In each of the 4 treatments , electroencephalography (EEG) tests were conducted in order to analyze changes in absolute beta power (ABP) in the frontal lobe in 3 moments: baseline (before ingestion), peak (before exercise) and post-exercise. In the PL treatment, the frontal areas showed decrease in ABP after exercise. However, in the ET+TA treatment, ABP values were greater after exercise, except for Fp1. The ET treatment had no effect on the Superior Frontal Gyrus area  and ABP decreased after exercise in Fp1 and Fp2. In the TA treatment, ABP increased after exercise, while it decreased at the peak moment in most of the frontal regions, except for Fp1, F3 and Fz. We concluded that after a moderate intensity exercise, a decrease in cortical activity occurs in placebo treatment. Moreover, we found a inhibitory effect of TA on cortical activity before exercise and a increased in cortical activity after exercise. A small ET dose is not enough to alter ABP in all regions of the frontal cortex and, in combination with TA, it showed an increase in the frontal cortex activity at the post-exercise moment.Ethanol (ET) is a substance that modulates the Central Nervous System (CNS). Frequently, ET intake occurs combined with energy drinks, which contain taurine (TA), an important amino acid found in the body (i.e brain and muscles). Although TA administration has been used in the improvement of physical performance, the impact of TA, ET and exercise remains unknown. This study aimed to analyze the acute effect of 6g of Taurine (TA), 0.6 mL∙kg Ethanol (ET), or Ethyl Alcohol, is a substance widely consumed by population; however, its effects on the Central Nervous System (CNS) are not completely known yet. ET is able to alter the CNS excitatory and inhibitory neurotransmitter balance, most times favoring the inhibitory influence . The acuEthanol intake commonly occurs together with energy drinks, which contain an amino acid called taurine (TA), which objective is to reduce the symptons of depression . Due to Quantitative electroencephalography (qEEG) is a non-invasive tool of electrocortical activity analysis, and it has been widely used to assess the influence of physical exercise and of different substances in the central nervous system. After exercise, cortical activity may increase or decrease, depending on the physical exercise protocol and on the analyzed cortical region . Beta frthe cortical activity (ABP) may be affected by these substances in the frontal cortex areas before and after exercise. Furthermore, TA may modulate ET effect when ingested together.Our objective was to apply the qEEG in order to investigate the acute effect of ET, TA and both of these substances together in the frontal cortex before and after exercise. In particular, beta absolute power (13–30 Hz) was analyzed; this is a fast frequency and it is associated with the alertness/attention state and with motor activity. We hypothesize that All participants, five healthy women (22 ± 3 years) and four healthy men (26 ± 5 years), were right-handed, regular drinkers of alcoholic beverages, amateur practitioners of physical exercise and non-smokers. The participants were asked to avoid physical activities with more than 5 metabolic equivalents (METs) and any food containing caffeine, alcohol and taurine for 48 hours before the test. Individuals with liver disorders or who were taking medications, as well as alcohol users with a weekly intake greater than fifteen or less than two alcohol servings were excluded from this study. Volunteers read and signed an informed consent form. All experimental procedures were approved by the local ethics committee of University Hospital Clementino Fraga Filho (HUCFF) at Federal University of Rio de Janeiro (03899312.5.0000.5257). All of research protocols described here were carried out in accordance to the declaration of Helsinki".®, 21 g.L-1) and used as the placebo (PL) solution, while six grams of powdered taurine (TA) were used for the experimental solution. Ethanol  was administered in doses of 0.6 ml. kg-1, combined with the ingestion of artificial orange juice in a proportion of 2:1 (juice: vodka).This study lasted approximately five weeks for each participant. The experiment began with an anthropometric and an effort test. During the following visits (once a week), a particular intervention was applied in randomized order . The experimental design of these tests was in agreement with a specific treatment, using a protocol described previously . Six graThe TA and PL solutions were ingested two hours before the exercise, while the ET alcoholic beverage was ingested thirty minutes before the exercise. Such ingestion time was determined according to the peak plasma levels of each substance after intake . In the ®, Porto Alegre, RS, Brazil) was used to determine maximal power output (Wmax), maximal aerobic power ®, Vacumed®, Ventura, CA, USA).A continuous and maximal load ramp testing on a cycle ergometer with an electromagnetic brake , with an intensity 10% lower than the load of the anaerobic threshold set for the maximum effort test was adopted for 10 minutes at a rate of 60 revolutions per minute (RPM) as a physical tool for the ergometric test, causing a stress on the body, in order to help in the analysis of ABP under the influence of PL, TA, ET and TA+ET.® Chemical System and plasma Ethanol levels by Siemens Dimension® Series.Serum and plasma were obtained from peripheral blood samples at three moments  for each treatment (ET and TA+ET). Serum levels of liver enzymes were determined using the VITROSData Acquisition software  from the Brain Mapping and Sensory Motor Integration Lab was employed with the digital notch filter (60 Hz).The EEG signal capture was performed using the BrainNet-BNT device 36 . Twenty monopolar electrodes were arranged following the 10/20 International System Protocol. The impedance of the electrodes was maintained between 5 and 10 kΩ. Recorded data had a total range of less than 70 μV. The data signal was amplified with a gain of 22,000, analogically filtered between 0.01 Hz (high-pass) and 80 Hz (low-pass), and sampled at 200 Hz. The Visual inspection and independent component analysis (ICA) were applied to remove possible sources of artifacts produced during data collection. The data were collected using a bi-auricular reference, and they were transformed using the average reference after ICA was applied and artifact elimination was concluded. Through ICA and visual inspection, all the ranges which clearly showed artifacts such as blinking and muscle-related movements were removed. A classic estimator was applied for the power spectral density (PSD) performed by MATLAB 5.3 .® , SigmaPlot®  and Microsoft Excel® for Windows® . In order to analyze the absolute power, two-way ANOVA was used (treatment vs. moment) in order to assess the interaction of absolute beta power (ABP) between treatment and moment for all frontal electrodes. When an interaction between factors was found, a one-way ANOVA (Bonferroni post-hoc) was applied to each treatment for all frontal electrodes.Statistical analysis was performed using the Statistical Package for the Social SciencesA ANOVA one-way was conducted to compare ethanol concentration in the plasma between moments  to each treatment (ET and TA+ET). A Student t-test was used to compare ethanol concentration in the plasma moments in different treatments .Descriptive statistics were used with the mean ± standard error (se) (p ≤ 0.05). The p-value was adjusted through the bonferroni correction for multiple comparisons. The effect size was estimated using the Cohen’s d method..L-1). However, there was no significant difference between baseline, peak and post-exercise to each treatment. Also, there was no significant difference between treatments when comparing the specific moments   .A two-way ANOVA (moment vs. treatment) demonstrated interaction between the two factors for all investigated electrodes . With the aim to analyze in detail all interactions found between moment and treatment, a one-way ANOVA was conducted separately for each treatment . Interaction analyses are reported below. The effect sizes for all variables were summarized in Difference was found at Fp1 between the baseline and post-exercise moments (p<0.05) and between peak and post-exercise (p<0.05) for the PL, ET and TA treatments. On the other hand, at Fp2, difference was found among moments for all treatments. For the PL, ET and TA treatments, difference was observed among all moments (p<0.05). For ET+TA, significant difference occurred between the baseline and post-exercise (p<0.001) and between the peak and post-exercise (p = 0.009) moments .For the F7 electrode, difference was found between the baseline and peak (p<0.05), and between peak and post-exercise (p<0.05) moments for the ET and TA treatments. For the TA+ET treatment, difference occurred between the baseline and peak moments (p<0.001), and between baseline and post-exercise (p = 0.021). On the other hand, in the PL treatment, difference was observed between the baseline and post-exercise moments (p<0.001), and between peak and post-exercise (p<0.001).At F8, significant difference was found between the baseline and post-exercise moments (p<0.05) and between peak and post-exercise (p<0.05) for the ET and ET+TA treatments. For the PL treatment, significant difference was identified between the baseline and peak moments (p<0.001) and between baseline and post-exercise (p<0.001). And for the TA treatment, difference was found at all moments (p<0.05) .For the F3 electrode, significant difference was only found for PL and ET+TA. In the PL treatment, significant difference was observed between all moments (p<0.05); in the ET+TA treatment, difference occurred between the baseline and peak moments (p<0.001) and baseline and post-exercise (p<0.001).For the F4 electrode, significant difference was found among all moments in the TA treatment (p<0.05). In the ET+TA treatment, significant difference was found