Publications

BACKGROUND AND OBJECTIVES

Previous studies have found that a major proportion of patients with chronic hepatitis B (CHB) do not receive antiviral therapy. The objective of this study was to characterize treatment eligibility on the basis of current guidelines, determine whether eligible patients actually receive treatment, and examine associated predictors.

METHODS

We conducted a retrospective study of patients who were evaluated for CHB at two community gastroenterology clinics between April 2007 and February 2009. Using criteria published by the American Association for the Study of Liver Diseases (AASLD) in 2007-2009 and by a panel of US hepatologists (US Panel) in 2006-2008, treatment eligibility was determined for the patients.

RESULTS

Of 612 consecutive CHB patients included, mean age was 44 ± 13 years, 54 % were male, and 99 % were Asian. Half (51 %) were eligible for treatment on the basis of the US Panel algorithm and 47 % of these patients also met AASLD treatment criteria. Overall, antiviral therapy was initiated for 50 % of eligible patients: 72 % of AASLD-eligible patients and 29 % of patients who were US Panel-eligible only. Independent predictors for actual treatment initiation were higher ALT for AASLD-eligible patients and higher ALT and older age for patients who were US Panel-eligible only. The leading reasons for nontreatment were further observation recommended by the physician, followed by loss of follow-up and patient refusal.

CONCLUSIONS

Approximately half of the CHB patients evaluated at community referral clinics met treatment criteria of at least one guideline; however, only about half received antiviral therapy within 12 months of presentation. Further studies are needed to optimize treatment of eligible CHB patients.

Biological oscillators naturally exhibit stochastic fluctuations in period and amplitude due to the random nature of molecular reactions. Accurately measuring the precision of noisy oscillators and the heterogeneity in period and strength of rhythmicity across a population of cells requires single-cell recordings of sufficient length to fully represent the variability of oscillations. We found persistent, independent circadian oscillations of clock gene expression in 6-week-long bioluminescence recordings of 80 primary fibroblast cells dissociated from PER2::LUC mice and kept in vitro for 6 months. Due to the stochastic nature of rhythmicity, the proportion of cells appearing rhythmic increases with the length of interval examined, with 100% of cells found to be rhythmic when using 3-week windows. Mean period and amplitude are remarkably stable throughout the 6-week recordings, with precision improving over time. For individual cells, precision of period and amplitude are correlated with cell size and rhythm amplitude, but not with period, and period exhibits much less cycle-to-cycle variability (CV 7.3%) than does amplitude (CV 37%). The time series are long enough to distinguish stochastic fluctuations within each cell from differences among cells, and we conclude that the cells do exhibit significant heterogeneity in period and strength of rhythmicity, which we measure using a novel statistical metric. Furthermore, stochastic modeling suggests that these single-cell clocks operate near a Hopf bifurcation, such that intrinsic noise enhances the oscillations by minimizing period variability and sustaining amplitude.

BACKGROUND

Epidemiologic studies suggest that LDL particle concentration (LDL-P) may remain elevated at guideline recommended LDL cholesterol goals, representing a source of residual risk. We examined the following seven separate lipid parameters in achieving the LDL-P goal of <1000 nmol/L goal for very high risk secondary prevention: total cholesterol to HDL cholesterol ratio, TC/HDL, <3; a composite of ATP-III very high risk targets, LDL-C<70 mg/dL, non-HDL-C<100 mg/dL and TG<150 mg/dL; a composite of standard secondary risk targets, LDL-C<100, non-HDL-C<130, TG<150; LDL phenotype; HDL-C ≥ 40; TG<150; and TG/HDL-C<3.

METHODS

We measured ApoB, ApoAI, ultracentrifugation lipoprotein cholesterol and NMR lipoprotein particle concentration in 148 unselected primary and secondary prevention patients.

RESULTS

TC/HDL-C<3 effectively discriminated subjects by LDL-P goal (F = 84.1, p<10(-6)). The ATP-III very high risk composite target (LDL-C<70, nonHDL-C<100, TG<150) was also effective (F = 42.8, p<10(-5)). However, the standard secondary prevention composite (LDL-C<100, non-HDL-C<130, TG<150) was also effective but yielded higher LDL-P than the very high risk composite (F = 42.0, p<10(-5)) with upper 95% confidence interval of LDL-P less than 1000 nmol/L. TG<150 and TG/HDL-C<3 cutpoints both significantly discriminated subjects but the LDL-P upper 95% confidence intervals fell above goal of 1000 nmol/L (F = 15.8, p = 0.0001 and F = 9.7, p = 0.002 respectively). LDL density phenotype neared significance (F = 2.85, p = 0.094) and the HDL-C cutpoint of 40 mg/dL did not discriminate (F = 0.53, p = 0.47) alone or add discriminatory power to ATP-III targets.

CONCLUSIONS

A simple composite of ATP-III very high risk lipoprotein cholesterol based treatment targets or TC/HDL-C ratio <3 most effectively identified subjects meeting the secondary prevention target level of LDL-P<1000 nmol/L, providing a potential alternative to advanced lipid testing in many clinical circumstances.