Circadian rhythms in solid organ transplantation.

Circadian rhythms are daily cycles in physiology that can affect medical interventions. This review considers how these rhythms may relate to solid organ transplantation. It begins by summarizing the mechanism for circadian rhythm generation known as the molecular clock, and basic research connecting the clock to biological activities germane to organ acceptance. Next follows a review of clinical evidence relating time of day to adverse transplantation outcomes. The concluding section discusses knowledge gaps and practical areas where applying circadian biology might improve transplantation success.

Circadian immunity from bench to bedside: a practical guide.

The immune system is built to counteract unpredictable threats, yet it relies on predictable cycles of activity to function properly. Daily rhythms in immune function are an expanding area of study, and many originate from a genetically based timekeeping mechanism known as the circadian clock. The challenge is how to harness these biological rhythms to improve medical interventions. Here, we review recent literature documenting how circadian clocks organize fundamental innate and adaptive immune activities, the immunologic consequences of circadian rhythm and sleep disruption, and persisting knowledge gaps in the field. We then consider the evidence linking circadian rhythms to vaccination, an important clinical realization of immune function. Finally, we discuss practical steps to translate circadian immunity to the patient's bedside.

Biological rhythms in COVID-19 vaccine effectiveness in an observational cohort study of 1.5 million patients.

BACKGROUNDCircadian rhythms are evident in basic immune processes, but it is unclear if rhythms exist in clinical endpoints like vaccine protection. Here, we examined associations between COVID-19 vaccination timing and effectiveness.METHODSWe retrospectively analyzed a large Israeli cohort with timestamped COVID-19 vaccinations (n = 1,515,754 patients over 12 years old, 99.2% receiving BNT162b2). Endpoints included COVID-19 breakthrough infection and COVID-19-associated emergency department visits and hospitalizations. Our main comparison was among patients vaccinated during morning (800-1159 hours), afternoon (1200-1559 hours), or evening hours (1600-1959 hours). We employed Cox regression to adjust for differences in age, sex, and comorbidities.RESULTSBreakthrough infections differed based on vaccination time, with lowest the rates associated with late morning to early afternoon and highest rates associated with evening vaccination. Vaccination timing remained significant after adjustment for patient age, sex, and comorbidities. Results were consistent in patients who received the basic 2-dose series and who received booster doses. The relationship between COVID-19 immunization time and breakthrough infections was sinusoidal, consistent with a biological rhythm that modifies vaccine effectiveness by 8.6%-25%. The benefits of daytime vaccination were concentrated in younger (<20 years old) and older patients (>50 years old). COVID-19-related hospitalizations varied significantly with the timing of the second booster dose, an intervention reserved for older and immunosuppressed patients (HR = 0.64, morning vs. evening; 95% CI, 0.43-0.97; P = 0.038).CONCLUSIONWe report a significant association between the time of COVID-19 vaccination and its effectiveness. This has implications for mass vaccination programs.FUNDINGNIH.

Age-dependent rebound in asthma exacerbations after COVID-19 lockdown.

Background: Virus mitigation measures enacted early in the coronavirus infectious disease 2019 (COVID-19) pandemic suppressed common respiratory viruses and reduced the number of obstructive lung disease exacerbations. However, many localities began to ease these precautions in the year 2021, leading to a resurgence of non-COVID viruses. How asthma and chronic obstructive pulmonary disease (COPD) activity responded to this upswing in viral abundance is unclear. Objective: Our aim was to examine how viral resurgence during the relaxation of COVID-19 restrictions affected asthma and COPD exacerbations. Methods: We analyzed electronic medical records for emergency department (ED) respiratory virus positivity, asthma visits, and COPD visits. We compared the 52-week interval before the COVID-19 restrictions (the pre-lockdown period [March 22, 2019-March 19, 2020]), the 52-week period immediately following enactment of the restrictions (the lockdown period [March 20, 2020-March 18, 2021]), and the 52-week period thereafter (the post-lockdown period [March 19, 2021-March 18, 2022]). We used MetaCYCLE to analyze seasonal trends in our data. Results: The post-lockdown period was marked by a 400% increase in viral positivity compared with during the lockdown period. Asthma- and COPD-related ED visits each rose 37% compared with during the lockdown, with the rebound in asthma ED visits concentrated in individuals younger than 20 years. Interestingly, after the lockdown period, asthma ED visits overcorrected in children younger than 5 years, rising 81% compared with before the lockdown. Seasonal rhythms in asthma and COPD exacerbations were suppressed during the lockdown and recovered after the lockdown. Conclusions: COVID-19 precautions had the unexpected effect of magnifying early-childhood asthma activity once common respiratory viruses recurred. These results may have implications for the future use of virus mitigation strategies in young children.