between the baseline and post-exercise moments (p<0.001), and between baseline and peak (p<0.001). On the contrary, for the PL treatment, difference was observed between the baseline and post-exercise moments (p<0.001) and between peak and post-exercise (p<0.001).At Fz, just like at F4, significant difference occurred among all moments (p<0.05) for the TA treatment. Significant difference was found between the baseline and post-exercise moments (p<0.001) and between baseline and peak (p<0.001) for the ET+TA treatment. In the PL treatment, significant difference was observed between the baseline and post-exercise moments (p<0.001), and between peak and post-exercise (p<0.001) .The present study aimed to analyze the effect of TA, ET and these two substances administered together on the electrocortical activity, before and after moderate intensity exercise. An overwiew of these results was available as a cartoon . SpecifiBrodmann area 8 is considered to be an important area for motor learning. Studies from the literature have demonstrated this area to be responsible for starting, keeping, coordinating and planning complex movement sequences . The trath and 30th minute after exercise.As expected, no difference was found between the baseline and peak moments in the PL treatment for most of the electrodes relate to this region , except in F3. However, a decrease in beta power was observed at the post-exercise moment, when compared to the others. Kubitz and Pothakos  have alsIn the TA treatment, difference was found for the Fz and F4 electrodes, with TA causing beta increase at Fz and beta decrease at F4. With regards to the post-exercise moment, an increase in beta power was found for both electrodes, when comparing this moment to the others. Taurine is used to improve exercise performance. Reports from the literature highlight some metabolic benefits for the membrane, fat oxidation, insulin sensitivity and cardiac muscle; however, its acute and chronic effects on the CNS need to be better investigated during exercise , 15 , with an increase in ABP at the peak and exercise moments, when compared to the baseline moment. Since no changes in ABP were found in this region for the ET treatment, and since similar results were found for the TA treatment after exercise, TA is suggested to stand out, with similar physiological adaptations to the TA treatment during exercise, thus influencing beta values increase after exercise. No reports about the effect of both TA and TA+ET on this region are present in the literature.Network changes in this region may cause impairment in motor and executive functions, working memory and high-demand cognitive functions . Li et aThe pre-frontal cortex (Brodmann area 10) has been associated with complex executive functions  and it plays an important role in memory control and manipulation, in addition to being also related to emotional and cognitive tasks . On the This region is strictly related to risk decision making; according to Kwon et al. , risk deAccording to Arnsten , the PFCAs with regards to specific treatments, decrease in ABP was found in the PL treatment for the post-exercise moment, when compared to the baseline moment. The different intensities and duration of exercise have an influence in the acute physiological adaptations, which could interfere in the electrocortical activity. For example, catecholamines and temperature regulation, also modulated by the hypothalamic nucleus, may influence beta activity . HoweverWhen analyzing the ET+TA combination, a significant effect was found only in the right anterior pre-frontal cortex, with ABP increase at the post- moment, when compared to the others. Our results suggest the intake of the ET+TA combination alone do not provoke any changes in the anterior pre-frontal cortex; however, exercise potentializes the combination of these two substances, thus causing significant beta power increase in the right anterior pre-frontal cortex. As previously said, this area is directly related to executive control, specifically motor and behavioral executive control, attention, and inhibitory control. In particular, the right hemisphere features characteristics related to spatiality and development of direction sense. Therefore, this study hypothesized beta power increase at Fp2 to be associated with an increase in attention and executive motor control, required for the performance of physical exercise.Despite a beta decrease at the peak moment, TA provokes an increase in beta power during the exercise moment in both hemispheres of the anterior pre-frontal cortex, when ingested alone. Therefore, depending on the region, taurine may decrease electrocortical activity; this finding is in agreement with other studies demonstrating the inhibitory effect of this amino-acid on the central nervous system . HoweverIn the ET treatment, this substance was found to also play an important role in the right anterior pre-frontal cortex; however, in addition to the ET intake alone decreasing ABP, the combination of ET and exercise also provokes decrease in beta power. Such results are in agreement with the literature about ethanol effects before and after intake, with lower cortical activity caused by the acute effect of the substance  mainly aFew studies have related beta band to this region (PFC). Researches in the literature performed with animals (monkeys) affirm that beta neuronal synchronization involves execution tasks, such as rule selection. A given rule is represented by a group of PFC neurons, oscillating in synchrony at this frequency . BuschmaStudies with humans highlight beta oscillations to start the cognitive control and selective inhibition process in the PFC . In otheTraditionally, the IFG has been widely associated with aspects related to language and semantics . In addiIn the PL treatment, decrease in ABP occurred at the baseline moment, compared to the post-exercise moment in this area. Schneider et al.  have alsOn the other hand, in the ET+TA treatment, increase in ABP was found for the peak moment, when compared to baseline only at F7, demonstrating this treatment to influence beta power only in the left IFG. However, beta increase was verified at the post-exercise moment for both left and right IFG, showing an influence of exercise on absolute beta power in both hemispheres. Despite acamprosate (a substance containing TA) being used in the treatment of alcoholics in order to reduce ethanol-abstinence symptoms Plosker , there aOn the other hand, in the right hemisphere, the TA effect together with ET did not modify beta activity, considering that the TA+ET results were similar to the ET ones. In great part of the frontal cortex, TA seems to increase beta activity after exercise, even with ET intake. We hypothesized the increase in cortical activity after exercise to be related to the TA effects on the modulation of the glutamate receptor activation, through the cytoplasmic and intramitochondrial calcium regulation . In a stIn the ET treatment, a substance influence on the left hemisphere of this area (F7) was found, provoking an increase in beta power. However, when ET is combined with exercise, an increase in beta power is found in the right hemisphere (F8), while decrease in beta power is found in the left hemisphere (F7) of this region. The area correspondent to the right hemisphere (F8) is activated when cognitive tasks require inhibition . In addiTherefore, it is possible to observe this small dose of ET to alter the left IFG activity, thus possibly affecting some specific functions of this region, such as attention . In termStudies involving the effect of TA have been increasing in recent years due to their potential physiological influence. In addition, the simultaneous use of TA and ET justifies a better understanding of the acute effects of these substances. The complexity of CNS and the multiple, distinct, and important functions that each of its regions play, generate innumerable interpretations of brain functions. Thus, the combination of two substances that appear to be metabolically associated, and exercise as a physiological stressor, provide a more comprehensive understanding of the relationship of those compounds and the operation of CNS.Although our work has shown attractive results, some limitations could be highlighted: the amount of ET administered in comparison to some studies was small. It would be applicable to evaluate these effects in higher ET concentration. The taurine peak levels were defined from literature data. The analysis of taurine serum levels could avoid possible problems involving individual variability of this measure and also improve the explanation of the results. It is a fact that counterbalanced design favors the number of cell cases for each condition and, consequently, the sample size. However, evaluating a larger number of subjects and the gender effect would be interesting due to the great interindividual variability of neural measures.In summary, due to many different results, we can highlight that the acute effect of placebo ingestion decreased the electrocortical activity after exercise. The TA acute effect seems to inhibit the superior frontal region at the plasma peak; however, in such region, the TA effect increases ABP after exercise. A small ET dose was not enough to alter beta activity in the superior frontal area and it was sufficient to diminish it on the left side of the brain (Fp1 and F7) after exercise. We could observe that the ingestion of taurine in combination with ethanol showed different results of the ingestion of ethanol separately. TA when ingested together with ET had an similar effect in the right side  of the frontal cortex that TA treatment after exercise. More research is thus needed to better understand the mechanisms involved in the CNS response, such as electrocortical activities and frontal cortex functions, to such substances (TA and ET) with different dosage, exercise type and intensity.S1 Table(DOCX)Click here for additional data file.


