***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: The circadian pacemaker is differentially sensitive to the re setting effects of retinal light exposure , depending upon the circadian phase at which the light exposure occurs . Previously reported human phase response curves ( PRCs ) to single bright light exposures have employed small sample sizes , and were often based on relatively imprecise estimates of circadian phase and phase re setting . In the present study , 21 healthy , entrained subjects underwent pre- and post-stimulus constant routines ( CRs ) in dim light ( approximately 2 - 7 lx ) with maintained wakefulness in a semi-recumbent posture . The 6.7 h bright light exposure stimulus consisted of alternating 6 min fixed gaze ( approximately 10 000 lx ) and free gaze ( approximately 5000 - 9000 lx ) exposures . Light exposures were scheduled across the circadian cycle in different subjects so as to derive a PRC . Plasma melatonin was used to determine the phase of the onset , offset , and midpoint of the melatonin profiles during the CRs . Phase shifts were calculated as the difference in phase between the pre- and post-stimulus CRs . The result ant PRC of the midpoint of the melatonin rhythm revealed a characteristic type 1 PRC with a significant peak-to-trough amplitude of 5.02 h. Phase delays occurred when the light stimulus was centred prior to the critical phase at the core body temperature minimum , phase advances occurred when the light stimulus was centred after the critical phase , and no phase shift occurred at the critical phase . During the subjective day , no prolonged ' dead zone ' of photic insensitivity was apparent . Phase shifts derived using the melatonin onsets showed larger magnitudes than those derived from the melatonin offsets . These data provide a comprehensive characterization of the human PRC under highly controlled laboratory conditions CONTEXT Both light and melatonin can be used to phase shift the human circadian clock , but the phase-advancing effect of the combination has not been extensively investigated . OBJECTIVE The objective of the study was to determine whether phase advances induced by morning intermittent bright light and a gradually advancing sleep schedule could be increased with afternoon melatonin . PARTICIPANTS Healthy adults ( 25 males , 19 females , between the ages of 19 and 45 yr ) participated in the study . DESIGN There were 3 d of a gradually advancing sleep/dark period ( wake time 1 h earlier each morning ) , bright light on awakening [ four 30-min bright-light pulses ( approximately 5000 lux ) alternating with 30 min room light < 60 lux ] and afternoon melatonin , either 0.5 or 3.0 mg melatonin timed to induce maximal phase advances , or matching placebo . The dim light melatonin onset was measured before and after the treatment to determine the phase advance . RESULTS There were significantly larger phase advances with 0.5 mg ( 2.5 h , n = 16 ) and 3.0 mg melatonin ( 2.6 h , n = 13 ) , compared with placebo ( 1.7 h , n = 15 ) , but there was no difference between the two melatonin doses . Subjects did not experience jet lag-type symptoms during the 3-d treatment CONCLUSIONS Afternoon melatonin , morning intermittent bright light , and a gradually advancing sleep schedule advanced circadian rhythms almost 1 h/d and thus produced very little circadian misalignment . This treatment could be used in any situation in which people need to phase advance their circadian clock , such as before eastward jet travel or for delayed sleep phase syndrome SINCE the first report in unicells1 , studies across diverse species have demonstrated that light is a powerful synchronizer which resets , in an intensity-dependent manner , endogenous circadian pacemakers1–5 . Although it is recognized that bright light ( ∼7,000 to 13,000 lux ) is an effective circadian synchronizer in humans6–10 , it is widely believed that the human circadian pacemaker is insensitive to ordinary indoor illumination (∼50–3001ux)11 . It has been proposed that the relationship between the re setting effect of light and its intensity follows a compressive nonlinear function12 , such that exposure to lower illuminances still exerts a robust effect13 . We therefore undertook a series of experiments which support this hypothesis and report here that light of even