Negative bias pressures exceeding -10 cm H2O are not needed in ITPR-CPR.

The wide range of tests for laboratory animal behavior after neurological injury or disease each have their benefits and detriments. The varied behavior an animal exhibits makes it difficult to decide which test to use. However, a fundamental instinct for the laboratory animal is to explore when placed in a new environment. A way to test exploratory behavior is in the open field. Here, we introduce a simple activity box without the use of video equipment to determine the exploratory movement of a rat after traumatic brain injury. The activity box is an open field and the rat explores its surroundings when placed inside. Four infrared beams were placed in both the X and Y-axis inside the box. Using a novel system to determine which beam the rat breaks, we describe where the rat is in space and time while in the activity box. Other models can show the number of beams broken, but here we elucidate the methods to additionally determine the amount of area explored, the total distance traveled by the rat and percent time exploring.

Skeletal muscle atrophy results from an imbalance in protein degradation and protein synthesis and occurs in response to injury, various disease states, disuse, and normal aging. Current treatments for this debilitating condition are inadequate. More information about mechanisms involved in the onset and progression of muscle atrophy is necessary for development of more effective therapies. Here we show that expression of the mouse ether-a-go-go related gene (Merg1a) K+ channel is up-regulated in skeletal muscle of mice experiencing atrophy as a result of both malignant tumor expression and disuse. Further, ectopic expression of Merg1a in vivo induces atrophy in healthy wt-bearing mice, while expression of a dysfunctional Merg1a mutant suppresses atrophy in hindlimb-suspended mice. Treatment of hindlimb-suspended mice with astemizole, a known Merg1a channel blocker, inhibits atrophy in these animals. Importantly, in vivo expression of Merg1a in mouse skeletal muscle activates the ubiquitin proteasome pathway that is responsible for the majority of protein degradation that causes muscle atrophy, yet expression of a dysfunctional Merg1a mutant decreases levels of ubiquitin-proteasome proteolysis. Thus, expression of Merg1a likely initiates atrophy by activating ubiquitin-proteasome proteolysis. This gene and its product are potential targets for prevention and treatment of muscle atrophy.

Unlabelled: Periodic z-axis acceleration (pGz)-CPR involves an oscillating motion of a whole patient in the head-to-foot dimension on a mechanized table. The method is able to sustain blood flow and long-term survival during and after prolonged cardiac arrest in anesthetized pigs. However, the exact mechanism by which circulation of blood is created has remained unknown., Objectives: To explain the hemodynamic mechanism of pGz-CPR and to suggest some theoretically useful improvements., Method: Computer modeling using a hybrid analytical-numerical approach, based upon Newton's second law of motion for fluid columns in the aorta and vena cavae, Ohm's law for resistive flow through vascular beds, and a 10-compartment representation of the adult human circulation. This idealized 70-kg human model is exercised to explore the effects upon systemic perfusion pressure of whole body z-axis acceleration at frequencies ranging from 0.5 to 5 Hz. The results, in turn, suggested studies of abdominal compression at these frequencies., Results and Conclusions: Blood motion induced in great vessels by periodic z-axis acceleration causes systemic perfusion when cardiac valves are competent. Blood flow is a function of the frequency of oscillation. At 3.5 Hz, periodic acceleration using +/-0.6G and +/-1.2 cm oscillations induces forward blood flow of 2.1L/min and systemic perfusion pressure of 47 mmHg. A form of resonance occurs at the frequency for peak-flow, in which the period of oscillation matches the round-trip transit time for reflected pulse waves in the aorta. For +/-1.0 G acceleration at 3.5 Hz, systemic perfusion pressure is 80 mmHg and forward flow is 3.8L/min in the adult human model with longitudinal z-axis motion of only +/-2 cm. Similar results can be obtained using abdominal compression to excite resonant pressure-volume waves in the aorta. For 20 mmHg abdominal pressure pulses at 3.8 Hz, systemic perfusion pressure is 7 mmHg and forward flow is 2.8L/min. pGz-CPR and high-frequency abdominal CPR are the physically realistic means of generating artificial circulation during cardiac arrest. These techniques have fundamental mechanisms and practical features quite different from those of conventional CPR and the potential to generate superior systemic perfusion.