In 2009, the European Medicines Agency recommended withdrawal of dextropropoxyphene (DXP); in March 2011 it was withdrawn from the market in France. Up until that time the combination dextropropoxyphene-paracetamol (DXP/PC) was widely used for analgesia. At withdrawal, French regulators recommended that DXP/PC be replaced by other step 2 analgesics, i.e. tramadol, codeine, or opium-containing drugs, or by PC for a weak level of pain. To investigate prescribing behaviours after DXP/PC withdrawal, dispensations of analgesics before and after withdrawal were analysed.Aggregated dispensation data of analgesics prescribed between January 2009 and December 2012 in the Rhône-Alpes region were obtained from the general health insurance claims data; changes in analgesic dispensation over time were analysed with the ATC/DDD methodology. Pre (Jan-June 2009) and post-withdrawal (Jan-June 2012) changes of DDDs where computed for each analgesic step.The dispensations of DXP/PC experienced a two-step decrease until 2011. Over the withdrawal period 2009-2012, there was a 14% decrease in the overall use of analgesic (from 109 to 94 DDDs), while the use of step 2 analgesics declined by 46% . This latter decline included a cessation of use of DXP/PC (29 DDDs in 2009) that were only in part  compensated by increased use of codeine, tramadol and opium, in monotherapy or combined with PC. For step 1 analgesics, use increased with 9%, mostly PC . Step 3 analgesics dispensations remained largely unchanged over this period (around 3 DDDs).In the Rhône-Alpes region, DXP/PC withdrawal was accompanied in part by an increased use of same level analgesics, and in part by an increased use of PC in monotherapy. The extent of DXP/PC use before withdrawal, and the increased use of PC after DXP withdrawal, underline the complexity of pain management. A rational approach to the treatment of pain is to combine treatments that act on distinct pain mechanisms in order to improve analgesia and, hopefully, to reduce the incidence of adverse events . This isHowever, DXP-related hepatotoxicity and its frequent use for suicidal poisoning reported in North Europe, United States and Australia, led to its progressive withdrawal. For instance, in the United Kingdom (UK), co-proxamol was withdrawn in 2007 . In 2009DXP/PC was widely used in France with more than 70 million of DXP/PC packs sold per year . Until mTo accompany the withdrawal, the French Regulators, in collaboration with scientific societies, provided recommendations regarding therapeutic alternatives to DXP/PC. It was suggested to replace DXP/PC by another step 2 analgesic, e.g. tramadol or codeine, and by PC for weaker pain level .While the consequences of DXP/PC withdrawal on suicidal deaths have been studied –15, its To provide a first set of data, an analysis of the Rhône-Alpes URCAM  database with 5 million inhabitants covered by the general health insurance scheme was performed, to describe analgesics dispensation between 2009 and 2012, around the time of DXP/PC withdrawal.To investigate DXP/PC replacement, dispensation data of all prescribed analgesics were requested for the period January 2009 to December 2012 for the Rhône-Alpes region of France. The regional fund that is part of the national health insurance system  providedThe aggregated number of packs monthly dispensed was computed (in France drugs are sold as indivisible units). For the analyses, the Anatomical Therapeutic Chemical classification/defined daily dose (ATC/DDD) methodology of the WHO Collaborating Centre for Drug Statistics Methodology was used . The disThe changes of DDDs between January-June 2009 and January-June 2012 for each analgesic step were computed by subtracting the numbers of DDDs/1000 inhabitants/day of each medicinal product reimbursed during the pre-withdrawal period (Jan-June 2009) from the numbers of DDDs reimbursed during the post-withdrawal period (Jan-June 2012), divided by the total numbers of DDDs reimbursed during the pre-withdrawal period.All analyses were performed using SAS software, version 9.4 .A total of 36 different DXP-containing medications were identified. In 2009, the most common DXP-containing medication was a fixed combination containing 30 mg DXP, and 400 mg PC (DXP 27MG/PC 400 MG). This combination represented 69.6% of all dispensations of DXP-containing medications. All profiles of use evolved similarly, with a two-step decrease of DXP/PC between 2009 and 2012. A first decrease occurred in June 2009, following an EMA announcement of DXP/PC withdrawal from the European market. A second, and final, decrease occurred in March 2011 at the time of withdrawal in France.Between 2009 and 2012, the total use of analgesics - expressed in DDDs - decreased with 14%  of 2009 and the first six months of 2012  and scientific societies – to be disputable. For instance, in 2008, a consensus conference on postoperative pain care concluded that DXP/PC should not be prescribed for this indication . SurveysHowever, the use of analgesics after DXP withdrawal had not been predicted. Before withdrawal, step 2 analgesics, particularly tramadol/PC and codeine/PC, were expected to be used much more frequently, but our data show that after DXP withdrawal, the use of PC increased more than the use of step 2 analgesics. The reasons for this limited increase of step 2 analgesics could be related to safety concerns as tramadol is known for its poor tolerability, while codeine is under surveillance for its respiratory effects –22. AlsoOf interest, the results of this study differ from the results of a survey performed among Pain specialists asked to describe alternatives to DXP in France . HCPs deBy contrast, another study conducted in a teaching hospital in 1997, i.e. long before withdrawal, suggested that DXP/PC should be predominantly replaced by PC alone, in agreement with our findings . AltogetThe effects of DXP withdrawal have also been investigated in other countries, notably in the UK, where withdrawal was effective in 2008. In the UK, a 23%-increase in codeine/PC, a 19%-increase in tramadol and a 16%-increase in PC prescriptions were reported , confirmOur findings had some limitations. This study relied on the use of aggregated data, i.e. monthly dispensations delivered to a population of five million people after analgesic prescribing by regional physicians. As such, it was not possible to distinguish successive episodes of use of analgesics in individuals, to identify analgesic therapy prescribed after DXP/PC withdrawal in chronic or repeated users. It was also not possible to assess the impact of therapeutic changes on the effectiveness of pain therapy, in the absence of patient-reported data. Access to individual drug histories would have allowed exploring differences in patients’ characteristics, such as gender, age or comorbidities, and differences in prescribers’ specialties, in addition to providing some markers of treatment effectiveness.Also, our data did not allow to verify the occurrence of a storage phenomenon that was shown to delay DXP replacement in the UK, where 30% of patients were still using DXP/PC one year following its withdrawal .A last limitation refers to the absence of over-the-counter data, since claims data include only information on drugs that were both prescribed and dispensed. However, prior research on this issue support the validity of the results obtained with claims data, as in France, PC is mostly used as prescribed therapy, while step 2 and step 3 analgesics are Prescription-Only-Medicines .In conclusion, after DXP withdrawal, large increases in PC use were observed, while the use of other step 2 analgesics increased to a lesser extent. Detailed analyses of individual longitudinal drug histories would be helpful to confirm the nature and the effectiveness of replacement therapy according to patients’ and prescribers’ characteristics, and the kinetics of this process, besides allowing investigations of quality of care in analgesia, and much-needed international comparisons.


To address different outcome types, we applied the Theory of Planned Behavior when coding the studies. FTP relationships with outcomes were small-to-medium, were generalizable across domains, and were strongest when the FTP construct included a mixture of cognition, behavioral intention, and affect and, in education, when the FTP measure was domain specific rather than general. There were cross-cultural differences in FTP-outcome relationships. The strength of the FTP-outcome types relationship varied for attitudes, perceived behavioral control, behavioral intention, and behaviors. The lowest effect sizes were found for FTP predicting actual behaviors in education, work, and health and between FTP and health attitudes. Theoretical implications of the findings and future research directions are discussed.Future time perspective (FTP) may predict individual attitudes and behaviors. However, FTP research includes different FTP conceptualizations and outcomes which hinder generalizing its findings. To solve the inconsistencies in FTP research and generalize the magnitude of FTP as a driver of motivation and behavior, we conducted the first systematical synthesis of FTP relationships in three crucial life domains. Our meta-analyses of FTP studies in education ( The future is not a result of a choice among alternative paths offered by the present, but a place that is created—created first in the mind and will, created next in activity. The future is not some place we are going to, but one we are creating. The paths are not to be found, but made, and the activity of making them changes both the maker and the destination .The human capacity for contemplating the future is a basis of human motivation and behavior in everyday life. Imagine a student preparing for an exam who lacks insight into the ultimate purpose of his or her learning effort, an employee who lacks career perspective, or a person who is told to lose weight but who cannot envision what said weight loss could afford him or her. None of these people would be motivated to put much effort into their learning-, work-, or health-related endeavors, and perhaps the lack of a future time perspective (FTP) prevented them from planning and regulating their daily actions.To what extent are people’s present motivation, intentions, and behaviors affected by their FTP?By definition, people’s motivational goals are situated in the future. Thinking about the future can concern the short term  and the long term or more distant future . Short-To achieve an in-depth understanding of human motivation and actions and reasons for those actions, the future merits a great deal more attention than it has received from the social sciences thus far . From diAs the concept of psychological time may include various aspects such are time succession, time duration, and time perspective , thinkinAnother research tradition of thinking about the future originates in research on social cognition and neuroscience. This research tradition investigates future-oriented cognitions such as mental simulation , episodThe current meta-analysis draws upon Lewin’s  and FranThe FTP construct differs from other motivational constructs. For example, Atkinson’s theory of achievement orientation  views a life space consists of geographical and social surroundings