Rotavirus Vaccination Likely to Be Cost Saving to Society in the United States.

BACKGROUND: Following the introduction of rotavirus immunization in 2006 in the United States, there were substantial declines in the domestic rotavirus disease burden. In this study, we assess the value for money achieved by the program in the decade following vaccine introduction. METHODS: We applied an age-specific, static, multicohort compartmental model to examine the impact and cost-effectiveness of the US rotavirus immunization program in children <5 years of age using healthcare utilization data from 2001 to 2015 inclusive. We calculated the incremental cost-effectiveness ratio (ICER) per quality-adjusted life year (QALY) gained from both a healthcare system and societal perspective. RESULTS: Declines in healthcare use associated with the rotavirus and acute gastroenteritis occurred from 2006 and continued to grow before stabilizing from 2010 through 2011. From 2011 to 2015, an estimated annual average of approximately 118 000 hospitalizations, 86 000 emergency department presentations, and 460 000 outpatient and physician office visits were prevented. From a societal perspective during this same period, the program was estimated to be cost saving in the base case model and in >90% of probabilistic sensitivity analysis simulations and from a healthcare system perspective >98% of simulations found an ICER below $100 000 per QALY gained. CONCLUSIONS: After the program stabilized, we found the rotavirus immunization in the United States was likely to have been cost saving to society. The greater than expected healthcare and productivity savings reflect the success of the rotavirus immunization program in the United States.

A model-based Bayesian estimation of the rate of evolution of VNTR loci in Mycobacterium tuberculosis.

Variable numbers of tandem repeats (VNTR) typing is widely used for studying the bacterial cause of tuberculosis. Knowledge of the rate of mutation of VNTR loci facilitates the study of the evolution and epidemiology of Mycobacterium tuberculosis. Previous studies have applied population genetic models to estimate the mutation rate, leading to estimates varying widely from around 10⁻5 to 10⁻² per locus per year. Resolving this issue using more detailed models and statistical methods would lead to improved inference in the molecular epidemiology of tuberculosis. Here, we use a model-based approach that incorporates two alternative forms of a stepwise mutation process for VNTR evolution within an epidemiological model of disease transmission. Using this model in a Bayesian framework we estimate the mutation rate of VNTR in M. tuberculosis from four published data sets of VNTR profiles from Albania, Iran, Morocco and Venezuela. In the first variant, the mutation rate increases linearly with respect to repeat numbers (linear model); in the second, the mutation rate is constant across repeat numbers (constant model). We find that under the constant model, the mean mutation rate per locus is 10⁻²·°6 (95% CI: 10⁻²·6¹,10⁻¹·58)and under the linear model, the mean mutation rate per locus per repeat unit is 10⁻²·45 (95% CI: 10⁻³·°7,10⁻¹·94). These new estimates represent a high rate of mutation at VNTR loci compared to previous estimates. To compare the two models we use posterior predictive checks to ascertain which of the two models is better able to reproduce the observed data. From this procedure we find that the linear model performs better than the constant model. The general framework we use allows the possibility of extending the analysis to more complex models in the future.

Impact of homoplasy on variable numbers of tandem repeats and spoligotypes in Mycobacterium tuberculosis.

Homoplasy is the occurrence of genotypes that are identical by state but not by descent. It arises through a number of means including convergent and reverse evolution, and horizontal gene transfer. When using molecular markers that are based on sequences possessing a finite number of character states, such as VNTR or spoligotypes, this is an unavoidable phenomenon. Here we discuss the extent of homoplasy and its impact on inferences drawn from spoligotypes and VNTR in epidemiological studies of tuberculosis. To further explore this problem, we developed a computer simulation model combining the processes of mutation and transmission. Our results show that while the extent of homoplasy is not negligible, its effect on the proportion of isolates clustered ("n-1 method") is likely to be relatively low for spoligotyping. For VNTR-typing, homoplasy occurs at a low rate provided the number of loci used is high and the mutation rate is relatively high. However, deep phylogenetic inferences using spoligotypes or VNTRs with a small number of loci are likely to be unreliable.

