You will be presented with a collection of medical randomized controlled trial (RCT) reports addressing a shared clinical question -- for instance, the efficacy of a medical intervention on a disease or condition. Given the titles and abstracts of these reports, your task is to generate the conclusion of the systematic review article synthesizing the key findings. Your conclusion should be a few sentences long. In your response, include only the conclusion and no other text. The RCT reports are below.



Title 1:
Efficacy of Bright Light Treatment, Fluoxetine, and the Combination in Patients With Nonseasonal Major Depressive Disorder: A Randomized Clinical Trial.
Abstract 1:
IMPORTANCE Bright light therapy is an evidence -based treatment for seasonal depression  , but there is limited evidence for its efficacy in nonseasonal major depressive disorder ( MDD ) . OBJECTIVE To determine the efficacy of light treatment , in monotherapy and in combination with fluoxetine hydrochloride , compared with a sham-placebo condition in adults with nonseasonal MDD . DESIGN , SETTING , AND PARTICIPANTS R and omized , double-blind , placebo- and sham-controlled , 8-week trial in adults ( aged 19 - 60 years ) with MDD of at least moderate severity in outpatient psychiatry clinics in academic medical centers . Data were collected from October 7 , 2009 , to March 11 , 2014 . Analysis was based on modified intent to treat ( r and omized patients with ≥1 follow-up rating ) . INTERVENTIONS Patients were r and omly assigned to ( 1 ) light monotherapy ( active 10,000-lux fluorescent white light box for 30 min/d in the early morning plus placebo pill ) ; ( 2 ) antidepressant monotherapy ( inactive negative ion generator for 30 min/d plus fluoxetine hydrochloride , 20 mg/d ) ; ( 3 ) combination light and antidepressant ; or ( 4 ) placebo ( inactive negative ion generator plus placebo pill ) . MAIN OUTCOMES AND MEASURES Change score on the Montgomery-Åsberg Depression Rating Scale ( MADRS ) from baseline to the 8-week end point . Secondary outcomes included response ( ≥50 % reduction in MADRS score ) and remission ( MADRS score ≤10 at end point ) . RESULTS A total of 122 patients were r and omized ( light  monotherapy , 32 ;  fluoxetine monotherapy , 31 ; combination therapy , 29 ; placebo , 30 ) . The mean ( SD ) changes in MADRS score for the light , fluoxetine , combination , and placebo groups were 13.4 ( 7.5 ) , 8.8 ( 9.9 ) , 16.9 ( 9.2 ) , and 6.5 ( 9.6 ) , respectively . The combination ( effect size [ d ] = 1.11 ; 95 % CI , 0.54 to 1.64 ) and light monotherapy ( d = 0.80 ; 95 % CI , 0.28 to 1.31 ) were significantly superior to  placebo in the MADRS change score , but fluoxetine monotherapy ( d = 0.24 ; 95 % CI , -0.27 to 0.74 ) was not superior to placebo . For the respective placebo , fluoxetine , light , and combination groups at the end point , response was achieved by 10 ( 33.3 % ) , 9 ( 29.0 % ) , 16 ( 50.0 % ) , and 22 ( 75.9 % ) and remission was achieved by 9 ( 30.0 % ) , 6 ( 19.4 % ) , 14 ( 43.8 % ) , and 17 ( 58.6 % ) . Combination therapy was superior to placebo in MADRS response ( β = 1.70 ; df = 1 ; P = .005 ) and remission ( β = 1.33 ; df = 1 ; P = .02 ) , with numbers needed to treat of 2.4 ( 95 % CI , 1.6 to 5.8 ) and 3.5 ( 95 % CI , 2.0 to 29.9 ) , respectively . All treatments were generally well tolerated , with few significant differences in treatment-emergent adverse events . CONCLUSIONS AND RELEVANCE Bright light treatment , both as monotherapy and in combination with fluoxetine , was efficacious and well tolerated in the treatment of adults with nonseasonal MDD .  The combination treatment had the most consistent effects . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00958204


