Meta-analysis of on-the-road experimental studies of hypnotics: effects of time after intake, dose, and half-life.

BACKGROUND: The use of hypnotics is prevalent in the general population. Though these drugs have been shown to be effective, their residual effects may cause significant impairment to the user's driving ability. The objective of this meta-analysis is to determine whether there is a residual effect on driving and better evaluate the safety of hypnotics. METHOD: Randomized double-blind placebo-controlled studies were selected that employed a commonly used and valid driving measure to determine the user's driving ability the day after drug administration. The primary outcome measure for the driving task in all included studies was the Standard Deviation of Lateral Position (SDLP). Fixed effects model meta-analyses were performed. RESULTS: Fourteen studies, published from 1984 to 2013 (295 subjects), were included in this meta-analysis. Overall, significant impairment was found when morning testing (i.e., 10-11 h after initiating sleep) was compared to afternoon testing (i.e., 16-17 h after initiating sleep; P = .0001). Twice the standard dose also showed significant impairment (P = .0001) relative to the standard dose. The time of the test, morning versus afternoon, also had an impact on individual drugs. Middle of the night administration (MOTN) of zolpidem and zopiclone caused significant impairment the following morning, though no such impairment was seen with zaleplon. Finally, half-life was also assessed (short: <6 h, intermediate: 6-12 h, long: >12 h) and both intermediate- and long-acting drugs caused significant impairment the morning after bedtime administration, whereas short acting hypnotics did not. CONCLUSIONS: These analyses indicate that the half-life, dose of the hypnotic, as well as time between treatment and driving, as measured by SDLP, all significantly impact the ability to drive a car after taking hypnotic drugs.

Beyond sleep duration: distinct sleep dimensions are associated with obesity in children and adolescents.

OBJECTIVE: Short sleep duration is recognized as a significant risk factor in childhood obesity; however, the question as to how sleep contributes to the development of obesity remains largely unknown. The majority of pediatric studies have relied on sleep duration as the exclusive measure of sleep; this insular approach may be misleading given that sleep is a dynamic multidimensional construct beyond sleep duration, including sleep disturbances and patterns. Although these sleep dimensions partly overlap, it is necessary to determine their independent relation with obesity, which in turn, may inform a more comprehensive understanding of putative pathophysiological mechanisms linking sleep and obesity. The aim of the present study was to investigate whether sleep dimensions including sleep duration, disturbances, and patterns were individually associated with obesity, independent of multiple covariates. The second objective was to examine whether sleep disturbances and patterns were independently associated with obesity, after adjusting for sleep duration. METHODS: Participants included 240 healthy children and adolescents (Mage=12.60, s.d.=1.98; 45.8% females). Anthropometric measures included measured waist and hip circumference, body mass index Z-score, and percent body fat. Subjective sleep measures included sleep duration, sleep disturbances, sleep quality, and sleep patterns from youth- and parental report. RESULTS: Youth with larger adiposity and body composition measures reported poorer sleep quality (ß avg=-0.14, P<0.01), more sleep disturbances (ß avg=0.13, P<0.05), and showed a delayed sleep phase pattern (ß avg=0.15, P<0.05), independent of age, sex, pubertal status, physical activity, screen time, socioeconomic status, and sleep duration. Shorter sleep duration was significantly associated with obesity; however, this link was attenuated after adjustment of covariates. CONCLUSIONS: The results suggest that sleep measures beyond duration may more precisely capture influences that drive the negative association between sleep and obesity, and thus, yield more robust associations. As such, future studies are needed to better understand how distinct sleep dimensions confer risk for childhood obesity.

ICA methods for MEG imaging.

Activity of individual cortical sources cannot be uniquely imaged when MEG data is a sequence of complex spatial patterns of multiple cortical sources. Auxiliary constraints integrated into the imaging equations are required to remove the mathematical ambiguity. Therefore, it is important to adapt source separation techniques to MEG imaging. It is much easier to accurately image field patterns of isolated brain electric sources. We demonstrate how a combination of second and fourth order Independent Component Analysis (ICA) methods can be used to remove noise and isolate source activity for improved MEG imaging accuracy. A second order ICA technique was used to extract respiratory and eye movement artifact by exploiting cross-correlation differences over time between cortical sources and artifact. For brain electric source separation, a fourth order ICA technique that quantified probabilities of simultaneous source activity was used to separate brain electric sources characterized by bursts of oscillatory circuit activity.

Effects of rapid versus slow accumulation of eight hours of sleep loss.