Patient-reported barriers are associated with lower hepatocellular carcinoma surveillance rates in patients with cirrhosis.

Over 20% of patients with cirrhosis are nonadherent with hepatocellular carcinoma (HCC) surveillance recommendations; however, few studies have evaluated the impact of patient-level factors on surveillance receipt. We characterized the association between HCC surveillance receipt and patient knowledge, attitudes, and perceived barriers in a racially diverse and socioeconomically disadvantaged cohort of patients with cirrhosis. Patients with cirrhosis followed at a large urban hospital were invited to complete a survey about HCC surveillance between August 2014 and December 2015. Multivariable logistic regression was performed to identify factors associated with HCC surveillance receipt during the 12-month period preceding and 6-month period after survey administration. We achieved a response rate of 71.8% (n = 541 of 753). Patients demonstrated high levels of HCC-related knowledge (summary score, 77.7%); however, 48.6% believed that eating a healthy diet precluded the need for HCC surveillance, and 34.0% believed that HCC surveillance was not necessary if they had a normal physical exam and/or lacked clinical symptoms. Patients expressed worry about developing and dying from HCC, but nearly half (49.9%) of patients reported barriers to receiving HCC surveillance, including difficulty with the scheduling process (30.5%), costs of surveillance testing (25.3%), and transportation difficulties (17.3%). HCC surveillance receipt was significantly higher in patients who knew cirrhosis is a risk factor for developing HCC (odds ratio [OR], 3.09; 95% confidence interval [CI], 1.25-7.62) and significantly lower in those reporting barriers to surveillance (OR, 0.42; 95% CI, 0.25-0.70). CONCLUSION: Patients with cirrhosis are knowledgeable and interested in HCC surveillance; however, patient-reported barriers are associated with lower surveillance rates in clinical practice and represent potential intervention targets to improve HCC surveillance effectiveness. (Hepatology 2017;65:875-884).

Role functioning is associated with survival in patients with hepatocellular carcinoma.

BACKGROUND: Prior studies assessing quality of life (QOL) in patients with hepatocellular carcinoma (HCC) primarily included patients with preserved liver function and/or early HCC, leading to overestimation of QOL. Our study's aim was to evaluate the association of QOL with survival among a cohort of cirrhotic patients with HCC that was diverse with respect to liver function and tumor stage. METHODS: We conducted a prospective cohort study among cirrhotic patients with HCC from a large urban safety-net hospital between April 2011 and September 2013. Patients completed two self-administered surveys, the EORTC QLQ-C30 and QLQ-HCC18, prior to the treatment. We used generalized linear models to identify correlates of QOL. Survival curves were generated using Kaplan-Meier analysis and compared using log rank test to determine whether QOL is associated with survival. RESULTS: A total of 130 treatment-naïve patients completed both surveys. Patients reported high cognitive and social function (median scores 67) but poor global QOL (median score 50) and poor role function (median score 50). QOL was associated with cirrhosis-related (p = 0.02) and tumor-related (p = 0.02) components of Barcelona Clinic Liver Cancer (BCLC) tumor stage. QOL was associated with survival on univariate analysis (HR 0.37, 95 % CI 0.16-0.85) but became nonsignificant (HR 0.82, 95 % CI 0.37-1.80) after adjusting for BCLC stage and treatment. Role functioning was significantly associated with survival (HR 0.40, 95 % CI 0.20-0.81), after adjusting for Caucasian race (HR 0.31, 95 % CI 0.16-0.59), BCLC stage (HR 1.51, 95 % CI 0.21-1.89), and treatment (HR 0.57, 95 % CI 0.33-0.97). CONCLUSIONS: Role function has prognostic significance and is important to assess in patients with HCC.