Plasma pharmacokinetics of high-dose oral busulfan in children and adults undergoing bone marrow transplantation

Abstract: We have analyzed the plasma pharmacokinetics of busulfan in 272 patients receiving high-dose oral busulfan and intravenous cyclophosphamide in conjunction with allogeneic or autologous bone marrow transplantation. The patients ranged in age from 2 months to 59 yr (mean 10, median 12 yr) and had the following diagnoses: thalassemia or sickle cell anemia (n = 74); leukemia or myelodysplasia (n = 112); inborn errors of metabolism (n = 41) or immunodeficiency (n = 45). Plasma specimens were collected following the first dose for each patient which ranged from 1 to 4 mg/kg (mean ± SD, 1.21 ± 0.41, median 1.15). Busulfan was quantitated using ultraviolet absorbance detection after derivatization and HPLC separation. Pharmacokinetic parameters were derived by modeling the raw data to fit first-order single compartment kinetics. The kinetic parameters showed wide interpatient variability independent of age and diagnosis. There was a statistically significant correlation of age with the following parameters: area under the curve (AUC); maximal concentration; minimum concentration; clearance; volume of distribution and absorption half-time. The coefficients of determination (i.e. correlation coefficient squared) were low ranging from 0.04 to 0.12 implying only a small part (i.e. 4–12%) of the variance was explained by age. Although busulfan pharmacokinetics are age-related most of the variability is not explained by age or diagnosis.     

Overview of Disease Management Approaches

Corporations have engaged in sponsorship of health management programs and, more recently, disease management programs to facilitate healthy and productive work environments. The purpose of this review is to examine the health and financial outcomes from these corporate-sponsored disease management programs. This article focuses on seven diseases or chronic conditions (arthritis, asthma, cancer, depression, diabetes mellitus, heart disease, and migraine) that potentially impact employee productivity (both in time away from work and in loss of effectiveness at work) and health status including medical and pharmaceutical utilization and costs.Corporate-sponsored disease management programs typically focus on education and screening for selected diseases or chronic conditions. Partnerships have been formed with health plans and third-party program providers to reach employees with interventions and treatment. The typical outcome measures from these programs have primarily been clinical indicators and medical utilization. Measures of productivity need to be incorporated as important outcome measures for disease management programs.The estimated financial opportunity for the corporation is a reflection of the cost differential for a given disease and the prevalence of that disease within the employee population. Primary diseases, chronic conditions, and health risks contribute to increased medical utilization and decreased productivity within the corporation. Promoting programs that focus on the whole person, including health risks, chronic conditions, and diseases, will likely increase the possibility of success in helping the employee to better self-manage their health conditions and consequently provide gains for both the individual and the corporation.     

An electrophysiological investigation of the relationship between conceptual fluency and familiarity

Brain potentials associated with the manipulation of conceptual fluency in a recognition memory paradigm were recorded. Enhanced fluency was associated with attenuation of the N400 and an increased rate of subjects' endorsing both studied and non-studied items as having been studied ("old" responses) in the recognition test. Differences were also found in latencies previously associated with post-retrieval processing, such that in the setting of enhanced fluency (1) non-studied items were associated with a positive wave from 800 to 1600 ms and (2) items endorsed as "new" were more positive than those endorsed as "old" from 1200 to 1600 ms. The effects on the N400 may be related to the impact of fluency on familiarity, whereas later processing may be involved in the attribution of fluency to prior experience.     

Assessment of the epidemic potential of a new strain of rotavirus associated with the novel G9 serotype which caused an outbreak in the United States for the first time in the 1995-1996 season

Rotavirus causes severe morbidity in developed countries and frequent deaths (> or = 500,000 per year) in less-developed countries. Historically, four serotypes--G1, G2, G3, and G4-have predominated; they are distinguished by one of two surface neutralization antigens (VP7). However, in 1983 and 1984 we described a new rotavirus serotype, designated G9, in five children hospitalized for diarrhea in Philadelphia, Pa. G9 rotavirus was not identified again in the Western Hemisphere until it caused ca. 50% of the rotavirus disease detected in Philadelphia in the 1995-1996 season. This outbreak allowed us to question whether a rotavirus strain completely new to a well-studied community would target either very young infants or older children, cause especially severe disease, or completely displace previously extant serotypes. We observed a significant excess of G9 infections in younger infants (especially in those < 6 months old) that might be attributed to the lack of G9-specific antibodies in mothers. Of further note, six of the seven oldest patients with rotavirus diarrhea were infected with the G9 strains (not significant). However, the age distribution of children with rotavirus did not differ over a 5-year study period regardless of the infecting serotype. Patients with diarrhea associated with G9 strains did not have disease more severe than that caused by the G1, G2, or G3 serotype. G9 strains did not displace the other serotypes but were virtually completely replaced by G1 or G2 serotypes in the three subsequent rotavirus seasons. We conclude that the abrupt appearance of this novel rotavirus serotype did not present a special threat to public health in the community.     

Utilization of the 2017 diagnostic criteria for hEDS by the Toronto GoodHope Ehlers–Danlos syndrome clinic: A retrospective review

The new 2017 diagnostic criteria for hypermobile Ehlers–Danlos Syndrome (hEDS) provide a framework for diagnosing hEDS but are more stringent than the previous Villefranche criteria. Our clinical experience at the GoodHope EDS clinic was that the 2017 criteria left many highly symptomatic patients without a diagnosis of hEDS. We conducted a retrospective cohort study to confirm our clinic experience and assess the accuracy of the 2017 diagnostic criteria for hEDS in patients who had a previous hEDS diagnosis based on the Villefranche criteria. Our study found that 15% (n = 20 of 131) of patients with a prior diagnosis of hEDS met the 2017 diagnostic criteria, and many of the traits used to distinguish hEDS were not significantly more frequent in patients who met 2017 criteria versus those who did not. In both groups objective systemic manifestations were found less frequently than subjective systemic manifestations. Beighton score (BS) as assessed by primary care practitioner was found to be higher than assessment by EDS practitioner in 81% (n = 74 of 91) of cases. Generalized joint hypermobility was confirmed in only 46% (n = 51 of 111) of patients who had a previous diagnosis of hEDS. Higher BS did not correlate with increased number of systemic manifestations in our cohort. Common comorbidities of hEDS were found with similar frequency in those who met 2017 criteria and those who did not. Based on our cohort, the 2017 hEDS diagnostic criteria require refinement to improve its diagnostic accuracy.