but also includes a time dimension. Lewin defined FTP as the “scope of time ahead which influences present behavior” (p. 879) and he claimed that change in FTP is one of the “most fundamental facts of development” (p. 879). Corroborating this view, Nuttin ) Second, we required that the FTP construct be measured with a self-report method, which is dominant in FTP research and matches the psychological nature of the construct , 112. WeThird, FTP had to relate to outcomes that refer to attitudes, motivations, behavioral intentions, and behaviors in the life domains of education, work, and health. Studies that linked FTP to themes and constructs in other domains  were omitted.Fourth, we selected empirical field studies but excluded qualitative reviews and conceptual articles. After reviewing studies based on the abovementioned criteria, we found only five experimental  studies relating to educational, work, and health outcomes; only one intervention study in the work  and heaFifth, we required studies to include a general, nonclinical sample. For example, we excluded studies with adjudicated adolescents  because k = 28 in the education domain, k = 17 in the work domain, and k = 32 in the health domain). The studies were published between 1984 and 2014 and involved N = 31,558 participants. Samples originated from the USA (35), Western Europe (34), Australia and New Zealand (5), Asia-Pacific (2), and Eastern Europe (1). The mean age of the total sample was 22.33. On average, the sample included 46.16% male respondents. Tables The literature search resulted in 6,481 reports. After having removed the duplicate studies 652 reports) and screened 301 potentially relevant studies, 65 reports met our inclusion criteria . These 6 reports All studies were double coded by a trained research assistant and the first author. Based on the recommendations by Lipsey and Wilson  and CoopWe coded the FTP scales and subscales based on our developed conceptual model for grouping the FTP construct types  that relWe coded the FTP measure as “general” if the measure did not specify a certain life domain or “specific” if the FTP items referred to a specific life domain .Gender was coded as the percentage of males in the sample. The mean age of the sample was entered for age. If age was missing, we calculated the age average based on the provided grade level (in the education life domain) or averaged the age groups. Culture was coded based on Hofstede et al.’s  culturalThe study design was coded as cross-sectional versus longitudinal, and we also included the publication year of the report.Based on the TPB, we distinguished four outcome types: (a) attitude toward behavior, (b) behavioral intention, (c) perceived behavioral control, and (d) behavior. We did not code for the subjective norm because there were no studies concerning this outcome type. Regarding the behavior outcome, we distinguished between unverifiable behavior (UB) and verifiable behavior (VB), that is, self-reported behavior that is potentially verifiable. See r was used as the effect size index. It is the recommended effect size measure , p < .0001. We also found a significant heterogeneity, Q = 128, 65, p < .0001. This finding is further supported by the I2 (I2 = 79.01), meaning that 79.01% of the observed variance stemmed from real differences between studies and, as such, may potentially be explained by the moderators  concerning the relationships between FTP and work outcomes. r = .24, 95% CI , p < .0001. The significant Q results and the high amount of heterogeneity, I2 = 88.28%, again indicated the likelihood of variables moderating the overall effect (see There were 17 independent samples (fect see .k = 32) concerning the relationships between FTP and outcomes in the health domain. The effect sizes and study characteristics are displayed in r = .20, 95% CI , p < .0001  = .17, p = .87. Under the random effect trim and fill procedure, two studies were added below the estimated average effect size, but no studies were added above the average effect size. The imputed point estimate was again the same as for the fixed-effect model, r = .24, 95% CI . The Egger’s regression coefficient was nonsignificant and the same as for the fixed-effect, showing no bias in the data.Using Duval and Tweedie’s  trim andt(15) = .27, p = .80For the relationship between FTP and work outcomes, there were no added studies below or above the average effect size for either the fixed or random-effect trim and fill procedure. The absence of study bias was further supported by the nonsignificant Egger’s test, intercept = .41, r = .20, 95% CI . Again, the Egger’s regression coefficient was not significant, intercept = .55, t(30) = .81, p = .43. The trim and fill procedure under the random-effect model added only one study above the average effect size, resulting in the same effect size as in the initial random-effect overall analysis, r = .21, 95% CI . Taken together, these results confirmed that the three data sets did not contain publication bias for the effect size estimates and that the computed mean effect of the meta-analysis will not be biased.Regarding the relationship between FTP and health outcomes under the fixed-effect trim and fill procedure, two studies were added below the average effect size, resulting in the same effect size as in the initial fixed-effect overall analysis, Q(3) = 27.32, p < .001, and a marginally significant moderator in the random-effect model, Q(3) = 6.93, p = .07. The strongest relationship was found for the FTP mixture of cognition, behavioral intention, and affect  and for FTP cognition and behavioral intention construct . The weakest relationship was found for FTP cognition  and for the FTP cognition and affect construct .For the relationship between FTP and educational outcomes, the FTP construct was a significant moderator in the fixed-effect model, Q(2) = 8.39, p < .05 (for random model). The largest effect size was for studies that included an FTP measure that represented a mixture of cognition, behavioral intention, and affect . Studies that included a cognition and behavioral intention FTP construct had a smaller effect size . Studies with a cognition FTP construct yielded the smallest effect size . This was true for the analyisis with or without the one study that used the cognition and affect FTP construct .Q(2) = 8.89, p < .01 (for random-effect). All studies included either one of the FTP construct types—except for the cognition and affect FTP construct. The largest effect size was for one study that included FTP cognition , followed by studies that applied a mixture of cognition, behavioral intention, and affect , and then followed by the cognition and behavioral intention FTP construct . However, after removing the only study in the FTP-cognition subgroup  = 8.83, p < .01. Again, the stronger effect was found for studies that used an FTP measure that consisted of a mixture of cognition, behavioral intention, and affect , compared to studies that applied a cognition and behavioral intention FTP construct .The FTP construct significantly moderated the relationship between FTP and health outcomes in both fixed- and random-effect models, p , we fouQ(1) = 8.94, p < .01. FTP measures with a specific focus related more strongly to educational outcomes  than FTP measures with a general focus .For the FTP–educational outcomes relationship, FTP focus was a significant moderator in the fixed-effect model only, k = 28), and only four studies included the specific FTP.We were unable to perform the moderation analysis for the FTP–work outcomes relationships because only one study included the specific FTP measure . FTP foQ(1) = 3.16, p < .08, and significantly predicted the FTP–health outcomes relationship in the fixed effect model, Q(1) = 8.06, p < .005. Higher individualism went together with a stronger relationship between FTP and work and health outcomes.The individualism/collectivism cultural dimension did not moderate the FTP–educational outcomes relationship in either the fixed- or random-effect models. However, this cultural dimension marginally predicted the FTP–work outcomes relationship in the fixed effect model, Q(1) = 18.06, p < .001. This result indicates that the relationship between FTP and educational outcomes was stronger in countries with a long-term orientation.The long-term/short-term cultural dimension was a significant moderator only for the FTP–educational outcomes relationship and in the random-effect model, Q(1) = 2.78, p < .09. The indulgence/restraint cultural dimension only significantly predicted the effect size of the FTP–work outcomes relationship in the fixed-effect model, Q(1) = 18.78, p < .001. Greater indulgence was associated with a weaker relationship between FTP and work outcomes.The uncertainty-avoidance cultural dimension was a marginally significant predictor of the FTP–educational outcomes relationship but only in the fixed-effect meta-regression, p < .001, k = 17. This result indicates that the older the sample of participants were, the weaker the relationships between FTP and working outcomes would be. In testing the FTP–health outcomes relationship, age did not predict the overall effect sizes in either fixed- or random-effect models.Age was not a significant predictor in either the fixed or random-effect meta-regressions testing the FTP–educational outcomes relationship. However, age significantly moderated the relationship between FTP and work outcomes but only in the fixed-effect model, B = −.01, p = 06, k = 27. This result indicates that the relationship between FTP and educational outcomes was stronger when the sample was comprised of a higher percentage of males. However, the magnitude of the slope was very small. One study had missing data on gender .p < .001, k = 15. The relationship between FTP and working outcomes was stronger when the sample was comprised of a higher percentage of males; however, the magnitude of the slope was very small, and two studies had missing data on gender ..p < .001p < .001, k = 28. Although the magnitude of the slope was very small, this result indicates that the FTP–health outcomes relationship was weaker when the sample was comprised of a higher percentage of males. It is important to note that four studies had missing data on gender ..p < .001k = 25) and longitudinal studies (k = 3) in the education domain in both the fixed- and random-effect models, Q(1) = .04, p = .85. Because the data consisted of only one longitudinal study in both the work domain  and in n , we couQ(1) = 8.46, p < .005. This result indicates that the strength of the relationships between FTP and health outcomes increased over time.Regressing the relationship between FTP and educational outcomes onto the year when a study was published yielded a null effect in both fixed- and random-effect models. The meta-regression analysis in the work domain showed no evidence that the effect size changed across years. However, publication year moderated the relationship between FTP and health outcomes in the fixed-effect model, After including all significant moderators  in the regression model as we tested the overall effect size of FTP on educational outcomes, we found a significant fixed-effect model. FTP construct type and FTP focus remained significant moderators, but FTP focus