Large Interpatient Variability Research Articles

Model-based segmentation of pediatric and adult joints for orthopedic measurements in digital radiographs of the lower limbs

The growth of human bones forms a major problem when automatically segmenting orthopedic radiographs. Any template-based segmentation methods fails to fully capture these non-linear developments. However to extract orthopedic measurements or the bone age for patients of arbitrary age it is mandatory to have a segmentation scheme that deals with growth related changes. In this paper we propose a robust method based on Active Shape Models (ASMs) that on the one hand is invariant against the patient's age and on the other hand generalizes well over the large inter-patient variability. Our method achieves an accuracy of 0.48 mm for adult patients and 0.64 mm for children on a large test set of 180 images, with the patient's age covering a high range from less than one month to 93 years.

Short-chain methotrexate polyglutamate MTXPG2 as outcome parameter in rheumatoid arthritis

Background Due to its positive benefit-risk-ratio, methotrexate (MTX) is a first-line therapy in the treatment of rheumatoid arthritis (RA). Although MTX is very effective, the large interpatient variability in drug response is a major drawback in clinical practice. Erythrocyte methotrexate polyglutamates (MTXPG1–7) — intracellular storage products of methotrexate — are supposed to correlate with clinical efficacy. In particular, long-chain polyglutamates (MTXPG4–5) are strongly retained in the cells and are therefore discussed to be potential markers for clinical response in rheumatoid arthritis. We hypothesized that concentrations of methotrexate polyglutamates could correlate with clinical response parameters in rheumatoid arthritis.

Myelosuppression by sunitinib is flt-3 genotype dependent

Sir, Myelosuppression is frequently observed during treatment with the multi tyrosine kinase inhibitors (TKIs) (Motzer et al, 2007; Bhojani et al, 2008). The frequency and severity of myelosuppression varies among the drug class with sunitinib being a relative myelotoxic compound leading to leukopenia and thrombocytopenia in 56–78% and 41–65% of the patients, respectively (Demetri et al, 2006; Motzer et al, 2007). In a previous issue of the British Journal of Cancer, Kumar et al (2009) have investigated the potency of three TKIs that target the vascular endothelial growth factor receptor; sunitinib, sorafenib and pazopanib, against a large panel of kinases in in vitro and cellular assays. They further evaluated the potential for myelosuppression by measuring the ability of these TKIs to inhibit human bone marrow progenitor growth. Both c-kit and flt-3 seemed to be important kinases for the development of early stem and progenitor cells, as determined by Kumar et al (2009). The differences in activity against these kinases provide a plausible explanation for the observed differences in clinical myelosuppression between sunitinib, sorafenib and pazopanib (Hartmann et al, 2009; Kumar et al, 2009). As there is considerable variability among patients with regard to sunitinib-induced myelosuppression, additional patient characteristics could very well contribute to the development of bone marrow toxicity. In a recent study, we have investigated the relationship between germ-line variants in genes encoding proteins involved in sunitinib disposition, metabolism and mechanism of action and the development of common toxicities, including haematological toxicities (van Erp et al, 2009). We found a strong association between the presence of the flt-3 738C-allele, which is a non-synonymous polymorphism in the flt-3 receptor with currently unknown functionality, and a 2.8-fold reduction in the risk for developing leukopenia after one cycle of sunitinib treatment. This finding not only underlines the role of flt-3 in myelosuppression as suggested by Kumar et al (2009) but might also explain the large interpatient variability in sunitinib-related leukopenia response. In our study, only 29% of the patients developed thrombocytopenia in the first treatment cycle as compared with 46% of the patients who developed leukopenia scored according to the criteria of Common Toxicity Criteria for Adverse Events version 3.0. An explanation for this difference might be the high baseline thrombocyte counts (mean: 319 × 109 l–1, range: 92–864 × 109 l–1) in these patients. As a consequence, a larger decrease in thrombocytes is necessary to develop thrombocytopenia. We, therefore, performed a sub-analysis, in 193 patients, in which the thrombocyte count ratios (counts after 4 weeks of treatment/baseline counts) were univariately tested for an association with the flt-3 polymorphism 738T/C. The flt-3 genotype was divided into two groups wild type (TT) (n=59) vs C-allele carriers (CT/CC) (n=134) since a protective effect was observed in C-allele carriers in developing leukopenia in our earlier analysis (van Erp et al, 2009). In line with our previous analysis, a protective effect in thrombocyte reduction was indeed observed for the flt-3 738C-allele carriers. After 4 weeks of sunitinib treatment, the mean thrombocyte count ratios for carriers of the flt-3 738 TT genotype vs carriers of the flt-3 738 CT/CC genotype were 0.54 vs 0.65 (P=0.024) (Figure 1). Figure 1 Trombocyte counts decrease after sunitinib start in flt3 738 TT vs CT and CC carriers. We conclude that the flt-3 738C allele has a protective effect against sunitinib-induced thrombocytopenia. Combined with our earlier finding with regard to leukopenia it seems that the flt-3 738C>T polymorphism has a role in the variability of sunitinib-induced bone marrow toxicities.

