An assessment of health hazard/health risk appraisal.

A state-of-the-art review of a widely-used health promotion technique, the health hazard/health risk appraisal (HHA/HRA), was conducted. The review included preparing a 212-item annotated bibliography, compiling an inventory of 217 programs that have used HHA/HRA, holding discussions with HHA/HRA developers and users, conducting formal site visits to 15 HHA/HRA programs, and consultation with experts on epidemiology, biostatistics, and behavioral science as well as developers and users of HHA/HRA. Programs use HHA/HRA primarily as a promotional device, as a tool for structuring education about health-related behaviors, and as a motivational device for stimulating behavioral change. The scientific basis for HHA/HRA risk predictions is problematic, but their arithmetic imprecision is of less concern than insufficiency of the scientific evidence for certain behavioral recommendations, and inaccuracies in client-supplied data. Widely-held beliefs in HHA/HRA's efficacy for motivating behavioral change cannot be substantiated from available evidence, nor can the assumed absence of adverse effects. The importance of this particular health promotion technique appears to have been exaggerated

Effects of aggregation of drug and diagnostic codes on the performance of the high-dimensional propensity score algorithm: an empirical example

BACKGROUND: The High-Dimensional Propensity Score (hd-PS) algorithm can select and adjust for baseline confounders of treatment-outcome associations in pharmacoepidemiologic studies that use healthcare claims data. How hd-PS performance is affected by aggregating medications or medical diagnoses has not been assessed. METHODS: We evaluated the effects of aggregating medications or diagnoses on hd-PS performance in an empirical example using resampled cohorts with small sample size, rare outcome incidence, or low exposure prevalence. In a cohort study comparing the risk of upper gastrointestinal complications in celecoxib or traditional NSAIDs (diclofenac, ibuprofen) initiators with rheumatoid arthritis and osteoarthritis, we (1) aggregated medications and International Classification of Diseases-9 (ICD-9) diagnoses into hierarchies of the Anatomical Therapeutic Chemical classification (ATC) and the Clinical Classification Software (CCS), respectively, and (2) sampled the full cohort using techniques validated by simulations to create 9,600 samples to compare 16 aggregation scenarios across 50% and 20% samples with varying outcome incidence and exposure prevalence. We applied hd-PS to estimate relative risks (RR) using 5 dimensions, predefined confounders, ≤ 500 hd-PS covariates, and propensity score deciles. For each scenario, we calculated: (1) the geometric mean RR; (2) the difference between the scenario mean ln(RR) and the ln(RR) from published randomized controlled trials (RCT); and (3) the proportional difference in the degree of estimated confounding between that scenario and the base scenario (no aggregation). RESULTS: Compared with the base scenario, aggregations of medications into ATC level 4 alone or in combination with aggregation of diagnoses into CCS level 1 improved the hd-PS confounding adjustment in most scenarios, reducing residual confounding compared with the RCT findings by up to 19%. CONCLUSIONS: Aggregation of codes using hierarchical coding systems may improve the performance of the hd-PS to control for confounders. The balance of advantages and disadvantages of aggregation is likely to vary across research settings

GaAs Photoconductive Closing Switches with High Dark Resistance and Microsecond Conductivity Decay

Silicon-doped n-type gallium arsenide crystals, compensated with diffused copper, were studied with respect to their application as photoconductive, high-power closing switches. The attractive features of GaAs:Cu switches are their high dark resistivity, their efficient activation with Nd:YAG laser radiation, and their microsecond conductivity decay time constant. In the authors\u27 experiment, electric fields are high as 19 kV/cm were switched, and current densities of up to 10 kA/cm2 were conducted through a closely compensated crystal. At field strengths greater than approximately 10 kV/cm, a voltage `lock-on\u27 effect was observed

Simulations of Intracellular Calcium Release Dynamics in Response to a High-Intensity, Ultrashort Electric Pulse

Numerical simulations for electrically induced, intracellular calcium release from the endoplasmic reticulum are reported. A two-step model is used for self-consistency. Distributed electrical circuit representation coupled with the Smoluchowski equation yields the ER membrane nanoporation for calcium outflow based on a numerical simulation. This is combined with the continuum Li-Rinzel model and drift diffusion for calcium dynamics. Our results are shown to be in agreement with reported calcium release data. A modest increase (rough doubling) of the cellular calcium is predicted in the absence of extra-cellular calcium. In particular, the applied field of 15 kV/cm with 60 ns pulse duration makes for a strong comparison. No oscillations are predicted and the net recovery period of about 5 min are both in agreement with published experimental results. A quantitative explanation for the lack of such oscillatory behavior, based on the density dependent calcium fluxes, is also provided

