A Hybrid Markov Chain–von Mises Density Model for the Drug-Dosing Interval and Drug Holiday Distributions

Lack of adherence is a frequent cause of hospitalizations, but its effects on dosing patterns have not been extensively investigated. The purpose of this work was to critically evaluate a novel pharmacometric model for deriving the relationships of adherence to dosing patterns and the dosing interval distribution. The hybrid, stochastic model combines a Markov chain process with the von Mises distribution. The model was challenged with electronic medication monitoring data from 207 hypertension patients and against 5-year persistence data. The model estimates distributions of dosing runs, drug holidays, and dosing intervals. Drug holidays, which can vary between individuals with the same adherence, were characterized by the patient cooperativity index parameter. The drug holiday and dosing run distributions deviate markedly from normality. The dosing interval distribution exhibits complex patterns of multimodality and can be long-tailed. Dosing patterns are an important but under recognized covariate for explaining within-individual variance in drug concentrations.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-014-9713-5) contains supplementary material, which is available to authorized users.KEY WORDS: adherence, circular distribution, compliance, dosing patterns, runs     

Impact Strength of Preplaced Aggregate Concrete Comprising Glass Fibre Mesh and Steel Fibres: Experiments and Modeling

Concrete is the most widely used and most affordable construction material. The structural damage that concrete cracks and fractures may cause can be severe. These concerns have lately been alleviated by new developments in fibre concretes. Recent advancements in fibrous concrete and its evolution have been rapidly drawing researchers’ attentions worldwide, which motivates the development of a new type of composite with superior impact resistance. Preplaced aggregate fibrous concrete (PAFC) is a revolutionary composite comprising a higher dosage of fibres. It has outstanding impact resistance that surpasses those of traditional fibrous concrete. The impact behaviour of PAFC in addition to glass fibre mesh (GFM) has not been investigated thoroughly. To fill this research gap, this study investigates the impact performance of three-layered PAFC comprising steel fibres and GFM insertion. Eight different mixtures were prepared and can be divided into two groups. In the first group, specimens were made with 4% fibres and two single, double and triple layers of GFM insertion between the three-layered concrete. The second group of specimens was reinforced with 5, 2 and 5% steel fibres at the top, middle and bottom layers, respectively. However, the GFM insertion scheme for the second group was the same as the first. Rectangular specimens of size 500 × 100 × 100 mm were cast and tested against drop weight impact. The parameters studied were cracking impact numbers, failure impact number, ductility index and failure patterns. In addition, an analytical model was used to evaluate the impact failure energies. Results indicate that the combined action of steel fibre and GFM exhibited an excellent impact resistance. Increasing the number of GFM insertions between the specimen layer led to increased impact strength. The dose of the fibres utilized in the outer layer of the PAFC was increased, resulting in the material having a higher impact resistance. The cracking impact numbers improved from 28 to 40%, and failure impact numbers ranged from 58.8 to 92.2% when the GFM insertion numbers increased from one to three.     

Intravenous injection of oncolytic picornavirus SVV-001 prolongs animal survival in a panel of primary tumor–based orthotopic xenograft mouse models of pediatric glioma

Background

Seneca Valley virus (SVV-001) is a nonpathogenic oncolytic virus that can be systemically administered and can pass through the blood–brain barrier. We examined its therapeutic efficacy and the mechanism of tumor cell infection in pediatric malignant gliomas.

Methods

In vitro antitumor activities were examined in primary cultures, preformed neurospheres, and self-renewing glioma cells derived from 6 patient tumor orthotopic xenograft mouse models (1 anaplastic astrocytoma and 5 GBM). In vivo therapeutic efficacy was examined by systemic treatment of preformed xenografts in 3 permissive and 2 resistant models. The functional role of sialic acid in mediating SVV-001 infection was investigated using neuraminidase and lectins that cleave or competitively bind to linkage-specific sialic acids.

Results

SVV-001 at a multiplicity of infection of 0.5 to 25 replicated in and effectively killed primary cultures, preformed neurospheres, and self-renewing stemlike single glioma cells derived from 4 of the 6 glioma models in vitro. A single i.v. injection of SVV-001 (5 × 10¹² viral particles/kg) led to the infection of orthotopic xenografts without harming normal mouse brain cells, resulting in significantly prolonged survival in all 3 permissive and 1 resistant mouse models (P < .05). Treatment with neuraminidase and competitive binding using lectins specific for α2,3-linked and/or α2,6-linked sialic acid significantly suppressed SVV-001 infectivity (P < .01).

Conclusion

SVV-001 possesses strong antitumor activity against pediatric malignant gliomas and utilizes α2,3-linked and α2,6-linked sialic acids as mediators of tumor cell infection. Our findings support the consideration of SVV-001 for clinical trials in children with malignant glioma.     

