Correlations between urinary excretion of catecholamines and electrocardiographic parameters of vagal hyperreactivity in infants with fainting spells. Implication of sympathetic hypotonia?

SummaryBackgroundVagal hyperreactivity (VHR) is a frequent etiology of infant fainting spells; but it is sometimes difficult to diagnose. A biochemical test would therefore be useful, especially as the oculocardiac reflex (OCR) test innocuity is not absolute.AimsTo evaluate urinary excretions of norepinephrine, epinephrine and dopamine as markers for vagal hyperreactivity.MethodsDuring check-up of 55 infants from 0.5 to 11months of age, for discomfort episodes, including OCR and Holter recording, 24h urinary assays of total norepinephrine, epinephrine and dopamine were carried out to evaluate sympathetic activity.ResultsEpinephrine and norepinephrine urinary excretions were negatively correlated with VHR intensity, as measured by the OCR ECG parameters: RRmax, % cardiac deceleration and minimal frequency; dopamine excretion was not. When RRmaxOCR was greater or equal to 800ms, epinephrine urinary excretion tended to be less or equal to 9nmol/mmol creatinine and norepinephrine excretion less or equal to 190nmol/mmol creatinine.ConclusionA delay in maturation of the sympathetic system and/or adrenomedullary glands with low secretion of norepinephrine and epinephrine inducing a desequilibrium of the sympathetic/parasympathetic balance may contribute to the fainting spells observed with VHR. Epinephrine and norepinephrine urinary excretions may provide informative complementary noninvasive markers for VHR

The Citius End: World Records Progression Announces the Completion of a Brief Ultra-Physiological Quest

World records (WR) in sports illustrate the ultimate expression of human integrated muscle biology, through speed or strength performances. Analysis and prediction of man's physiological boundaries in sports and impact of external (historical or environmental) conditions on WR occurrence are subject to scientific controversy. Based on the analysis of 3263 WR established for all quantifiable official contests since the first Olympic Games, we show here that WR progression rate follows a piecewise exponential decaying pattern with very high accuracy (mean adjusted r2 values = 0.91±0.08 (s.d.)). Starting at 75% of their estimated asymptotic values in 1896, WR have now reached 99%, and, present conditions prevailing, half of all WR will not be improved by more than 0,05% in 2027. Our model, which may be used to compare future athletic performances or assess the impact of international antidoping policies, forecasts that human species' physiological frontiers will be reached in one generation. This will have an impact on the future conditions of athlete training and on the organization of competitions. It may also alter the Olympic motto and spirit

Athlete Atypicity on the Edge of Human Achievement: Performances Stagnate after the Last Peak, in 1988

The growth law for the development of top athletes performances remains unknown in quantifiable sport events. Here we present a growth model for 41351 best performers from 70 track and field (T&F) and swimming events and detail their characteristics over the modern Olympic era. We show that 64% of T&F events no longer improved since 1993, while 47% of swimming events stagnated after 1990, prior to a second progression step starting in 2000. Since then, 100% of swimming events continued to progress

Latent variables and structural equation models for longitudinal relationships: an illustration in nutritional epidemiology

<p>Abstract</p> <p>Background</p> <p>The use of structural equation modeling and latent variables remains uncommon in epidemiology despite its potential usefulness. The latter was illustrated by studying cross-sectional and longitudinal relationships between eating behavior and adiposity, using four different indicators of fat mass.</p> <p>Methods</p> <p>Using data from a longitudinal community-based study, we fitted structural equation models including two latent variables (respectively baseline adiposity and adiposity change after 2 years of follow-up), each being defined, by the four following anthropometric measurement (respectively by their changes): body mass index, waist circumference, skinfold thickness and percent body fat. Latent adiposity variables were hypothesized to depend on a cognitive restraint score, calculated from answers to an eating-behavior questionnaire (TFEQ-18), either cross-sectionally or longitudinally.</p> <p>Results</p> <p>We found that high baseline adiposity was associated with a 2-year increase of the cognitive restraint score and no convincing relationship between baseline cognitive restraint and 2-year adiposity change could be established.</p> <p>Conclusions</p> <p>The latent variable modeling approach enabled presentation of synthetic results rather than separate regression models and detailed analysis of the causal effects of interest. In the general population, restrained eating appears to be an adaptive response of subjects prone to gaining weight more than as a risk factor for fat-mass increase.</p

