Semantic Representations during Language Comprehension Are Affected by Context.

The meaning of words in natural language depends crucially on context. However, most neuroimaging studies of word meaning use isolated words and isolated sentences with little context. Because the brain may process natural language differently from how it processes simplified stimuli, there is a pressing need to determine whether prior results on word meaning generalize to natural language. fMRI was used to record human brain activity while four subjects (two female) read words in four conditions that vary in context: narratives, isolated sentences, blocks of semantically similar words, and isolated words. We then compared the signal-to-noise ratio (SNR) of evoked brain responses, and we used a voxelwise encoding modeling approach to compare the representation of semantic information across the four conditions. We find four consistent effects of varying context. First, stimuli with more context evoke brain responses with higher SNR across bilateral visual, temporal, parietal, and prefrontal cortices compared with stimuli with little context. Second, increasing context increases the representation of semantic information across bilateral temporal, parietal, and prefrontal cortices at the group level. In individual subjects, only natural language stimuli consistently evoke widespread representation of semantic information. Third, context affects voxel semantic tuning. Finally, models estimated using stimuli with little context do not generalize well to natural language. These results show that context has large effects on the quality of neuroimaging data and on the representation of meaning in the brain. Thus, neuroimaging studies that use stimuli with little context may not generalize well to the natural regime.SIGNIFICANCE STATEMENT Context is an important part of understanding the meaning of natural language, but most neuroimaging studies of meaning use isolated words and isolated sentences with little context. Here, we examined whether the results of neuroimaging studies that use out-of-context stimuli generalize to natural language. We find that increasing context improves the quality of neuro-imaging data and changes where and how semantic information is represented in the brain. These results suggest that findings from studies using out-of-context stimuli may not generalize to natural language used in daily life.

Impact of electronic health record-based, pharmacist-driven valganciclovir dose optimization in solid organ transplant recipients.

BACKGROUND: Prophylaxis with valganciclovir reduces the incidence of cytomegalovirus (CMV) infection following solid organ transplant (SOT). Under-dosing of valganciclovir is associated with an increased risk of CMV infection and development of ganciclovir-resistant CMV. METHODS: An automated electronic health record (EHR)-based, pharmacist-driven program was developed to optimize dosing of valganciclovir in solid organ transplant recipients at a large transplant center. Two cohorts of kidney, pancreas-kidney, and liver transplant recipients from our center pre-implementation (April 2011-March 2012, n = 303) and post-implementation of the optimization program (September 2012-August 2013, n=263) had demographic and key outcomes data collected for 1 year post-transplant. RESULTS: The 1-year incidence of CMV infection dropped from 56 (18.5%) to 32 (12.2%, P = .05) and the incidence of breakthrough infections on prophylaxis was cut in half (61% vs 34%, P = .03) after implementation of the dose optimization program. The hazard ratio of developing CMV was 1.64 (95% CI 1.06-2.60, P = .027) for the pre-implementation group after adjusting for potential confounders. The program also resulted in a numerical reduction in the number of ganciclovir-resistant CMV cases (2 [0.7%] pre-implementation vs 0 post-implementation). CONCLUSIONS: An EHR-based, pharmacist-driven valganciclovir dose optimization program was associated with reduction in CMV infections.

Combinations of bright light, scheduled dark, sunglasses, and melatonin to facilitate circadian entrainment to night shift work.

Various combinations of interventions were used to phase-delay circadian rhythms to correct their misalignment with night work and day sleep. Young participants (median age = 22, n = 67) participated in 5 consecutive simulated night shifts (2300 to 0700) and then slept at home (0830 to 1530) in darkened bedrooms. Participants wore sunglasses with normal or dark lenses (transmission 15% or 2%) when outside during the day. Participants took placebo or melatonin (1.8 mg sustained release) before daytime sleep. During the night shifts, participants were exposed to a moving (delaying) pattern of intermittent bright light (approximately 5000 lux, 20 min on, 40 min off, 4-5 light pulses/night) or remained in dim light (approximately 150 lux). There were 6 intervention groups ranging from the least complex (normal sunglasses) to the most complex (dark sunglasses + bright light + melatonin). The dim light melatonin onset (DLMO) was assessed before and after the night shifts (baseline and final), and 7 h was added to estimate the temperature minimum (Tmin). Participants were categorized by their amount of reentrainment based on their final Tmin: not re-entrained (Tmin before the daytime dark/sleep period), partially re-entrained (Tmin during the first half of dark/sleep), or completely re-entrained (Tmin during the second half of dark/ sleep). The sample was split into earlier participants (baseline Tmin < or = 0700, sunlight during the commute home fell after the Tmin) and later participants (baseline Tmin > 0700). The later participants were completely re-entrained regardless of intervention group, whereas the degree of re-entrainment for the earlier participants depended on the interventions. With bright light during the night shift, almost all of the earlier participants achieved complete re-entrainment, and the phase delay shift was so large that darker sunglasses and melatonin could not increase its magnitude. With only room light during the night shift, darker sunglasses helped earlier participants phase-delay more than normal sunglasses, but melatonin did not increase the phase delay. The authors recommend the combination of intermittent bright light during the night shift, sunglasses (as dark as possible) during the commute home, and a regular, early daytime dark/sleep period if the goal is complete circadian adaptation to night-shift work.