Pharmacokinetics and Pharmacodynamics of Mycophenolic Acid and Their Relation to Response to Therapy of Childhood-Onset Systemic Lupus Erythematosus

Mycophenolic acid (MPA) is the active form of mycophenolate mofetil (MMF), which is currently used off-label as immunosuppressive therapy in childhood-onset SLE (cSLE). The objectives of this study were to (1) characterize the pharmacokinetics (MPA-PK) and pharmacodynamics (MPA-PD) of MPA and (2) explore the relationship between MPA-PK and cSLE disease activity. MPA-PK [area under the curve from 0-12 hours (AUC(0-12))] and MPA-PD [inosine-monophosphate dehydrogenase (IMPDH) activity] were evaluated in cSLE patients on stable MMF dosing. Change in SLE disease activity while on MMF therapy was measured using the British Isles Lupus Assessment Group (BILAG) index. A total of 19 AUC(0-12) and 10 IMPDH activity profiles were included in the analysis. Large interpatient variability in MPA exposure (AUC(0-12)) was observed (mean ± SE: 32 ± 4.2 mg h/L; coefficient of variation: 57%). Maximum MPA serum concentrations coincided with maximum IMPDH inhibition. AUC(0-12) and weight-adjusted MMF dosing were only moderately correlated (r = 0.56, P = 0.01). An AUC(0-12) of ≥30 mg h/L was associated with decreased BILAG scores while on MMF therapy (P = 0.002). Weight-adjusted MMF dosing alone does not reliably allow for the prediction of exposure to biologically active MPA in cSLE. Individualized dosing considering MPA-PK appears warranted as this allows for better estimation of immunologic suppression (IMPDH activity). Additional controlled studies are necessary to confirm that an MPA AUC(0-12) of at least 30 mg h/L is required for cSLE improvement.

Voriconazole concentrations and outcome of invasive fungal infections

Twenty-five patients with proven or probable invasive fungal infections (IFIs) who experienced two or more episodes of voriconazole therapeutic drug monitoring (TDM) at a tertiary referral hospital were reviewed to explore the association between serum trough concentrations and outcomes of IFI. Microbiological and/or clinical success, in addition to IFI-related mortality, was assessed. We performed two separate analyses, one based on the initial trough voriconazole concentration at steady state, and the other on the median trough voriconazole concentration (derived from repeated TDM episodes) for each patient. Large interpatient and intrapatient variability of trough plasma voriconazole concentrations was observed, with no correlation between dose and concentration (r = 0.065). Classification and regression tree analysis revealed an association between IFI-related mortality and initial trough voriconazole concentrations, with patients more likely to die when their initial steady-state concentration was ≤0.35 mg/L (p 0.004; OR 11, 95% CI 2.9–41.2). Successful outcomes were more likely among patients with a median trough voriconazole concentration >2.2 mg/L (p 0.003; OR 2.7, 95% CI 1.4–5). Nineteen adverse events, with four severe events, were documented in 14 patients. Patients with severe adverse events had higher median voriconazole concentrations than the remaining cohort (2.38 mg/L vs. 1.30 mg/L; p <0.04). All adverse events resolved after cessation of voriconazole treatment. Our data suggest that voriconazole TDM is appropriate for all patients as soon as steady state is achieved. For non-responding patients with low trough concentrations, the association with IFI-related mortality indicates the need for dose adjustments to achieve and sustain voriconazole concentrations.