Title 2:
Ageing and the circadian and homeostatic regulation of human sleep during forced desynchrony of rest, melatonin and temperature rhythms.
Abstract 2:
1 . The circadian timing system has been implicated in age-related changes in sleep structure , timing and consolidation in humans . 2 . We investigated the circadian regulation of sleep in 13 older men and women and 11 young men by forced desynchrony of polysomnographically recorded sleep episodes ( total , 482 ; 9 h 20 min each ) and the circadian rhythms of plasma melatonin and core body temperature . 3 . Stage 4 sleep was reduced in older people . Overall levels of rapid eye movement ( REM ) sleep were not significantly affected by age . The latencies to REM sleep were shorter in older people when sleep coincided with the melatonin rhythm . REM sleep was increased in the first quarter of the sleep episode and the increase of REM sleep in the course of sleep was diminished in older people . 4 . Sleep propensity co-varied with the circadian rhythms of body temperature and plasma melatonin in both age groups . Sleep latencies were longest just before the onset of melatonin secretion and short sleep latencies were observed close to the temperature nadir . In older people  sleep latencies were longer close to the crest of the melatonin rhythm . 5 . In older people sleep duration was reduced at all circadian phases and sleep consolidation deteriorated more rapidly during the course of sleep , especially when the second half of the sleep episode occurred after the crest of the melatonin rhythm . 6 . The data demonstrate age-related decrements in sleep consolidation and increased susceptibility to circadian phase misalignment in older people . These changes , and the associated internal phase advance of the propensity to awaken from sleep , appear to be related to the interaction between a reduction in the homeostatic drive for sleep and a reduced strength of the circadian signal promoting sleep in the early morning


Title 3:
Temporal Prediction Errors in a Passive Learning Task Activate Human Striatum
Abstract 3:
Functional MRI experiments in human subjects strongly suggest that the striatum participates in processing information about the predictability of rewarding stimuli . However , stimuli can be unpredictable in character ( what stimulus arrives next ) , unpredictable in time ( when the stimulus arrives ) , and unpredictable in amount ( how much arrives ) . These variables have not been dissociated in previous imaging work in humans , thus conflating possible interpretations of the kinds of expectation errors driving the measured brain responses . Using a passive conditioning task and fMRI in human subjects , we show that positive and negative prediction errors in reward delivery time correlate with BOLD changes in human striatum , with the strongest activation lateralized to the left putamen . For the negative prediction error , the brain response was elicited by expectations only and not by stimuli presented directly ; that is , we measured the brain response to nothing delivered ( juice expected but not delivered ) contrasted with nothing delivered ( nothing expected )


Title 4:
Temporal Difference Models and Reward-Related Learning in the Human Brain
Abstract 4:
Temporal difference learning has been proposed as a model for Pavlovian conditioning , in which an animal learns to predict delivery of reward following presentation of a conditioned stimulus ( CS ) . A key component of this model is a prediction error signal , which , before learning , responds at the time of presentation of reward but , after learning , shifts its response to the time of onset of the CS . In order to test for regions manifesting this signal profile , subjects were scanned using event-related fMRI while  undergoing appetitive conditioning with a pleasant taste reward  . Regression analyses revealed that responses in ventral striatum and orbitofrontal cortex were significantly correlated with this error signal , suggesting that , during appetitive conditioning , computations described by temporal difference learning are expressed in the human brain


Title 5:
Detection Power, Estimation Efficiency, and Predictability in Event-Related fMRI
Abstract 5:
Experimental design s for event-related functional magnetic resonance imaging can be characterized by both their detection power , a measure of the ability to detect an activation , and their estimation efficiency , a measure of the ability to estimate the shape of the hemodynamic response . R and omized design s offer maximum estimation efficiency but poor detection power , while block design s offer good detection power at the cost of minimum estimation efficiency . Periodic single-trial design s are poor by both criteria . We present here a theoretical model of the relation between estimation efficiency and detection power and show that the observed trade-off between efficiency and power is fundamental . Using the model , we explore the properties of semir and om design s that offer intermediate trade-offs between efficiency and power . These design s can simultaneously achieve the estimation efficiency of r and omized design s and the detection power of block design s at the cost of increasing the length of an experiment by less than a factor of 2 . Experimental design s can also be characterized by their predictability , a measure of the ability to circumvent confounds such as habituation and anticipation . We examine the relation between detection power , estimation efficiency , and predictability and show that small increases in predictability can offer significant gains in detection power with only a minor decrease in estimation efficiency


Title 6:
Sleep and mealtime misalignment alters functional connectivity: A pilot resting state study
Abstract 6:
Delayed sleep and meal times promote metabolic dysregulation and obesity . Altered coordination of sleeping and eating times may impact food-reward valuation and interoception in the brain , yet the independent and collective contributions of sleep and meal times are unknown . This r and omized , in-patient crossover study experimentally manipulates sleep and meal times while preserving sleep duration ( 7.05±0.44 h for 5 nights ) . Resting-state functional magnetic resonance imaging scans ( 2 × 5-minute runs ) were obtained for four participants ( three males ; 25.3±4.6 years ) , each completing all study phases ( normal sleep/normal meal ; late sleep/normal meal ; normal sleep/late meal ; and late sleep/late meal ) . Normal mealtimes were 1 , 5 , 11 and 12.5 h after awakening ; late mealtimes were 4.5 , 8.5 , 14.5 and 16 h after awakening . Seed-based resting-state functional connectivity ( RSFC ) was computed for a priori regions-of-interest ( seeds ) and contrasted across conditions . Statistically significant ( P<0.05 , whole-brain corrected ) regionally specific effects were found for multiple seeds . The strongest effects were linked to the amygdala : increased RSFC for late versus normal mealtimes ( equivalent to skipping breakfast ) . A main effect of sleep and interaction with meal time were also observed . Preliminary findings support the feasibility of examining the effects of sleep and meal-time misalignment , independent of sleep duration , on RSFC in regions relevant to food reward and interoception