Objective: To discover design principles underlying the optimal waveforms for external chest and abdominal compression and decompression during cardiac arrest and cardiopulmonary resuscitation (CPR)., Method: A 14-compartment mathematical model of the human cardiopulmonary system is used to test successive generations of randomly mutated external compression waveforms during cardiac arrest and resuscitation. Mutated waveforms that produced superior mean perfusion pressure became parents for the next generation. Selection was based upon either systemic perfusion pressure (SPP = thoracic aortic minus right atrial pressure) or upon coronary perfusion pressure (CPP = thoracic aortic pressure minus myocardial wall pressure). After simulations of 64,414 individual CPR episodes, 40 highly evolved waveforms were characterized in terms of frequency, duty cycle, and phase. A simple, practical compression technique was then designed by combining evolved features with a constant rate of 80 min(-1) and duty cycle of 50%., Results: All ultimate surviving waveforms included reciprocal compression and decompression of the chest and the abdomen to the maximum allowable extent. The evolved waveforms produced 1.5-3 times the mean perfusion pressure of standard CPR and greater perfusion pressure than other forms of modified CPR reported heretofore, including active compression-decompression (ACD)+ITV and interposed abdominal compression (IAC)-CPR. When SPP was maximized by evolution, the chest compression/abdominal decompression phase was near 70% of cycle time. When CPP was maximized, the abdominal compression/chest decompression phase was near 30% of cycle time. Near-maximal SPP/CPP of 60/21 mmHg (forward flow 3.8 L/min) occurred at a compromise compression frequency of 80 min(-1) and duty cycle for chest compression of 50%., Conclusions: Optimized waveforms for thoraco-abdominal compression and decompression include previously discovered features of active decompression and interposed abdominal compression. These waveforms can be used by manual (Lifestick-like) and mechanical (vest-like) devices to achieve short periods of near normal blood perfusion non-invasively during cardiac arrest.

We have tested the effectiveness of polyethylene glycol (PEG) to restore the integrity of neuronal membranes after mechanical damage secondary to severe traumatic brain injury (TBI) produced by a standardized head injury model in rats. We provide additional detail on the standardization of this model, particularly the use and storage of foam bedding that serves to both support the animal during the impact procedure-and as a dampener to the acceleration of the brass weight. Further, we employed a dye exclusion technique using ethidium bromide (EB; quantitative evaluation) and horseradish peroxidase (HRP; qualitative evaluation). Both have been successfully used previously to evaluate neural injury in the spinal cord since they enter cells when their plasma membranes are damaged. We quantified EB labeling (90 microM in 110 microL of sterile saline) after injection into the left lateral ventricle of the rat brain 2 h after injury. At six h after injection and 8 h after injury, the animals were sacrificed and the brains were analyzed. In the injured rat brain, EB entered cells lining and medial to the ventricles, particularly the axons of the corpus callosum. There was minimal EB labeling in uninjured control brains, limited to cells lining the luminal surfaces of the ventricles. Intravenous injections of PEG (1 cc of saline, 30% by volume, 2000 MW) immediately after severe TBI resulted in significantly decreased EB uptake compared with injured control animals. A similar result was achieved using the larger marker, HRP. PEG-treated brains closely resembled those of uninjured animals.

Unlabelled: Interposed abdominal compression, IAC-CPR incorporates alternating chest and abdominal compressions to generate enhanced artificial circulation during cardiac arrest. The technique has been generally successful in improving blood flow and survival compared to standard CPR; however, some questions remain., Objective: To determine "why does IAC-CPR produce more apparent benefit in some subjects than in others?" and "what is the proper compression rate, given that there are actually two compressions (chest and abdomen) in each cycle?", Method: Computer models provide a means to search for subtle effects in complex systems. The present study employs a validated 12-compartment mathematical model of the human circulation to explore the effects upon systemic perfusion pressure of changes in 35 different variables, including vascular resistances, vascular compliances, and rescuer technique. CPR with and without IAC was modeled., Results and Conclusions: Computed results show that the effect of 100 mmHg abdominal compressions on systemic perfusion pressure is relatively constant (about 16 mmHg augmentation). However, the effect of chest compression depends strongly upon chest compression frequency and technique. When chest compression is less effective, as is often true in adults, the addition of IAC produces relatively dramatic augmentation (e.g. from 24 to 40 mmHg). When chest compression is more effective, the apparent augmentation with IAC is relatively less (e.g. from 60 to 76 mmHg). The optimal frequency for uninterrupted IAC-CPR is near 50 complete cycles/min with very little change in efficacy over 20-100 cycles/min. In theory, the modest increase in systemic perfusion pressure produced by IAC can make up in part for poor or ineffective chest compressions in CPR. IAC appears relatively less effective in circumstances when chest pump output is high.