was only marginally significant, whereas long-term orientation, uncertainty-avoidance, and gender were no longer significant moderators. This analysis was based on 27 studies; one study did not provide information on gender .R2 = .11, p < .05.A multiple regression analysis with FTP construct type, individualism/collectivism, indulgence/restraint, and age in the model yielded both significant fixed- and random-effect models. Due to collinearity among the covariates, we could not preform multiple regression analysis that included the gender of sample in the model . In the R2 = .30, p < .05. This result is based on k = 28 because four studies had missing data on gender ..R2 = .30k = 12 for FTP and UB, and k = 14 for FTP and VB relationships). The educational behaviors mainly concerned students’ GPAs or learning engagement such as investment in learning or study effort. Fewer studies were related to FTP and attitudes toward behavior relationships (k = 7), FTP and behavioral intention (k = 4), and FTP and perceived behavioral control (k = 3). The overall effect sizes for FTP and educational outcome types were significant, positive, and small-to-medium . The strongest effect (r = .33) was for UB; the smallest effect (r = .16) was for VB.In the education domain, most of the studies included behavioral outcome types (k = 12), followed by studies examining FTP and perceived behavioral control (k = 9) and FTP and behavioral intention (k = 7), and fewer studies included relationships between FTP and UB (k = 5), and FTP and VB (k = 2). After conducting five separate meta-analyses on FTP and outcome type, we found a medium-to-large effect size for the relationship between FTP and UB, r = .40, k = 5, and for the relationship between FTP and perceived behavioral control, r = .32, k = 9. We found the smallest effect size in the relationship between FTP and attitudes toward work behaviors, r = .21, k = 12. Notably, we found two nonsignificant overall effect sizes: FTP and behavioral intention (k = 7) and FTP and VB (k = 2). Because the FTP and the VB relationship included only two studies, resulting in reduced power, this result, as well as the other results that were based on a small sample of studies, should be taken cautiously.In the work domain, most of the studies included correlations between FTP and work attitudes , FTP and behavioral intention , and FTP and perceived behavioral control . Again, we found the largest effect size in the FTP and UB relationship  and a smaller effect size in the FTP and VB relationship (r = .14); however, this result was only based on three studies.Examining the separate relationships between FTP and outcome types in the health domain, we found significant and small-to-medium effect sizes for most of the relationships in both random- and fixed-effect models: FTP and attitudes toward behavior  cognition, (b) cognition and behavioral intention, (c) cognition and affect, and (d) a mixture of cognition, behavioral intention, and affect.Consistent with FTP researchers who advocate that affect and behavioral intention play a pivotal role in goal-directed behavior e.g., , 50, 84), 8450, 8Overall, our findings highlight that the way in which individuals contemplate about their more distant future matters. Although the associations between FTP and outcomes were significant for each FTP construct type, they were stronger when individuals’ thinking about the future involved cognitions, affect, and behavioral intention. Based on these findings we recommend that researchers use these more comprehensive FTP measures when relevant.We also examined whether FTP focus  would affect the FTP–outcome relationship. Based on the principle of compatibility , 88—thatk = 28), whereas only very few studies (k = 4) applied a specific FTP measure. Our findings did not allow us to draw conclusions about the moderating role of FTP focus in the work domain because only one study in this domain included the specific FTP measure.The distinction between specific and general thoughts about the future seems less important for health outcomes. We should note, however, that most health studies in our meta-analyses applied a general FTP measure , but long-term desirable outcomes  in the education domain, and short-term attractive behaviors , but long-term undesirable outcomes , present mainly in the work and health domains. These outcomes seem to initiate different self-control systems, namely, stop and start control [Regarding cultural differences in the temporal orientation, we found that FTP and outcomes were more strongly associated in countries with a long-term orientation. However, this result only appeared in the education domain and not in the work and health domains. A possible explanation for this finding may be the dominance of the  control . Stop coAs expected, high uncertainty-avoidance cultures displayed a stronger association between FTP and educational outcomes, yet this was not the case for work and health outcomes in our study. It is possible that individuals feel that they can control their educational achievements more so than their work and health achievements. Indeed, a recent study in the education domain  showed tOur study indicates that the motivational strength of FTP is higher for accomplishing educational outcomes in cultures where individuals are uncomfortable with novel and unknown situations. Individuals in these cultures may view educational achievement as a way to avoid negative outcomes in the future, such as a low income and associated adverse life conditions. This finding challenges the assumption that the future is less motivating for individuals seeking to achieve educational goals in countries experiencing great political or economic uncertainty . InsteadBuilding on recent results by Sircova et al. , we founIn our findings, age played a significant moderating role in the relationship between FTP and work outcomes. That is, FTP was less motivating for work-related attitudes and behaviors as people age. An explanation for this finding can be derived from socioemotional selectivity theory . This liIn addition to age effects, we found gender differences in the degree of strength in FTP–outcome relationships, which corroborate extant research , 55, 77.The other study characteristics that we tested as possible moderators of the FTP–outcome relationships concerned study design  and the year of publication. Study design could not be tested in the work and health domains due to a lack of longitudinal studies in these domains. However, the design of the study did not moderate the relationships between FTP and educational outcomes.The year of publication emerged only as a significant moderator of the relationships between FTP and health outcomes—the strength of these relationships increased over the years. This finding can be explained by the fact that more recent studies , 164 appThe final aim of our review was to identify whether the strength of the relationships between FTP and outcomes varies with outcome types as based on the TPB . For each of the five outcome types we conducted additional meta-analyses per life domain. We anticipated that FTP would have stronger associations with attitudinal outcomes and behavioral intentions than with actual behaviors. From our findings emerged a novel insight into the observed relationships and revealed different patterns of FTP associations relative to the outcome type.As expected, FTP was more strongly related to educational, work, and health attitudes and to educational and health behavioral intention than to behaviors in these life domains. However, this was only true when VBs were taken into account . This finding that measures of FTP had a stronger relationship with social cognitions than with measures of actual behavior, is consistent with research on the gap between intentions and behavior , 201. WhIt is important to acknowledge that we found two nonsignificant associations in the work domain between FTP and behavioral intention as well as FTP and VB. The first nonsignificant association may be due to one large sample that showed a negative association —this had a strong influence on estimating the overall effect size. After removing this large sample, we found a significant small-to-medium association between FTP and behavioral intention. The second nonsignificant association was only based on two studies.Although we did not anticipate strong associations between FTP and perceived behavioral control, our meta-analyses revealed robust and generalizable relationships across the three life domains. We found medium-to-large associations between FTP and perceived behavioral control in education and work and small-to-medium associations between FTP and perceived behavioral control in the context of health. These findings suggest that individuals engage in reflecting about their future to the extent that they perceive their actions to be under their own control. For example, students who think more about their futures may feel more capable about their ability to do homework or to prepare for an exam than students who involve themselves less in reflections about their futures. In the health domain we also found significant and positive relationships between FTP and perceptions of behavioral control, but these relationships were small-to-medium. Individuals who engage in thinking about future may have faith in their ability to engage in health-related behaviors .(p. 257). It seems that individuals who feel capable, and who reflect on their future, also see the importance of their future achievements and consequently work harder to develop the skills needed to achieve their goals. In this way, they develop realistic aspirations and select tasks they feel they can master.Our notion that individuals particularly reflect on future that they believe is controllable is supported by recent studies , 203, whAfter eight decades of FTP research, powerful evidence of the aggregated research efforts is required to appraise and lift FTP theory to the next level. Our meta-analyses contribute to current theory on FTP as a driver of human motivation and behavior in several ways. First, our findings synthesize research on the relationships between FTP and outcomes from different disciplines of psychology: education, work, and health. To date, the overall relationships between FTP and outcomes and their possible moderators were unknown within each of the three disciplines. Moreover, although there was meta-analytic evidence on the relationship between FTP and attitudes and behavior within the environmental domain , there wSecond, we developed a framework for grouping the FTP construct types and distinguished specific from general FTP measures in order to synthesize contradictory research findings across the life domains , 205. OuThe finding that FTP construct type in the three life domains and FTP focus in the education domain can explain variation in the FTP–outcome relationships solves, to some extent, the present inconsistencies in FTP research. Furthermore, this finding contributes to the discussion about the operationalization and measurement of FTP—a recognized obstacle in FTP research. Researchers in the education domain have stressed the importance of a comprehensive FTP measure , 39. OurA third contribution of our study is that we tested