Population Pharmacokinetics of Midazolam and Its Metabolites during Venoarterial Extracorporeal Membrane Oxygenation in Neonates

Midazolam is used to sedate children during extracorporeal membrane oxygenation (ECMO). Pharmacokinetic changes are expected because of extracorporeal circulation and maturation. We present a population pharmacokinetic model for midazolam and its major metabolites in neonates during venoarterial ECMO. We studied 20 neonates on venoarterial ECMO, with a median postnatal age of 0.79 (range 0.17-5.8) days and a bodyweight of 3.0 (range 2.7-3.9) kg at the onset of ECMO. The median ECMO duration was 124 (range 70-275) hours. Serum concentrations were measured at the initiation and discontinuation of the midazolam infusion (100-300 microg/kg/h). Analysis of concentrations of midazolam, 1-hydroxymidazolam and its glucuronide were performed using nonlinear mixed-effects modelling. A two-compartment model for midazolam and a one-compartment model for the metabolites 1-hydroxymidazolam and hydroxymidazolam glucuronide adequately described the data, with allometric scaling of all parameters. Following the start of ECMO, the volume of distribution of midazolam increased from 4.29 to 14.6 L/3 kg, with an elimination half-life of 1.85 hours. The median midazolam and 1-hydroxymidazolam clearance values increased 3-fold within the first 5 days (up to 1.38 and 5.31 L/h/3 kg, respectively), whereas hydroxymidazolam glucuronide clearance remained constant at 0.18 L/h/3 kg. Interpatient variability estimates of midazolam, 1-hydroxymidazolam and hydroxymidazolam glucuronide clearance and midazolam and hydroxymidazolam glucuronide volumes of distribution varied between 87% and 129%. Concomitant inotropic infusion increased hydroxymidazolam glucuronide clearance by 23%. After allometric scaling, clearance of midazolam and 1-hydroxymidazolam increases as a result of maturation or recovery from critical illness. In ECMO patients weighing 2.7-3.9 kg, continuously infused midazolam doses of 300 microg/kg/h for 6 hours and 150 microg/kg/h thereafter provide adequate serum concentrations for sedation. The dose must be increased substantially after 5-7 days. Hydroxymidazolam glucuronide accumulates during ECMO, providing an increased proportion of the overall effect, up to 34% after 7 days. Large unexplained interpatient variability warrants careful titration of sedation and adverse effects.

Role of brainstem centers in cardiorespiratory phase difference during mechanical ventilation

During mechanical ventilation, large inter-patient and intra-patient variations of the phase of respiratory sinus arrhythmia (RSA) were described. To determine whether these variations were neurally mediated, we compared the RSA phase between: (1) 12 control subjects, (2) 23 mechanically ventilated patients without brain injury (MV group) and (3) 12 brain dead, mechanically ventilated patients, whose central nervous functions were abolished (BD group). ECG and ventilatory flow were recorded during 15 min and the RSA phase was then continuously computed by complex demodulation. Control group exhibited RSA phases between 180° and 250° whereas an opposite pattern, between 0° and 90°, was observed in the BD group. For the two groups, the phase was stable over time. In the MV group, the RSA phases were distributed between 0° and 260°, with a greater variability over time than the other groups. Therefore, during mechanical ventilation, brainstem centers may induce large variations of the RSA phase, not synchronous with the mechanical effect of ventilation.

Antiretroviral Therapeutic Drug Monitoring in Canada: Current Status and Recommendations for Clinical Practice