relatively low intensity ( ∼180 lux ) significantly phase-shifts the human circadian pacemaker . Our results clearly demonstrate that humans are much more sensitive to light than initially suspected and support the conclusion that they are not qualitatively different from other mammals in their mechanism of circadian entrainment14 The effects of melatonin ( MT ) and placebo ( P ) on adaptation to a rapid 9-h advance phase shift , in the presence and absence of inappropriate bright light ( BL ) exposure were examined . Volunteers were initially subjected to a gradual 9-h delay phase shift over 5 days ( D1-D5 ) using a combination of bright light and darkness/sleep . Readaptation to a subsequent rapid 9-h advance phase shift was studied using : 1 ) MT , 5 mg , 2300 h , D6-D8 , 2 ) BL , 2,000 lx , 0800 - 1200 h , D7-D8 , 3 ) MT+BL and 4 ) P , 2300 h , D6-D8 . MT treatment was timed to phase advance and BL to phase delay . BL delayed the 6-sulphatoxymelatonin rhythm in five out of seven subjects . Two subjects delayed and five phase advanced with both MT and MT+BL . MT consistently improved subjective sleep , alertness , and performance even in the presence of inappropriate BL and before phase readaptation had occurred . BL improved alertness and performance transiently . The beneficial effects of MT are not wholly mediated through an effect on the biological clock Although bright light can alter circadian timing , the practicality and effectiveness of supplementary bright light for reducing jet-lag symptoms in world-class athletes is unclear . Therefore , we r and omised 22 world class female footballers to a bright light intervention or control group before a flight from USA to Europe . Intra-aural temperature , grip strength , sleep and various jet-lag symptoms were measured serially . For 4 days , the intervention participants were exposed , in pairs within their rooms , to 2 500 lux of bright light at ≈50 cm for 45 - 60 min at a time-of-day predicted to accelerate circadian adjustment . On post-flight day 1 , indoor light transiently increased intra-aural temperature by 0.38 ° C ( 95%CI : 0.16 to 0.60 , P=0.001 ) and increased overall jet-lag rating by ≈1 unit . Light had negligible effects on functioning , diet , bowel and sleep symptoms , which varied substantially between- and within-subjects . In conclusion , supplementary indoor light administered within the schedule of world-class athletes was not substantially effective for reducing jet-lag symptoms after a flight from the USA-Europe . Ours is the first study of the practical effectiveness of supplementary bright light in world class athletes , although sample size was naturally small , compromises were required to implement the intervention and there appears to be large inter-individual variation in the perception of what constitutes jet-lag STUDY OBJECTIVES To determine whether appropriately timed administration of a short-acting benzodiazepine hypnotic , which has proven effective in an animal model of jet lag , also facilitates adaptation of circadian rhythmicity and sleep-wake homeostasis in a human model of jet lag . DESIGN Subjects participated in two double-blind , placebo-controlled studies of adaptation to an 8-hr delay shift of sleep-wake and dark-light cycles simulating westward travel . Each 9-day laboratory study began with a 3-day habituation period followed by a 24-hr study to obtain basal hormonal and sleep profiles ( 23:00 - 07:00 ) . Subjects were then kept awake until 07:00 the next day and slept in darkness 07:00 - 15:00 for the next five 24-hr spans post-shift . SETTING N/A. PARTICIPANTS 6 normal , healthy men 24 - 31 years of age . INTERVENTIONS Oral Triazolam ( 0.5 mg ) or placebo given at 04:00 before the first shifted sleep/dark period ( 3 hours before bedtime ) and at 07:00 ( at bedtime ) on days 2 - 5 post-shift . MEASUREMENTS AND RESULTS Sleep recordings and 24-hr cortisol and growth hormone profiles were obtained at baseline and on the first , third , and fifth days post-shift . Global measures of treatment efficacy were calculated for multiple endpoints representing circadian rhythmicity and sleep-wake homeostasis . With placebo , the shift induced disturbances of sleep and hormonal secretion , and a gradual re-entrainment of circadian rhythmicity . Triazolam significantly facilitated adaptation by