Unlabelled: An impedance threshold valve (ITV) is a new airway adjunct for resuscitation that permits generation of a small vacuum in the chest during the recoil phase of chest compression., Objectives: To explore in detail the expected magnitude and the hemodynamic mechanisms of circulatory augmentation by an ITV in Standard CPR., Method: A 14-compartment mathematical model of the human cardiopulmonary system--upgraded to include applied chest compression force, elastic recoil of the chest wall, anatomic details of the heart and lungs, and the biomechanics of mediastinal compression--is exercised to explore the conditions required for circulatory augmentation by an ITV during various modes of CPR., Results: The ITV augments systemic perfusion pressure by about 5 mmHg compared to any particular baseline perfusion pressure without the ITV. When baseline perfusion is low, owing to either diminished chest compression force, the existence of a thoracic pump mechanism of blood flow, or the presence of an effective compression threshold, then the relative improvement produced by an ITV is significant. With an ITV the heart expands into soft pericardiac tissue, which makes the heart easier to compress., Conclusions: An ITV can augment perfusion during CPR. The observed effectiveness of ITVs in the laboratory and in the clinic suggests a thoracic pump mechanism for Standard CPR, and perhaps also an effective compression threshold that must be exceeded to generate blood flow by external chest compression.

This paper presents a comparison of feature selection methods for a unified detection of breast cancers in mammograms. A set of features, including curvilinear features, texture features, Gabor features, and multi-resolution features, were extracted from a region of 512x512 pixels containing normal tissue or breast cancer. Adaptive floating search and genetic algorithm were used for the feature selection, and a linear discriminant analysis (LDA) was used for the classification of cancer regions from normal regions. The performance is evaluated using Az the area under ROC curve. On a dataset consisting 296 normal regions and 164 cancer regions (53 masses, 56 spiculated lesions, and 55 calcifications), adaptive floating search achieved Az = 0.96 with comparison to Az = 0.93 of CHC genetic algorithm and Az = 0.90 of simple genetic algorithm.

Background: Electroporation (EP) is a widely used non-viral gene transfer method. We have attempted to develop an exact protocol to maximize DNA expression while minimizing tissue damage following EP of skeletal muscle in vivo. Specifically, we investigated the effects of varying injection techniques, electrode surface geometry, and plasmid mediums., Results: We found that as the amount of damage increased in skeletal muscle in response to EP, the level of beta-galactosidase (beta-gal) expression drastically decreased and that there was no evidence of beta-gal expression in damaged fibers. Two specific types of electrodes yielded the greatest amount of expression. We also discovered that DNA uptake in skeletal muscle following intra-arterial injection of DNA was significantly enhanced by EP. Finally, we found that DMSO and LipoFECTAMINE, common enhancers of DNA electroporation in vitro, had no positive effect on DNA electroporation in vivo., Conclusions: When injecting DNA intramuscularly, a flat plate electrode without any plasmid enhancers is the best method to achieve high levels of gene expression.

To expedite the timely creation of medical practice guidelines, a meta-analytic method was developed to combine both dichotomous survival data and continuous physiologic data from multiple studies of differing experimental design, which compare the same innovative clinical intervention to standard care. An aggregate ratio, R*, of the observed treatment effect to a clinically optimal treatment effect for studies in a series is computed and compared to the 95% confidence limit for R* under the null hypothesis. Input data for continuous variables include sample means, standard errors, and sample sizes. Input data for dichotomous variables include group proportions and sizes. The analysis can be done using a simple, 1-page spreadsheet. It allows one to judge biological significance, to test for statistical significance, to compare subgroups of studies, to test for outliers, and to compute the power of the meta-analysis. These features are demonstrated for studies of interposed abdominal compression-cardiopulmonary resuscitation.

Objective: To estimate the optimum ratio of chest compressions to ventilations for one-rescuer CPR that maximizes systemic oxygen delivery in children., Method: Equations describing oxygen delivery and blood flow during CPR as functions of the number of compressions and the number of ventilations delivered over time were adapted from the former work of Babbs and Kern. These equations were solved explicitly as a function of body weight, using scaling algorithms based upon principles of developmental anatomy and physiology., Results: The optimal compression to ventilation (C/V) ratios for infants and younger children increase sharply as a function of body weight. Optimal C/V ratios are lower for professional rescuers, who take less time to deliver a rescue breath, than for lay rescuers, who interrupt chest compressions for longer to perform ventilations. For professional rescuers the optimal C/V ratio, x*, is approximately 1.6 square root W where the W is the patient's body weight in kg. For lay rescuers the optimum C/V ratio is approximately 2.8 square root W. These values can be approximated for children and teens by the following rules of thumb, based upon the age of the victim: "5 + one half the age in years" for professional rescuers and "5 + age in years" for lay rescuers., Conclusions: Compression to ventilation ratios in CPR should be smaller for children than for adults and gradually increase as a function of body weight. Optimal CPR in children requires relatively more ventilation than optimal CPR in adults. A universal compression/ventilation ratio of 50:2, targeted to optimize adult resuscitation, would not be appropriate for infants and young children.