Heart Rate and Risk of Cancer Death in Healthy Men

BACKGROUND: Data from several previous studies examining heart-rate and cardiovascular risk have hinted at a possible relationship between heart-rate and non-cardiac mortality. We thus systematically examined the predictive value of heart-rate variables on the subsequent risk of death from cancer. METHODS: In the Paris Prospective Study I, 6101 asymptomatic French working men aged 42 to 53 years, free of clinically detectable cardiovascular disease and cancer, underwent a standardized graded exercise test between 1967 and 1972. Resting heart-rate, heart-rate increase during exercise, and decrease during recovery were measured. Change in resting heart-rate over 5 years was also available in 5139 men. Mortality including 758 cancer deaths was assessed over the 25 years of follow-up. FINDINGS: There were strong, graded and significant relationships between all heart-rate parameters and subsequent cancer deaths. After adjustment for age and tobacco consumption and, compared with the lowest quartile, those with the highest quartile for resting heart-rate had a relative risk of 2.4 for cancer deaths (95% confidence interval: 1.9-2.9, p<0.0001) This was similar after adjustment for traditional cardiovascular risk factors and was observed for the commonest malignancies (respiratory and gastrointestinal). Similarly, significant relationships with cancer death were observed between poor heart rate increase during exercise, poor decrease during recovery and greater heart-rate increase over time (p<0.0001 for all). INTERPRETATION: Resting and exercise heart rate had consistent, graded and highly significant associations with subsequent cancer mortality in men

Prediction discrepancies for the evaluation of nonlinear mixed-effects models.

Reliable estimation methods for non-linear mixed-effects models are now available and, although these models are increasingly used, only a limited number of statistical developments for their evaluation have been reported. We develop a criterion and a test to evaluate nonlinear mixed-effects models based on the whole predictive distribution. For each observation, we define the prediction discrepancy (pd) as the percentile of the observation in the whole marginal predictive distribution under H(0). We propose to compute prediction discrepancies using Monte Carlo integration which does not require model approximation. If the model is valid, these pd should be uniformly distributed over (0, 1) which can be tested by a Kolmogorov-Smirnov test. In a simulation study based on a standard population pharmacokinetic model, we compare and show the interest of this criterion with respect to the one most frequently used to evaluate nonlinear mixed-effects models: standardized prediction errors (spe) which are evaluated using a first order approximation of the model. Trends in pd can also be evaluated via several plots to check for specific departures from the model

Instrumental variable analysis in the context of dichotomous outcome and exposure with a numerical experiment in pharmacoepidemiology

International audienceBACKGROUND:In pharmacoepidemiology, the prescription preference-based instrumental variables (IV) are often used with linear models to solve the endogeneity due to unobserved confounders even when the outcome and the endogenous treatment are dichotomous variables. Using this instrumental variable, we proceed by Monte-Carlo simulations to compare the IV-based generalized method of moment (IV-GMM) and the two-stage residual inclusion (2SRI) method in this context.METHODS:We established the formula allowing us to compute the instrument's strength and the confounding level in the context of logistic regression models. We then varied the instrument's strength and the confounding level to cover a large range of scenarios in the simulation study. We also explore two prescription preference-based instruments.RESULTS:We found that the 2SRI is less biased than the other methods and yields satisfactory confidence intervals. The proportion of previous patients of the same physician who were prescribed the treatment of interest displayed a good performance as a proxy of the physician's preference instrument.CONCLUSIONS:This work shows that when analysing real data with dichotomous outcome and exposure, appropriate 2SRI estimation could be used in presence of unmeasured confounding

Accounting for indirect protection in the benefit–risk ratio estimation of rotavirus vaccination in children under the age of 5 years, France, 2018