Title 7:
Seasonality and circadian phase delay: prospective evidence that winter lowering of mood is associated with a shift towards Eveningness.
Abstract 7:
BACKGROUND Lewy 's phase shift hypothesis ( PSH ) of seasonal affective disorder ( SAD ) asserts that winter depression is caused by an abnormal delay of circadian phase in winter . The aim of this study was to further investigate the PSH by testing the novel hypothesis that winter pattern seasonality of mood in the general population is associated with a phase delay of circadian rhythms in winter . METHODS Using a r and om community sample of 244 adults in Melbourne , seasonality of mood was measured prospect ively as the within-subject difference between self-reports of behavioural engagement in summer and winter across 3 years . The  Horne-Ostberg Morningness-Eveningness question naire ( MEQ )  was used as a  self-report estimate of circadian phase . Phase delay in winter was measured as the within-subject difference between summer and winter estimates of circadian phase , with relative shifts towards Eveningness being interpreted as phase delay . RESULTS As expected , a significant association was found between winter pattern seasonality of mood and within-subject phase delay in winter ( r=0.17 , P<0.01 ) . LIMITATIONS Circadian phase was operationalised on the MEQ . While a number of studies have shown the MEQ to correlate with physiological measures of circadian phase , the findings await replication using a more direct measure of the circadian system . CONCLUSIONS A positive association was found between lowered mood in winter and winter phase delay amongst a r and om community sample . This provisional finding adds support to Lewy 's PSH by demonstrating that phase delay may be causally important not just in clinical cases of SAD , but across the continuum of mood seasonality


Title 8:
Publication bias: evidence of delayed publication in a cohort study of clinical research projects
Abstract 8:
Abstract Objectives : To determine the extent to which publication is influenced by study outcome . Design : A cohort of studies su bmi tted to a hospital ethics committee over 10 years were examined retrospectively by review ing the protocol s and by question naire . The primary method of analysis was Cox 's proportional hazards model . Setting : University hospital , Sydney , Australia . Studies : 748 eligible studies su bmi tted to Royal Prince Alfred Hospital Ethics Committee between 1979 and 1988 . Main outcome measures : Time to publication . Results : Response to the question naire was received for 520 ( 70 % ) of the eligible studies . Of the 218 studies analysed with tests of significance , those with positive results ( P<0.05 ) were much more likely to be published than those with negative results ( P0.10 ) ( hazard ratio 2.32 ( 95 % confidence interval 1.47 to 3.66 ) , P=0.0003 ) , with a significantly shorter time to publication ( median 4.8 v 8.0 years ) . This finding was even stronger for the group of 130 clinical trials ( hazard ratio 3.13 ( 1.76 to 5.58 ) , P=0.0001 ) , with median times to publication of 4.7 and 8.0 years respectively . These results were not material ly changed after adjusting for other significant predictors of publication . Studies with indefinite conclusions ( 0.05 P<0.10 ) tended to have an even lower publication rate and longer time to publication than studies with negative results ( hazard ratio 0.39 ( 0.13 to 1.12 ) , P=0.08 ) . For the 103 studies in which outcome was rated qualitatively , there was no clear cut evidence of publication bias , although the number of studies in this group was not large . Conclusions : This study confirms the evidence of publication bias found in other studies and identifies delay in publication as an additional important factor . The study results support the need for prospect i ve registration of trials to avoid publication bias and also support restricting the selection of trials to those started before a common date in undertaking systematic review s. Key messages This retrospective cohort study of clinical research projects confirms the findings of publication bias found in previous studies Delay in the publication of studies with negative results has been identified as an additional important factor in publication bias With the recognised importance of evidence based medicine , these results have important implication s for the selection of studies included in systematic review s Prospect i ve registration of clinical research projects will avoid many of the problems associated with publication bias However , it is also important to restrict inclusion in systematic review s to studies started before a certain date to allow for the delay in completing studies with negative
Circadian moderation was observed in measures of both reward anticipation and reward receipt , with more consistent evidence for the latter .
The circadian effect was observed in measures of both reward anticipation and reward receipt , with more consistent evidence for the latter .