cultural context as a factor that could influence the strength of FTP effects. Researchers often state that findings should be explored in a generalized manner, taking different research contexts into account . Extant Fourth, we added to FTP theory and research by identifying age and gender as significant moderators. Both the content of FTP and the strength of its effect seem associated with age; therefore, FTP theory could incorporate age as a significant variable and could develop propositions about its specific role. FTP and age are, by definition, time-related constructs that cannot be studied independently. Future studies could, for example, investigate how the content of the FTP construct develops over people’s lives. In addition, the identified gender differences in the three life domains signal that gender should be controlled for in future FTP research. FTP theory should also adopt the notion that FTP effects depend on individuals’ stereotypical gender roles and expectations.Fifth, we used the TPB as the theoretical framework to distinguish FTP outcomes across different research domains. Our results stress the need to better integrate seminal theories on motivation and self-regulation into FTP theory. We found that FTP exhibits the strongest relationships with attitudes across domains and with behavioral intention in the education and health domains; we found the weakest relationships to be between FTP and actual (verified) behaviors in the three life domains. However, the week relationships between FTP and actual behaviors, versus strong relationships between FTP and other (non-verifiable) outcome types might be–at least partly–due to the overlapping nature of measures based on its content and/or methodology . NevertAlthough the current study provides the first synthesis of research on the relationship between FTP and educational, work, and health outcomes, it is not without limitations. Below, we highlight the limitations of our study and offer directions for future research in order to guide researchers and to advance the FTP field.First, because the studies included in our meta-analyses used correlational designs, causal inferences cannot be made for the examined relationships. Although the findings of the included studies provide guidelines for further theory development, research, and interventions in the education, work, and health domain, we recommend that future studies explore the causal effects of FTP with longitudinal study designs and intervention studies. For example, a longitudinal study by Chua, Milfont, and Jose  exploredSecond, future studies should be careful when using and interpreting FTP and outcome measures that include content overlap  or apply the same methodology , which was the case in some of the included studies in our meta-analyses. In survey data, specific FTP measures  and self-reported measures of behavioral intention  may, despite their different orientation (the future vs. the present), correlate at least partly because of common method variance that tend to inflate the effect sizes . SimilarThird, because some subgroup analyses were based on five or fewer independent correlations, the generalizability of these findings is restricted. This calls for more studies to be conducted—particularly in the domain of work. Fourth, regression analyses examining the moderation effects required us to synthesize correlation matrices despite missing data in a few cases; however, this was only in the case of gender.cognitions, feelings, and behavioral intentions with respect to the future) and we used a conceptual model for grouping the different FTP measures within this research tradition. This meant that some FTP measures and subscales were omitted . Also, n & Lang , 212. Hofuture in the different FTP measures. Although most of the included studies in our meta-analyses (and particularly in the education domain) defined the future in terms of length (a long-term or distant future), some studies were less clear about its meaning. For example, although Husman and Shell’s [An issue that merits special attention in FTP research is the meaning of the term  Shell’s  FTP meas Shell’s  is more  Shell’s .Finally, although our conceptual framework for coding the FTP measures offered a systematical and useful way for organizing FTP studies within the time perspective research tradition , 32, a rAlthough we have demonstrated that FTP is a significant motivator across cultures, it is important to note that these results (except for the long-term/short-term orientation dimension) are preliminary because they are only generalizable to the sample of studies included in the meta-analyses. The majority of FTP studies were conducted in Western countries , thus, future studies should include samples from other regions as well . This would enable researchers to more deeply explore cross-cultural differences among diverse study samples.Although Hofstede’s cultural dimensions  are the Because of a lack of longitudinal FTP studies, little is known about whether and how FTP–outcome relationships change over time. Longitudinal studies are needed, not only to test causal relationships but also to study the processes that explain the FTP–outcome relationship. Moreover, the strength of this relationship may vary with life stages or periods of transfer . Although longitudinal studies are particularly needed in the work and health domains, the education domain could also benefit from longitudinal research designs; our nonsignificant results for study design in the education domain might have been due to a lack of power.A large majority of empirical studies have explored FTP as a precursor of attitudes and behaviors , 47, 48.Although we included some relevant moderators that could influence the FTP–outcome relationships, research is needed to investigate whether and in what ways other variables can moderate these relationships. For example, Fieulaine and Martinez  providedWe started our paper by arguing that the future is a premise of human motivation in everyday life. In the present study, we found substantial evidence that FTP is a successful motivator in three indispensable domains of life: education, work, and health. Reviewing the relationships between FTP and educational, work, and health outcomes and establishing their robustness and generalizability across life domains and cultures is a unique feature of this study. The present meta-analyses offer important results and conclusions that could be considered when developing future research on FTP. We mention here only a few. With regard to the FTP construct type, we found that FTP measures that include a combination of cognition, affect, and behavioral intention yield the strongest relationship with educational, work, and health outcomes even when controlling for identified confounds. Furthermore, we demonstrated that the FTP that involves domain-specific thinking exhibits a stronger relationship with educational outcomes than a more general FTP. Also, we showed that FTP has stronger relationships with attitudes, behavioral intention, and perceived behavioral control than with objective (verifiable) behaviors. Finally, our study identified cross-cultural differences in the strength of FTP–outcome relationships.Our comprehensive meta-analyses add to FTP theory and research by providing the first meta-analytical evidence of the motivational force of FTP across life domains, by solving inconsistencies in study findings, and by stressing the need for further reflection on the conceptualization of FTP and its relationship with other future-oriented constructs. Ultimately, individuals’ motivation to succeed in central life domains should be built on a future that is created in their minds, hearts, and intentions.S1 File(DOCX)Click here for additional data file.S2 File(DOCX)Click here for additional data file.S1 TablePRISMA checklist.(DOC)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.


The health effects of a Roundup-tolerant NK603 genetically modified (GM) maize (from 11% in the diet), cultivated with or without Roundup application and Roundup alone (from 0.1 ppb of the full pesticide containing glyphosate and adjuvants) in drinking water, were evaluated for 2 years in rats. This study constitutes a follow-up investigation of a 90-day feeding study conducted by Monsanto in order to obtain commercial release of this GMO, employing the same rat strain and analyzing biochemical parameters on the same number of animals per group as our investigation. Our research represents the first chronic study on these substances, in which all observations including tumors are reported chronologically. Thus, it was not designed as a carcinogenicity study. We report the major findings with 34 organs observed and 56 parameters analyzed at 11 time points for most organs.Biochemical analyses confirmed very significant chronic kidney deficiencies, for all treatments and both sexes; 76% of the altered parameters were kidney-related. In treated males, liver congestions and necrosis were 2.5 to 5.5 times higher. Marked and severe nephropathies were also generally 1.3 to 2.3 times greater. In females, all treatment groups showed a two- to threefold increase in mortality, and deaths were earlier. This difference was also evident in three male groups fed with GM maize. All results were hormone- and sex-dependent, and the pathological profiles were comparable. Females developed large mammary tumors more frequently and before controls; the pituitary was the second most disabled organ; the sex hormonal balance was modified by consumption of GM maize and Roundup treatments. Males presented up to four times more large palpable tumors starting 600 days earlier than in the control group, in which only one tumor was noted. These results may be explained by not only the non-linear endocrine-disrupting effects of Roundup but also by the overexpression of the EPSPS transgene or other mutational effects in the GM maize and their metabolic consequences.Our findings imply that long-term (2 year) feeding trials need to be conducted to thoroughly evaluate the safety of GM foods and pesticides in their full commercial formulations. Empirical natural and social sciences produce knowledge (in German: Wissenschaften schaffen Wissen) which should describe and explain past and present phenomena and estimate their future development. To this end quantitative methods are used. Progress in science needs controversial debates aiming at the best methods as basis for objective, reliable and valid results approximating what could be the truth. Such methodological competition is the energy needed for scientific progress. In this sense, ESEU aims to enable rational discussions dealing with the article from G.