Interposed abdominal compression (IAC)-CPR includes all steps of standard external CPR with the addition of manual mid-abdominal compressions in counterpoint to the rhythm of chest compressions. IAC-CPR can increase blood flow during CPR about 2-fold compared with standard CPR without IAC, as shown by six of six studies in computer models and 19 of 20 studies in various animal models. The addition of IAC has clinical benefit in humans, as indicated in 10 of 12 small to medium sized clinical studies. The technique increases the frequency of immediate return of spontaneous circulation for in-hospital resuscitations from roughly 25 to 50%. Improved survival to discharge is also likely on the basis of two small in-hospital trials. Possible harm from abdominal compression is minimal on the basis of 426 humans, 151 dogs and 14 pigs that received IAC in published reports. The complexity of performing IAC is similar to that of opening the airway and is less than that of other basic life support maneuvers. The aggregate evidence suggests that IAC-CPR is a safe and effective means to increase organ perfusion and survival, when performed by professionally trained responders in a hospital and when initiated early in the resuscitation protocol. Cost and logistical considerations discourage use of IAC-CPR outside of hospitals.

Objective: To present and demonstrate a new simplified method for synthesizing results of multiple clinical trials in resuscitation research., Methods: The mean difference across studies in the proportion of favorable outcomes between experimental and control groups is calculated. This difference is shown to have a t-distribution. Its significance can be ascertained with a simple t-test. The analysis can be implemented in a one-page computer spreadsheet., Results: Simplified meta-analysis provides high sensitivity and can be extended to include weighting of studies according to size or quality, comparison of subgroups of studies, tests for outliers, and calculation of the power of the meta-analysis. Sample analyses are presented for two experimental forms of cardiopulmonary resuscitation (CPR): interposed abdominal compression (IAC) CPR and active compression-decompression (ACD) CPR., Conclusions: Traditional narrative reviews, taking note of the proportion of individual studies with statistically significant results, can lead to erroneous conclusions and unnecessary delays in the clinical use of research findings. Simplified meta-analysis can provide rapid, quantitative, and accurate estimates of the amount of benefit or harm from an experimental intervention and can further empower physicians to practice evidence-based medicine.

The human femoral artery can bleed dangerously following the removal of a catheter uring cardiac catheterization. In this study, a modified technique of needle insertion, simply inserting the needle bevel-down instead of the standard bevel-up approach, was tested as a means to reduce bleeding after catheter removal. Large bore needle punctures were made in surgically exposed arteries of anesthetized pigs using either a standard technique (45 degree approach, bevel up) or a modified technique (25 degree approach, bevel down). For half the punctures, topical phenylephrine solution (1 mg/ml) was applied to the adventitia of the artery to cause constriction. Median bleeding rates were reduced from 81 to less than 1 ml/min/100 mmHg intraluminal pressure by the modified technique with application of phenylephrine. In most cases zero bleeding, that is self-sealing, of the arteries occurred. It is postulated that a flap-valve of tissue created by the modified technique produced this self-sealing behavior. Sophisticated modeling studies are needed to fully understand this new phenomenon.

Objective: To develop and evaluate a practical formula for the optimum ratio of compressions to ventilations in cardiopulmonary resuscitation (CPR). The optimum value of a variable is that for which a desired result is maximized. Here the desired result is assumed to be either oxygen delivery to peripheral tissues or a combination of oxygen delivery and waste product removal., Method: Equations describing oxygen delivery and blood flow during CPR as functions of the number of compressions and the number of ventilations delivered over time were developed from principles of classical physiology. These equations were solved explicitly in terms of the compression/ventilation ratio and evaluated for a wide range of conditions using Monte Carlo simulations., Results: As the compression to ventilation ratio was increased from 0 to 50 or more, both oxygen delivery and the combination of oxygen delivery with blood flow increased to maximum values and then gradually declined. For variables typical of standard CPR as taught and specified in international guidelines, maximum values occurred at compression/ventilation ratios near 30:2. For variables typical of actual lay rescuer performance in the field, maximal values occurred at compression/ventilation ratios near 60:2., Conclusion: Current guidelines overestimate the need for ventilation during standard CPR by two to four-fold. Blood flow and oxygen delivery to the periphery can be improved by eliminating interruptions of chest compression for these unnecessary ventilations.

