Pegylated interferon pharmacokinetics and self-reported depressive symptoms during antiviral treatment for chronic hepatitis C.

BACKGROUND: Pegylated interferon-2a (PegIFN-2a)+ribavirin treatment for chronic hepatitis C is often associated with depressive symptoms. Previous studies have failed to explore whether PegIFN-2a pharmacokinetic variability plays an etiologic role in PegIFN-2a-induced mood disorders. The objective of this investigation was to evaluate the association between trough PegIFN-2a concentration at treatment week 4 ("PegIFN-2a Cmin4") and an increase in depressive symptoms. METHODS: Using data from Virahep-C, the association between PegIFN-2a Cmin4 and the following depression outcomes were evaluated using the Center for Epidemiological Studies-Depression scale (CES-D): (1) change in CES-D score from baseline to week 12; (2) greatest difference in CES-D score between baseline and weeks 4, 12, or 24; and (3) occurrence of severe depressive symptoms (CES-D greater than 23) at weeks 4, 12, or 24. One post-hoc analysis examined whether PegIFN-2a exposure during the first week of treatment was associated with change in CES-D score from baseline to week 4. RESULTS: No significant associations between PegIFN-2a Cmin4 and the depression outcomes were observed (p>0.05). Exploratory analyses suggest a possible relationship between PegIFN-2a exposure during the first week of therapy and CES-D score change from baseline to week 4 (p=0.03). CONCLUSIONS: PegIFN-2a concentration levels from baseline to week 4 do not predict the onset and severity of depressive symptoms during 24 weeks of antiviral therapy; however PegIFN-2a levels during the first week of treatment may predict depressive symptoms in the first 4 weeks, earlier than anticipated and warrants further exploration.

Adherence to PEG/ribavirin treatment for chronic hepatitis C: prevalence, patterns, and predictors of missed doses and nonpersistence.

Adherence to treatment for hepatitis C virus (HCV) maximizes treatment efficacy. Missed doses and failing to persist on treatment are two patient-level processes that are rarely defined or analysed separately from other factors affecting treatment adherence. We evaluated the prevalence and patterns of missed doses and nonpersistence, and identified patient characteristics associated with these outcomes. Missed doses of ribavirin (RBV) and peginterferon (PEG), measured prospectively in Virahep-C using electronic monitoring technology, were analysed using generalized estimating equations. Cox proportional hazards models analysed time to nonpersistence from baseline to week 24 (N = 401) and from week 24 to 48 in Responders (N = 242). Average proportion of PEG- and RBV-missed doses increased over time from 5% to 15% and 7% to 27%, respectively. Patients who were younger, African-American, unemployed, or unmarried were at greater risk of missing PEG from week 0 to 24; higher baseline depression predicted missing PEG from weeks 24 to 48. Patients who were younger or African-American were more likely to miss daily RBV from weeks 0 to 24; and those without private insurance or employment were more likely to miss RBV from weeks 24 to 48. Fifty-two patients failed to persist on treatment for patient-driven deviations. Predictors of nonpersistence from weeks 0 to 24 included younger age, lower education, public or no insurance, or worse baseline headaches. In conclusion, electronic monitoring and the prospective Virahep-C design afforded a unique opportunity to evaluate missing doses and nonpersistence separately, and identify patients at risk of nonadherence. These processes will be important to investigate as the dosing schedules of antiviral regimens become increasingly complex.

Reliability and validity of a self-efficacy instrument for hepatitis C antiviral treatment regimens.

Self-efficacy or confidence in one's ability to successfully engage in goal-directed behaviour has been shown to influence medication adherence across many chronic illnesses. In the present study, we investigated the psychometric properties of a self-efficacy instrument used during treatment for chronic hepatitis C viral infection (HCV). Baseline (n = 394) and treatment week 24 (n = 254) data from the prospective, longitudinal Viral Resistance to Antiviral Therapy of Chronic Hepatitis C study were examined. Baseline participants were randomly split into two equal-sized subsamples (S(1) and S(2) ). Initial exploratory and confirmatory factor analyses (EFA/CFA) were performed on S(1), while S(2) was used to validate the factor structure of the S(1) results using CFA. An additional CFA was performed on the treatment week 24 participants. Convergent and discriminant validity were assessed by comparing the revised instrument with other psychosocial measures: depression, social support, quality of life and medication-taking behaviour. Our findings supported a reduced 17-item global measure of HCV treatment self-efficacy (HCV-TSE) with four underlying factors: patient communication self-efficacy, general physical coping self-efficacy, general psychological coping self-efficacy and adherence self-efficacy. The global score (0.92-0.94) and four factors (0.85-0.96) demonstrated good internal consistency. Correlations of convergent and discriminant validity yielded low to moderate associations with other measures of psychosocial functioning. The revised HCV-TSE instrument provides a reliable and valid global estimate of confidence in one's ability to engage in and adhere to HCV antiviral treatment. The four-factor structure suggests different types of efficacy beliefs may function during HCV treatment and should be explored further in relation to clinical outcomes.

Lower birth weight indicates higher risk of autistic traits in discordant twin pairs.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder of complex etiology. Although strong evidence supports the causal role of genetic factors, environmental risk factors have also been implicated. This study used a co-twin-control design to investigate low birth weight as a risk factor for ASD. METHOD: We studied a population-based sample of 3715 same-sex twin pairs participating in the Child and Adolescent Twin Study of Sweden (CATSS). ASD was assessed using a structured parent interview for screening of ASD and related developmental disorders, based on DSM-IV criteria. Birth weight was obtained from medical birth records maintained by the Swedish Medical Birth Registry. RESULTS: Twins lower in birth weight in ASD-discordant twin pairs (n=34) were more than three times more likely to meet criteria for ASD than heavier twins [odds ratio (OR) 3.25]. Analyses of birth weight as a continuous risk factor showed a 13% reduction in risk of ASD for every 100 g increase in birth weight (n=78). Analysis of the effect of birth weight on ASD symptoms in the entire population (most of whom did not have ASD) showed a modest association. That is, for every 100 g increase in birth weight, a 2% decrease in severity of ASD indexed by scores on the Autism - Tics, attention-deficit hyperactivity disorder (AD/HD), and other Comorbidities (A-TAC) inventory would be expected in the sample as a whole. CONCLUSIONS: The data were consistent with the hypothesis that low birth weight confers risk to ASD. Thus, although genetic effects are of major importance, a non-genetic influence associated with birth weight may contribute to the development of ASD.

