Introduction: Several sports demand an early start into long-term athlete development (LTAD) because peak performances are achieved at a relatively young age . However, the challenging combination of high training volumes and academic demands may impede youth athletes' cognitive and academic performances. Thus, the aims of this study were to examine the effects of a 1-year sport-specific training and/or physical education on physical fitness, body composition, cognitive and academic performances in youth athletes and their non-athletic peers.Methods: Overall, 45 prepubertal fourth graders from a German elite sport school were enrolled in this study. Participating children were either youth athletes from an elite sports class  or age-matched peers from a regular class . Over the 1-year intervention period, the elite sports class conducted physical education and sport-specific training  during school time while the regular class attended physical education only. Of note, BMX is a specialized form of cycling that is performed on motocross tracks and affords high technical skills. Before and after intervention, tests were performed for the assessment of physical fitness , body composition , cognitive (d2-test) and academic performance . In addition, grades in German, English, Mathematics, and physical education were documented.Results: At baseline, youth athletes showed better physical fitness performances , less relative body fat mass, more relative skeletal muscle mass , and similar cognitive and academic achievements compared to their non-athletic peers. Athletes' training volume amounted to 620 min/week over the 1-year period while their peers performed 155 min/week. After the intervention, significant differences were found in 6 out of 7 physical fitness tests  and in the physical education grades  in favor of the elite sports class. No significant between-group differences were found after the intervention in measures of body composition , cognition and academics . Our findings revealed no significant between-group differences in growth rate (deltas of pre-post-changes in body height and leg length).Discussion: Our results revealed that a school-based 1-year sport-specific training in combination with physical education improved physical fitness but did not negatively affect cognitive and academic performances of youth athletes compared to their non-athletic peers. It is concluded that sport-specific training in combination with physical education promotes youth athletes' physical fitness development during LTAD and does not impede their cognitive and academic development. The long-term athlete development (LTAD) is a planned, structured and progressive development of youth's athleticism to achieve elite sport success and to engage in lifelong, health-enhancing physical activity  sport-specific training and/or physical education on physical fitness, body composition, cognitive and academic performances in a sample of 9–10 year old athletes from sports with relatively young peak performance age compared to age-matched peers. Based on the relevant literature . Four youth athletes of ESC were gymnasts , three trampoline jumpers , three swimmers , four track and field athletes , one BMX cyclist , and five soccer players . In order to cope with athletic and academic demands, a specific training schedule was developed for ESC. Training included three PE lessons per week (Tuesday to Thursday from 7:00 a.m. to 9:30 a.m.) administered in the form of sport-specific training in addition to after-school sport-specific training.RC included 25 students aged 9.6 ± 0.6 years who performed four regular PE lessons per week that followed the regular PE curriculum of the state of Brandenburg, Germany . Baseline characteristics of the participating students are presented in Table To assess the effects of sport-specific training and/or physical education on physical fitness, body composition, cognitive and academic performances in youth athletes and their non-athletic peers, a controlled study design with repeated measures  was applied. Pre tests were conducted in January 2014 while our participants attended grade four and post-tests were performed after the 1-year intervention period in January 2015 (grade five). Pre and post-tests of physical fitness and body composition were realized in the local school gym and they were scheduled for the same time of the day . In order not to confound bioimpedance data, subjects were kindly asked to appear in a fasted state on the test day. After the bioimpedance analysis was completed, a rest of 60 min was granted so that subjects were able to have a small breakfast. Physical fitness testing started after the break. Cognitive and academic performance testing was realized at the same daytime on the following day.Health and skill-related components of physical fitness were tested using seven single tests from different motor fitness test batteries  of 0.73  for the assessment of upper-extremity muscle power  in 6- to 10-year-olds  for the assessment of flexibility  to analyze balance . Biological maturity was estimated by means of assessing years from peak-height-velocity (PHV) derived from sitting and standing body height, body mass, and age , relative skeletal muscle mass (%), and relative body fat mass (%). Of note, Tompuri et al.  was applied to assess students' body composition. According to published BIA guidelines . The test developer provided age-specific reference values for all tests. In addition, grades in German, Mathematics, English, and PE were documented and used for further analysis .The ELFE 1–6 test was used to evaluate reading performance  was used for further data analysis. The ELFE 1–6 proved to be reliable with an ICC of 0.91 in primary school children.  to analyze selective attention and concentration in 9–60 year olds , training volume , main training content of each session , and number of participating students   for interval scaled data or the non-parametric Quade test was applied with baseline data entered as covariate. In addition, in a within- and between-subject approach, pre-post-changes in body height and leg length were computed for each participant. Using an independent sample t-test, between-group differences from deltas in body height and leg length were calculated to examine whether growth speed/rate differently affected the two experimental groups over the course of the intervention period. Our findings revealed no significant.Normal distribution of data was examined using the Shapiro-Wilk test. If normal distribution was confirmed, descriptive data were presented as group means and standard deviations (SD) otherwise as median and interquartile range. Between-group baseline differences were assessed using either independent sample p < 0.05. Effect sizes were calculated by converting partial eta-squared to Cohen's d , medium (0.50 ≤ d ≤ 0.79), and large (d ≥ 0.80)  Cohen, . The SPSn = 20 ESC, n = 25 RC). None of the participating students reported any test- or training-related injuries over the 12 months intervention period. No significant baseline differences were found between classes in terms of age, sex, Tanner stages, and time to PHV . More specifically, participants in the ESC were shorter (3%), lighter (31%), had a lower BMI (22%), more relative skeletal muscle mass (6%), and less relative body fat mass (14%) . No between-group baseline differences were found for the 1-kg ball push and the single-leg stance test. After the intervention period significant between-group differences were observed in six out of seven test items  in favor of the ESC (Table p > 0.05). No statistically significant between-group differences were detected for deltas in body height (p = 0.945) and leg length (p = 0.498).Table p > 0.05). In addition, post-intervention, no significant between-group differences were found for grades in German, Mathematics, and English (p > 0.05). The PE grade was significantly better in the ESC compared to the RC at post-test . Even though our analyses revealed no significant between-group differences post-intervention in measures of cognitive and academic performances, ESC showed higher scores in all cognitive and academic measures   compared to the RC over the 1-year intervention period. Further, the total duration of sport-specific training sessions and PE lessons per week was significantly larger in ESC compared to RC  over the 1-year training period. The average weekly duration of ESC sport-specific training and physical education is illustrated in Figure p < 0.05, d = 1.39). Students of both classes showed high adherence rates in PE lessons and sport-specific training with no significant between-group differences .Training and PE data for the ESC and the RC are presented in Table This is the first study to evaluate the effects of long-term sport-specific training and/or physical education on physical fitness, body composition, cognitive and academic performances in youth athletes and their age-matched peers. The main findings of this study were: (i) at baseline, ESC compared to RC showed better performances in physical fitness, less relative body fat mass and more relative skeletal muscle mass but no significant differences in cognitive or academic performances; (ii) mean training volume and intensity over the 1-year intervention period were significantly higher in the ESC compared to the RC; (iii) high sport-specific training and physical education volumes proved to be feasible and safe (no training-related injuries) with high adherence rates (96%) in the ESC; (iv) better performance levels in physical fitness were maintained or even enlarged in the ESC compared to the RC over the course of the 12 months intervention period; (v) high volume sport-specific training and physical education did not have any negative effects on cognitive or academic development in the ESC compared to the RC. Given that we controlled for potential between-group differences at baseline and that we did not detect any significant between-group difference in deltas of body height and leg length, it appears legitimate to ascribe the observed effects to sport-specific training and/or physical education and not to growth speed/rate.www.emotikon-grundschulsport.de). Each year, between 14,000 and 16,000 children (3rd graders) are tested for their physical fitness in Brandenburg's primary schools , and percentage of body fat. The authors concluded that soccer training resulted in additional behavioral and physiological adaptations which are beyond growth and maturation. Further, Golle et al.  after having participated in regular PE and additional sport-specific training compared to RC. These findings are supported by recently published articles  for cross-sectional studies and an effect size of 0.35  for longitudinal studies  and considers individual maturation level rather than chronological age . After the 1-year sport-specific training in combination with physical education, performances in physical fitness were maintained or even increased in the ESC compared to the RC while there were no negative effects of ESC's high training volumes on cognitive and/or academic performances. Thus, it is concluded that sport-specific training in combination with regular school demands promotes physical fitness development and does not impede youth athletes' cognitive and academic performances. The results of the present study represents an example of a sport-specific training program that can be implemented at a relatively young age in schools and sports with early peak performances during the stages of LTAD. Our findings are crucial for parents and policy makers responsible for the well-being of their children. It has to be noted though that more longitudinal studies (>2 years) are needed to achieve in-depths knowledge on the development of youth athletes physical fitness and cognitive/academic performances during the stages of LTAD.This study was carried out in accordance with the recommendations of the ethical committee, University of Potsdam, Germany. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the local ethical committee of the University of Potsdam, Germany.UG was involved in the design of the study, data collection and analysis, statistical computation, and the writing of the manuscript. RB was involved in the design of the study, implementation of the intervention, data collection and analysis, statistical computation, and the writing of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Relations between impulsigenic traits and alcohol-related outcomes have been the focus of much research, yet precise relations remain elusive. Historically, research used broadband conceptualizations of impulsivity, which yielded inconclusive findings. Attempts to ameliorate this problem led to more work on narrowband assessments of impulsivity. Despite that several narrowband self-report measures exist, few demonstrate adequate psychometric properties. Given the limits of self-report, researchers have also utilized laboratory-based measures of impulsive dispositions; however, this seems to have contributed more uncertainty to the literature.We review commonly used self-report and laboratory-based measures of narrowband impulsivity, as well as assessments of alcohol-related constructs . We discuss remaining issues in impulsivity and alcohol assessment, which limit understanding of how impulsigenic traits influence alcohol-related behaviors. Cutting-edge conceptualizations and assessment of state-level impulsivity are also discussed.More work is necessary to further this area of research, including establishing consistent nomenclature and a cohesive conceptualization of impulsigenic traits as they relate to alcohol use and alcohol use disorders. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), including borderline personality disorder and attention-deficit/hyperactivity disorder  r = .17; hypothetical delay discounting r = .09), except for the Iowa Gambling Task  and the Stroop Color-Word Test  [r = .73) [Typically, effect sizes for relations between laboratory tasks of impulsigenic traits and alcohol outcomes are small. In a recent meta-analysis, weighted relations of laboratory tasks and self-reported alcohol use, broadly, were small-to-medium (Go/No Go Task r = .41) . Age at r = .41) . Howeverr = .41)  used ther = .41) ), and for = .41)  examinedr = .41) . Delay dr = .73) . Combinir = .73)  used a mAlcohol challenge studies are another approach to examine the impulsivity-alcohol relation. In these studies, experimentally controlled alcohol use is typically treated as the independent variable to determine its influence on behavioral task performance. These studies eliminate some limitations inherent to self-report methods and may yield more causal inferences.For example, in some alcohol administration studies, individuals who consumed alcohol tended to discount smaller, more immediate hypothetical rewards at lower rates than sober individuals . This isAlthough notable methodological advances have been made in the area of impulsivity and alcohol research , much work is needed to elucidate relations between impulsive dispositions and alcohol-related outcomes. Research aiming to establish a conceptual model of impulsivity that integrates self-report and laboratory-based constructs is worthy of attention, as this would advance the field by increasing interpretability of findings and facilitating comparability across studies. The studies reviewed represent a necessary and important first step in this process. We now provide some notable limitations, as well as potential solutions and associated future directions we hope will advance the understanding of the impulsive disposition-alcohol relation.One concern is the possibility that self-report and laboratory-based tasks are conceptually distinct constructs. More specifically, it is arguable that laboratory tasks are a measure of “ability” as opposed to a “response style,” and modest correlations are typical for ability vs. response style measures . If thiIs impulsivity related to psychopathology and how?” (p. 2). Plainly stated, we caution the reader from using the term “impulsivity.”We agree with Cyders , who asswhen an impulsive behavior occurs  is equally (or perhaps more) clinically relevant than if a person has the proclivity for impulsive behavior . Assessment of state-level impulsivity is a burgeoning area of research, and future directions including examination of the MIS factor structure , convergent and discriminant validity using laboratory-based tasks , as well as investigating its criterion validity .Further, distinguishing between state- and trait-level impulsivity is an important consideration when examining alcohol use and related problems, as it is arguable that One obstacle we continue to face as we attempt to bridge the gap between self-report and laboratory-based findings is the confounding impact of method variance. Indeed, previous attempts to examine self-report and laboratory-based impulsivity measures simultaneously resulted in method components, aptly named by Meda et al. . CurrentFurther, we believe some considerations may be useful for future research utilizing existing measures. For example, when using the UPPS-P, items should be modeled as ordinal, as a 4-point Likert-type response scale for individual items does not reflect a continuous variable. Additionally, although work examining latent structures of impulsive traits use advanced methods and multimethod approaches, exploratory factor analyses (EFAs) are conducted using suboptimal methods , or areIn line with current trends in impulsivity assessment, incorporating EMA designs when assessing alcohol use and associated variables  will also serve to further research on the impulsive trait-alcohol link (see Trull & Ebner-Priemer ). To utiAlthough multiple associations have been identified between various types of impulsive dispositions and alcohol-related outcomes, advancements in conceptualization, assessment, and methodology are necessary before a clearer understanding of these relations can be obtained. Research efforts have made great strides toward examining these complex relations, though much more is needed to discern the role of impulsigenic traits on alcohol use and related outcomes to better inform prevention and treatment of alcohol use problems and disorders. Nevertheless, with advances in statistical analytic procedures, this is a particularly exciting area of study, as researchers may now be able to better understand within-person relations of impulsivity and problematic alcohol use (see Lievens  for a re


Early research indicates its beneficial effects on acute physical performance, such as increased maximum oxygen consumption and higher power output. Later studies point to the positive impact of dietary supplementation with l-carnitine on the recovery process after exercise. It is demonstrated that l-carnitine alleviates muscle injury and reduces markers of cellular damage and free radical formation accompanied by attenuation of muscle soreness. The supplementation-based increase in serum and muscle l-carnitine contents is suggested to enhance blood flow and oxygen supply to the muscle tissue via improved endothelial function thereby reducing hypoxia-induced cellular and biochemical disruptions. Studies in older adults further showed that l-carnitine intake can lead to increased muscle mass accompanied by a decrease in body weight and reduced physical and mental fatigue. Based on current animal studies, a role of l-carnitine in the prevention of age-associated muscle protein degradation and regulation of mitochondrial homeostasis is suggested.Given its pivotal role in fatty acid oxidation and energy metabolism,  After the discovery of l-carnitine in muscle extracts in 1905 [l-carnitine in fatty acid oxidation in the liver and the heart was first described by Fritz in 1959 [l-carnitine to acetyl groups via carnitine acyltransferase is essential for the shuttle of the acetylated fatty acids into the mitochondria and for their subsequent β-oxidation in the matrix  regulate tissue distribution and intracellular homeostasis of l-carnitine and function both on its intestinal absorption and renal reabsorption. Hereditary or acquired defects in the transport mechanisms are the major cause of l-carnitine deficiency, leading to pathologies such as cardiomyopathy and skeletal muscle myopathy [thionine ,6 or ingthionine  and requofactors . Biosyntly needs ,9. Thus,e plasma . It is ee plasma . Therefomyopathy ,13.l-carnitine is highly variable. The primary source is red meat, providing up to 140–190 mg l-carnitine per 100 g uncooked meat  [l-carnitine. As a consequence, vegetarians obtain very little l-carnitine from dietary sources. However, the benefit of l-carnitine supplementation in this population is still controversial as they possess comparable bioavailability for l-carnitine to the general population [l-carnitine deficit among vegetarians is modest [l-carnitine stores in plasma as compared to omnivores, 12-weeks supplementation with l-carnitine increased both plasma and muscle carnitine, though muscle function and energy metabolism remained unaffected [l-carnitine [l-carnitine deficiency and reduce the loss by urinary excretion. Such possible adaptation has been reported in vegetarians [It is estimated that, in omnivorous humans, 75% of the body’s carnitine pool is derived from dietary intake . Howeverpulation . Indeed,s modest . With smaffected . It is parnitine , and/or arnitine  take plaetarians .l-carnitine from dietary sources was estimated to be 54–86% [l-carnitine ingested can be metabolized by microbial species in the gut. It was demonstrated in animal studies that unabsorbed quaternary amines such as choline, phosphatidylcholine, betaine or l-carnitine can be metabolized by gut microorganisms to produce the intermediate compound trimethylamine (TMA). TMA is subsequently absorbed by the gut and oxidized by flavin-monooxygenases (FMOs) in the liver to produce trimethylamine-N-oxide (TMAO) [l-carnitine is an aerobic process, suggesting that l-carnitine is an inefficient source of TMA production. Similar process can take place in the gut [While the bioavailability of e 54–86% , absorpte 54–86% ,19. Parte (TMAO) . However the gut .l-carnitine supplementation is proposed to play crucial roles in diseased populations where it has been shown to impact the management of ischaemic heart disease, myopathy, and peripheral arterial disease [Because of its accumulation in the muscle and the heart, its ergogenic nature, and its role in energy metabolism,  disease ,23,24, a disease ,26,27,28l-carnitine plays in muscle physiology with a focus on the recovery after exercise among athletes, describe some of the trials, and the potential mechanisms involved. Based on this learning and the proposed role of l-carnitine in muscle structure and function, the role of l-carnitine in muscle health during aging is also discussed.This comprehensive review aims to summarize the role l-carnitine was given in combination with other products (multi-ingredient supplements) or the outcome was not related to post exercise recovery. Further publications written in languages other than English, German or French were excluded. Additional clinical trials were identified by carefully reading the publication list of the identified articles.The literature search was done in the database “PubMed”. As a basic search string “carnitine AND exercise AND recovery” combined with the filter for human clinical trials was used. Based on the titles and abstracts, the relevance of the publications was judged. Excluded were trials were l-carnitine levels, particularly in the plasma and the muscle, and enhanced exercise capacity have been reported in many trials  compared to placebo [l-carnitine as a result of exercise only. These levels were reversed by l-carnitine supplementation [l-carnitine given twice daily for a period of 3 months did not alter l-carnitine muscle levels [l-carnitine depletion in the muscle [l-carnitine for two weeks led to an improvement in glucose and ammonia plasma levels, as well as lowering in heart rate without affecting the fat and carbohydrate metabolisms [The link between y trials . With th placebo . Enduranentation . In a die levels . Howevere muscle . In two abolisms ,32. It il-carnitine with or without protein during training, have been reported to enhance exercise capacity and endurance [l-carnitine to footballers before increasing speed run led to increased speed at corresponding lactate plasma levels, and decreased heart rate, suggesting a prolonged exhaustion exercise [l-carnitine enhances high-intensity exercise by maintaining the acetyl CoA/CoA ratio constant, thereby allowing continuous flux through the pyruvate dehydrogenase complex and preventing lactate accumulation [l-carnitine content explaining possibly the lack of benefit [l-carnitine supplementation in particular. It has been reported that muscle l-carnitine content increased following l-carnitine long-term oral administration [l-carnitine bioavailability does not always mirror its levels in the muscle, the driver for performance. In combination with certain mineral complexes, l-carnitine has been shown to improve aerobic exercise performance in 18–30 years old women [Other studies looked at the effect of supplementation on aerobic capacity, fat oxidation, maximum oxygen uptake, and physical performance ,36,37,38ndurance ,34. Orermulation ,41,42,43stration ,44,45 whstration . In addild women .l-carnitine has been suggested to spare muscle glycogen and promote fat oxidation during exercise, and a proposed conversion of fat into energy seems likely to be reflected by a reduction in body weight [l-carnitine supplementation has been shown to spare amino acid usage as a source of energy making them available potentially for new protein synthesis [l-carnitine experienced less protein degradation as a result of exercise [During low to moderate exercise, long chain fatty acids represent the main source of energy. y weight ,49,50. Iynthesis . It was exercise . These eexercise ,53.l-carnitine has been described to help with recovery after exercise through different mechanisms. In a pilot trial, Maggini et al. addressed whether power output during a recovery period following strenuous workout can be raised by l-carnitine intake [l-carnitine daily over a period of 5 days, there was a significant increase in power output after initial strenuous exercise. In contrast, single administration of l-carnitine before exhaustive cycling exercise did not improve performance during a second round of exercise after 3 h [Exercise-induced muscle damage and pain can both decrease quality of life and limit further training activity. In addition to its effects on exercise performance, e intake . In 9 oufter 3 h .l-carnitine alleviated pain, tenderness and release of creatine kinase—a marker of muscle injury-indicating that the nutrient was effective in reducing tissue disruption and subsequent leakage of cytosolic proteins [l-carnitine on reducing exercise-induced hypoxia, subsequent muscle damage, and delayed onset muscle soreness (DOMS) was further substantiated [l-carnitine compared to placebo [l-carnitine were compared with respect to an influence on these metabolic markers and subjectively perceived muscle soreness [l-carnitine [l-carnitine l-tartrate, equivalent to 2 g l-carnitine daily, over a period of 3 weeks increases the level of androgen receptors on muscle cells, thereby improving protein signaling, needed for recovery after exercise [In a cross-over study, Giamberardino et al. showed that supplementation with proteins . In a seantiated ,58,61,62 placebo ,61. In aexercise .l-carnitine on endothelial function and nitric oxide release have been demonstrated in animal studies and human clinical trials [The effects of l trials ,67,68,69l-carnitine reduced structural and biochemical muscle damage and facilitated tissue repair by protecting against carnitine deficiency in the endothelial cells, thereby ameliorating blood flow and oxygen supply [l-carnitine and in the absence of increased muscle l-carnitine content [l-carnitine prolonged the ability of endothelial cells to regulate blood flow during ischemia [l-carnitine accretion and energy production. The authors hypothesized that improved force was due to an effect on the vasculature surrounding of the muscle [l-carnitine, plasma carnitine levels remained elevated after maximal exercise compared to a significant decrease in athletes without supplementation [l-carnitine on endothelial cell function in a cross-over study. After 3 weeks of l-carnitine supplementation, post-prandial brachial artery FMD in response to 5 min upper arm occlusion increased, whereas in the placebo arm, peak FMD decreased [l-carnitine has a beneficial impact on vascular function through endothelial function modulation.Kraemer and colleagues developed a new hypothesis, suggesting that supplementation with n supply . The newn supply ,69. Here content . In addie muscle . It was entation . By inveecreased . These rl-carnitine supplementation during exercise recovery is its effect in mitigating oxidative stress during exercise. Muscle damage especially during eccentric exercise (active force generating lengthening contractions) is caused by immediate cellular and structural injury and subsequent biochemical responses during tissue repair [One of the potential mechanisms involved in the role of e repair ,71. Altee repair . It is ae repair . Molecule repair .l-carnitine upon exercise-induced oxidative stress were also reported by Parandak et al. [l-carnitine over 14 days significantly increased total antioxidant capacity compared to placebo before and 24 h post-exercise, whereas markers of muscle damage and lipid peroxidation remained significantly lower in comparison to placebo [l-carnitine improved the total antioxidant status, which was otherwise observed in basketball players in the absence of supplementation [The antioxidant effects of k et al. . Daily s placebo . Furtherentation .l-carnitine supplementation.While the vast majority of these studies were performed in young, healthy subjects, Ho and colleagues first provided experimental evidence for a favorable impact on recovery following exercise in middle-aged healthy men, with a mean age of 45 years, and women, aged 52 year average . Again, l-carnitine research and use. While clinical research indicated that the healthy young to middle-aged population can benefit from l-carnitine intake under physically challenging situations, effects of l-carnitine are still unknown in elderly suffering from physically fatigued conditions. The age-associated decline in skeletal muscle mass, strength, and overall activity, termed sarcopenia, is a multifactorial age-related condition. Factors such as decreased mobility, nutritional status, and mitochondrial function decline are all contributors to sarcopenia [Caenorhabditis elegans suggested specific aggregation proteins that contribute to the age-associated loss of muscle mass [The aging may provide the future direction for the rcopenia . Alteratrcopenia . While icle mass . Anothercle mass . In addicle mass .Sarcopenia is influenced by factors such as diet and physical activity . A synerl-carnitine can positively affect muscle mass and revert the age-dependent decrease in muscle functioning. Muscle l-carnitine content has been shown to decline with age in healthy people [l-carnitine transporter, indicating that tissue distribution and homeostasis of l-carnitine is hampered with advanced age. Consequently, a number of studies investigated the role of l-carnitine in the process of aging.Growing evidence suggests that y people . Furthery people , the l-cl-carnitine/day or placebo over a period of 6 months and investigated the effects on physical and mental fatigue. Compared with the placebo group, supplementation resulted in improved muscle mass, reduced total fat mass, and improved walking capacity, suggesting a beneficial effect in this population [l-carnitine, the acetylated derivative of l-carnitine, also decreased physical and mental fatigue in subjects 70 year old [l-carnitine per day [l-carnitine, creatine, and leucine favorably affects muscle mass and performance [l-carnitine supplementation alone did not show a significant improvement in the composite parameter compared to placebo, yet, subjects maintained both the composite score and their leg muscle strength compared to baseline, whereas, in the placebo group, both declined during the course of the study [Malaguarnera et al. performed a clinical study with centenarians who received 2 g of pulation . These fpulation . Supplemyear old . In a do per day . A recenformance . In thishe study .l-carnitine [l-carnitine compared with the control groups. The studies that were included in the meta-analysis were mostly performed in obese and/or diabetic subjects [Although, in the younger population, a number of studies could not show weight loss after intake of arnitine , in a resubjects .l-carnitine in promoting muscle mass and function in older people are still unknown, some of the general mechanisms of action of l-carnitine effects shown in animal studies and younger athletes can apply. By converting fat into energy, supplemental l-carnitine allowed for sparing of amino acids thereby leading to protein accretion in the muscle of swine [l-carnitine in the transcriptional regulation of genes involved in the ubiquitin proteasome system of the skeletal muscle of piglets, indicating a potential mechanism by which l-carnitine prevents muscle protein degradation [l-carnitine was reported to increase IGF-1 and Akt, thereby inducing the mammalian target of rapamycin (mTOR) signaling pathway, which is a key modulator of protein anabolism [Although the mechanisms underlying the effects of of swine . Keller radation . In addinabolism .l-carnitine have been indicated by several clinical studies [l-carnitine may impede the biochemical mechanisms underlying tissue aging.As postulated by the free radical theory of aging, peroxidative damage promotes the process of aging . Antioxi studies ,74,94, sl-carnitine on mitochondria homeostasis in the brains of old rats [Another hallmark of aging is accelerated neuronal cell injury and death leading to brain shrinkage and a decline in the brain function. It was suggested that mitochondrial decay may be the predominant underlying event . Recentlold rats .l-carnitine in diverse indications has been matter of scientific investigations. l-carnitine has been used as an ergogenic aid for professional athletes and as a dietary supplement in the physically active population. An abundance of human studies performed in healthy active subjects, resistance-trained athletes, or untrained men and women examined the effect of the nutritional supplement on physical performance, oxygen capacity, or muscle strength. More recently, clinical research shifted to evaluating the hypothesis that l-carnitine intake facilitates the recovery process after exercise. Scientific data indicates that the athletic population can benefit from l-carnitine intake as it attenuates the side effects of high-intensity training by reducing the magnitude of exercise-induced hypoxia and muscle injury. As a key player in fatty acid metabolism and energy production, the role of l-carnitine availability is not a limiting factor in fatty acid β-oxidation. Its homeostasis is highly regulated by bioavailability, transport, and urinary excretion. Yet, under conditions with aberrations, such as inborn or acquired carnitine deficiency, hemodialysis, or in sarcopenic and frail subjects, supplementation with l-carnitine has been shown to increase physical performance and muscle mass and function. The age-related muscle decline can be reversed by both physical activity and nutritional means. While endurance exercise can be arduous in elderly, nutritional supplementation in conjunction with moderate exercise may be a potential strategy to slow down sarcopenia, as one hallmark of frailty, in older adults.Under healthy conditions and in the absence of stress, l-carnitine exerts its beneficial action on increased protein synthesis and reduced muscle degradation. In addition, regulation of mitochondrial homeostasis by l-carnitine during aging is postulated to impact the age-related declines. Thus, dietary supplementation with l-carnitine may contribute to help during the aging process by impeding the progression of muscle mass and function decline as well as neurodegeneration. Further research in warranted in this area.A growing number of animal studies provided evidence for the multifaceted mechanisms, by which l-carnitine supplementation is particularly beneficial to the healthy young active population. Moreover, elderly experiencing lean muscle mass and function decline, reduced muscle l-carnitine content and mitochondrial dysfunction can also benefit from the positive impact of supplementation with l-carnitine. In particular, with a growing number of older subjects engaged in moderate exercise, the role of l-carnitine in this demographic will continue to gain importance. In conclusion, given the impact of the structural and symptomatic consequences of high-intensity exercise, i.e., impairment of muscle sarcomeres and pain, which do not only reduce quality of life but diminish further training capacities, facilitation of recovery from exercise by


N-methyl-d-aspartate receptor (NMDAR) encephalitis is rarely reported. Here, we report a case of an urgent, successful management of severe orofacial dyskinesia in an 8-year-old girl with anti-NMDAR encephalitis using BoNT-A injection. The patient presented with de novo unilateral paroxysmal movement disorder progressing to generalized dystonia and repetitive orofacial dyskinesia. Diagnosis was confirmed by the presence of NMDAR antibodies in serum and cerebrospinal fluid. The orofacial dyskinesia worsened despite the aggressive use of first-line immunotherapy and second-line immunotherapy (rituximab), and resulted in a potentially fatal self-inflicted oral injury. We urgently attempted symptomatic management using BoNT-A injections in the masseter, and induced muscle paralysis using vecuronium. The patient’s severe orofacial dyskinesia was controlled. We observed the effects of the BoNT-A injections and a tapering off of the effects of vecuronium 10 days after the treatment. The movement disorder had improved significantly 4 weeks after the first administration of rituximab. The injection of BoNT-A into the masseter may be an effective treatment for medically refractory orofacial dyskinesia in pediatric patients with anti-NMDAR encephalitis. We propose that the use of BoNT-A injections should be considered early to avoid self-inflicted oral injury due to severe refractory orofacial dyskinesia in patients with anti-NMDAR encephalitis.The use of botulinum neurotoxin serotype A (BoNT-A) injections for the treatment of orofacial dyskinesia secondary to anti- N-methyl-d-aspartate receptor (NMDAR) encephalitis is caused by autoimmune mechanisms associated with anti-NMDAR antibodies. This condition may appear in patients of all ages with or without tumors  (Anti-eratoma) –3. Most eratoma) . Movemeneratoma) .Data regarding the symptomatic treatment of movement disorders secondary to anti-NMDAR encephalitis before the action of immunotherapy are limited –10. To tAn 8-year-old Chinese girl without any previous medical history presented with a new-onset paroxysmal movement disorder one month prior to hospitalization. The patient’s paroxysms, which comprised brief unilateral dystonic posturing of the left limb that lasted for minutes, had appeared after she was scolded by her parents. Routine video-electroencephalography (V-EEG) performed 1 week after the clinical onset (day 7) revealed no abnormal findings. On day 20, the patient presented with episodes of dystonia comprising wry neck and an irregular dystonic tremor in the limbs bilaterally, which was more prominent on the left side. Mild cognitive and memory deficits were also observed. 4 days prior to hospitalization, the patient’s mother had decided to seek medical assistance at our department, as the patient had developed insomnia and showed agitation, with occasional slurred speech.−1) with normal protein and glucose levels. The immunological analysis revealed the presence of anti-NMDAR immunoglobulin G antibodies in the blood (titer: 1:32) and cerebrospinal fluid (titer: 1:10). Brain magnetic resonance imaging revealed no remarkable abnormalities. Serologic tests and polymerase chain reaction analysis of cerebrospinal fluid were performed for the detection of viruses, including the herpes simplex virus; however, no viral infection was detected. The results of tumor screening using thoracoabdominal computed tomography, pelvis magnetic resonance imaging, and assessment of serum tumor markers were negative.On day 30 (the day of admission), a 2-h V-EEG revealed diffuse background slowing, which was more severe in the right hemisphere, and involuntary movements without paroxysmal activity or epileptiform discharges. This ruled out the possibility that the movements were associated with an epileptic pathophysiology. Cerebrospinal fluid analysis revealed pleocytosis  and methylprednisolone  on day 32. During the next few days, the patient developed coma and episodes of opisthotonus, chorea, limb myorhythmia, and orofacial stereotypy. We attempted to treat the patient using several oral anti-dystonia drugs, including clonazepam, baclofen, benzhexol hydrochloride, risperidone, and valproate, but they had minimal effects on her dyskinesia. Because there was no adequate response during the 10 days following treatment with first-line immunotherapy, we began treatment with intravenous rituximab (375 mg m−2 weekly for 6 weeks) on day 39. During this time, the patient developed self-inflicted oral injuries due to forceful stereotypic movements of the jaw and masticatory-like movements. The child frequently bit her tongue, lip, and buccal mucosa. After 2 days, she developed a high fever and neutrophilic leukocytosis in the blood . Burkholderia cepacia was cultured from the patient’s oral secretion and was successfully treated using antibiotics. The self-inflicted oral injury progressed gradually from minor bruising to deep lacerations requiring suture repair, obvious bleeding, and two broken incisors. In order to control the stereotypic movements of the jaw, we began treatment with BoNT-A  and continuous infusion of midazolam (up to 0.25 mg kg−1 h−1) for muscle relaxation on day 44. Respiratory depression was noted following midazolam administration. Additionally, the patient’s orofacial stereotypy had led to potentially fatal oral bleeding. We were thus forced to start mechanical ventilation and continuous infusion of vecuronium (0.07–0.08 mg kg−1 h−1), to control the patient’s injurious movements. This resulted in complete control of all movement disorders, allowing surgical debridement and suturing of the tongue and lip. On day 54 (10 days after injection of BoNT-A), the intensity and frequency of the orofacial stereotypy was obviously reduced in a therapeutic window of a few hours after withholding the intravenous vecuronium drip, but opisthotonus, chorea, and limb myorhythmia had still not improved. Vecuronium administration was tapered following this observation and was discontinued after 12 h. On day 58 (3 weeks after the first administration of rituximab), with the tapering of vecuronium and midazolam, hypoventilation was markedly improved and artificial ventilation was discontinued. On day 67 (4 weeks after the first administration of rituximab), B cells were effectively depleted, and the effect of immunotherapy appeared. Opisthotonus, chorea, limb myorhythmia, and consciousness disturbance improved gradually. However, the patient was unable to move her legs, had a left drop foot, and could not eat or sit unassisted. On day 100, she regained the ability to perform daily activities with