Is Sustained Virological Response a Marker of Treatment Efficacy in Patients with Chronic Hepatitis C Viral Infection with No Response or Relapse to Previous Antiviral Intervention?

Background: Randomised clinical trials (RCTs) of antiviral interventions in patients with chronic hepatitis C virus (HCV) infection use sustained virological response (SVR) as the main outcome. There is sparse information on long-term mortality from RCTs.  Methods: We created a decision tree model based on a Cochrane systematic review on interferon retreatment for patients who did not respond to initial therapy or who relapsed following SVR. Extrapolating data to 20 years, we modelled the outcome from three scenarios: (1) observed medium-term (5 year) annual mortality rates continue to the long term (20 years); (2) long-term annual mortality in retreatment responders falls to that of the general population while retreatment non-responders continue at the medium-term mortality; (3) long-term annual mortality in retreatment non-responders is the same as control group non-responders (i.e., the increased treatment-related medium mortality “wears off”).  Results: The mean differences in life expectancy over 20 years with interferon versus control in the first, second, and third scenarios were -0.34 years (95% confidence interval (CI) -0.71 to 0.03), -0.23 years (95% CI -0.69 to 0.24), and -0.01 (95% CI -0.3 to 0.27), respectively. The life expectancy was always lower in the interferon group than in the control group in scenario 1. In scenario 3, the interferon group had a longer life expectancy than the control group only when more than 7% in the interferon group achieved SVR.  Conclusions: SVR may be a good prognostic marker but does not seem to be a valid surrogate marker for assessing HCV treatment efficacy of interferon retreatment. The SVR threshold at which retreatment increases life expectancy may be different for different drugs depending upon the adverse event profile and treatment efficacy. This has to be determined for each drug by RCTs and appropriate modelling before SVR can be accepted as a surrogate marker

Seasonal Variation in Vitamin D3 Levels Is Paralleled by Changes in the Peripheral Blood Human T Cell Compartment

It is well-recognized that vitamin D3 has immune-modulatory properties and that the variation in ultraviolet (UV) exposure affects vitamin D3 status. Here, we investigated if and to what extent seasonality of vitamin D3 levels are associated with changes in T cell numbers and phenotypes. Every three months during the course of the entire year, human PBMC and whole blood from 15 healthy subjects were sampled and analyzed using flow cytometry. We observed that elevated serum 25(OH)D3 and 1,25(OH)2D3 levels in summer were associated with a higher number of peripheral CD4+ and CD8+ T cells. In addition, an increase in naïve CD4+CD45RA+ T cells with a reciprocal drop in memory CD4+CD45RO+ T cells was observed. The increase in CD4+CD45RA+ T cell count was a result of heightened proliferative capacity rather than recent thymic emigration of T cells. The percentage of Treg dropped in summer, but not the absolute Treg numbers. Notably, in the Treg population, the levels of forkhead box protein 3 (Foxp3) expression were increased in summer. Skin, gut and lymphoid tissue homing potential was increased during summer as well, exemplified by increased CCR4, CCR6, CLA, CCR9 and CCR7 levels. Also, in summer, CD4+ and CD8+ T cells revealed a reduced capacity to produce pro-inflammatory cytokines. In conclusion, seasonal variation in vitamin D3 status in vivo throughout the year is associated with changes in the human peripheral T cell compartment and may as such explain some of the seasonal variation in immune status which has been observed previously. Given that the current observations are limited to healthy adult males, larger population-based studies would be useful to validate these findings

Follicular Dendritic Cell-Specific Prion Protein (PrPc) Expression Alone Is Sufficient to Sustain Prion Infection in the Spleen

Prion diseases are characterised by the accumulation of PrPSc, an abnormally folded isoform of the cellular prion protein (PrPC), in affected tissues. Following peripheral exposure high levels of prion-specific PrPSc accumulate first upon follicular dendritic cells (FDC) in lymphoid tissues before spreading to the CNS. Expression of PrPC is mandatory for cells to sustain prion infection and FDC appear to express high levels. However, whether FDC actively replicate prions or simply acquire them from other infected cells is uncertain. In the attempts to-date to establish the role of FDC in prion pathogenesis it was not possible to dissociate the Prnp expression of FDC from that of the nervous system and all other non-haematopoietic lineages. This is important as FDC may simply acquire prions after synthesis by other infected cells. To establish the role of FDC in prion pathogenesis transgenic mice were created in which PrPC expression was specifically “switched on” or “off” only on FDC. We show that PrPC-expression only on FDC is sufficient to sustain prion replication in the spleen. Furthermore, prion replication is blocked in the spleen when PrPC-expression is specifically ablated only on FDC. These data definitively demonstrate that FDC are the essential sites of prion replication in lymphoid tissues. The demonstration that Prnp-ablation only on FDC blocked splenic prion accumulation without apparent consequences for FDC status represents a novel opportunity to prevent neuroinvasion by modulation of PrPC expression on FDC

The Future of Rheumatoid Arthritis and Hand Surgery - Combining Evolutionary Pharmacology and Surgical Technique

Rheumatoid arthritis is a systemic autoimmune disease of uncertain aetiology, which is characterized primarily by synovial inflammation with secondary skeletal destructions

Probation Length and Teacher Salaries: Does Waiting Pay Off?

Tenure policies for elementary and secondary school teachers is a controversial issue in many states, but there is virtually no empirical evidence on how tenure affects teacher labor markets. This paper begins to fill this research void by using cross-state variation in tenure policies to identify the effects, if any, of the length of the probationary period on entry-level teacher salaries. Using data from the Schools and Staffing Survey, the authors investigate whether districts in states with longer probationary periods offer higher wages to teachers as a way to compensate for the extended evaluative period. Results suggest that they do, although effects are concentrated in districts that are most likely to be competing for teachers with districts in neighboring states with shorter probation periods. The authors also find that the relationship between probation length and wages is stronger for experienced teachers and in districts that engage in collective bargaining

Tiebout choice and universal school vouchers

This paper examines who is likely to gain and who is likely to lose under a universal voucher program. Following Epple and Romano [D. Epple, R.E. Romano, Competition between private and public schools, vouchers, and peer group effects, American Economic Review 88 (1998) 33-62; D. Epple, R.E. Romano, Neighborhood schools, choice, and the distribution of educational benefits, in: C.M. Hoxby (Ed.), The Economics of School Choice, The Univ. of Chicago Press, Chicago, 2003, pp. 227-286], and Nechyba T.J. Nechyba, Mobility, targeting, and private school vouchers, American Economic Review 90 (2000) 130-146; T.J. Nechyba, Introducing school choice into multidistrict public school systems, in: C.M. Hoxby (Ed.), The Economics of School Choice, The Univ. of Chicago Press, Chicago, 2003, pp. 145-194], we focus on the idea that gains and losses under a universal voucher depend on two effects: changes in peer group composition and changes in housing values. We show that the direction and magnitude of each of these effects hinge critically on market structure, i.e., the amount of school choice that already exists in the public sector. In markets with little or no Tiebout choice, potential changes in peer group composition create an incentive for high-socioeconomic (SES) households to vote for the voucher and for low-SES households to vote against voucher. In contrast, in markets with significant Tiebout choice, potential changes in housing values create an incentive for high-SES households to vote against the voucher and for low-SES households to vote for the voucher. Using data on vote outcomes from California's 2000 voucher initiative, we find evidence consistent with those predictions.School vouchers Tiebout choice Peer effects Capitalization