Therapeutic drug monitoring (TDM) is a strategy whereby the plasma concentration of one or more drugs is measured and drug doses are adjusted accordingly to achieve concentrations within an acceptable therapeutic range. The goal of TDM is to maximize pharmacologic efficacy and minimize the drug’s toxic effects, and hence to contribute to optimizing the patient’s outcomes. In general, TDM is indicated if the following conditions are present: there is a direct relationship between drug exposure and pharmacologic response, the drug has a narrow therapeutic index and is used to treat a condition for which drug failure or toxicity is associated with substantial morbidity or mortality, and there is limited intrapatient but wide interpatient pharmaco kinetic variation. Differences in pharmacokinetic factors among patients are multifactorial and may include age, sex, ethnic background, pregnancy, and body weight, as well as comorbid conditions causing variations in hepatic function, renal function, drug absorption, and drug disposition. In some cases, genetic polymorphisms in the cytochrome P450 enzymes may explain the large interpatient variability for certain antiretroviral agents. For example, certain CYP2B6 and CYP2A6 polymorphisms are independent predictors of plasma concentrations of efavirenz. Moreover, the potential for complex or unpredictable drug–drug or drug–food interactions can significantly affect plasma drug concentrations. Finally, TDM depends on the availability of an accurate and feasible analytical method for a given drug. Among antiretroviral agents, the protease inhibitors and the non-nucleoside reverse transcriptase inhibitors (NNRTIs) are considered suitable candidates for TDM. Evidence exists of a relation between exposure to antiretrovirals and virologic response and, in more limited instances, between exposure to the drug and toxic effects. Recent data have suggested that intraindividual variation is limited (19.0% for NNRTIs and 38.1% for protease inhibitors). Preliminary data have also suggested that trough levels of maraviroc, a chemokine (C–C motif) receptor 5 (CCR5) antagonist, are predictive of virologic outcome, although TDM experience with this agent is extremely limited. In retrospective and prospective studies, observed interindividual variability in drug concentrations has been 45% to 112% for protease inhibitors and 75% for NNRTIs. Thus, a given dose of a particular antiretroviral agent may result in unacceptable toxic effects in some patients while yielding subtherapeutic concentrations in others. TDM represents a tool by which the effectiveness of these agents in clinical practice can be optimized through dosage adjustments tailored to patient-specific pharmacokinetic and pharmaco dynamic parameters. The current article reviews the literature on antiretroviral TDM, describes the development of an antiretroviral TDM program in Canada, and illustrates the role of the pharmacist in the clinical application of TDM. Given current evidence and personal experience, the authors support the use of antiretro viral TDM as a clinical tool in special patient populations and for specific clinical situations.

Statistical modelling of the whole human femur incorporating geometric and material properties

When analysing the performance of orthopaedic implants the vast majority of computational studies use either a single or limited number of bone models. The results are then extrapolated to the population as a whole, overlooking the inherent and large interpatient variability in bone quality and geometry. This paper describes the creation of a three dimensional, statistical, finite element analysis (FEA) ready model of the femur using principal component analysis. To achieve this a registration scheme based on elastic surface matching and a mesh morphing algorithm has been developed. This method is fully automated enabling registration and generation of high resolution models. The variation in both geometry and material properties was extracted from 46 computer tomography scans and captured by the statistical model. Analysis of mesh quality showed this was maintained throughout the model generation and sampling process. Reconstruction of the training femurs showed 35 eigenmodes were required for accurate reproduction. A set of unique, anatomically realistic femur models were generated using the statistical model, with a variation comparable to that seen in the population. This study illustrates a methodology with the potential to generate femur models incorporating material properties for large scale multi-femur finite element studies.

Steady-State Imatinib Trough Levels as Well as Dose Interruptions Are Associated with Clinical Response (CCyR and MMR) and Adverse Events (AEs) in Patients with Chronic Myeloid Leukemia (CML) Receiving IM as Frontline Therapy.

