Pharmacokinetics of mycophenolate mofetil in stable pediatric liver transplant recipients receiving mycophenolate mofetil and cyclosporine.

There are few pharmacokinetic data for mycophenolate mofetil (MMF) when used in combination with cyclosporine (CsA) in pediatric liver transplant recipients. The aim of this study was to assess the pharmacokinetics of MMF in stable pediatric liver transplant patients and estimate the dose of MMF required to provide a mycophenolic acid (MPA) exposure similar to that observed in adult liver transplant recipients receiving the recommended dose of MMF (target area under the plasma concentration-time curve from 0 to 12 hours [AUC(0-12)] for MPA of 29 mug.hour/mL in the immediate posttransplantation period and 58 microg x hour/mL after 6 months). A 12-hour pharmacokinetic profile was collected for 8 pediatric patients (mean age 20.9 months) on stable doses of MMF and CsA who had received a liver transplant > or = 6 months prior to entry and who had started on MMF within 2 weeks of transplantation. Mean MMF dosage was 285 mg/m(2) (range, 200-424 mg/m(2)). Of 8 patients, 7 had a MPA AUC(0-12) (range, 11.0-37.2 microg x hour/mL) well below the target. One patient had an AUC(0-12) > or = 58 microg x hour/mL but was considered an outlier and was excluded from analyses. Mean MPA AUC(0-12) and maximum plasma concentration values were 22.7 +/- 10.5 microg x hour/mL and 7.23 +/- 3.27 microg/mL, respectively; values normalized to 600 mg/m(2) (the approved pediatric dose in renal transplantation) were 47.0 +/- 21.8 microg x hour/mL and 14.5 +/- 4.21 microg/mL. In conclusion, assuming that MPA exhibits linear pharmacokinetics, when used in combination with CsA, a MMF dose of 740 mg/m(2) twice daily would be recommended in pediatric liver transplant recipients to achieve MPA exposures similar to those observed in adult liver transplant recipients. This finding should be confirmed by a prospective trial.     

Comparison of Laparoscopic vs Open Sigmoid Colectomy for Benign and Malignant Disease at Academic Medical Centers

Few studies have examined outcomes of laparoscopic and open sigmoid colectomy performed at US academic centers. Using ICD-9 diagnosis and procedural codes, data was obtained from the University HealthSystem Consortium (UHC) Clinical Database of 10,603 patients who underwent laparoscopic or open sigmoid colectomy for benign and malignant disease between 2003–2006. A total of 1,092 patients (10.3%) underwent laparoscopic sigmoid colectomy. Laparoscopic sigmoid colectomy was associated with a significantly shorter length of stay (5.4 vs 7.4 days), lower overall complication rate (19.7 vs 26.0%), lower 30-day readmission rate (3.4 vs 4.6), and a lower hospital cost ($13,814 vs $15,626). When a subset analysis of malignant and benign groups was performed, a significantly shorter length of stay in both the malignant laparoscopic group (6.4 ± 6.4 vs 7.8 ± 6.6 days) and in the benign laparoscopic groups (5.1 ± 3.5 vs 7.2 ± 7.6) exists. A lower wound complication rate (2.1 vs 5.5%, malignant and 4.0 vs 6.1, benign) is also evident. Laparoscopic sigmoid colectomy was associated with a shorter length of stay, less complications, and a lower 30-day readmission rate. The shorter length of stay and wound infection rate maintain significance when comparing laparoscopic vs open sigmoid resections for malignant and benign disease. Presented at the 48th annual meeting of the Society for Surgery of the Alimentary Tract at Digestive Disease Weak, Washington, DC, May 21st 2007. The information contained in this article was based on the Clinical Data Base provided by the University HealthSystem Consortium.     

Understanding the minimum clinically important difference: a review of concepts and methods.