Principles of cardiovascular physiology tell us that during cardiac arrest and CPR, forward flow of blood can be generated by external compression or decompression of either the chest or the abdomen. Standard CPR utilizes only one of these modes--chest compression--and generates roughly 1 L/min forward flow in an adult human, which is 20% of normal cardiac output. IAC-CPR uses two of these modes--chest compression and abdominal compression--and generates roughly twice the forward flow, or 2 L/min in an adult human. ACD-CPR uses two of these modes--chest compression and chest decompression--and also generates roughly twice the forward flow as standard CPR, although the results are somewhat model dependent. The studies by Sack et al with IAC-CPR and by Plaisance et al with ACD-CPR suggest that when methods that double perfusion are employed methodically, resuscitation outcome in terms of short- and long-term survival are also roughly doubled. This state of affairs is fortunate, because it is possible that factors, such as severe underlying disease or the quality of postresuscitation care, could blunt or cancel positive effects of improved blood flow during the brief resuscitation period. Theoretically, full four-phase CPR, including active compression and decompression of both chest and abdomen, is capable of generating 4 L/min forward flow or greater, which is 80% of normal, and there is a reasonable prospect of achieving 100% of normal flow under conditions in which all four phases are optimized. Standard CPR is clearly not the ultimate form of external CPR. There is real, credible evidence that substantial improvements in resuscitation methods and results will be possible in the next decade.

Objective: This paper addresses the following statistical question: 'if genuine improvements in cardiopulmonary resuscitation (CPR) were discovered that doubled the probability of resuscitation success in a series of randomized clinical trials, would they be recognized and incorporated into consensus guidelines?'., Methods: Statistical powers for hypothetical individual clinical trials comparing experimental and control CPR were computed as a function of the study N when the true probabilities for immediate survival, 24 h survival, and discharge survival in the experimental group were twice those in the control group. Next, the binomial distributions describing the numbers of statistically significant studies in a series of equally powered trials of the same intervention were determined. These were compared with varying criteria for consensus among expert reviewers, expressed in terms of the number of 'positive' studies showing a statistically significant difference that reviewers would require before approving the experimental method., Results: False-negative evaluations (i.e. failures to approve a technique that actually doubled survival) were extremely common under a wide range of realistic assumptions and consensus criteria, especially when simulated long-term survival data were considered. Similar methods showed that false-positive evaluations would be extremely rare, provided that at least two of the clinical trials in a series showed a statistically significant benefit of the experimental method., Conclusions: Optimization of evidence evaluation can and should be carried out to make better use of available data in creating resuscitation guidelines. One simple approach is the 'two and one quarter test': if at least two well-conducted studies in a series are significantly positive (P<0.05) comprising at least one-quarter of all studies in the series, a positive effect can be inferred with small Type I and Type II errors. In addition, greater reliance on modern, unbiased methods such as cumulative meta-analysis is needed to increase the sensitivity of evidence evaluation for detecting useful innovations in resuscitation.

To better understand the risk and safety of heading a soccer ball, the author created a set of simple mathematical models based upon Newton's second law of motion to describe the physics of heading. These models describe the player, the ball, the flight of the ball before impact, the motion of the head and ball during impact, and the effects of all of these upon the intensity and the duration of acceleration of the head. The calculated head accelerations were compared to those during presumably safe daily activities of jumping, dancing, and head nodding and also were related to established criteria for serious head injury from the motor vehicle crash literature. The results suggest heading is usually safe but occasionally dangerous, depending on key characteristics of both the player and the ball. Safety is greatly improved when players head the ball with greater effective body mass, which is determined by a player"s size, strength, and technique. Smaller youth players, because of their lesser body mass, are more at risk of potentially dangerous headers than are adults, even when using current youth size balls. Lower ball inflation pressure reduces risk of dangerous head accelerations. Lower pressure balls also have greater "touch" and "playability", measured in terms of contact time and contact area between foot and ball during a kick. Focus on teaching proper technique, the re-design of age-appropriate balls for young players with reduced weight and inflation pressure, and avoidance of head contact with fast, rising balls kicked at close range can substantially reduce risk of subtle brain injury in players who head soccer balls.