Rate-dependent propagation of cardiac action potentials in a one-dimensional fiber

Action potential duration (APD) restitution, which relates APD to the preceding diastolic interval (DI), is a useful tool for predicting the onset of abnormal cardiac rhythms. However, it is known that different pacing protocols lead to different APD restitution curves (RCs). This phenomenon, known as APD rate-dependence, is a consequence of memory in the tissue. In addition to APD restitution, conduction velocity restitution also plays an important role in the spatiotemporal dynamics of cardiac tissue. We present new results concerning rate-dependent restitution in the velocity of propagating action potentials in a one-dimensional fiber. Our numerical simulations show that, independent of the amount of memory in the tissue, waveback velocity exhibits pronounced rate-dependence and the wavefront velocity does not. Moreover, the discrepancy between waveback velocity RCs is most significant for small DI. We provide an analytical explanation of these results, using a system of coupled maps to relate the wavefront and waveback velocities. Our calculations show that waveback velocity rate-dependence is due to APD restitution, not memory.Comment: 17 pages, 7 figure

Uncovering the Dynamics of Cardiac Systems Using Stochastic Pacing and Frequency Domain Analyses

Alternans of cardiac action potential duration (APD) is a well-known arrhythmogenic mechanism which results from dynamical instabilities. The propensity to alternans is classically investigated by examining APD restitution and by deriving APD restitution slopes as predictive markers. However, experiments have shown that such markers are not always accurate for the prediction of alternans. Using a mathematical ventricular cell model known to exhibit unstable dynamics of both membrane potential and Ca2+ cycling, we demonstrate that an accurate marker can be obtained by pacing at cycle lengths (CLs) varying randomly around a basic CL (BCL) and by evaluating the transfer function between the time series of CLs and APDs using an autoregressive-moving-average (ARMA) model. The first pole of this transfer function corresponds to the eigenvalue (λalt) of the dominant eigenmode of the cardiac system, which predicts that alternans occurs when λalt≤−1. For different BCLs, control values of λalt were obtained using eigenmode analysis and compared to the first pole of the transfer function estimated using ARMA model fitting in simulations of random pacing protocols. In all versions of the cell model, this pole provided an accurate estimation of λalt. Furthermore, during slow ramp decreases of BCL or simulated drug application, this approach predicted the onset of alternans by extrapolating the time course of the estimated λalt. In conclusion, stochastic pacing and ARMA model identification represents a novel approach to predict alternans without making any assumptions about its ionic mechanisms. It should therefore be applicable experimentally for any type of myocardial cell

Prevention of HIV-1 Infection with Early Antiretroviral Therapy

Antiretroviral therapy that reduces viral replication could limit the transmission of human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples

Prevention of HIV-1 Infection with Early Antiretroviral Therapy

Background: Antiretroviral therapy that reduces viral replication could limit the transmission of human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples. Methods: In nine countries, we enrolled 1763 couples in which one partner was HIV-1–positive and the other was HIV-1–negative; 54% of the subjects were from Africa, and 50% of infected partners were men. HIV-1–infected subjects with CD4 counts between 350 and 550 cells per cubic millimeter were randomly assigned in a 1:1 ratio to receive antiretroviral therapy either immediately (early therapy) or after a decline in the CD4 count or the onset of HIV-1–related symptoms (delayed therapy). The primary prevention end point was linked HIV-1 transmission in HIV-1–negative partners. The primary clinical end point was the earliest occurrence of pulmonary tuberculosis, severe bacterial infection, a World Health Organization stage 4 event, or death. Results: As of February 21, 2011, a total of 39 HIV-1 transmissions were observed (incidence rate, 1.2 per 100 person-years; 95% confidence interval [CI], 0.9 to 1.7); of these, 28 were virologically linked to the infected partner (incidence rate, 0.9 per 100 person-years, 95% CI, 0.6 to 1.3). Of the 28 linked transmissions, only 1 occurred in the earlytherapy group (hazard ratio, 0.04; 95% CI, 0.01 to 0.27; P<0.001). Subjects receiving early therapy had fewer treatment end points (hazard ratio, 0.59; 95% CI, 0.40 to 0.88; P = 0.01). Conclusions: The early initiation of antiretroviral therapy reduced rates of sexual transmission of HIV-1 and clinical events, indicating both personal and public health benefits from such therapy. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 052 ClinicalTrials.gov number, NCT00074581.

Prevention of HIV-1 Infection with Early Antiretroviral Therapy

BACKGROUND: Antiretroviral therapy that reduces viral replication could limit the transmission of human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples. METHODS: In nine countries, we enrolled 1763 couples in which one partner was HIV-1-positive and the other was HIV-1-negative; 54% of the subjects were from Africa, and 50% of infected partners were men. HIV-1-infected subjects with CD4 counts between 350 and 550 cells per cubic millimeter were randomly assigned in a 1:1 ratio to receive antiretroviral therapy either immediately (early therapy) or after a decline in the CD4 count or the onset of HIV-1-related symptoms (delayed therapy). The primary prevention end point was linked HIV-1 transmission in HIV-1-negative partners. The primary clinical end point was the earliest occurrence of pulmonary tuberculosis, severe bacterial infection, a World Health Organization stage 4 event, or death. RESULTS: As of February 21, 2011, a total of 39 HIV-1 transmissions were observed (incidence rate, 1.2 per 100 person-years; 95% confidence interval [CI], 0.9 to 1.7); of these, 28 were virologically linked to the infected partner (incidence rate, 0.9 per 100 person-years, 95% CI, 0.6 to 1.3). Of the 28 linked transmissions, only 1 occurred in the early-therapy group (hazard ratio, 0.04; 95% CI, 0.01 to 0.27; P<0.001). Subjects receiving early therapy had fewer treatment end points (hazard ratio, 0.59; 95% CI, 0.40 to 0.88; P=0.01). CONCLUSIONS: The early initiation of antiretroviral therapy reduced rates of sexual transmission of HIV-1 and clinical events, indicating both personal and public health benefits from such therapy

Tobacco sales to underage buyers in France: findings from a mystery shopping study

International audienceObjectives: In 2017, one in four French 17-year-olds was a daily smoker, even though France prohibited the sale of tobacco to under-18 minors in 2009. This research aims to evaluate the retail violation rate for sale to minors (RVRms) and the associated factors.Study design: The study design used is observational mystery shopping study.Methods: We conducted a mystery shopping study enlisting 12-year-old and 17-year-old youths in a representative sample of 527 tobacco outlets during three weeks in spring 2019. Multinomial Logit and Probit regressions were estimated on the data collected.Results: The law is not respected. Two of three sellers (65.2%) were willing to make an illegal sale to a 17-year-old minor, and almost one in 12 (8.1%) were willing to sell to a 12-year-old child attempting to buy tobacco. Illegal sales were more likely to be made by male sellers, retailing in big cities, when there were no in-shop queues, and to 17-year-old females. The absence of the mandatory enforcement poster flagging up the ban on the sale of tobacco to minors appears to be a strong factor associated with RVRm.Conclusions: These findings show that progress needs to be made to better enforce tobacco control legislation to help decrease underage smoking in France. Rate of compliance with the law could be improved by stronger enforcement measures and tougher sanctions, but also by training and the provision of age-verification tools for sellers, as demonstrated by experiments in other countries