Complete or partial circadian re-entrainment improves performance, alertness, and mood during night-shift work.

STUDY OBJECTIVES: To assess performance, alertness, and mood during the night shift and subsequent daytime sleep in relation to the degree of re-alignment (re-entrainment) of circadian rhythms with a night-work, day-sleep schedule. DESIGN: Subjects spent 5 consecutive night shifts (11:00 pm-7:00 am) in the lab and slept at home in darkened bedrooms (8:30 am-3:30 pm). Subjects were categorized by the degree of re-entrainment attained after the 5 night shifts. Completely re-entrained: temperature minimum in the second half of daytime sleep; partially re-entrained: temperature minimum in the first half of daytime sleep; not re-entrained: temperature minimum did not delay enough to reach daytime sleep. SETTING: See above. PARTICIPANTS: Young healthy adults (n = 67) who were not shift workers. INTERVENTIONS: Included bright light during the night shifts, sunglasses worn outside, a fixed dark daytime sleep episode, and melatonin. The effects of various combinations of these interventions on circadian re-entrainment were previously reported. Here we report how the degree of re-entrainment affected daytime sleep and measures collected during the night shift. MEASUREMENTS AND RESULTS: Salivary melatonin was collected every 30 minutes in dim light (<20 lux) before and after the night shifts to determine the dim light melatonin onset, and the temperature minimum was estimated by adding a constant (7 hours) to the dim light melatonin onset. Subjects kept sleep logs, which were verified by actigraphy. The Neurobehavioral Assessment Battery was completed several times during each night shift. Baseline sleep schedules and circadian phase differed among the 3 re-entrainment groups, with later times resulting in more re-entrainment. The Neurobehavioral Assessment Battery showed that performance, sleepiness, and mood were better in the groups that re-entrained compared to the group that did not re-entrain, but there were no significant differences between the partial and complete re-entrainment groups. Subjects slept almost all of the allotted 7 hours during the day, and duration did not significantly differ among the re-entrainment groups. CONCLUSIONS: In young people, complete re-entrainment to the night-shift day-sleep schedule is not necessary to produce substantial benefits in neurobehavioral measures; partial re-entrainment (delaying the temperature minimum into the beginning of daytime sleep) is sufficient. The group that did not re-entrain shows that a reasonable amount of daytime sleep is not enough to produce good neurobehavioral performance during the night shift. Therefore, some re-alignment of circadian rhythms is recommended.

Circadian phase determined from melatonin profiles is reproducible after 1 wk in subjects who sleep later on weekends.

The aim of this study was to determine whether circadian phase from salivary melatonin profiles is the same when measured in phase assessments 1 wk apart. Eleven healthy young men and women maintained a fixed, home sleep-wake schedule, in bed, in the dark 23:00-07:00 hr on weekdays. On Friday and Saturday nights they were permitted to wake up and go to bed up to 1 hr later, and on Saturdays and Sundays they could nap between 13:30 and 16:30 hr. The study was run in the summer. Subjects wore sunglasses when outside during the day, and went outside for at least 15 min between 08:00 and 09:00 hr each morning. They maintained this schedule for 15 days before the first assessment and the 6 days in between the two assessments. During the assessments subjects remained awake overnight in <5 lux and gave saliva samples every 30 min. A recovery nap (13:00-17:00 hr) followed the first session. The dim light melatonin onset (DLMO), offset (DLMOff) and midpoint were used as phase markers. There was minimal change in their timing between the two phase assessments. The average absolute change in midpoint (the change in phase regardless of direction) was 20 min. There was a small, 30 min delay in the DLMO. Thus, circadian phase can be measured a week in advance of any phase shifting intervention and, as long as the prescribed sleep and morning light schedule is maintained, the phase at the start of treatment can be confidently estimated.