Pre- and postnatal determinants of childhood body size: cohort and sibling analyses.

Growing evidence suggests obesity may have its roots in early life but it is still uncertain whether prenatal factors operate primarily though altering early infant growth. It is also still unclear if rapid growth during selected time periods is more important than other time periods in predicting future body size. Using prospectively collected data on 20,523 participants born from 1959 to 1966 (10,327 boys; 10,196 girls) of the Collaborative Perinatal Project, we investigated the associations between pre- and postnatal factors and childhood body size at age 7 years and compared these associations across linear, logistic and quantile regression models. Maternal body mass index (BMI), maternal pregnancy weight gain, birth weight and postnatal weight change for three time periods (birth to 4 months; 4-12 months; 1-4 years) were all positively and independently associated with BMI at age 7 years. Rapid growth during each time period had a similar association BMI at age 7 years. For example, a 10-percentile increase in weight increased the probability of being overweight at age 7 years by approximately two-fold regardless of time period (OR = 1.8-2.2 for boys and girls). Using same-sex siblings (n = 571 boy sets; n = 651 girl sets) from the same cohort, we observed that siblings with higher BMI at age 7 years than their same-sex siblings were more likely to have higher maternal pregnancy weight gain, higher maternal pre-pregnancy BMI, higher birth weight and increased rate of weight gain during the three time periods. These consistent findings both from the overall cohort and the sibling analyses suggest that there are multiple, rather than specific critical periods of influence shaping childhood body size.

Barriers to accessing care in patients with chronic hepatitis C: the impact of depression.

BACKGROUND: Patients with hepatitis C viral (HCV) may perceive barriers to accessing speciality care for HCV, and these barriers may be related to depressive symptoms. AIM: To evaluate the relationship between barriers to care, demographics, and depressive symptoms. METHODS: A cross-sectional analysis of 126 patients referred for HCV at two speciality HCV clinics. Barriers to care, depressive symptoms and sociodemographics were measured using standardized instruments. A retrospective chart review was conducted to collect clinical outcome data. RESULTS: Depressive symptoms were reported in 26%. Common barriers included lack of personal financial resources; lack of HCV knowledge in the community; lack of professionals competent in HCV care; stigmatization of HCV; and long distances to clinics offering care. After we controlled for sociodemographics, depression accounted for an additional 7-18% of variability in all barriers (all p values <0.01). Lower depression, marital and employment status were associated with subsequent receipt of HCV treatment in 38% (45/120) of patients; perceived barriers were not. CONCLUSIONS: Depression is independently associated with perceived barriers to care. Higher depressive scores, but not perceived barriers, were associated with nontreatment. Healthcare providers who diagnose HCV need to be cognizant of numerous perceived barriers to accessing HCV care, and the impact that depression may have on these perceptions and receipt of treatment.

S100A9 is not essential for disease expression in an acute (K/BxN) or chronic (CIA) model of inflammatory arthritis.

OBJECTIVE: S100A8 (calgranulin A, MRP8) and S100A9 (calgranulin B, MRP14) are calcium-binding proteins highly expressed by activated myeloid cells and thought to be involved in the pathogenesis of inflammatory diseases. Circulating levels of S100A8/S100A9 are elevated in both human and experimental models of autoimmune disease, including rheumatoid arthritis (RA). METHODS: Mice deficient in S100A9 (S100A9 - /-) and wild-type controls were immunized using standard techniques for the K/BxN serum transfer or the collagen-induced arthritis (CIA) model. RESULTS: S100A9 - /- animals, with defective expression of both S100A8 and S100A9 proteins, had similar arthritis and histopathology to that of wild-type controls in both mouse models. CONCLUSION: S100A8 and S100A9 are not essential for disease expression in either the K/BxN serum transfer or the CIA model of inflammatory arthritis.

Multimodal optical and Gd-based nanoparticles for imaging in inflammatory arthritis.

OBJECTIVES: This report documents a multimodal nanoparticle (MNP) contrast agent, containing embedded luminophores and surface-immobilized gadolinium chelates, as a contrast agent of inflamed synovium in a collagen induced arthritis (CIA) model. METHODS: DBA-1J mice were immunized for CIA and imaged after disease onset by two independent modalities. After intravenous administration of MNP contrast, optical and magnetic resonance images were obtained and clinical disease was scored, which was followed by processing of hindlimbs for immunofluorescence and confocal microscopy. RESULTS: We show a correlation between disease severity and MNP optical luminescence that is dose dependent. Immunofluorescence of hindlimb sections reveal that MNP-labeled cells are monocytes/macrophages within the inflamed synovium. Magnetic resonance (MR) relaxation time maps, which determine the quantitative measure of T1 and T2 values at each imaging voxel, demonstrated a decreasing T2 signal in actively inflamed joints that was more pronounced earlier rather than later during disease. CONCLUSIONS: MNPs containing surface-immobilized gadolinium chelates and embedded luminophores are potential dual-modality contrast agents in inflammatory arthritis and localize to monocytes/macrophages within inflamed synovium.