minimal need for assistance with walking and was discharged  with anti-NMDAR encephalitis , and hav2 years wThe treatment of secondary movement disorders relies on the treatment of the underlying pathologic process. Patients with anti-NMDAR encephalitis usually respond to immunotherapy  and tumor removal. Second-line immunotherapy (rituximab and/or cyclophosphamide) has been shown to significantly improve outcomes in patients who do not respond to first-line therapy and to decrease the frequency of relapses , 3. ChilIn a retrospective series conducted in pediatric patients by Mohammad et al. , 85% of Almost invariably, dyskinesia secondary to anti-NMDAR encephalitis requires control using relaxation or deep sedation with a combination of drugs . In the Life-threatening movement disorders often require prompt, complex, and aggressive interventions. Stronger sedation and muscle paralysis are most likely to achieve prompt resolution of movement disorders , 17, 19.N-ethylmaleimide-sensitive factor attachment protein receptor complex. Binding to the complex enables the light chain of BoNT-A to cleave synaptosomal-associated proteins of 25 kDa, which mediate the docking and fusion of neurotransmitter-containing vesicles to the presynaptic membrane  in conjunction with drug therapy , 22. Aftmembrane , 24. Clemembrane . Moreovemembrane , 22. Themembrane , 22. TheOrofacial dyskinesia, which was the major concern for the patient in this study, was so severe that continuous infusion of a neuromuscular blocker was required to control self-harming activities, which were not predictable at the early stages of the disease. The injection of BoNT-A into the masseter successfully controlled the orofacial dyskinesia in our patient. Nevertheless, the suitable time to begin BoNT-A therapy for avoiding severe self-inflicted oral injury, and the need for more aggressive interventions, in patients with anti-NMDAR encephalitis is as yet unclear. Further studies are required to identify the early warning signs for severe orofacial dyskinesia in patients with anti-NMDAR encephalitis, and the appropriate timing for the initiation of BoNT-A therapy.Orofacial dyskinesia secondary to anti-NMDAR encephalitis may result in severe self-inflicted oral injury. However, BoNT-A therapy may be used to successfully control refractory orofacial dyskinesia in patients with anti-NMDAR encephalitis, while waiting for immunotherapy to aid in recovery. Therefore, to avoid severe self-inflicted oral injury, early aggressive injection of BoNT-A into the masseter should be considered as a treatment option for medically refractory orofacial dyskinesia in patients with anti-NMDAR encephalitis. Further studies on the early warning signs of severe orofacial dyskinesia in patients with anti-NMDAR encephalitis, and the appropriate timing for the initiation of BoNT-A therapy, are warranted.Written informed consent was obtained from the patient’s mother, in accordance with the Declaration of Helsinki, for the publication of this case report.Ethical approval was not required for this study, as per the national guidelines.FZ, XS, XY, and ZL treated the patient; FZ and ZL contributed to the conception of the study; FZ drafted the initial manuscript; ZL critically reviewed the manuscript; and NP reviewed and revised the manuscript. All authors have read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


It is challenging to predict the outcome of patients with hepatitis B virus related acute-on-chronic liver failure (HBV-ACLF) through existing prognostic models. Our aim was to establish a novel dynamic model to improve the predictive efficiency of 30-day mortality in HBV-ACLF patients.305 patients who were diagnosed as HBV-ACLF  were included in this study. The HBV-ACLF dynamic (HBV-ACLFD) model was constructed based on the daily levels of predictive variables in 7 days after diagnosis combined with baseline risk factors by multivariate logistic regression analysis. The HBV-ACLFD model was compared with the Child-Turcotte-Pugh (CTP) score, end-stage liver disease (MELD) score, and MELD within corporation of serum sodium (MELD-Na) score by the area under the receiver-operating characteristic curves (AUROC).The HBV-ACLFD model demonstrated excellent discrimination with AUROC of 0.848 in the derivation cohort and of 0.813 in the validation cohort (p=0.620). The performance of the HBV-ACLFD model appeared to be superior to MELD score, MELD-Na score and CTP score (P<0.0001).The HBV-ACLFD model can accurately predict 30-day mortality in patients with HBV-ACLF, which is helpful to select appropriate clinical procedures, so as to relieve the social and economic burden. Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome with varied etiology and manifestations with a short-term mortality of 50–90% . ACLF isVaried prognostic scoring systems have been developed to predict ACLF mortality and guide the decision-making of LT. The Child-Pugh-Turcotte (CPT) classification and the model of end-stage liver disease (MELD) score are the most commonly used for patient priority on the waiting list of LT –9. MELD However, each of the models above cannot apply reasonably to evaluate the clinical outcome in hepatitis B virus related acute-on-chronic liver failure (HBV-ACLF), mainly due to differences in patient background queues. There exist great differences between Eastern and Western ACLF in definition and diagnostic criteria, involving the basis of chronic liver disease, the concept of organ failure and the diagnostic criteria for organ failure –13. FurtOur aim was to establish a prognostic model according to early changes of independent predictive variables at admission in patients with HBV-ACLF; to identify whether the model was superior to the existing prognostic models such as CPT scores, MELD scores, and MELD-Na scores; and ultimately to validate the model by a cohort of 94 patients with HBV-ACLF from three different geographical spread medical centers, so as to confirm the potential value of model for clinical treatment decision making.305 patients who were diagnosed as HBV-ACLF  were included in this study. The comparisons of patients’ characteristics in the derivation and validation cohorts were shown in Table 30-day mortality was applied as the end-point in the multivariate logistic regression analysis, and all variables in univariate analyses were imported into the model. In this model, TBiL, albumin, HE, INR, blood neutrophils percentage count, and suspicion of infection were independent risk factors for death. The β-coefficient, OR and 95% CI for independent predictors were presented in Table The prognostic model derived from the derivation cohort Table . The iniThe HBV-ACLFD model retained a good discrimination when applied to a validation cohort  . On admiHBV-ACLF can cause irreversible liver failure, leading to severe liver function damage. If LT is not available, it may lead to an at least 70% mortality rate . TherefoA number of definitions of ACLF have been put forward, based on advice from experts rather than evidence-based data. The definitions of heterogeneity show the differences from the etiology of liver disease in Eastern and Western countries . In ChinThis study focuses on patients with HBV-ACLF from China. HBV-ACLF is one of the most lethal, costly, and pervasive diseases in China. Early predictors are essentially required to distinguish patients with ACLF who need orthotropic LT from those that can survive by only intensive medical care .et al [Currently, it remains difficult to identify appropriate indicators of poor outcome in HBV-ACLF . The estet al .HBV-ACLF is a dynamic process in which the variables at the time of hospitalization are predicted to vary over time, accompanied with the clinical processes and outcomes change accordingly. Meanwhile, prognosis predictions fluctuate over different clinical treatment. A study of acute liver failure (ALF) has shown that the model based on the early change of dynamic variables is better for the prediction than the model based on static baseline variables . The higOn admission, the AUROC for MELD, MELD-Na, and CTP scores were 0.6962, 0.6862, 0.5656, respectively, which is consistent with the results reported . HoweverWe also evaluated biochemical and clinical variables via multivariate logistic regression. HE, suspicion of infection, baseline and average daily changes of serum TBiL, INR, serum albumin and blood neutrophils percentage were independent prognostic factors for 30-day mortality. Meanwhile, on multivariate analysis, suspicion of infection is associated with mortality. The hazard ratio for mortality of patients with HBV-ACLF was 30.37 during the first 30-day. It is recommended that patients with high risk of complications and cirrhosis are highly suspected bacterial infection .The systemic inflammatory response syndrome (SIRS) occurs in patients with advanced cirrhosis and is correlated with poor prognosis . The defMoreover, the validation cohort data were collected from three different medical centers of geographic location in China, which means our model is validated in different regions of the population and in different areas of HBV-ACLF lesions. It also improves the accuracy and credibility of our HBV-ACLFD model, which is another principal strength of our model. Because this model is based on retrospective data on a great number of patients with HBV-ACLF from three different medical centers, it also means that homogeneous cohort managed with similar treatment regimens cannot be secured. It is indicated that this model has a broad spectrum of practicality.However, novel clinical strategies, including artificial liver support system and stem cell transplantation, apply to treat HBV-ACLF now. Our model cannot assess the effect of these novel clinical strategies for accurately predict outcome in patients with HBV-ACLF. Meanwhile, the comparison between the CLIF Consortium ACLF score (CLIF-C ACLFs) and the HBV-ACLFD model should be explored, despite the fact that the CLIF-C ACLFs is helpful to predicting short-term mortality in ACLF patients in Western countries –32, wherIn conclusion, we retrospectively deduced and validated the dynamic models of predictive outcomes in patients with HBV-ACLF. This model may be helpful in clinical decision making and risk stratification for patients with HBV-ACLF.All procedures and methods related to this research were accorded morally with current laws as well as the creeds of the Declaration of Helsinki. The research was permitted by the Ethical Committee of Beijing You-An Hospital, Capital Medical University.A total of 445 patients who were diagnosed as HBV-ACLF from January 2005 to February 2014 were included in this research. The minimum follow-up period for enrolled patients was 30-day after diagnosis. The diagnosis of cirrhosis was according to a composite of clinical signs and findings provided through laboratory test results, radiologic imaging, endoscopy and liver biopsy.The entry criteria comprised the following:HBV-ACLF is