Abstract 2213Poster Board II-190 Background:Correlations between IM trough plasma levels (Cmin) and clinical response have been previously reported [Picard et al. Blood 2007; Larson et al. (IRIS) Blood 2008; Guilhot et al. (TOPS) ASH 2008]. This analysis correlates IM Cmin on Day 29 of initial treatment with complete cytogenetic response (CCyR) and major molecular responses (MMR) at 12 months and with cumulative Grade 3&4 toxicity over 12 months based on data pooled from 2 studies, IRIS (400 mg qd) and TOPS (400 mg bid (800 mg/daily) vs 400 mg qd), in newly diagnosed, previously untreated, Ph+ CML-CP. Methods:Steady-state Cmin was defined as predose blood level collected within ±3 hours of the scheduled dosing time on Day 29 without any dose interruptions within 5 days prior to PK sampling. The correlation between IM Cmin and CCyR and MMR at 12 months was studied by two approaches: 1) analysis of outcomes by quartile groups based on patients' IM Cmin levels; 2) logistic regression analysis with Cmin as a continuous variable plus Sokal risk scores and cumulative days with any dose interruptions during the initial 12 months. Safety parameters included Grade 3&4 AEs, as well as all frequently-occurring (>10%) AEs of any grade that occurred during the 12 months. Patients with missing covariates were excluded. Results:Steady-state IM Cmin trough levels were available in 526 patients: 319 in IRIS and 207 from TOPS. At the time of assessment most patients received either 400 mg or 800 mg; 8 patients received reduced doses (6 at 300 mg; 2 at 600 mg). The median IM Cmin [25-75% quartiles] for 400 mg in the pooled dataset was 943 ng/mL [688-1280 ng/mL], and that for 800 mg was 2910 ng/mL [2333-3900 ng/mL]. IM Cmin showed large inter-patient variability for both 400 mg and 800 mg dose groups (52.7% and 39.9%, respectively). Both CCyR and MMR rates at 12 months were significantly correlated with IM Cmin on Day 29. Besides Cmin on Day 29, Sokal risk scores and cumulative dose interruptions (due either to treatment-related toxicities or non-adherence) were significant covariates for 12 month CCyR and MMR. Patients with high Sokal scores (H) had lower CCyR and MMR rates than those with low Sokal scores (L), 64% (H), 69% (intermediate (I)), and 83% (L), respectively, for CCyR, and 37%, 48%, and 59%, respectively, for MMR. Response rates at 12 months were significantly lower for patients with cumulative dose interruptions > 28 days (in the first 12 months): 45% vs 76% for CCyR, and 27% vs 48% for MMR. Modeling predicts that at a Cmin level of 1000 ng/mL and assuming no or minimal dose interruptions, the CCyR at 12 months would be 85%, 78%, and 68% for L, I, and H Sokal risk patients, respectively, and for MMR 55%, 45% and 36%, respectively. If the Cmin were 2000 ng/mL, the CCyR at 12 months would be 93%, 89%, and 83% for L, I, and H Sokal risk patients, respectively, and for MMR 65%, 55% and 44%, respectively. The predicted CCyR and MMR would be lower if there were dose interruptions. Patients who had Grade 3&4 AEs over first 12 months period (n=136) had a higher IM Cmin on Day 29 (median [25-75% quartiles], 1985 [982-2943] ng/mL vs 1010 [728-1468] ng/mL, P<0.001), than those without (n=390) as well as longer cumulative dose interruptions (20 [8-41] days vs 0 [0-2] days, P<0.001), lower CCyR rate (66%; 77/117 vs 75%; 277/369, P=0.05), and lower MMR rate (37%; 49/131 vs 48%; 155/323, P=0.006). Most Grade 3&4 AEs were treatment-related hematologic AEs with median times to onset between 50-63 days. Regression analysis showed the correlation between hematologic Grade 3&4 AEs and IM Cmin level for the population (Figure). Among all-grade non-hematologic AEs, rash and vomiting were associated with higher IM Cmin levels. [Display omitted] Conclusion:IRIS+TOPS pooled data confirmed earlier findings that higher steady-state IM levels correlate with better CCyR and MMR responses but also with more Grade 3&4 treatment-related toxicities. Dose interruptions compromise CCyR and MMR rates at 12 months. IM Cmin levels provide additional information together with clinical response and tolerability to inform dose changes for individual patients. Disclosures:Larson:Novartis: Consultancy, Honoraria, Research Funding. Chia:Novartis: Employment. Granvil:Novartis: Employment. Guilhot:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria. Druker:OHSU patent #843 - Mutate ABL Kinase Domains: Patents & Royalties; MolecularMD: Equity Ownership; Roche: Consultancy; Cylene Pharmaceuticals: Consultancy; Calistoga Pharmaceuticals: Consultancy; Avalon Pharmaceuticals: Consultancy; Ambit Biosciences: Consultancy; Millipore via Dana-Farber Cancer Institute: Patents & Royalties; Novartis, ARIAD, Bristol-Myers Squibb: Research Funding. O'Brien:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Wyeth: Research Funding. Baccarani:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Mayer Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Nedelman:Novartis: Employment, Equity Ownership. Wang:Novartis: Employment, Equity Ownership.

Safety, Efficacy, and Pharmacokinetics of Balsalazide in Pediatric Patients With Mild‐to‐Moderate Active Ulcerative Colitis: Results of a Randomized, Double‐blind Study

