Comparative effectiveness of triple versus dual inhaled therapy (ICS/LABA or LABA/LAMA) for chronic obstructive pulmonary disease: a systematic review and network meta-analysis.

The circadian clock organizes the physiology and behavior of most lifeforms on Earth into 24-h rhythms aligned with the solar cycle. This organization begins in most single cells, where a molecular clock driven by an oscillatory transcription/translation feedback loop regulates tissue-specific clock-controlled gene expression throughout the daily cycle. Core mammalian clock components include the heterodimeric transcription factors BMAL1 and CLOCK, which cooperatively promote the expression of their own negative regulatory and genes, ultimately leading to the inhibition of BMAL1:CLOCK driven transcription. At the circuit level, light input adjusts circadian phase in cells of the suprachiasmatic nucleus (SCN) in the brain, aligning clock-controlled genes that regulate SCN activity to the day:night cycle, which in turn orchestrates systemic autonomic, hormonal, and body temperature rhythms that entrain peripheral clocks to light. Ultimately, this organizes whole-body circadian rhythms in physiology and behavior, including sleep, feeding, and metabolism. The health impacts of these rhythms are salient in modern society. Widely available artificial lighting and refrigeration cause mis-timed exposure of most humans to circadian entrainment cues such as light and food at evolutionarily unprecedented levels. Moreover, many people live on “flipped” circadian schedules, with >15% of the US workforce employed at shift work hours outside of a standard diurnal schedule. Elevated risk of obesity and metabolic disease in shift workers suggests not only direct health impacts from their extreme circadian misalignment, but also more subtle contributions of mis-timed circadian inputs to our society-wide epidemic of these conditions. This underscores the importance of understanding how the circadian clock is coupled to metabolism. Such connections are widespread, with metabolism-relevant genes well represented among the ~15% of the mouse transcriptome under circadian control across tissues. One cell population of particular interest in linking circadian rhythms with metabolism is hypothalamic tanycytes. These radial glia-like cells line the floor of the 3rd ventricle (3V), adjacent to tuberal hypothalamic nuclei involved in feeding and metabolism: the ventromedial hypothalamus (VMH), arcuate nucleus (ARC), and median eminence (ME). Tanycytes play a number of roles in metabolism that are likely under some level of circadian control, including detection and import of peripheral metabolic hormones such as leptin, and gating of the central release of systemic TRH, CRH, and sex hormones.