BACKGROUND CONTEXT: The effectiveness of spinal surgery as a treatment option is currently evaluated through the assessment of patient-reported outcomes (PROs). The minimum clinically important difference (MCID) represents the smallest improvement considered worthwhile by a patient. The concept of an MCID is offered as the new standard for determining effectiveness of a given treatment and describing patient satisfaction in reference to that treatment. PURPOSE: Our goal is to review the various definitions of MCID and the methods available to determine MCID. STUDY DESIGN: The primary means of determining the MCID for a specific treatment are divided into anchor-based and distribution-based methods. Each method is further subdivided and examined in detail. METHODS: The overall limitations of the MCID concept are first identified. The basic assumptions, statistical biases, and shortcomings of each method are examined in detail. RESULTS: Each method of determining the MCID has specific shortcomings. Three general limitations in the accurate determination of an MCID have been identified: the multiplicity of MCID determinations, the loss of the patient's perspective, and the relationship between pretreatment baseline and posttreatment change scores. CONCLUSIONS: An ideal means of determining the MCID for a given intervention is yet to be determined. It is possible to develop a useful method provided that the assumptions and methodology are initially declared. Our efforts toward the establishment of a MCID will rely on the establishment of specific external criteria based on the symptoms of the patient and treatment intervention being evaluated.     

Cephalad Movement of Morphine and Fentanyl in Humans after Intrathecal Injection

Background: Despite decades of use, controversy remains regarding the extent and time course of cephalad spread of opioids in cerebrospinal fluid (CSF) after intrathecal injection. The purpose of this study was to examine differences between two often used opioids, morphine and fentanyl, in distribution in the CSF after intrathecal injection.

Methods: Eight healthy volunteers received intrathecal injection of morphine (50 [mu]g) plus fentanyl (50 [mu]g) at a lower lumbar interspace. CSF was sampled through a needle in an upper lumbar interspace for 60-120 min. At the end of this time, a sample was taken from the lower lumbar needle, and both needles were withdrawn. CSF volume was determined by magnetic resonance imaging. Pharmacokinetic modeling was performed with NONMEM.

Results: Morphine and fentanyl peaked in CSF at the cephalad needle at similar times (41 +/- 13 min for fentanyl, 57 +/- 12 min for morphine). The ratio of morphine to fentanyl in CSF at the cephalad needle increased with time, surpassing 2:1 by 36 min and 4:1 by 103 min. CSF concentrations did not correlate with weight, height, or lumbosacral CSF volume. The concentrations of morphine and fentanyl at both sampling sites were well described by a simple pharmacokinetic model. The individual model parameters did not correlate with the distance between the needles, CSF volume, patient height, or patient weight.     

On the road to automatic: dynamic aspects in the development of expertise.

One of the important steps on the road to becoming expert in a motor skill occurs when the individual can perform the movements in a seemingly effortless and automatic fashion. The authors review two lines of investigations, namely, fMRI and mathematically guided studies of the dynamics of skill acquisition, that suggest that this road to automatic involves two steps: (1) an increasing reliance on the self-regulatory aspects of the motor task, and (2) a minimization of the role of mechanisms based on intentionally directed corrective movements. The interplay between these two mechanisms implies that, at a given skill level, performance decreases whenever intention intervenes. The observation that psychological factors may be as important as mechanical repetition for the development of expertise has important implications for the design of neurorehabilitative strategies.     

Human leukocyte antigen and adult living-donor liver transplantation outcomes: an analysis of the organ procurement and transplantation network database.

Human leukocyte antigen (HLA) compatibility has no clinically significant impact in cadaveric liver transplantation. Less is known regarding living-donor liver transplantation (LDLT). Our prior analysis of the Organ Procurement and Transplantation Network (OPTN) database suggested a higher graft failure rate in patients who underwent LDLT from donors with close HLA match. We further investigated the effect of HLA-A, -B, and -DR matching on 5-yr graft survival in adult LDLT by analyzing OPTN data regarding adult LDLT performed between 1998 and 2005. We evaluated associations between 5-yr graft survival and total, locus-specific, and haplotype match levels. Separate analyses were conducted for recipients with autoimmune (fulminant autoimmune hepatitis, cirrhosis secondary to autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis) or nonautoimmune liver disease. Multivariable Cox proportional hazard models were used to evaluate interactions and adjust for potential confounders. Among 631 patients with available donor/recipient HLA data, the degree of HLA match had no significant effect on 5-yr graft survival, even when analyzed separately in recipients with autoimmune vs. nonautoimmune liver disease. To be able to include all 1,838 adult LDLTs, we considered a first-degree related donor as substitute for a close HLA match. We found no difference in graft survival in related vs. unrelated pairs. In conclusion, our results show no detrimental impact of close HLA matching on graft survival in adult LDLT, including in recipients with underlying autoimmune liver disease.