: A multicenter, double-blind study was conducted to evaluate the safety, efficacy, and pharmacokinetics of balsalazide in pediatric patients with mild-to-moderate ulcerative colitis (UC). : Sixty-eight patients, 5 to 17 years of age, with mild-to-moderate active UC based on the modified Sutherland UC activity index (MUCAI) were randomized to receive oral balsalazide 2.25 or 6.75 g/day for 8 weeks. The primary endpoint was clinical improvement (reduction of the MUCAI score by > or =3 points from baseline). Clinical remission (MUCAI score of 0 or 1 for stool frequency) and histological improvement after 8 weeks were also assessed. Pharmacokinetic parameters for balsalazide, 5-aminosalicylic acid, and N-acetyl-5-aminosalicylic acid were determined at 2 weeks. Adverse events and laboratory changes were monitored throughout the study. : Clinical improvement was achieved by 45% and 37% of patients and clinical remission by 12% and 9% of patients receiving 6.75 and 2.25 g/day, respectively. Improvement in histologic grade was achieved by 8 of 16 (50%) and 3 of 10 (30%) patients receiving 6.75 and 2.25 g/day, respectively. No significant differences were seen in efficacy. Pharmacokinetics in 12 patients were characterized by large interpatient variability and low systemic exposure. Adverse events were similar between the treatment groups, the most common being headache and abdominal pain. No clinically significant changes were observed in laboratory values, including those indicative of hepatic or renal toxicity. : Balsalazide is well tolerated and improves the signs and symptoms of mild-to-moderate active UC in pediatric patients 5 to 17 years of age.

UDP-Glucuronosyltransferase (UGT) Polymorphisms Affect Atorvastatin Lactonization In Vitro and In Vivo

The response to statins shows large interpatient variability. Atorvastatin delta-lactone is pharmacologically inactive but has been associated with toxicity. We investigated the role of UDP-glucuronosyltransferases (UGTs) in atorvastatin lactonization. In human liver microsomes, lactonization was correlated with UGT1A3 (r(s) = 0.61, P < 0.0001) but not with UGT1A1. Surprisingly, lactone formation was significantly higher in carriers of UGT1A1*28, an allele that is associated with lower UGT1A1 expression. We show that this inverse correlation is due to extensive linkage disequilibrium in the UGT1A locus and that several UGT1A3 haplotypes are associated with strong increases in UGT1A3 expression in vitro. Analyses of the pharmacokinetic parameters of atorvastatin and metabolites in genotyped volunteers confirmed that there is an increase in atorvastatin lactonization in carriers of UGT1A3*2 in vivo. The potential of UGT genotyping to identify patients who are at increased risk for failure of therapy and/or adverse effects of statins warrants further investigation.

Run-to-Run Tuning of Model Predictive Control for Type 1 Diabetes Subjects: In Silico Trial

The technological advancements in subcutaneous continuous glucose monitoring and insulin pump delivery systems have paved the way to clinical testing of artificial pancreas devices. The experience derived by clinical trials poses technological challenges to the automatic control expert, the most notable being the large interpatient and intrapatient variability and the inherent uncertainty of patient information. A new model predictive control (MPC) glucose control system is proposed. The starting point is an MPC algorithm applied in 20 type 1 diabetes mellitus (T1DM) subjects. Three main changes are introduced: individualization of the ARX model used for prediction; synthesis of the MPC law on top of the open-loop basal/bolus therapy; and a run-to-run approach for implementing day-by-day tuning of the algorithm. In order to individualize the ARX model, a sufficiently exciting insulin profile is imposed by splitting the premeal bolus into two smaller boluses (40% and 60%) injected 30 min before and 30 min after the meal. The proposed algorithm was tested on 100 virtual subjects extracted from an in silico T1DM population. The trial simulates 44 consecutive days, during which the patient receives breakfast, lunch, and dinner each day. For 10 days, meals are multiplied by a random variable uniformly distributed in [0.5, 1.5], while insulin delivery is based on nominal meals. Moreover, for 10 days, either a linear increase or decrease of insulin sensitivity (+/-25% of nominal value) is introduced. The ARX model identification procedure offers an automatic tool for patient model individualization. The run-to-run approach is an effective way to auto-tune the aggressiveness of the closed-loop control law, is robust to meal variation, and is also capable of adapting the regulator to slow parameter variations, e.g., on insulin sensitivity.

Determinants of red blood cell methotrexate polyglutamate concentrations in rheumatoid arthritis patients receiving long‐term methotrexate treatment

Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug (DMARD) in the management of rheumatoid arthritis (RA). MTX is transported into cells, where additional glutamate moieties are added and it is retained as MTX polyglutamates (MTXGlu [referred to as a group as MTXGlun]). There is large interpatient variability in MTXGlun concentrations. This study was undertaken to determine nongenetic factors that influence red blood cell (RBC) MTXGlun concentrations in patients receiving long-term stable low-dose oral MTX. One hundred ninety-two patients receiving long-term oral MTX for the treatment of RA were recruited. Trough MTXGlun concentrations were measured by high-performance liquid chromatography. Univariate analysis was performed to determine variables influencing MTXGlun concentrations. Backward stepwise multivariate regression analysis was done to determine variables that affect individual MTXGlun concentrations; variables with P values of <0.1 in the univariate analysis for any MTXGlun were included. Univariate analysis revealed that increased age, lower estimated glomerular filtration rate (GFR), higher MTX dosage, longer duration of MTX treatment, and use of prednisone were associated with significantly higher MTXGlun concentrations. Smokers had significantly lower concentrations of MTXGlu3, MTXGlu3-5, and MTXGlu1-5. Sex, rheumatoid factor and anti-cyclic citrullinated peptide status, RBC folate level, and body mass index had no significant effect on MTXGlun levels. Concomitant use of other DMARDs was associated with lower MTXGlu2 levels, and treatment with nonsteroidal antiinflammatory drugs was associated with lower MTXGlu3 and MTXGlu1-5 concentrations. Multivariate regression analysis revealed that age, MTX dosage, and estimated GFR were the major determinants of MTXGlun concentrations. Large interpatient variability in MTXGlun concentrations can be explained, at least in part, by a combination of factors, particularly age, MTX dosage, and renal function. There are complex interactions between smoking, RBC folate levels, and concentrations of MTXGlun.

High flow nasal cannula therapy as respiratory support in the preterm infant

We reviewed the literature on the effects of high flow nasal cannula (HFNC) and heated, humidified, high-flow, nasal cannula (HHHFNC) treatment in preterm infants. We found nine studies, but only two were randomized controlled trials. These studies show that: HFNC application is associated to the delivery of continuous distending pressure (CDP) in patients with closed mouth, whose value is proportional to the delivered flow only in smaller infants; the CDP delivered by HFNC is unpredictable and present large inter-patient and intra-patient variability; the use of recently available HHHFNC devices is effective in minimizing nasal mucosa injuries compared to traditional HFNC; the effectiveness of HHHFNC versus NCPAP for the treatment of apnoea of prematurity, respiratory distress syndrome, and the prevention of extubation failure, has been poor investigated and firm conclusions cannot be drawn on this matter. In conclusion, on the basis of published data, the routinary application of HFNC should be limited to patients requiring oxygen-therapy, HHHFNC devices should be preferred to HFNC, but their employment as an alternative to NCPAP should wait for the conclusion of randomized controlled trials.

Assessment of actigraphy as a method to assess sleep quality following inpatient tonsillectomy in children

Introduction: The aetiology of sleep disturbance in children following surgery is unclear, despite a reported incidence of 47% [1]. The Actiwatch, a small ‘wristwatch’ device, uses actigraphy, a technology based on the principle of movement detection, to assess sleep quality. It can be attached to a child and set to record details of movement at regular intervals. We sought to determine whether the Actiwatch is able to produce useful data for the assessment of sleep in inpatient children following tonsillectomy. Methods: Prior local ethics committee approval and informed parental consent were obtained. Fifteen ASA 1–2 children, aged 2–12 undergoing inpatient tonsillectomy were recruited. The Actiwatch monitor, programmed to record movement at 25 s intervals, was attached to each child after surgery and then retrieved the following morning. Additional data concerning operative details, drugs administered and adverse events were recorded and a sleep diary was provided for nursing staff and parents to record periods of sleep and wake overnight. Actigraph summary data was retrieved from each wristwatch the following day and details of asleep and awake periods recorded in the sleep diary were compared with actigraph data. Results: All parents approached agreed to take part, however one child refused to wear the ‘watch’ and was not included in the study. One further dataset was not collected due to a watch malfunction, leaving data from 13 children (five male, eight female) remaining. A total of 86 sleep assessments were made in the sleep diaries which, when compared with the actigraph data, gave a sensitivity and specificity of 82% and 90% respectively. The mean, range and standard deviation for overnight sleep parameters for all children were as follows: Total sleep time: 8 h 24 min (range 7:04–10:30 h), sd 70.7 min. Total awake time: 1 h 20 min (range 22 min–2:48 h), sd 41 min. Number of sleep bouts: 59.7 (range 33–109) sd 19.5. Sleep efficiency (% of total time spent asleep): 78.8% (range 69–95.8%), sd 8.8%. Discussion: Risk factors previously identified for poor postoperative sleep in the day case setting include pain, preoperative sleep patterns, parental anxiety and aggressive child behaviour [3]. However, there has been little work published using actigraphy in the inpatient setting to determine which factors are associated with poor sleep, such as the ward environment and perioperative medication. The actigraph is a small robust device that appears to be well tolerated by inpatient children, with only one refusal and one malfunction. We have illustrated a good correlation between observed and recorded sleep, indicating that the actigraph is indeed a useful tool for the assessment of postoperative sleep dysfunction in children. This correlates well with other authors [2] who have found a concordance rate of 85.3% compared with polysomnography in children. We have illustrated a large variation in the recorded sleep patterns between children in the inpatient setting. Both the range and standard deviations of the recorded parameters are large, implying that a direct comparative study of perioperative techniques, for example, would require large sample sizes to ensure adequate power. It is possible that more robust data may be obtained by recording control actigraphy data on a child preoperatively, such that a paired comparison can then be made. This approach will, however, be logistically more challenging as it will require multiple preoperative contacts with the child. Conclusions: We conclude that actigraphy is a practical and reasonably reliable tool for the assessment of sleep in children following tonsillectomy although we have also illustrated a large inter-patient variation of all measured sleep parameters.