defined as ACLF with previously diagnosed or undiagnosed HBV. All enrolled patients met the criteria for ACLF from the consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL) . All treThe exclusion criteria were the following: other factors induce severe liver injury, such as alcohol, drugs, hepatoviruses other than HBV, autoimmunity and pregnancy, as well as genetic and metabolic disorders. HBV-ACLF patients with hepatocellular carcinoma, known decompensated cirrhosis prior to onset of acute hepatic insult, age less than 18 years, jaundice induced by hemolytic jaundice and obstructive jaundice, absence of any chronic liver disease on investigations, and prolonged prothrombin time induced by blood system diseases were also excluded. The flowchart for the selection of HBV-ACLF patients was shown in Figure Derivation cohort data were screened from Beijing You-an Hospital from January 2005 to January 2013, while validation cohort data was collected from three different medical centers from January 2013 to February 2014. Specifically, 30 cases, 24 cases and 40 cases of HBV-ACLF as validation cohort data were collected from Beijing You-an Hospital, Tianjin Third Central Hospital and the Third Affiliated Hospital of Sun Yat-Sen University, respectively. The derivation cohort was applied to determine the predictors of mortality and thus established a prognostic model.Data on patient demographics, clinical and laboratory variables, evaluation of the underlying chronic liver disease, complications during the medication course, in-hospital special treatment  were retrospectively collected. All enrolled patients were followed up for a minimum of 30-day by clinic visits or telephone. The outcome  of each patient with HBV-ACLF was documented. Suspicion of infection based on at least one of the following: WBC count >10,000/mm3 or ≥50% increase with respect to baseline with a final value >8,000/mm3; more than 5% of band forms; and/or temperature >37.5°C.The results of blood tests performed on the day of diagnosis and within 7 days after diagnosis were recorded. The blood tests consisted of white blood count (WBC), platelet count (PLT), hemoglobin level, blood neutrophils percentage count (NEUT), international normalized ratio (INR), prothrombin time (PT), creatinine level, aspartate transaminase (AST) level, aspartate alanine transaminase (ALT) level, TBil level , direct bilirubin (DBil) level, cholinesterase, glucose, total cholesterol level, albumin level, triglyceride level, serum sodium level, ammonia level, serum chloride level, serum potassium level, serum magnesium level and total serum calcium level.Differences of biomarker (Δ biomarker) levels within 7 days after diagnosis were calculated. For example, a patient with HBV-ACLF with an ALT of 100U/L on the day of admission and 380U/L on day 7 after admission, had ΔALT= (380-100) /7=40. In the case of variceal hemorrhage or plasma exchange, the results of blood tests after variceal hemorrhage or plasma exchange were chosen after more than 2 days.Patients who were positive for HBV-DNA at presentation underwent antiviral therapy  with informed consent. In order to prevent/treat complications, comprehensive medical interventions were applied, including absolute bed rest, intravenous drop infusion of albumin or plasma, energy supplements, maintenance of acid-base equilibrium or electrolyte, plasma exchange the use of adenosylmethionine, glutathione or branched-chain amino acids to nourish liver cells, as well as antibiotics for infection. Patients with decompensation requiring organ support  were admitted to ICU.The MELD equation was applied to calculate the score of severity: 9.57×ln+3.78×ln+11.2×ln(INR)+6.43, in which the minimal values were forced to 1.0 for calculation purposes . The MELThe derivation cohort was applied to determine the predictors of mortality and thus established a prognostic model. Δbiomarker was calculated and constructed into the model together with baseline risk factors based on logistic regression, which is our dynamic prognostic model for HBV-ACLF, named the HBV-ACLF dynamic (HBV-ACLFD) model. AUROC were used as a control to compare the predictive values in the HBV-ACLFD model, i.e. MELD score, MELD-Na score and CTP score.All statistical analyses were conducted by STATA version 13.1. Univariate analyses were applied by appropriate tests to identify the variables which were significantly different in patients who died or survived in the derivation cohort. Multivariable logistic regression model was used by taking these predictor variables with the outcome (survived vs. death) through a stepwise forward selection procedure and thereby establish the dynamic prognostic model. The validity of this model was constructed by concordance (c) statistics, which is equivalent to the area under the AUROC curve. C-value >0.7 was recommended useful, and the C - value >0.8 would be considered excellent. Then, the performance of this model was finally verified in an independent cohort.


Introduction. During the 2014–2016 West-African Ebola virus disease (EVD) outbreak, some HCWs from Western countries became infected despite proper equipment and training on EVD infection prevention and control (IPC) standards. Despite their high awareness toward EVD, some of them could not recall the transmission routes. We explored these incidents by recalling the stories of infected Western HCWs who had no known directly exposures to blood/bodily fluids from EVD patients. Methodology. We carried out conventional and unconventional literature searches through the web using the keyword “Ebola” looking for interviews and reports released by the infected HCWs and/or the healthcare organizations. Results. We identified fourteen HCWs, some infected outside West Africa and some even classified at low EVD risk. None of them recalled accidents, unintentional exposures, or any IPC violation. Infection transmission was thus inexplicable through the acknowledged transmission routes. Conclusions. We formulated two hypotheses: inapparent exposures to blood/bodily fluids or transmission due to asymptomatic/mildly symptomatic carriers. This study is in no way intended to be critical with the healthcare organizations which, thanks to their interventions, put an end to a large EVD outbreak that threatened the regional and world populations. The West-African Ebola virus disease (EVD) 2014 outbreak was longer and more impactful than previous Central-African outbreaks, covering the largest geographic area, spreading to eight countries across three continents and lasting over 22 months . NosocomThe massive intervention of WHO and governmental and nongovernmental healthcare organizations from all over the world, with resources and “train-the-trainer” policies, improved this situation and the infectious risk among all HCWs decreased considerably, thus demonstrating that EVD infections among HCWs were preventable , 4, 5.Nevertheless, some HCWs still got infected and, among them, some HCWs were from Western countries. These subjects likely complied with IPC standards, were aware of the burden of the EVD epidemics, and had also less social contacts with the members of the communities where they were active .Even before the occurrence of the 2014 West-African outbreak, episodes of EVD transmission to HCWs from Western countries had been reported.In November 1976 the first case of a HCW who developed EVD outside Africa occurred, in a laboratory worker who accidentally pricked his thumb while transferring homogenized liver from a guinea-pig infected with Ebola virus. Following the standard safety protocol, he immediately removed his gloves and immersed his damaged thumb in hypochlorite solution, then squeezing it vigorously. There was no bleeding and careful examination did not reveal a puncture wound. Nevertheless, he became EVD infected and was treated with convalescent serum and within two weeks he showed symptom remission and Ebola virus was no longer detected in blood, urine, or faeces. Therefore, he was discharged from isolation, but Ebola virus persisted in his semen for months [In November 1989, during an Ebola-Reston virus outbreak among monkeys in the Philippines, some infected animals were imported into the US, where five animal handlers were daily exposed to these animals and four workers became infected without symptoms. One of them recalled cutting his finger while performing a necropsy on an infected animal, but among the remaining infected staff no transmission route was identified .http://www.nytimes.com/1995/05/12/world/virus-kills-a-3d-italian-nun-at-zaire-hospital.html). There were no specific EVD-transmission-based precautions in place at that time and transmission through percutaneous exposures to infectious blood was supposed but not confirmed [In 1995, during an Ebola virus outbreak in Kikwit (Democratic Republic of the Congo), four Italian missionary nurses developed EVD and three died (onfirmed .http://www.who.int/mediacentre/factsheets/fs103/en) . This study is not a field investigation or an epidemiologic study but was based on the interviews released by the EVD victims and/or the reports provided by the healthcare organizations. This was not a systematic review, and there could be other episodes of infected Western HCWs who could not recall the events that led to transmission; however, these stories could help formulate hypotheses regarding the existence and, possibly, the nature of alternative transmission routes.These episodes suggest that the events that led to Ebola virus infection could not always be known or recalled. Thus, the aim of this study was to report the anecdotal stories of some incidents occurring during the West-African EVD outbreak to HCWs from Western countries who did not recall any obvious contact of broken skin or mucous membranes with blood/bodily fluids of infected people or with surfaces and materials contaminated with these fluids, which are the acknowledged routes of human-to-human Ebola virus transmission  using the search terms “Ebola” and “healthcare worker”/“healthcare provider”/“health worker” or the actual names of the known infected HCWs. Much of the retrieved material had been constructed from interviews with the infected HCWs obtained from the healthcare organizations and from magazines and newspapers.The list of infected HCWs from Western countries amassed was then reduced to cases of unknown/unrecalled transmission routes in order to shed light over stories that may help provide a direction to the future research regarding Ebola virus transmission, rather than to evaluate EVD risk factors, case-fatality, incidence, or mortality rates.http://www.nbcnews.com/storyline/ebola-virus-outbreak/another-american-doctor-infected-ebola-charity-says-n193911) [http://www.dailymail.co.uk/news/article-2745037/Third-U-S-missionary-51-infected-deadly-Ebola-virus-West-Africa-arrives-Nebraska-treatment.html).Three HCWs  from the USA were infected in Liberia between July and August 2014. HCW-A, a doctor caring for EVD