Methodological issues in measuring health disparities

OBJECTIVES: This report discusses six issues that affect the measurement of disparities in health between groups in a population: Selecting a reference point from which to measure disparity. Measuring disparity in absolute or in relative terms. Measuring in terms of favorable or adverse events. Measuring in pair-wise or in summary fashion. Choosing whether to weight groups according to group size. Deciding whether to consider any inherent ordering of the groups. These issues represent choices that are made when disparities are measured. METHODS: Examples are used to highlight how these choices affect specific measures of disparity. RESULTS: These choices can affect the size and direction of disparities measured at a point in time and conclusions about the size and direction of changes in disparity over time. Eleven guidelines for measuring disparities are presented. CONCLUSIONS: Choices concerning the measurement of disparity should be made deliberately, recognizing that each choice will affect the results. When results are presented, the choices on which the measurements are based should be described clearly and justified appropriately.By Kenneth Keppel, Elsie Pamuk, John Lynch, Olivia Carter-Pokras, Insun Kim, Vickie Mays, Jeffrey Pearcy, Victor Schoenbach, and Joel S. Weissma

Design and statistical analysis of oral medicine studies: common pitfalls

A growing number of articles are emerging in the medical and statistics literature that describe epidemiological and statistical flaws of research studies. Many examples of these deficiencies are encountered in the oral, craniofacial and dental literature. However, only a handful of methodological articles have been published in the oral literature warning investigators of potential errors that may arise early in the study and that can irreparably bias the final results

Electroporation-Induced Electrosensitization

BACKGROUND: Electroporation is a method of disrupting the integrity of cell membrane by electric pulses (EPs). Electrical modeling is widely employed to explain and study electroporation, but even most advanced models show limited predictive power. No studies have accounted for the biological consequences of electroporation as a factor that alters the cell's susceptibility to forthcoming EPs. METHODOLOGY/PRINCIPAL FINDINGS: We focused first on the role of EP rate for membrane permeabilization and lethal effects in mammalian cells. The rate was varied from 0.001 to 2,000 Hz while keeping other parameters constant (2 to 3,750 pulses of 60-ns to 9-µs duration, 1.8 to 13.3 kV/cm). The efficiency of all EP treatments was minimal at high rates and started to increase gradually when the rate decreased below a certain value. Although this value ranged widely (0.1-500 Hz), it always corresponded to the overall treatment duration near 10 s. We further found that longer exposures were more efficient irrespective of the EP rate, and that splitting a high-rate EP train in two fractions with 1-5 min delay enhanced the effects severalfold. CONCLUSIONS/SIGNIFICANCE: For varied experimental conditions, EPs triggered a delayed and gradual sensitization to EPs. When a portion of a multi-pulse exposure was delivered to already sensitized cells, the overall effect markedly increased. Because of the sensitization, the lethality in EP-treated cells could be increased from 0 to 90% simply by increasing the exposure duration, or the exposure dose could be reduced twofold without reducing the effect. Many applications of electroporation can benefit from accounting for sensitization, by organizing the exposure either to maximize sensitization (e.g., for sterilization) or, for other applications, to completely or partially avoid it. In particular, harmful side effects of electroporation-based therapies (electrochemotherapy, gene therapies, tumor ablation) include convulsions, pain, heart fibrillation, and thermal damage. Sensitization can potentially be employed to reduce these side effects while preserving or increasing therapeutic efficiency

Nanoelectropulse-driven membrane perturbation and small molecule permeabilization

BACKGROUND: Nanosecond, megavolt-per-meter pulsed electric fields scramble membrane phospholipids, release intracellular calcium, and induce apoptosis. Flow cytometric and fluorescence microscopy evidence has associated phospholipid rearrangement directly with nanoelectropulse exposure and supports the hypothesis that the potential that develops across the lipid bilayer during an electric pulse drives phosphatidylserine (PS) externalization. RESULTS: In this work we extend observations of cells exposed to electric pulses with 30 ns and 7 ns durations to still narrower pulse widths, and we find that even 3 ns pulses are sufficient to produce responses similar to those reported previously. We show here that in contrast to unipolar pulses, which perturb membrane phospholipid order, tracked with FM1-43 fluorescence, only at the anode side of the cell, bipolar pulses redistribute phospholipids at both the anode and cathode poles, consistent with migration of the anionic PS head group in the transmembrane field. In addition, we demonstrate that, as predicted by the membrane charging hypothesis, a train of shorter pulses requires higher fields to produce phospholipid scrambling comparable to that produced by a time-equivalent train of longer pulses (for a given applied field, 30, 4 ns pulses produce a weaker response than 4, 30 ns pulses). Finally, we show that influx of YO-PRO-1, a fluorescent dye used to detect early apoptosis and activation of the purinergic P2X(7 )receptor channels, is observed after exposure of Jurkat T lymphoblasts to sufficiently large numbers of pulses, suggesting that membrane poration occurs even with nanosecond pulses when the electric field is high enough. Propidium iodide entry, a traditional indicator of electroporation, occurs with even higher pulse counts. CONCLUSION: Megavolt-per-meter electric pulses as short as 3 ns alter the structure of the plasma membrane and permeabilize the cell to small molecules. The dose responses of cells to unipolar and bipolar pulses ranging from 3 ns to 30 ns duration support the hypothesis that a field-driven charging of the membrane dielectric causes the formation of pores on a nanosecond time scale, and that the anionic phospholipid PS migrates electrophoretically along the wall of these pores to the external face of the membrane