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Discussion
The present study showed that CRAR disruptions, characterised by low amplitude, low mesor and high fragmentation, were significantly associated with an increased risk of all-cause, cancer and CVD mortalities. These associations were robust following a series of sensitivity and interaction analyses. Notably, these associations remained valid after controlling for age, sex, cancer prognosis, smoking status, alcohol consumption and depression. Moreover, the associations remained robust across the different cancer types. Comparative analyses demonstrated that the CRAR parameters, particularly low RA, exceeded multiple traditional risk factors for mortality, such as poor sleep, smoking, alcohol consumption, obesity and unhealthy diet, in predicting mortality outcomes. These findings highlight the robust predictive capacity of CRAR disruption for mortality risk in patients with cancer.
The findings of this study provide substantial evidence that a low I
In humans, circadian rhythm assessment encompasses the phase (timing), amplitude, central tendency (mesor), day-to-day regularity, fragmentation and robustness of the rhythms.30 Growing evidence suggests that disturbances in these circadian measures are the most common parameters that lead to diverse adverse health consequences, such as CVD, mood disorders and neurodegenerative diseases.11 31 However, the association between multidimensional CRAR parameters and mortality risk in patients with cancer remains unclear. In addition to I
Several possible mechanisms may contribute to the association between CRAR disruption and an increased mortality risk in patients with cancer. First, human genetic studies have indicated that decreased CRAR amplitude is associated with mutations in ZF21, which is involved in cell migration, a key process in tumour invasion.32 Second, CRAR disruption induces dysregulation of the natural immune response and T-cell cytokine production, implying that an impaired immune response leads to metastasis in different cancer types.33 34 Third, the mutation or deletion of circadian genes, such as Per1/2, Clock, Bmal1 and Cry1/2, can accelerate the progression of liver, lung, colorectal and ovarian cancers.35 36 Fourth, light-at-night can suppress endogenous melatonin secretion, a hormone with well-documented antineoplastic, antioxidant and immune-modulating properties and promote nocturnal activity, both of which may disturb circadian homeostasis. Although melatonin levels and light-at-night exposure were not directly assessed in this study, their potential role as mediators of circadian disruption and cancer mortality warrants investigation in future research. A better understanding provided by this study of how the CRAR amplitude affects pathophysiological processes can be leveraged to design disease prevention and treatment strategies for cancers.
Implications
First, this study identified CRAR parameters as robust markers for predicting survival in patients with cancer, demonstrating greater efficacy than other traditional risk factors. CRAR parameters can be readily and accurately measured, offering a promising avenue for identifying individuals at an ultrahigh risk in clinical practice. Second, CRAR may serve as a potential safety endpoint in cancer management. Previous studies have demonstrated that chemotherapy cycles can disrupt CRAR.37 Third, the finding that RA showed the strongest predictive ability highlights the importance of integrating the health effects of physical activity and its timing. Previous studies have typically measured and accumulated physical activity across nights and days, thus neglecting the health effects of the timing of physical activity. In terms of RA, high daytime physical activity is considered to be protective, whereas high night-time physical activity is detrimental. Lastly, our study indicates that improving CRAR could be a useful means to minimise the mortality risk in patients with cancer. In addition to physical exercise and good sleep, previous evidence has shown that chronotherapeutic interventions such as melatonin and bright light can improve CRAR in multiple disease conditions.38 Further interventional investigations should be performed to clarify the effects of improving the CRAR on cancer prognosis.
Limitations
First, although 7-day monitoring periods are commonly used in circadian rhythm monitoring studies because of their ability to capture CRAR across both weekdays and weekends and their reliability for within-year repeated assessments,39 it remains uncertain whether a 7-day accelerometer measurement adequately reflects longer-term behavioural patterns. Second, the observational nature of this study precludes causal inferences. Although we made extensive efforts to minimise the risks of confounding and reverse causality, such as controlling for a range of covariates and excluding events that occurred during the first year of follow-up, residual or unmeasured confounding factors cannot be ruled out. Third, the most population was white ethnicity (97.96%), and this homogeneity can limit the external validity of the study. Future studies should prioritise more representative sampling or validate findings in more diverse cohorts. Fourth, some covariates, such as lifestyle variables, were collected mainly during physical visits to the assessment centres, nearly a few years before the present study baseline. However, because these covariates are generally stable over time,40 this time lag is unlikely to weaken our findings. Fifth, this study encompassed diverse cancer types and performed subgroup analyses for several cancer categories, enabling the exploration of the widespread impact of CRAR dysregulation on survival across various cancer types. However, additional research is warranted to elucidate the relationship between CRAR and mortality in specific cancer types. Furthermore, information on cancer aggressiveness, such as stage, treatment and morphology, which are critical factors influencing prognosis and mortality, has been incorporated into the UK Biobank. Future studies investigations should consider these variables.
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