Drop Weight Impact Test on Prepacked Aggregate Fibrous Concrete—An Experimental Study

In recent years, prepacked aggregate fibrous concrete (PAFC) is a new composite that has earned immense popularity and attracted researchers globally. The preparation procedure consists of two steps: the coarse aggregate is initially piled into a mold to create a natural skeleton and then filled with flowable grout. In this instance, the skeleton was completely filled with grout and bonded into an integrated body due to cement hydration, yielding a solid concrete material. In this research, experimental tests were performed to introduce five simple alterations to the ACI 544 drop weight impact test setup, intending to decrease result dispersion. The first alteration was replacing the steel ball with a steel bar to apply a line impact instead of a single point impact. The second and third introduced line and cross notched specimens at the specimen’s top surface and the load applied through a steel plate of cross knife-like or line load types. These modifications distributed impact load over a broader area and decrease dispersion of results. The fourth and fifth were bedding with sand and coarse aggregate as an alternate to the solid base plate. One-hundred-and-eight cylindrical specimens were prepared and tested in 12 groups to evaluate the suggested alteration methods. Steel and polypropylene fibers were utilized with a dosage of 2.4% to produce PAFC. The findings indicated that the line notched specimens and sand bedding significantly decreased the coefficient of variation (COV) of the test results suggesting some alterations. Using a cross-line notched specimen and line of impact with coarse bedding also effectively reduced COV for all mixtures.     

Effect of the TNF-alpha-promoter polymorphism on cardiac allograft rejection.

BACKGROUND: A polymorphism exists in the tumor necrosis factor alpha (TNF-alpha) promoter (position -308, G/A = TNFA1/TNFA2). The TNFA2 allele is associated with increased TNF-alpha production in vitro and has been reported to increase the risk of allograft rejection in pediatric recipients of cardiac transplantation. We examined the effect of the TNFA2 allele on the risk of allograft rejection in adult cardiac transplant recipients. METHODS: We prospectively analyzed 57 subjects (aged 54 +/- 11 years, 84% men, 49% ischemic) who underwent cardiac transplantation between October 1996 and July 2001. Patients were observed after transplantation (mean, 910 +/- 605 days) and the frequency of allograft rejection (biopsy Grade > or =2) in patients with the TNFA2 allele (Group A, n = 15) was compared with TNFA1 homozygotes (Group B, n = 42). Overall survival and time to rejection episodes also were compared between groups. RESULTS: The frequency of allograft rejection was similar between groups (Group A, 8/15 [56%]; Group B, 22/42 [52%]; p = 0.77). Time to rejection also was comparable (Group A, 17 +/- 11 days; Group B, 20 +/- 20 days, p = 0.74). Overall post-transplant survival was similar between groups (1- and 2-year percentage survival: Group A, 87% and 78%, Group B, 88% and 82%, p = 0.35). CONCLUSION: The TNFA2 allele was not associated with increased risk of rejection in adult cardiac transplant recipients. The impact of this polymorphism on overall post-transplant outcomes will require investigation in larger multicenter studies.     

Effect of radiation, heat, and aging on in vitro wear resistance of polyethylene

Radiation cross-linking increases the wear resistance of polyethylene used in total hip replacement. Radiation also generates residual free radicals, which are detrimental to long-term properties of polyethylene. Two approaches are used to stabilize the residual free radicals and terminally sterilize the components. One is postirradiation annealing with gas sterilization and the other is postirradiation melting with gamma sterilization in nitrogen. The hypothesis of the current study is that postirradiation annealing followed by gamma sterilization in nitrogen will result in more free radicals in polyethylene than gamma sterilization either in air or in nitrogen alone. To test this hypothesis, concentration of residual free radicals was quantified in polyethylene that was annealed and gamma sterilized in nitrogen and control polyethylenes gamma sterilized in air versus in nitrogen. Three crosslinked polyethylenes that were melted and gas sterilized also were included in the study. The effects of residual free radicals were studied by accelerated aging. Oxidation levels and weight loss in bidirectional pin-on-disk tests were determined before and after aging. Polyethylene that was subjected to postirradiation annealing and gamma sterilization resulted in 58% more residual free radicals than control polyethylenes. Weight loss of the annealed polyethylene increased by 16-fold on accelerated aging and had three times higher oxidation levels than that measured in control polyethylenes after aging. In contrast, polyethylenes that were stabilized with postirradiation melting and terminally gas sterilized showed no detectable residual free radicals. Accelerated aging did not affect the weight loss and oxidation levels of melted polyethylenes.     

Widespread central nervous system cavernous malformations associated with café-au-lait skin lesions. Case report

The simultaneous presence of cavernous malformations in the brain and spinal cord is a very rare finding and is typically associated with familial cavernous malformations. Although they are uncommon, various skin lesions can manifest in patients with familial cavernous malformations. The authors report on a 60-year-old man in whom more than 100 lesions consistent in appearance with cavernous malformations, including several intramedullary spinal cord lesions, were found throughout the neuraxis. This patient also displayed prominent café-au-lait skin lesions, but had no additional signs of neurofibromatosis or other neurocutaneous disorders. Analysis of his DNA revealed a novel mutation in the KRIT1/CCM1 gene, thereby confirming the diagnosis of familial cavernous malformation. The presence of these lesions in every major compartment of this patient's central nervous system underscores their indiscriminate nature and the need to screen throughout the neuraxis in patients in whom familial cavernous malformations are suspected. The findings in this case add to the growing list of skin lesions associated with genetically confirmed familial cavernous malformations. In patients presenting with seizures, focal neurological deficits, or hemorrhagic stroke, the presence of unusual skin lesions should prompt consideration of familial cavernous malformations, and appropriate screening should be performed.