Mutation rates of spoligotypes and variable numbers of tandem repeat loci in Mycobacterium tuberculosis.

Variable numbers of tandem repeat (VNTR) loci and spoligotypes are molecular markers used to study genetic diversity of bacteria such as Mycobacterium tuberculosis. Knowledge about the rate at which molecular fingerprints change, or the mutation rate, is important for interpreting molecular epidemiological data and for studying quantitative models of the evolution and epidemiology of bacteria. In this paper we estimate the mutation rates of spoligotypes and VNTR loci of M. tuberculosis using published data sets from epidemiological studies. Our method makes use of a compound parameter: twice the product of the effective population size and the mutation rate. We use a standard procedure to estimate this population genetic parameter which describes genetic diversity. The ratio of estimated diversity parameters for different markers can be used to generate new estimates for markers with unknown mutation rates. We apply this method to generate new estimates along with confidence intervals. We found mutation rates for VNTR loci to be around 7x10(-4) to 1.5x10(-2) per locus per year, and for spoligotypes to be around 0.02-0.09 per year. The spoligotype rate is similar to previous estimates while the VNTR rates are at least an order of magnitude higher than previously reported. These findings confirm the high level of discrimination observed using multilocus VNTR typing, and suggest that caution should be taken not to underestimate the extent of recent transmission when using this marker.

Models of deletion for visualizing bacterial variation: an application to tuberculosis spoligotypes.

BACKGROUND: Molecular typing methods are commonly used to study genetic relationships among bacterial isolates. Many of these methods have become standardized and produce portable data. A popular approach for analyzing such data is to construct graphs, including phylogenies. Inferences from graph representations of data assist in understanding the patterns of transmission of bacterial pathogens, and basing these graph constructs on biological models of evolution of the molecular marker helps make these inferences. Spoligotyping is a widely used method for genotyping isolates of Mycobacterium tuberculosis that exploits polymorphism in the direct repeat region. Our goal was to examine a range of models describing the evolution of spoligotypes in order to develop a visualization method to represent likely relationships among M. tuberculosis isolates. RESULTS: We found that inferred mutations of spoligotypes frequently involve the loss of a single or very few adjacent spacers. Using a second-order variant of Akaike's Information Criterion, we selected the Zipf model as the basis for resolving ambiguities in the ancestry of spoligotypes. We developed a method to construct graphs of spoligotypes (which we call spoligoforests). To demonstrate this method, we applied it to a tuberculosis data set from Cuba and compared the method to some existing methods. CONCLUSION: We propose a new approach in analyzing relationships of M. tuberculosis isolates using spoligotypes. The spoligoforest recovers a plausible history of transmission and mutation events based on the selected deletion model. The method may be suitable to study markers based on loci of similar structure from other bacteria. The groupings and relationships in the spoligoforest can be analyzed along with the clinical features of strains to provide an understanding of the evolution of spoligotypes.

spolTools: online utilities for analyzing spoligotypes of the Mycobacterium tuberculosis complex.

spolTools is a collection of online programs designed to manipulate and analyze spoligotype datasets of the Mycobacterium tuberculosis complex. These tools are integrated into a repository currently containing 1179 spoligotypes and 6278 isolates across 30 datasets. Users can search this database to export for external use or to pass on to the integrated tools. These tools include the computation of basic population genetic quantities, the visualization of clusters of spoligotype patterns based on an estimated evolutionary history and a procedure to predict emerging strains - genotypes associated with elevated transmission.

Steady-state pharmacokinetics, pharmacodynamics and tolerability of donepezil hydrochloride in hepatically impaired patients.