International audienceBackgroundRotavirus is a major cause of severe gastroenteritis in children worldwide. The disease burden has been substantially reduced in countries where rotavirus vaccines are used. Given the risk of vaccine-induced intussusception, the benefit-risk balance of rotavirus vaccination has been assessed in several countries, however mostly without considering indirect protection effects.AimWe performed a benefit-risk analysis of rotavirus vaccination accounting for indirect protection in France among the 2018 population of children under the age of 5 years.MethodsTo incorporate indirect protection effects in the benefit formula, we adopted a pseudo-vaccine approach involving mathematical approximation and used a simulation design to provide uncertainty intervals. We derived background incidence distributions from quasi-exhaustive health claim data. We examined different coverage levels and assumptions regarding the waning effects and intussusception case fatality rate.ResultsWith the current vaccination coverage of < 10%, the indirect effectiveness was estimated at 6.4% (+/- 0.4). For each hospitalisation for intussusception, 288.2 (95% uncertainty interval: (173.8-480.0)) hospitalisations for rotavirus gastroenteritis were prevented. Should 90% of infants be vaccinated, indirect effectiveness would reach 57.9% (+/- 3.7) and the benefit-risk ratio would be 297.6 (95% uncertainty interval: 179.4-497.3). Indirect protection accounted for almost half of the prevented rotavirus gastroenteritis cases across all coverage levels. The balance remained in favour of the vaccine even in a scenario with a high assumption for intussusception case fatality.ConclusionsThese findings contribute to a better assessment of the rotavirus vaccine benefit-risk balance

Estimation of mid-and long-term benefits and hypothetical risk of Guillain-Barre syndrome after human papillomavirus vaccination among boys in France: A simulation study

International audienceBackground - The burden of human papillomavirus (HPV) infection can be substantially reduced through vaccination of girls, and gender-neutral policies are being adopted in many countries to accelerate disease control among women and expand direct benefits to men. Clinical direct benefit of boys HPV vaccination has been established for ano-genital warts and anal cancer. HPV vaccines are considered safe, but an association with Guillain-Barre syndrome has been found in French reimbursement and hospital discharge data.Methods - We conducted a Monte-Carlo simulation assuming a stable French population of 11- to 14-year-old boys, adult men and men having sex with men. We modelled and quantified the mid-term benefits as the annually prevented ano-genital warts among the 8.72 M men aged 15–35 years and the long-term benefits as the annually prevented anal cancer cases among the 17.4 M men aged 25–65 years. We also estimated the number of Guillain-Barre syndrome cases hypothetically induced by vaccination.Results - With a vaccine coverage of 30%, an annual number of 9310 (95% uncertainty interval [7050–11,200]) first ano-genital warts episodes among the 8.72 M men aged 15–35 years are prevented. According to more or less optimistic hypotheses on the proportion of HPV cancers covered by the vaccine, between 15.1 [11.7–17.7] and 19.2 [15.0–22.6] cases of anal cancer among the 17.4 M men aged 25–65 years would be annually avoided. Among men having sex with men, the corresponding figures were 1907 (1944–2291) for ano-genital warts and between 2.0 [0.23–4.5] and 2.6 [0.29–5.7] for anal cancer. Among 11- to 14-year-old boys, 0.82 (0.15–2.3) Guillain-Barre syndrome cases would be induced annually.Interpretation - A long-term program of HPV vaccination among boys in France would avoid substantially more cancer cases than hypothetically induce Guillain-Barre syndrome cases, in the general and specifically the homosexual population. Additional benefits may arise with the possible vaccine protection against oro-laryngeal and –pharyngeal cancer

Prescription drug use during pregnancy in France: a study from the national health insurance permanent sample

International audiencePurposeTo provide an up-to-date account of drug prescription during pregnancy in France from 2011 to 2014 using the permanent sample of the French national computerized healthcare database and with a focus on recommended supplementations, fetotoxic drugs and teratogenic drugs.MethodsAll pregnancies identified by the International Classification of Diseases, 10th Revision codes list in the hospitalization database, lasting more than 9 weeks of amenorrhea and whose delivery occurred between 01/01/2011 and 12/31/2014, were included. Drugs delivered between the trimester before and until the end of the pregnancy were included. Drug exposure prevalence was calculated for each year and according to pregnancy trimesters.ResultsThe study included 28,491 pregnancies with a median number of 9 [5–13] (median [IQ range]) drugs delivered. The most prescribed drug class was antianemia (in 72.5% of exposed). The prescription rate of recommended vitamins (B9 and D) increased over the study period (+10%). Influenza vaccination also increased but remained at a low rate (1%). Exposure to fetotoxic drugs decreased as pregnancy advanced. Exposure to the main teratogenic antiepileptics was stable over the study period. Low-income pregnant women had a higher average drug consumption except for recommended vitamins.ConclusionPregnant French women are among the largest consumers of prescription medications worldwide. Overall, the dispensation trends observed in this study are in line with the recommendations of the French National College of Gynecologists and Obstetricians. Nevertheless, while being low, exposure to fetotoxic drugs, teratogenic drugs or those under safety alerts still occurred. Supplementations and vaccines in low-income pregnant women should also be increased