patients, fell ill on 23 July 2014 and EVD was diagnosed four days later. No information regarding potential routes of transmission is available. HCW-B, a nurse who had no direct contact with EVD patients but assisted HCWs with donning and doffing PPE and performing decontamination, was diagnosed with EVD on 27 July .HCW-D, a UK nurse infected in Sierra Leone on 24 August 2014, spent five weeks caring for EVD patients. He and his colleagues could not recall any specific accident that might lead to Ebola virus transmission (http://www.theguardian.com/world/2014/aug/12/ebola-spanish-missionary-dies-madrid-liberia) .HCW-E and HCW-F from Spain became infected Between August and September 2014 in Sierra Leone and were repatriated to Spain, where they died from EVD on 12 August (HCW-E) and 26 September (HCW-F). No information is provided regarding transmission  [HCW-G was a nurse infected at a Spanish Hospital complex on 6 October 2014 while caring for one of the above two HCWs (HCW-E and HCW-F). She was the first HCW known to be infected outside of West Africa. Paradoxically, during the field investigation, among the 117 HCWs who had participated in the care of the two infected HCWs, HVW-G was classified as a “low-risk contact.” In addition, she had always used appropriate PPE such as waterproof long-sleeved clothing covering the feet, waterproof footwear, hood, face mask or goggles, double layer of gloves, and FP3 respirator and did not recall any accident during PPE use. Questioned as to how she may have contracted EVD, HCW-G replied “I really can't say, I haven't the slightest idea”(73.html) .http://www.who.int/features/2015/cuban-doctor-survivor/en/).HCW-H was one of hundreds of Cuban doctors sent as to Sierra Leone. WHO provided rigorous safety training and mentoring to the Cuban Medical Brigade and other foreign medical teams before starting work in the Ebola treatment centres. While working there, HCW-H contracted EVD but declared “I don't know how I got infected. There was no violation of protocols” .HCW-I and HCW-J were US nurses who cared for an EVD patient arriving from Liberia on 28 September 2014 who died from EVD on 8 October in Dallas. HCW-I and HCW-J became infected on 11 and 14 October, respectively, but did not report unprotected exposures with the index patients and had been categorized as low EVD risk. How these two HCWs contracted Ebola virus infection remains unknown [http://nymag.com/daily/intelligencer/2015/06/craig-spencer-after-ebola.html#).HCW-K was a US doctor, who treated EVD patients in Guinea. On 23 October 2014, nine days after returning to the US, he was diagnosed with EVD. He reported using all the prescribed PPE without any known breach . His chahttp://www.bbc.com/news/world-africa-30180345) .HCW-L, a doctor from Italy working in Sierra Leone, had an episode of vomiting and diarrhoea with low fever on 20 November 2014, testing positive for Ebola virus four days later. He was repatriated to Rome, hospitalized, and treated . Both thhttp://www.theguardian.com/world/2014/dec/30/uk-ebola-patient-named-pauline-cafferkey- scottish-nurse). She was transferred to London for care. A joint investigation performed by the charity and the Centre for Infectious Disease Surveillance and Control, Public Health England concluded that there was no conclusive evidence about when or how she contracted EVD including the possibility of infected social contacts. According to her employing charity, “We will never be 100% sure how HCW-M contracted Ebola” (http://www.savethechildren.org.uk/sites/default/files/images/Significant_Event_Review_Summary_Findings.pdf).HCW-M was a UK nurse who cared for EVD patients in Sierra Leone. On December 2014, on return home to Scotland, she became ill and was diagnosed with EVD HCW-N was an Italian nurse working in Sierra Leone assisting EVD patients. Two days after his return to Italy he fell ill and, two days later, on 12 May 2015, was diagnosed with Ebola virus infection. In an interview he reported to have no idea on how transmission may have occurred .The searches provided the stories of fourteen Western HCWs . AlthougThe common characteristics of the reported stories of these HCWs from Western countries are that, excluding the single case of HCW-D, whose colleagues suspected that he made mistakes with transmission precautions due to overworking, none of the remaining HCWs recalled any event that might lead to Ebola virus transmission  and epidThe observation that trained and equipped HCWs could not recall the event that led to Ebola virus infection transmission leaves room for two major hypotheses.Ebola virus transmission could be due to inapparent exposures to infected blood or bodily fluids, an acknowledged transmission route for other blood-borne pathogens, such as HCV and HBV , 19.Ebola virus transmission could be due to caring for asymptomatic or mildly symptomatic EVD carriers, an hypothesis corroborated by several elements. First, Ebola virus may persist at immunologically protected sites in the body including semen, vaginal fluids, sweat, aqueous humor, urine, and breast milk of convalescent patients for months and, indeed, some convalescent patients have transmitted the infection, suggesting an important role of convalescent carriers in EVD persistence within the community . Second,As already reported, this is not an epidemiologic investigation nor an inspection, and therefore, it is not possible to confirm that the EVD transmission route in these individuals was truly through inapparent exposure and/or due to asymptomatic/mildly symptomatic carriers. Even the more accurate investigations during the EVD outbreak failed to identify the exposures in more than one-fourth of infected patients  and, morPerhaps, knowledge about human-to-human EVD transmission will improve thanks to experimental studies and to observational studies focusing on infected individuals without any obvious exposure , but the


Idiosyncratic drug-induced liver injury (DILI) and hepatic injury due to herbal and dietary supplements (HDS) can adapt clinical characteristics of autoimmune hepatitis (AIH), such as the appearance of autoantibodies and infiltration of the liver by immune competent cells. To describe these cases of DILI/HDS, the poorly-defined term “autoimmune(-like)” DILI/HDS came up. It is uncertain if these cases represent a subgroup of DILI/HDS with distinct pathomechanistic and prognostic features different from “classical” DILI/HDS. Besides, due to the overlap of clinical characteristics of “immune-mediated” DILI/HDS and AIH, both entities are not easy to differentiate. However, the demarcation is important, especially with regard to treatment: AIH requires long-term, mostly lifelong immunosuppression, whereas DILI/HDS does not. Only through exact diagnostic evaluation, exclusion of differential diagnoses and prolonged follow-up can the correct diagnosis reliably be made. Molecular mechanisms have not been analysed for the subgroup of “autoimmune(-like)” DILI/HDS yet. However, several pathogenetic checkpoints of DILI/HDS in general and AIH are shared. An analysis of these shared mechanisms might hint at relevant molecular processes of “autoimmune(-like)” DILI/HDS. In drug-induced liver injury and hepatic injury due to herbal and dietary supplements (DILI/HDS), the triggering event has been identified by definition. The intake of a drug, herb or supplement leads to a usually acute hepatitis. A subgroup of idiosyncratic DILI/HDS cases show features of autoimmunity such as the presence of autoantibodies and pronounced hepatic infiltration of immune competent cells. To describe these cases of DILI/HDS, the term “autoimmune(-like)” DILI/HDS has been applied. This subgroup of DILI/HDS resembles autoimmune hepatitis (AIH). In contrast to DILI/HDS, the triggering event for AIH is elusive and the main antigen leading to chronic inflammation of the liver is unknown for the majority of AIH patients. The clinical similarities of “autoimmune(-like)” DILI/HDS and AIH have led to several questions: how can “immune-mediated” DILI/HDS be differentiated reliably from AIH? This is relevant for treatment, but also for previous and future pathogenetic studies: is the clinical diagnosis sufficiently certain to assure that the experimental results represent the suspected disease? What are the shared molecular mechanisms of both entities? Molecular mechanisms have not been analysed for the subgroup of “autoimmune(-like)” DILI/HDS yet. That is why this review deals with pathogenetic mechanisms of DILI/HDS in general and of AIH. Insights into these molecular processes may hint at relevant pathogenetic mechanisms of “autoimmune(-like)” DILI/HDS. Due to the similarities between idiosyncratic DILI/HDS and AIH, the general clinical context of both entities must, firstly, be clarified, before the respective molecular pathogenesis can be illustrated.Drug-induced liver injury (DILI) is characterized by a broad spectrum of clinical appearances . ManifesN-acetyl-p-benzoquinoneimine (NAPQI) accumulates in the liver after the depletion of glutathione and leads to hepatic necrosis. In addition, the immune system also takes part in APAP pathogenesis [DILI is grouped into idiosyncratic and intrinsic forms . This clogenesis . This suIn contrast to intrinsic forms, idiosyncratic DILI is less predictable and occurs only in a minority of patients exposed to a drug. Idiosyncratic DILI can be subdivided into allergic and non-allergic forms . The allThe diagnosis of DILI/HDS is difficult to make. It is supported by scores of causality assessment, e.g., RUCAM  ,16,17. FN-acetylcysteine (NAC) and thereby diminishing reactive metabolites. In a prospective, double-blind study, NAC improved transplant-free survival in early stages of non-acetaminophen ALF [Treatment of DILI/HDS starts with the correct identification and prompt stopping of the causative agent. In severe cases of acute liver failure, liver transplantation impends ,10. For phen ALF . Again, Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease with unknown aetiology . It is cThe detection of autoantibodies such as ANA (anti-nuclear antibodies), anti-SMA (antibodies directed against smooth muscle antigen), anti-LKM (antibodies directed against liver-kidney microsomes), anti-SLA/LP (antibodies directed against soluble liver antigen/liver-pancreas antigen) and/or anti-LC1 (antibodies directed against liver cytosol) supports the diagnosis of AIH . DiagnosO-phosphoseryl-tRNA:selenocysteinyl-tRNA synthase), an enzyme of selenocysteine formation [The respective antigens that are recognized by autoantibodies are only partly known for AIH: anti-SLA/LP are directed against SEPSECS ” and “immune-mediated” DILI/HDS came up. This subgroup has not been defined precisely. Therefore, such a subclassification of DILI remains artificial and is solely descriptive without scientific basis. However, the term has been used for cases of acute hepatocellular injury with elevated autoantibodies, female predominance and histological features resembling AIH