accelerating re-entrainment of circadian rhythms ( chronobiotic effect ) and normalizing markers of sleep/wake homeostasis ( hypnotic effect ) . CONCLUSIONS Appropriately timed administration of a benzodiazepine hypnotic appears to facilitate the adaptation of both circadian rhythmicity and sleep-wake homeostasis to a shifted dark/sleep cycle . Compounds with combined chronobiotic/hypnotic properties may be useful in conditions of jet lag or night work Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Introduction : The melatonin agonist LY 156735 ( LY ) is a new investigational drug under development to treat circadian rhythm disorders . The present study assessed the efficacy of LY to alleviate the symptoms of shift lag and to enhance readaptation of desynchronized circadian rhythms to a new time zone . Subjects and methods : Eight healthy male volunteers of age 25–35 yr participated in three identical trials of 13d duration in a temporal isolation unit separated by washout intervals . A high dose ( HD ) of 5 mg and a low dose ( LD ) of 0.5 mg of LY and placebo ( PL ) were administered double-blinded in a three-period cross-over design . Each trial consisted of an adaptation period , a pre-shift period for baseline measurements , a simulated 9h phase-advance shift , and a post-shift period for follow-up . The time shift was performed at 23:00h of day 6 by advancing the laboratory time to 08:00h of day 7 . Double-blind study medication was administered at 14:30h on day 6 , and at 22:30h on days 7–10 . Subjective ratings of jet lag , alertness , tenseness , and daytime fatigue were assessed using visual analog scales ( VAS ) and st and ardized question naires . The objective markers of readaptation included core body temperature , wrist actigraphy , cortisol and electrolyte excretion , and a battery of computerized performance tests . Results : HD but not LD enhanced the readaptation speed of all physiological rhythms investigated , as demonstrated by a significantly faster movement of acrophases towards the post-shift target time . HD ( p=0.05 ) significantly blunted the post-shift deterioration of performance in those tests that were sensitive to shift lag . Parameters of subjective well-being were not significantly affected by either dose . Conclusion : This pilot study demonstrates the chronobiotic efficacy of LY when taken at a dose of 5 mg/d We measured the effects of slow-release caffeine ( SRC ) and melatonin ( Mlt ) on  sleep and daytime sleepiness after a seven-time zone eastbound flight . In a double-blind , r and omized , placebo-controlled study , each of three groups of nine subjects was given either 300 mg SRC on recovery day 1 ( D1 ) to D5 ( 0800 ) or 5 mg Mlt on preflight D-1 ( 1700 ) , flight day D0 ( 1600 ) , and from D1 to D3 ( 2300 ) , or placebo ( Pbo ) at the same times . Nighttime sleep was evaluated by polysomnography and daytime sleepiness from measurements of sleep latencies and continuous wrist actigraphy . Compared with baseline , we found a significant rebound of slow-wave sleep on night 1 ( N1 ) to N2 under Pbo and Mlt and a significant decrease in rapid eye movement sleep on N1 ( Pbo ) and N1-N3 ( Mlt ) . Sleepiness was objective ly increased under Pbo ( D1-D6 ) and Mlt ( D1-D3 ) . SRC reduced sleepiness but also tended to affect sleep quality until the last drug day . In conclusion , both drugs have positive effects on some  jet lag symptoms after an eastbound flight : SRC on daytime sleepiness , and Mlt on sleep Abstract . The aim of this work was to investigate the potential chronobiotic properties of slow-release caffeine , in comparison with melatonin , on resynchronization of endogenous melatonin and cortisol secretions after an eastbound flight by jet incurring a time loss of 7 h. A group of 27 reservists of the US Air Force received either slow-release caffeine ( 300 mg ) , melatonin ( 5 mg ) or placebo before , during and /or after the transmeridian flight . Saliva and urine were sample d before the flight in the United States ( from day –2 to day 0 ) and after the flight in France ( from day 1 to day 10 ) . Saliva was collected once a day on waking to determine saliva melatonin and cortisol concentrations . In addition , concentrations of caffeine in saliva were 
    Output:
    
We found no literature pertaining to the management of travel fatigue .