IFNL3/4 genotype is associated with altered immune cell populations in peripheral blood in chronic hepatitis C infection.

Single-nucleotide polymorphisms near the interferon lambda 3 (IFNL3) gene predict outcomes to infection and anti-viral treatment in hepatitis C virus (HCV) infection. To identify IFNL3 genotype effects on peripheral blood, we collected phenotype data on 400 patients with genotype 1 chronic hepatitis C (CHC). The IFNL3 responder genotype predicted significantly lower white blood cells (WBCs), as well as lower absolute numbers of monocytes, neutrophils and lymphocytes for both rs8099917 and rs12979860. We sought to define the WBC subsets driving this association using flow cytometry of 67 untreated CHC individuals. Genotype-associated differences were seen in the ratio of CD4CD45RO+ to CD4CD45RO-; CD8CD45RO+ to CD8CD45RO-, NK CD56 dim to bright and monocyte numbers and percentages. Whole blood expression levels of IFNL3, IFNLR1 (interferon lambda receptor 1), IFNLR1-mem (a membrane-associated receptor), IFNLR1-sol (a truncated soluble receptor), MxA and T- and NK (natural killer) cell transcription factors TBX21, GATA3, RORC, FOXP3 and EOMES in two subjects were also determined. CHC patients demonstrated endogenous IFN activation with higher levels of MxA, IFNLR1, IFNLR1-mem and IFNLR1-sol, and IFNL3 genotype-associated differences in transcription factors. Taken together, these data provide evidence of an IFNL3 genotype association with differences in monocyte, T- and NK cell levels in the peripheral blood of patients with CHC. This could underpin genotype associations with spontaneous and treatment-induced HCV clearance and hepatic necroinflammation.

Hepatic metallothionein expression in chronic hepatitis C virus infection is IFNL3 genotype-dependent.

The IFNL3 genotype predicts the clearance of hepatitis C virus (HCV), spontaneously and with interferon (IFN)-based therapy. The responder genotype is associated with lower expression of interferon stimulated genes (ISGs) in liver biopsies from chronic hepatitis C patients. However, ISGs represent many interacting molecular pathways, and we hypothesised that the IFNL3 genotype may produce a characteristic pattern of ISG expression explaining the effect of genotype on viral clearance. For the first time, we identified an association between a cluster of ISGs, the metallothioneins (MTs) and IFNL3 genotype. Importantly, MTs were significantly upregulated (in contrast to most other ISGs) in HCV-infected liver biopsies of rs8099917 responders. An association between lower fibrosis scores and higher MT levels was demonstrated underlying clinical relevance of this association. As expected, overall ISGs were significantly downregulated in biopsies from subjects with the IFNL3 rs8099917 responder genotype (P=2.38 × 10(-7)). Peripheral blood analysis revealed paradoxical and not previously described findings with upregulation of ISGs seen in the responder genotype (P=1.00 × 10(-4)). The higher MT expression in responders may contribute to their improved viral clearance and MT-inducing agents may be useful adjuncts to therapy for HCV. Upregulation of immune cell ISGs in responders may also contribute to the IFNL3 genotype effect.

CCR5-Δ32 genotype does not improve predictive value of IL28B polymorphisms for treatment response in chronic HCV infection.

IL28B polymorphisms strongly predict spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection. A recent study proposed a 32-base pair deletion in the CC-chemokine receptor 5 (CCR5) gene (CCR5-Δ32) interacting with the IL28B polymorphisms to influence spontaneous HCV clearance. The aim of this study was to clarify the role of CCR5-Δ32 in treatment-induced clearance of chronic hepatitis C (CHC). A cross-sectional cohort of 813 Caucasian patients with CHC genotype 1 (365 responders and 448 non-responders) who had received standard of care dual therapy with interferon (IFN)-α and ribavirin (RBV) was genotyped for the CCR5-Δ32 and IL28B polymorphisms to examine their interaction with respect to treatment response. CCR5-Δ32 did not influence treatment-induced recovery to IFN-α/RBV in CHC, and did not improve prediction of sustained virological response in the context of the IL28B polymorphisms in a multivariate model. CCR5-Δ32 homozygotes were significantly more frequent in those with CHC than healthy controls in the European cohorts (2.9% vs 0.4%, P<0.0001), but not in Australians of European ancestry. In conclusion, CCR5-Δ32 does not influence treatment response in the context of IL28B polymorphisms. Although CCR5-Δ32 may affect viral clearance within closely controlled geographical and genetic environments, we found no effect in larger cohorts treated with dual therapy.

Women's knowledge of hormone therapy.

The aim of this study was to assess women's knowledge of hormone therapy. Two hundred and seven women were interviewed by telephone. The median score to 24 questions concerning the benefits, risks and side effects of therapy was 54.2%. Almost three-quarters of women knew that hormone therapy may decrease the risk of osteoporosis, but half were unaware that it should be taken for at least 10 years for maximum protection against bone loss. While many women knew that hormone therapy may increase the risk of breast cancer, 13.5% believed that it would decrease their risk. Many women overestimated the potential reduction in lifetime risk of hip fracture and the potential increase in lifetime risk of breast cancer with hormone therapy. Women may have insufficient knowledge to make informed choices about hormone therapy. This has implications for physicians who wish to ensure that women are able to participate in informed decision-making.

Do parents and professionals agree on the developmental status of high-risk infants?

OBJECTIVES: To examine the degree of agreement between parental reporting of the development of high-risk infants and professional assessment by a multidisciplinary team. METHODS: The developmental status of 196 infants discharged from neonatal intensive care units (NICUs) was assessed by their parents using the Infant Monitoring Questionnaire (IMQ) at 4, 8, or 12 months' corrected age. On the same day, a clinical assessment was done by a multidisciplinary team consisting of a developmental pediatrician, physical therapist, and psychologist. The kappa statistic was used to measure agreement between the assessments. Logistic regression was used to investigate factors that might influence agreement. RESULTS: Both the IMQ and the multidisciplinary team classified infants as developing normally ("normal"), being at risk for abnormal development ("suspect"), or developing abnormally ("abnormal"). Although the same proportion of children fell into the three categories by both assessments, parents and the multidisciplinary team showed poor agreement with respect to the classification of individual infants (kappa = 0.276). No infant or family characteristic was found to have an influence on agreement. CONCLUSIONS: For a group of high-risk infants discharged from NICUs, the agreement between parental assessment of developmental status using the IMQ and the professional assessment by a multidisciplinary team is poor in the first year of life. We do not recommend the use of this questionnaire as a substitute for clinical assessment of biologically at-risk infants discharged from NICUs. However, it may be useful for those groups of infants for whom no other information is available or as an adjunct to clinical assessment when infants are not behaving typically because of an unfamiliar setting or concurrent illness.