that are timely associated with a drug, herb or supplement intake as a trigger. The relevant difference to AIH is that cases of “autoimmune(-like)” DILI do not recur after discontinuation of immunosuppression . Some caIn summary, there is a considerable overlap of the clinical characteristics of idiosyncratic DILI/HDS and AIH, especially in cases of “autoimmune(-like)”, “immune-mediated” DILI/HDS. Interpretation and definition of these cases are highly controversial and diagnostic uncertainties are the consequence. But the correct diagnosis is of importance: in contrast to acute DILI/HDS, chronic AIH needs long-term immunosuppression. DILI/HDS misdiagnosed as AIH leads to unnecessary long-term immunosuppression with potential side effects like non-melanoma skin cancer or lymphoma. In cases of AIH misdiagnosed as DILI/HDS, long-term immunosuppression is not started and a second, potentially fulminant relapse of AIH impends. Only few characteristics help to differentiate AIH from DILI/HDS. During withdrawal or after complete cessation of steroids, AIH will relapse in almost all cases . In contAdditional to clinical characteristics, DILI/HDS in general and AIH share several molecular checkpoints in their respective pathogenesis . For theThe strongest genetic association of both DILI/HDS and AIH is located within the major histocompatibility complex (MHC)/human leucocyte antigen (HLA) region. This genetic association underscores the relevance of antigen presentation by MHC molecules to T cells for the pathogenesis of both entities. In Europe and North America, susceptibility for type 1 AIH is increased by the alleles DRB1*03:01 and DRB1*04:01 encoding HLA-DR3 and HLA–DR4 ,67. HLA-HLA variants that have been associated with susceptibility to AIH are different from those for DILI/HDS. HLA risk alleles have been analysed in DILI caused by flucloxacillin, amoxicillin-clavulanate, isoniazid, rifampicin, lapatinib, ticlopidine, terbinafine and nevirapine ,71. As aImmunological genes outside the HLA-region have been associated with susceptibility to DILI/HDS and AIH. In North American AIH patients, susceptibility to AIH is increased by genetic variants of regulatory and pro-inflammatory receptors and molecules like CTLA-4 (Cytotoxic T lymphocyte antigen 4) and TNFα ,77. Yet The liver is naturally exposed to a diversity of antigens: it is one of the first organs to come into contact with ingested food and drugs. Neoantigen formation is a result of metabolized and processed antigens and takes place in the liver. Haptenization is part of this process: small molecules only lead to an immunological response when they are attached to bigger, but harmless carrier proteins.In DILI/HDS, the immune reaction can be directed against the drug, the metabolite(s) of the drug or against the drug/metabolite attached to a self-protein (hapten). Though the main antigen has not been identified for AIH, it is assumed that its pathogenesis is antigen-specific and directed against a self-protein. In this case, DILI/HDS and AIH share primarily the same pathomechanism, the only differences being the kind of the antigen  and the Hapten-formation has been detected in flucloxacillin-induced DILI: conjugates of flucloxacillin and albumin are critical for the generation of flucloxacillin-specific T cells . HapteniThe liver provides a microenvironment that induces tolerance, even to self-antigens that are naturally located outside the liver. In a mouse model of multiple sclerosis (MS), hepatic expression of myelin basic protein, one of the main neuronal autoantigens, protected against the neurological phenotype . In thisTo trigger hepatic inflammation, antigen presentation may not be sufficient. Reactive metabolites of various drugs form haptens, but do not consequently lead to DILI . A virall-carnetine promotes valproate-induced DILI [Impaired metabolism of drugs, herbs or supplements causes liver damage by the toxic effect of reactive metabolites and danger signals. Metabolism starts with basic pharmacological characteristics of the agent: hepatobiliary excretion, lipophilicity and a minimal dosage of a drug are associated with the risk for DILI/HDS ,99,100. ced DILI . Alcoholced DILI . Some ofced DILI . The conced DILI . Murine ced DILI ,109.S-transferase (GST), have been associated with DILI/HDS [N-acetyltransferase 2 (NAT2) result in slow acetylation and increase susceptibility to isoniazide-induced DILI [Drug metabolism includes two pathways: phase I of biotransformation includes oxidative, reductive, and hydrolytic reactions resulting in reactive metabolite formation. For some drugs, the pharmaceutical effect is based on reactive metabolite formation, whereas for others it results from metabolite inactivation. As a side effect, intermediate reactive metabolites such as reactive oxygen species (ROS) can covalently bind proteins and form neoantigens . AlternaDILI/HDS . As an eced DILI . The conced DILI . Damage-ced DILI .Hepatobiliary excretion is one of the last steps of drug metabolism. The biliary transporter multidrug resistance protein 3 (MDR3) is a phospholipid flippase located in the canalicular membrane of hepatocytes. It mediates the biliary excretion of phosphatidylcholine. Phosphatidylcholine promotes the formation of micelles and thereby prevents damage of the biliary epithelium by bile acids. MDR3 activity is inhibited by antifungal and antipsychotic drugs ,116. ImpMolecular mechanisms that have been analysed in HDS particularly involve checkpoints of metabolism. Several herbs contain pyrrolizidine alkaloids that can induce sinusoidal obstruction syndrome ,119. On Drug-specific T cells have been identified in DILI/HDS. CD8+ T cells have been detected in peripheral blood of patients with flucloxacillin- and amoxicillin-clavulanate-induced DILI ,124. Perd-penicillamine-induced “autoimmune-like” adverse reaction [Mouse models gave insight into pro-inflammatory mechanisms contributing to DILI/HDS. In addition to impaired metabolic pathways, pro-inflammatory immune reactions have been analysed in models of APAP-induced liver injury . Knockoureaction .A thorough characterization of peripheral and intrahepatic drug-specific T cells in human DILI/HDS is pending. Cytokine profiling seems to support an involvement of IL-17 . IntraheFor the majority of AIH patients, the main antigen is unknown. Therefore, pro-inflammatory mechanisms have been analysed in a more general and not antigen-specific way in the past. It is not clear which kind of T cells response  is predominating in human AIH or its mouse models ,139,140.In addition to immune competent cells and cytokines, microRNAs (miRNAs) also seem to be involved in molecular mechanisms of DILI/HDS. MiRNAs are small, non-coding RNAs regulating diverse biological processes including inflammation and apoptosis . Due to Regulatory T cells (Treg) are the main cellular mediators of immune tolerance. Their impairment is associated with various immune-mediated and autoimmune diseases . By the “Immune-mediated”, idiosyncratic DILI/HDS might be, at least partly, a result of impaired immune regulation. However, the contribution of Treg is not clear. Other regulatory mechanisms than Treg-mediated tolerance have been investigated in DILI/HDS. In a model of amodiaquine-induced DILI, mice with a knockout for Cbl-b (Casitas B-cell lymphoma), an E3 ubiquitin-protein ligase that negatively regulates T cell activity, or a knockout for PD-1 developed more severe liver injury after drug exposure than wildtype mice . HoweverThe role of eosinophilia in blood and livers of DILI/HDS deserves more attention in future studies: it is unclear whether their presence is an unspecific epiphenomenon or whether they mediate specific pro-inflammatory or even regulatory signals. Low levels of peripheral eosinophils have been associated with a worse clinical outcome in DILI patients . RecentlIn mild forms of DILI/HDS, drug intake results in slight elevation of liver enzymes returning to normal levels spontaneously during continuation of the drug. This kind of adaptation is probably the result of restored regulatory mechanisms. Adaptation has been taken advantage for drugs that cannot be replaced easily and have to be continued with acceptable risks. For these drugs, re-challenge after the first episode of liver injury can be considered. Such an approach has been applied successfully for tuberculostatic drugs, for instance . HoweverSome forms of DILI/HDS can adapt clinical characteristics of AIH, such as the presence of autoantibodies and infiltration of the liver by immune competent cells. Definition and nomenclature of this “autoimmune(-like)” subgroup of DILI/HDS is not standardized. Differentiation between AIH and “autoimmune(-like)” DILI/HDS is not easy. Nonetheless, the correct diagnosis is important since AIH requires long-term immunosuppression, whereas DILI/HDS does not. Cases of misdiagnosis, incorrect treatment and insufficient surveillance have certainly been the consequence of this mix-up in the past.Molecular mechanisms have not been analysed in the subgroup of “autoimmune(-like)” DILI/HDS yet. However, several pathogenetic mechanisms are shared by classical DILI/HDS and AIH. They hint at potential molecular processes of “autoimmune(-like)” DILI/HDS. Genetic associations with HLA-variants point to a relevant role of antigen presentation for both DILI/HDS and AIH. Indirectly, these associations suggest a role of T effector cells in conveying hepatic inflammation in both entities. Still, a thorough characterization of intrahepatic, pro-inflammatory immune competent cells is pending for both DILI/HDS and AIH. In addition to pro-inflammatory mechanisms, molecular and cellular representatives of tolerance, such as regulatory T cells, could be impaired in “autoimmune(-like)” DILI/HDS and deserve further research.Currently, in comparison to AIH, there is one big advantage for the investigation of molecular mechanisms of DILI/HDS in general and of “autoimmune(-like)” DILI/HDS: the main antigen is known for DILI/HDS , but not for AIH. The relevant question for DILI/HDS in general remains which dysregulated molecular mechanisms render an individual susceptible to DILI/HDS. Possibly, not a single defect, but instead a combination of defects increases susceptibility. Therefore, the whole cascade of mechanisms needs to be analysed for a single drug, including checkpoints like metabolism, neoantigen formation, haptenization, antigen presentation, co-stimulation and co-regulation as well as pro- and anti-inflammatory mechanisms. Due to shared molecular checkpoints of DILI/HDS and AIH, deeper pathomechanistic insights into one entity can improve the understanding of the other and can promote more target-oriented treatment. In the past, the research fields of DILI/HDS and primary autoimmune liver diseases like AIH have mostly been worked on separate from one another. But as lessons can be learned from each other, especially with regard to “autoimmune(-like)” DILI/HDS, scientific exchange must be encouraged.