-E. Séralini et al.  by re-publishing it. By doing so, any kind of appraisal of the paper’s content should not be connoted. The only aim is to enable scientific transparency and, based on this, a discussion which does not hide but aims to focus methodological controversies. -Winfried Schröder, Editor of the Thematic Series “Implications for GMO-cultivation and monitoring” in Environmental Sciences Europe.There is an ongoing international debate as to the necessary length of mammalian toxicity studies, including metabolic analyses, in relation to the consumption of genetically modified (GM) plants . Current3 times below the MRL can induce endocrine disturbances in human cells [in vivo [Though the petitioners conclude in general that no major physiological changes is attributable to the consumption of the GMO in subchronic toxicity studies –5, signian cells  and toxian cells . This ma[in vivo  as well [in vivo . After s[in vivo –14. Furt[in vivo .More recently, long-term and multi-generational animal feeding trials have been performed, with some possibly providing evidence of safety, while others conclude on the necessity of further investigation because of metabolic modifications . Howeverin vivo for acute toxicity [in vitro [Furthermore, evaluation of long-term toxicity of herbicides is generally performed on mammalian physiology employing only their active principle, rather than the complete formulations as used in agriculture. This was the case for glyphosate (G) , the dectoxicity . In thisin vitro . When G in vitro . Adjuvanin vitro . The halin vitro . As a rein vitro –28. On tWith a view to address this lack of information, we performed a 2-year detailed rat feeding study. Our study was designed as a chronic toxicity study and as a direct follow-up to a previous investigation on the same NK603 GM maize conducted by the developer company, Monsanto . HoweverOur study is the first and to date the only attempt to follow up Monsanto's investigation and to determine whether the differences found in the NK603 GM maize-fed rats, especially with respect to liver and kidney function, were not biologically meaningful, as claimed, or whether they developed into serious diseases over an extended period of time.The Monsanto authors adapted Guideline 408 of the Organization for Economic Co-operation and Development (OECD) for their experimental design . Our stuWe used the Sprague-Dawley strain of rat, as recommended for chronic toxicology tests by the National Toxicology Program in the USA , and as Overall, our study is the first in-depth life-long toxicology study on the full commercial Roundup formulation and NK603 GM maize, with observations on 34 organs and measurement of 56 parameters analyzed at 11 time points for most organs, and utilizing 3 doses. We report here the major toxicological findings on multiple organ systems. As there was no evidence in the literature on GM food safety evaluation to indicate anything to the contrary, this initial investigation was designed as a full chronic toxicity and not a carcinogenicity study. Thus, we monitored in details chronologically all behavioral and anatomical abnormalities including tumors. A full carcinogenicity study, which usually focuses only on observing incidence and type of cancers , would be a rational follow-up investigation to a chronic toxicity study in which there is a serious suspicion of carcinogenicity. Such indications had not been previously reported for GM foods.Our findings show that the differences in multiple organ functional parameters seen from the consumption of NK603 GM maize for 90 days  escalatep < 0.01) decrease in certain phenolic acids in treatment diets, namely ferulic and caffeic acids. Ferulic acid was decreased in both GM maize and GM maize + R diets by 16% to 30% in comparison to the control diet  and caffeic acid in the same groups by 21% to 53% .Standard biochemical compositional analysis revealed no particular differences between the different maize types and diets, the GM and non-GM maize being classified as substantially equivalent, except for transgene DNA quantification. For example, there was no difference in total isoflavones. In addition, we also assayed for other specific compounds, which are not always requested for establishing substantial equivalence. This analysis revealed a consistent and statistically significant  ≥ 80%, and a cross-validated predictive ability Q2(Y) ≥ 60%, were used for selection of the discriminant variables . Statistical analysis of results employed OPLS-DA 2-class models built between each treated group per sex and controls. Only models with an explained variance Rs Figure , when ths Figure . In GM mFurthermore, in females Table , the andTumors are reported in line with the requirements of OECD chronic toxicity protocols 452 and 453, which require all ‘lesions’ (which by definition include tumors) to be reported. These findings are summarized in Figure In female animals, the largest tumors were in total five times more frequent than in males after 2 years, with 93% of these being mammary tumors. Adenomas, fibroadenomas, and carcinomas were deleterious to health due to their very large size Figure A,B,C ratp < 0.05, Kruskal-Wallis test with post hoc Dunn's test). All females except one (with metastatic ovarian carcinoma) presented in addition mammary hypertrophies and in some cases hyperplasia with atypia . By the beginning of the 24th month, 50% to 80% of female animals had developed tumors in all treatment groups, with up to three tumors per animal, whereas only 30% of controls were affected. A summary of all mammary tumors at the end of the experiment, independent of size, is presented in Table The second most affected organ in females was the pituitary gland, in general around two times more than in controls for most treatments Table J,K,L,M. The large palpable tumors in males (in kidney and mostly skin) were by the end of the experimental period on average twice as frequent as in controls, in which only one skin fibroma appeared during the 23rd month. At the end of the experiment, internal non-palpable tumors were added, and their sums were lower in males than in females. They were not significantly different from controls, although slightly increased in females  rodent (rat) feeding study investigating possible toxic effects arising from consumption of an R-tolerant GM maize NK603) and a complete commercial formulation of R herbicide. The aims of this investigation were essentially twofold. First, to evaluate whether the signs of toxicity, especially with respect to liver and kidney functions, seen after 90 days' consumption of a diet containing NK603 R-tolerant GM maize  and a co escalate studies ,9. The p studies .Our data show that the signs of liver and kidney toxicity seen at 90 days from the consumption of NK603 GM maize  do indeeWhat is also evident from our data is that ill effects were not proportional to the dose of either the NK603 GM maize ± R or R alone. This suggests that the observed disease may result from endocrine disruptive effects, which are known to be non-monotonic. Similar degrees of pathological symptoms occurred from the lowest to the highest doses, suggesting a threshold effect . This coDeath in male rats was mostly due to the development of severe hepatorenal insufficiencies, confirming the first signs of toxicity observed in 90-day feeding trials with NK603 GM maize . In femaDisturbances that we found to occur in the male liver are characteristic of chronic toxicity, confirmed by alterations in biochemical liver and kidney function parameters. The observation that liver function in female animals was less negatively affected may be due to the known protection from oxidative stress conferred by estrogen . EstrogeThe disruptions of at least the estrogen-related pathways and/or enhancement of oxidative stress by all treatments need further confirmation. This can be addressed through the application of transcriptomic, proteomic, and metabolomic methods to analyze the molecular profile of kidneys and livers, as well as the GM NK603 maize –48. OtheThe lifespan of the control group of animals corresponded to the mean for the strain of rat used (Harlan Sprague-Dawley), but as is frequently the case with most mammals, including humans , males oin vitro, G alone is known to induce human breast cancer cell growth via estrogen receptors [in vivo in males [In females, induced euthanasia due to suffering and deaths corresponded mostly to the development of large mammary tumors. This was observed independently of the cancer grade but according to impact on morbidity. These appeared to be related to the various treatments when compared to the control groups. These tumors are generally known to be mostly estrogen-dependent . We obseeceptors . In addieceptors , and to eceptors . Furtherin males . Sex stein males ,66. The Interestingly and perhaps surprisingly, in the groups of animals fed with the NK603 GM maize without R application, similar effects with respect to enhanced tumor incidence and mortality rates were observed. For instance, comparing the 11% GMO-treated female group to the controls, the assumption that the tumors are equally distributed is rejected with a level of significance of 0.54% with the Westlake exceedance test . The claA possible explanation for this finding is the production of specific compound(s) in the GM feed that are either directly toxic and/or cause the inhibition of pathways, which in turn generates toxic effects. This is despite the fact that the variety of GM maize used in this study was judged by industry and regulators as being substantially equivalent to the corresponding non-GM closest isogenic line ,30. As tAgrobacterium tumefaciens 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS-CP4) [A cause of the ill effects resulting from NK603 GM maize alone observed in this study could be the fact that it is engineered to overexpress a modified version of the SPS-CP4) . A limitSPS-CP4) ,70. MoreSPS-CP4) . This doIn conclusion, the consumption of NK603 GM maize with or without R application or R alone gave similar pathologies in male and female rats fed over a 2-year period. It was previously known that G consumption in water above authorized limits may provoke hepatic and kidney failure . The resTaken together, the significant biochemical disturbances and physiological failures documented in this work reveal the pathological effects of these GMO and R treatments in both sexes, with different amplitudes. They also show that the conclusion of the Monsanto authors  that theWe propose that agricultural edible GMOs and complete pesticide formulations must be evaluated thoroughly in long-term studies to measure their potential toxic effects.The experimental protocol was conducted in an animal care unit authorized by the French Ministries of Agriculture and Research (Agreement Number A35-288-1). Animal experiments were performed according to ethical guidelines of animal experimentations (CEE 86/609 regulation), including the necessary observations of all tumors, in line with the requirements for a long-term toxicological study , up to aConcerning the cultivation of the maize used in this study, no specific permits were required. This is because the maize was grown (MON-00603-6 commonly named NK603) in Canada, where it is authorized for unconfined release into the environment and for use as a livestock feed by the Canadian Food Inspection Agency (Decision Document 2002-35). We confirm that the cultivation did not involve endangered or protected species. The GM maize was authorized for import and consumption into the European Union (CE 258/97 regulation).