AIMS: To evaluate the pharmacokinetics (PK), pharmacodynamics (PD), tolerability and safety of donepezil HCl 5 mg following oral doses for 1 and 24 days in hepatically impaired patients compared with healthy controls under steady-state, multiple-dose conditions. METHODS: In this single-centre, multiple-dose, open-label study, patients with impaired hepatic function (Child-Pugh grade A or B) and healthy controls (matched by gender, age and weight to the hepatically impaired patients) received a single 5 mg dose of donepezil on day 1 and then donepezil HCl 5 mg once daily from days 6 to 29. PK and PD (determination of erythrocyte acetylcholinesterase inhibition) parameters were evaluated on days 1 and 29. Treatment-emergent adverse events (AEs), vital signs, physical examination and clinical laboratory test parameters were monitored throughout the study. RESULTS: A total of 35 subjects (18 patients with hepatic impairment and 17 healthy controls) were enrolled and 32 subjects (16 in each group) completed the study. On day 1 (following a single dose) hepatically impaired patients showed a significant decrease in T(max), while t((1/2)) and AUC(0-infinity) were significantly increased compared with the healthy controls. On day 29 (following multiple doses), AUC(0-24 h), C(max), t((1/2)), C(SS), and R(A) were significantly increased in hepatically impaired patients compared with healthy controls. AUC(0-24 h) increased by 47.6% in the patients with hepatic impairment compared with the healthy controls. There were no significant differences in PD between the groups, although at steady state, the mean AChE inhibition was 16.2% higher in the hepatically impaired patients. No serious AEs were reported and no subject withdrew from the study due to AEs. The most common AEs in both groups were headache and diarrhoea. No clinically significant changes from baseline were observed in vital signs, physical examination findings or electrocardiograms. There was a significant difference in the number of hepatically impaired subjects with abnormalities in serum glucose compared with healthy subjects. However, these elevations were not associated with AEs. CONCLUSIONS: The results of this study suggest that patients with AD and mild to moderate hepatic impairment (Child-Pugh grade A or B) can be safely given donepezil 5 mg once daily and that this dose is associated with a nonsignificantly higher AChE inhibition than age-matched volunteers.

Concurrent administration of donepezil HCl and risperidone in patients with schizophrenia: assessment of pharmacokinetic changes and safety following multiple oral doses.

AIM: This open-label, multiple-dose trial investigated the effect of concurrent administration of donepezil HCl with risperidone on the pharmacokinetics (PK) and safety profiles of both drugs. METHODS: Sixteen male patients with schizophrenia, who were receiving stable, physician-optimized risperidone (1-4 mg twice daily), and 15 healthy age- and weight-matched male controls, received donepezil HCl 5 mg daily for 7 days. Patients with schizophrenia remained on their physician-optimized dose of risperidone throughout the study. Pharmacokinetic parameters (C(max), t(max) and AUC) were assessed from plasma drug concentrations measured in blood collected before, during and after administration (for 12 h after risperidone on days 0 and 7, and for 24 h after donepezil HCl on day 7). RESULTS: The mean age of all the subjects was 38.5 years. Donepezil PK parameters were similar between patients taking donepezil HCl + risperidone (AUC(0-24 h) = 329.0 +/- 17.2 ng x h ml(-1)) and controls taking donepezil HCl alone (AUC(0-24 h) = 354.7 +/- 28.2 ng x h ml(-1)). Pharmacokinetic parameters for risperidone and 9-OH risperidone were not altered in patients with schizophrenia after 7 days of donepezil HCl administration (AUC(0-12 h) standardized by dose: risperidone = 59.6 +/- 16.3 ng.h ml(-1) at day 0, 56.0 +/- 15.8 ng x h ml(-1) at day 7; 9-OH risperidone = 162.1 +/- 19.2 ng x h ml(-1) at day 0, 163.3 +/- 15.0 ng x h ml(-1) at day 7). The most common adverse event in both treatment groups was diarrhoea (6/16 risperidone + donepezil HCl patients and 9/16 donepezil HCl only subjects). There were no significant changes in physical examination, ECG, vital signs or treatment-emergent abnormal laboratory values associated with either of the treatment regimens. No subject developed extrapyramidal side-effects following donepezil administration. CONCLUSIONS: These results suggest that once-daily dosing of 5 mg donepezil HCl does not alter the PK of risperidone in patients with schizophrenia. The combination of risperidone and donepezil HCl was well tolerated.