The present study assessed alertness, memory, and performance following three schedules of approximately 8 hr of sleep loss (slow, intermediate, and rapid accumulation) in comparison to an 8-hr time in bed (TIB) sleep schedule. Twelve healthy individuals aged 21-35 completed each of four conditions according to a Latin Square design: no sleep loss (8-hr TIB for 4 nights; 2300-0700), slow (6-hr TIB for 4 nights; 0100-0700), intermediate (4-hr TIB for 2 nights; 0300-0700), and rapid (0-hr TIB for 1 night) sleep loss. On each day, participants completed a multiple sleep latency test (MSLT), a probed-recall memory task, a psychomotor vigilance task, a divided attention task, and the Profile of Mood States. "Rapid" sleep loss produced significantly more impairment on tests of alertness, memory, and performance compared to the "slow" accumulation of a comparable amount of sleep loss. The impairing effects of sleep loss vary as a function of rate, suggesting the presence of a compensatory adaptive mechanism operating in conjunction with the accumulation of a sleep debt.

Scoring reliability of the multiple sleep latency test in a clinical population.

STUDY OBJECTIVES: To determine intrarater and interrater scoring reliability of the multiple sleep latency test (MSLT) in a population of sleep clinic patients. DESIGN: N/A. SETTING: Urban sleep center. PATIENTS: 200 consecutive sleep center patients (diagnoses included: obstructive sleep apnea, narcolepsy, periodic-limb-movement, and individuals with no diagnosis). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: MSLTs were recorded and scored according to standard clinical procedures. One of four clinical polysomnographers and one of seven polysomnographic technologists scored each MSLT. All MSLTs were then rescored by the same polysomnographer. The intrarater reliability coefficient for mean MSLT score was .87 and interrater reliability was .90. Coefficients for the mean number of REM onsets during the MSLT were .81 for intrarater and .88 for interrater reliability. Intrarater and interrater agreement (kappa coefficients) for the presence of at least one REM onset during the MSLT was .78 and .86, respectively. For the presence of greater than one REM onset, a kappa of .78 was obtained for intrarater agreement and .91 for interrater agreement. CONCLUSIONS: The clinical MSLT displays excellent interrater and intrarater reliability estimates for both sleep latency and REM onset scores in a sleep-disordered population.

Acute effects of bright light and caffeine on nighttime melatonin and temperature levels in women taking and not taking oral contraceptives.

Caffeine and bright light effects on nighttime melatonin and temperature levels in women were tested during the luteal phase of the menstrual cycle (n=30) or the pseudo luteal phase for oral contraceptive users (n=32). Participants were randomly assigned to receive either bright (5000 lux) or dim room light (<88 lux) between 20:00 and 08:00 h under a modified constant routine protocol. Half the subjects in each lighting condition were administered either caffeine (100 mg) or placebo in a double-blind manner at 20:00, 23:00, 02:00 and 05:00 h. Results showed that the combination of bright light and caffeine enhanced nighttime temperature levels to a greater extent than did either caffeine or bright light alone. Both of the latter groups had higher temperature levels relative to the dim light placebo condition and the two groups did not differ. Temperature levels in the bright light caffeine condition were maintained at near peak circadian levels the entire night in the luteal and pseudo luteal phase. Melatonin levels were reduced throughout the duration of bright light exposure for all women. Caffeine reduced the onset of melatonin levels for women in the luteal phase, but it had little effect on melatonin levels for oral contraceptive users. The results for women in the luteal phase of the menstrual cycle are consistent with our previous findings in men. The results also suggest that oral contraceptives may alter the effects of caffeine on nighttime melatonin levels.

Effects of an experimentally induced rhinovirus cold on sleep, performance, and daytime alertness.

STUDY OBJECTIVES: There is accumulating evidence that the common cold produces impairments in psychomotor vigilance. This has led some investigators to hypothesize that such illnesses may also have disruptive effects on sleep. While several self-report studies suggest that viral illness may influence sleep parameters, no studies have assessed polysomnographically recorded sleep following viral infections. DESIGN: Parallel control group comparison. SETTING: Sleep laboratory in a large urban medical center. PARTICIPANTS: Twenty-one men and women with susceptibility to the rhinovirus type 23. INTERVENTIONS: Nasal inoculation with rhinovirus type 23. MEASUREMENTS: Polysomnographically recorded sleep for five nights (2300-0700 h) post-viral inoculation. Twice daily (1030 and 1430 h) performance assessment during each experimental day using auditory vigilance and divided attention tasks. A multiple sleep latency test (MSLT) was performed daily for the duration of the study. RESULTS: In symptomatic individuals, total sleep time decreased an average of 23 min, consolidated sleep decreased an average of 36 min, and sleep efficiency was reduced by an average of 5% during the active viral period (experimental days/nights 3-5) compared with the incubation period. Psychomotor performance was impaired. These changes were significantly greater than those observed in asymptomatic individuals. CONCLUSIONS: The common cold can have detrimental effects on sleep and psychomotor performance in symptomatic individuals during the initial active phase of the illness.

Seasonal variation in core temperature regulation during sleep in patients with winter seasonal affective disorder.

