Separation of circadian- and behavior-driven metabolite rhythms in humans provides a window on peripheral oscillators and metabolism.

Misalignment between internal circadian rhythmicity and externally imposed behavioral schedules, such as occurs in shift workers, has been implicated in elevated risk of metabolic disorders. To determine underlying mechanisms, it is essential to assess whether and how peripheral clocks are disturbed during shift work and to what extent this is linked to the central suprachiasmatic nuclei (SCN) pacemaker and/or misaligned behavioral time cues. Investigating rhythms in circulating metabolites as biomarkers of peripheral clock disturbances may offer new insights. We evaluated the impact of misaligned sleep/wake and feeding/fasting cycles on circulating metabolites using a targeted metabolomics approach. Sequential plasma samples obtained during a 24-h constant routine that followed a 3-d simulated night-shift schedule, compared with a simulated day-shift schedule, were analyzed for 132 circulating metabolites. Nearly half of these metabolites showed a 24-h rhythmicity under constant routine following either or both simulated shift schedules. However, while traditional markers of the circadian clock in the SCN-melatonin, cortisol, and PER3 expression-maintained a stable phase alignment after both schedules, only a few metabolites did the same. Many showed reversed rhythms, lost their rhythms, or showed rhythmicity only under constant routine following the night-shift schedule. Here, 95% of the metabolites with a 24-h rhythmicity showed rhythms that were driven by behavioral time cues externally imposed during the preceding simulated shift schedule rather than being driven by the central SCN circadian clock. Characterization of these metabolite rhythms will provide insight into the underlying mechanisms linking shift work and metabolic disorders.

Cardiac autonomic activity during simulated shift work.

Shift work leads to adverse health outcomes including increased risk of cardiovascular disease. Heart rate (HR) and heart rate variability (HRV) are measures of cardiac autonomic activity and markers of cardiovascular disease and mortality. To investigate the effects of shift work on cardiac autonomic activity, we assessed the influence of simulated night work on HR and HRV, and dissociated the direct effects of circadian misalignment from those of sleep displacement and altered physical activity patterns. A total of 29 subjects each participated in one of two in-laboratory, simulated shift work studies. In both studies, EKG was continuously monitored via Holter monitors to measure HR and the high frequency (HF) component of HRV (HF-HRV). We found endogenous circadian rhythmicity in HR and HF-HRV. Sleep and waking physical activity, both displaced during simulated night work, had more substantial, and opposite, effects on HR and HF-HRV. Our findings show systematic but complex, interacting effects of time of day, sleep/wake state, and physical activity on cardiac autonomic activity. These effects need to be taken into account when evaluating HR and HRV in shift work settings and when interpreting these measures of cardiac autonomic activity as markers of cardiovascular disease.

The circadian clock regulates cisplatin-induced toxicity and tumor regression in melanoma mouse and human models.

Cisplatin is one of the most commonly used chemotherapeutic drugs; however, toxicity and tumor resistance limit its use. Studies using murine models and human subjects have shown that the time of day of cisplatin treatment influences renal and blood toxicities. We hypothesized that the mechanisms responsible for these outcomes are driven by the circadian clock. We conducted experiments using wild-type and circadian disrupted Per1/2-/- mice treated with cisplatin at selected morning (AM) and evening (PM) times. Wild-type mice treated in the evening showed an enhanced rate of removal of cisplatin-DNA adducts and less toxicity than the morning-treated mice. This temporal variation in toxicity was lost in the Per1/2-/- clock-disrupted mice, suggesting that the time-of-day effect is linked to the circadian clock. Observations in blood cells from humans subjected to simulated day and night shift schedules corroborated this view. Per1/2-/- mice also exhibited a more robust immune response and slower tumor growth rate, indicating that the circadian clock also influences the immune response to melanoma tumors. Our findings indicate that cisplatin chronopharmacology involves the circadian clock control of DNA repair as well as immune responses, and thus affects both cisplatin toxicity and tumor growth. This has important implications for chronochemotherapy in cancer patients, and also suggests that influencing the circadian clock (e.g., through bright light treatment) may be explored as a tool to improve patient outcomes.

Predicting falls in older adults using the four square step test.

The Four Square Step Test (FSST) is a performance-based balance tool involving stepping over four single-point canes placed on the floor in a cross configuration. The purpose of this study was to evaluate properties of the FSST in older adults who lived independently. Forty-five community dwelling older adults provided fall history and completed the FSST, Berg Balance Scale (BBS), Timed Up and Go (TUG), and Tinetti in random order. Future falls were recorded for 12 months following testing. The FSST accurately distinguished between non-fallers and multiple fallers, and the 15-second threshold score accurately distinguished multiple fallers from non-multiple fallers based on fall history. The FSST predicted future falls, and performance on the FSST was significantly correlated with performance on the BBS, TUG, and Tinetti. However, the test is not appropriate for older adults who use walkers. Overall, the FSST is a valid yet underutilized measure of balance performance and fall prediction tool that physical therapists should consider using in ambulatory community dwelling older adults.

Predicting falls in community dwelling older adults using the Activities-specific Balance Confidence Scale.

OBJECTIVES: Falls are a significant problem associated with aging, and can lead to serious consequences including injury and death. The purpose of this study was to determine whether balance confidence differed between future fallers and non-fallers, and whether the construct prospectively predicted falls. METHODS: Forty-five community dwelling older adults aged 65 or older completed the Activities-specific Balance Confidence scale (ABC) and reported falls experienced during the next 6 months. RESULTS: Eleven (24.4%) subjects were fallers, and had significantly poorer ABC scores (x=50.6%) than their non-faller counterparts (x=76.3%). The regression model was significant, where the ABC score predicted falls at 6 months. DISCUSSION: Our findings suggest that balance confidence differs between fallers and non-fallers, and that ABC scores can predict future falls in community dwelling older adults. CONCLUSION: Balance confidence is a fall risk predictor, and thus a critical component of fall risk assessment. Balance confidence should be measured regularly in community dwelling older adults using the ABC.

Sleep and performance in simulated Navy watch schedules.

To operate Navy ships 24h per day, watchstanding is needed around the clock, with watch periods reflecting a variety of rotating or fixed shift schedules. The 5/15 watch schedule cycles through watch periods with 5h on, 15h off watch, such that watches occur 4h earlier on the clock each day - that is, the watches rotate backward. The timing of sleep varies over 4-day cycles, and sleep is split on some days to accommodate nighttime watchstanding. The 3/9 watch schedule cycles through watch periods with 3h on, 9h off watch, allowing for consistent sleep timing over days. In some sections of the 3/9 watch schedule, sleep may need to be split to accommodate nighttime watchstanding. In both the 5/15 and 3/9 watch schedules, four watch sections alternate to cover the 24h of the day. Here we compared sleep duration, psychomotor vigilance and subjective sleepiness in simulated sections of the 5/15 and 3/9 watch schedules. Fifteen healthy male subjects spent 6 consecutive days (5 nights) in the laboratory. Sleep opportunities were restricted to an average of 6.5h daily. Actigraphically estimated sleep duration was 5.6h per watch day on average, with no significant difference between watch sections. Sleep duration was not reduced when sleep opportunities were split. Psychomotor vigilance degraded over watch days, and tended to be more variable in the 5/15 than in the 3/9 watch sections. These laboratory-based findings suggest that Navy watch schedules are associated with cumulative sleep loss and a build-up of fatigue across days. The fixed watch periods of the 3/9 watch schedule appear to yield more stable performance than the backward rotating watch periods of the 5/15 watch schedule. Optimal performance may require longer and more consistent daily opportunities for sleep than are typically obtained in Navy operations.