−1 , and another field of NK603 was not treated with R. Corn cobs were harvested when the moisture content was less than 30% and were dried at a temperature below 30°C. From these three cultivations of maize, laboratory rat chow was made based on the standard diet A04 . The dry rat feed was made to contain 11%, 22%, or 33% of GM maize, cultivated either with or without R, or 33% of the non-transgenic control line. The concentrations of the transgene were confirmed in the three doses of each diet by qPCR. All feed formulations consisted of balanced diets, chemically measured as substantially equivalent except for the transgene, with no contaminating pesticides over standard limits. All secondary metabolites cannot be known and measured in the composition. However, we measured isoflavones and phenolic acids including ferulic acid by standard HPLC-UV. All reagents used were of analytical grade. The herbicide diluted in the drinking water was the commercial formulation of R . Herbicide levels were assessed by G measurements in the different dilutions by mass spectrometry.The varieties of maize used in this study were the DKC 2678 R-tolerant NK603 , and its nearest isogenic non-transgenic control DKC 2675. These two types of maize were grown under similar normal conditions, in the same location, spaced at sufficient distance to avoid cross-contamination. The genetic nature, as well as the purity of the GM seeds and harvested material, was confirmed by qPCR analysis of DNA samples. One field of NK603 was treated with R at 3 L ha2, Genestil, France) with two animals of the same sex per cage. The litter  was replaced twice weekly. The animals were maintained at 22 ± 3°C under controlled humidity (45% to 65%) and air purity with a 12 h-light/dark cycle, with free access to food and water. The location of each cage within the experimental room was regularly changed. This 2-year life-long experiment was conducted in a Good Laboratory Practice (GLP) accredited laboratory according to OECD guidelines. After 20 days of acclimatization, 100 male and 100 female animals were randomly assigned on a weight basis into ten equivalent groups. For each sex, one control group had access to plain water and standard diet from the closest isogenic non-transgenic maize control; six groups were fed with 11%, 22%, and 33% of GM NK603 maize either treated or not treated with R. The final three groups were fed with the control diet and had access to water supplemented with respectively 1.1 × 10−8% of R , 0.09% of R , and 0.5% of R . This was changed weekly. Twice-weekly monitoring allowed careful observation and palpation of animals, recording of clinical signs, measurement of any tumors, food and water consumption, and individual body weights.Virgin albino Sprague-Dawley rats at 5 weeks of age were obtained from Harlan . All animals were kept in polycarbonate cages  and at the end of the study by exsanguination under isoflurane anesthesia. In each case, detailed observations and anatomopathology was performed and the following organs were collected: brain, colon, heart, kidneys, liver, lungs, ovaries, spleen, testes, adrenals, epididymis, prostate, thymus, uterus, aorta, bladder, bone, duodenum, esophagus, eyes, ileum, jejunum, lymph nodes, lymphoreticular system, mammary glands, pancreas, parathyroid glands, Peyer's patches, pituitary, salivary glands, sciatic nerve, skin, spinal cord, stomach, thyroid, and trachea. The first 14 organs . These linear combinations of X-variables give PLS components (score vectors t). A PLS component can be thought of as a new variable - a latent variable - reflecting the information in the original X-variables that is of relevance for modeling and predicting the response Y-variable by means of the maximization of the square of covariance ). The number of components is determined by cross validation. SIMCA software uses the nonlinear iterative partial least squares algorithm (NIPALS) for the PLS regression. Orthogonal partial least squares discriminant analysis (OPLS-DA) was used in this study [Biochemical data were treated by multivariate analysis with the SIMCA-P (V12) software . The use of chemometrics tools, for example, principal component analysis (PCA), partial least squares to latent structures (PLS), and orthogonal PLS (OPLS), are robust methods for modeling, analyzing, and interpreting complex chemical and biological data. OPLS is a recent modification of the PLS method. PLS is a regression method used in order to find the relationship between two data tables referred to as gression  analysisis study ,74.X variables. The X matrix consists of the biochemical data. The Y matrix contains dummy variables which describe the group membership of each observation. Binary variables are used in order to encode a group identity. Discriminant analysis finds a discriminant plan in which the projected observations are well separated according to each group. The objective of OPLS is to divide the systematic variation in the X-block into two model parts, one linearly related to Y , and the other one unrelated  to Y. Components related to Y are called predictive, and those unrelated to Y are called orthogonal. This partitioning of the X data results in improved model transparency and interpretability [The purpose of discriminant analysis is to find a model that separates groups of observations on the basis of their tability . Prior t


In high-income temperate countries, the number of hospitalizations for heart failure (HF) and acute myocardial infarction (AMI) increases during the winter. This finding has not been fully investigated in low- and middle-income countries with tropical and subtropical climates. We investigated the seasonality of hospitalizations for HF and AMI in Sao Paulo (Brazil), the largest city in Latin America.This was a retrospective study using data for 76,474 hospitalizations for HF and 54,561 hospitalizations for AMI obtained from public hospitals, from January 2008 to April 2015. The average number of hospitalizations for HF and AMI per month during winter was compared to each of the other seasons. The autoregressive integrated moving average (ARIMA) model was used to test the association between temperature and hospitalization rates.vs. 767 per month, p<0.001; and AMI: 678 vs. 586 per month, p<0.001). Monthly average temperatures were moderately lower during winter than other seasons and they were not associated with hospitalizations for HF and AMI.The highest average number of hospital admissions for HF and AMI per month occurred during winter, with an increase of up to 30% for HF and 16% for AMI when compared to summer, the season with lowest figures for both diseases (respectively, HF: 996 The winter season was associated with a greater number of hospitalizations for both HF and AMI. This increase was not associated with seasonal oscillations in temperature, which were modest. Our study suggests that the prevention of cardiovascular disease decompensation should be emphasized during winter even in low to middle-income countries with tropical and subtropical climates. Coronary artery disease and heart failure (HF) are leading causes of morbidity and mortality worldwide. In low- High-income countries with temperate climates are characterized by large seasonal oscillations in ambient temperature. In these countries, the association between winter and decompensated cardiovascular diseases has been clearly demonstrated. , 5 BioloIn low- and middle-income countries with a tropical and subtropical climate, the effect of mild winters on cardiovascular decompensation has not been fully investigated. In these countries, temperature does not oscillate much across seasons but other social and environmental factors such as precarious housing conditions, lack of thermal insulation, and greater pollution might increase the seasonal effect of winter on risk.–10In our study, we investigated the seasonality of hospitalizations for HF and AMI and tested the association between monthly average temperatures and hospitalizations for these diseases in the public health system of Sao Paulo, Brazil, the largest city in Latin America. We hypothesize that in Sao Paulo, the winter season is associated with increased cardiovascular risk even if seasonal temperature oscillations remain modest. We also speculate that this association might be rooted in the socio-economic circumstances faced by our studied population, i.e. the users of the public health system, such as greater exposure to air pollution, lack of thermal insulation, precarious housing, and other tribulations faced by those who live with low-income in such a megacity.This was an observational, retrospective study of data obtained from 61 public hospitals in Sao Paulo.  The dataFor our study, the inclusion criteria were: Age >20 years and admission for HF or AMI as defined by the International Classification of Diseases (ICD-10) , in whicFor each diagnosis, the average number of hospitalizations per month was compared across the four seasons—both for all patients and within separate gender and ten-year age groups—using generalized linear models with Poisson distribution, identity link function and Bonferroni multiple comparisons. The boundaries of each season followed the meteorological definition for the South Hemisphere , i.e. wiDuring the study period, the National Registry of Public Health recorded a total of 4,823,761 hospital admissions. Using the inclusion criteria outlined above, we identified 76,474 hospitalizations for HF  and 54,561 hospitalizations for AMI . Monthly average temperature levels and the number of hospitalizations for HF and AMI per month are illustrated in Figs vs. 767 per month, p<0.001; and AMI: 678 vs. 586 per month, p<0.001). These findings were not affected by gender , found higher mortality in AMI patients during winter. In BanglTwo previous studies have examined the influence of winter on cardiovascular risk in Sao Paulo, Brazil. One study found an increase in mortality for AMI during winter but it relied exclusively on data for a single year (1997) . AnotherIn our study, we found an increase in hospitalizations for HF and AMI during the winter despite a moderate average winter temperature of 17.5°C, only 2.8 to 5.8°C lower than the other seasons. Besides the direct effects of low ambient temperatures on the cardiovascular system, environmental aspects linked to winter could help explain our findings. Sao Paulo winters are characterized by low humidity, limited rains and a higher frequency of thermal inversions, which occur when cold air gets trapped near the surface and underneath a layer of warmer air.  TogetherOn the socio-economic side, Sao Paulo is the economic engine of Brazil, with an estimated 11,253,503 inhabitants.  The cityOur study has several limitations. First, this was an observational study and despite statistical adjustments, a causal and definite relationship between seasonality and hospital admissions for HF and AMI cannot be determined. Second, we analyzed data maintained by the Brazilian Public Health System that accounts for 66% of hospital admissions in the country . Data peIn conclusion, in the megacity of Sao Paulo, winters were associated with an increased number of hospitalization for both HF and AMI. This relationship did not hinge on seasonal temperature oscillations. Our findings suggest that the prevention of cardiovascular disease decompensation should be emphasized during winter even in low to middle-income countries with modest temperature oscillations.S1 Dataset(XLS)Click here for additional data file.