Nocturnal core temperature during sleep is elevated during depression compared with remission in nonseasonally depressed patients. Similarly, nocturnal core temperature is higher during winter depression compared with remission induced by light treatment in seasonal affective disorder (SAD) patients. We investigated whether nocturnal core temperature in SAD patients naturally becomes lower in summer (during remission) compared with winter (during depression). Twenty-four-hour core temperature profiles were obtained in winter and summer in 22 SAD patients and 22 controls. The nocturnal core temperature minima were lower in summer compared with winter in SAD patients (p < .005), but not controls (p > .4). The seasonal changes in nocturnal core temperatures in SAD patients may reflect a unique physiological responsiveness of SAD patients to the change of seasons, and may be intimately related to the seasonal disturbances of mood and energy that are characteristic of SAD.

Bimodal patterns of human melatonin secretion consistent with a two-oscillator model of regulation.

In many animals, changes in duration of nocturnal melatonin secretion chemically mediate effects of seasonal changes in nightlength on behavior and physiology. According to one model, the changes in duration of secretion result from adjustments in the timing of two circadian oscillators, one entrained to dusk, controlling onset, and another entrained to dawn, controlling offset. Consistent with this model, in six women, we found separate and reproducible evening and morning peaks of melatonin secretion that might represent the separate expressions of rhythms of two oscillators.

Systemic anaphylaxis after ingestion of a psyllium-containing breakfast cereal.

Allergic reactions have been described as an occupational hazard among nurses and pharmaceutical workers who handle psyllium-containing laxatives. This study reports the case of a 38-year-old female nurse who ingested a bowl of psyllium-containing Heartwise Cereal (Kelloggs, Battle Creek, MI) and 25 minutes later developed severe systemic anaphylaxis manifested by hypotension, a feeling of constriction in the throat, hoarseness, dyspnea, wheezing, generalized pruritus, urticaria, and vomiting. She was treated with epinephrine, normal saline, diphenhydramine, and methylprednisolone, and recovered completely. Subsequent IgE immunoblot assay was strongly reactive to psyllium. Ingestion of psyllium-containing breakfast foods by sensitized individuals can be associated with life-threatening systemic anaphylaxis.

Terminal cretaceous environmental events.

The geologic record of terminal Cretaceous environmental events indicates that iridium and other associated elements were not deposited instantaneously but during a time interval spanning some 10,000 to 100,000 years. The available geologic evidence favors a mantle rather than meteoritic origin for these elements. These results are in accord with the scenario of a series of intense eruptive volcanic events occurring during a relatively short geologic time interval and not with the scenario of a single large asteroid impact event.

The cretaceous-tertiary transition.

The fossil sequences from cores across the Cretaceous-Tertiary boundary show a, range of transition times and transition time intervals depending on the fossil indicators and the location of the site. These variations, together with the pattern of iridium distribution with depth at some sites, differences in total amounts of iridium, variations in noble metal abundances normalized to extraterrestrial concentrations, the depositional effects that might be expected in a reducing environment, and the clay mineralogy of the boundary layer clays, put into question the interpretation that an extraterrestrial event was the cause of the faunal changes and the iridium anomaly in the vicinity of the Cretaceous-Tertiary transition. It seems more likely that an explanation for the changes during the transition will come from continued examination of the great variety of terrestrial events that took place at that time, including extensive volcanism, major regression of the sea from the land, geochemical changes, and paleoclimatic and paleoceanographic changes.

Geodynamics--where are we and what lies ahead?

The introduction and evolution of the plate tectonics hypothesis during the past two decades has sparked the current renaissance of research in the earth sciences. An outgrowth of active geophysical and geological exploration of the oceans, the plate tectonics model has come under intense scrutiny by geologists, geochemists, and geophysicists who have attempted to apply the model to the origin and growth of continents, the generation of oceanic and continental crust, and the nature of the lithosphere, asthenosphere, and underlying mantle with respect to their evolution through time and to the driving mechanism or mechanisms for plate tectonics. The study of other terrestrial planets and moons has been helpful in understanding the earth model. The unequal distribution of geological features, both in the continents and oceans, emphasizes the need for ongoing studies of international scope such as the recently completed International Geodynamics Project and its successor, the International Lithosphere Program, both stressing studies related to the dynamics of the lithosphere.

The Earth and planetary sciences.

During the last two decades the earth sciences community has become persuaded that the earth is a dynamic body; an engine driven by its internal heat. The major surface manifestation of this dynamism has been fragmentation of the earth's outer shell and subsequent relative horizontal movement of the pieces on a large scale. The driving force is convection within the earth, but much remains to be learned about the nature of the convection and the composition of the earth's interior. The other terrestrial planets show evidence of once having been hot, but their surfaces suggest long-term stability and lack evidence of continuing convection.