CYP3A polymorphisms and immunosuppressive drugs in solid-organ transplantation

Most immunosuppressive drugs have a narrow therapeutic index and large interpatient variabilities in their pharmacokinetic and pharmacodynamic profiles. Identification of functional single-nucleotide polymorphisms in genes encoding for drug metabolizing enzymes has great potential to improve the drug efficacy and safety profiles, since these genetic factors may be important biomarkers for individualization of immunosuppressive therapy. This article summarizes current knowledge regarding the impact of CYP3A polymorphisms on immunosuppressive drug pharmacokinetics. Many retrospective studies have shown a clear relationship between CYP3A5*1/*3 polymorphism and tacrolimus pharmacokinetics, while the influence of CYP3A5*1/*3 or CYP3A4*/*1B on ciclosporin and sirolimus exposure are still questionable. CYP3A polymorphisms may partially contribute to the clinical variability of the enzyme-mediated drug interactions. Drug–drug interactions may also influence the phenotypic consequence of CYP3A polymorphisms. Population pharmacodynamic/kinetic/genomic modeling was proposed as an emerging and promising approach to quantitatively explore the contribution of genetic polymorphisms to the large interpatient variability in the pharmacokinetic and pharmacodynamic profiles of immunosuppressive drugs. Prospective, randomized studies in large patient populations are needed to further clarify the genetic effects of CYP3A on immunosuppressive drug exposure and response.

Automatic segmentation of the facial nerve and chorda tympani in CT images using spatially dependent feature values

In cochlear implant surgery, an electrode array is permanently implanted in the cochlea to stimulate the auditory nerve and allow deaf people to hear. A minimally invasive surgical technique has recently been proposed-percutaneous cochlear access-in which a single hole is drilled from the skull surface to the cochlea. For the method to be feasible, a safe and effective drilling trajectory must be determined using a preoperative CT. Segmentation of the structures of the ear would improve trajectory planning safety and efficiency and enable the possibility of automated planning. Two important structures of the ear, the facial nerve and the chorda tympani, are difficult to segment with traditional methods because of their size (diameters as small as 1.0 and 0.3 mm, respectively), the lack of contrast with adjacent structures, and large interpatient variations. A multipart, model-based segmentation algorithm is presented in this article that accomplishes automatic segmentation of the facial nerve and chorda tympani. Segmentation results are presented for ten test ears and are compared to manually segmented surfaces. The results show that the maximum error in structure wall localization is approximately 2 voxels for the facial nerve and the chorda, demonstrating that the method the authors propose is robust and accurate.

Influence of uridine diphosphate (UDP)-glucuronosyltransferases and ABCC2 genetic polymorphisms on the pharmacokinetics of mycophenolic acid and its metabolites in Chinese renal transplant recipients

The aim was to investigate the effect of UGT1A9, UGT1A8, UGT2B7 and ABCC2 polymorphism on the pharmacokinetics of mycophenolic acid (MPA) and its metabolites phenolic glucuronide (MPAG) and acyl glucuronide (AcMPAG) in Chinese renal transplant recipients. Single nucleotide polymorphisms (SNP) in UGT1A9-118(dT)9/10, UGT1A9 T-440C/C-331T, UGT1A8*3, UGT2B7 G211T, UGT2B7 C802T, ABCC2 C-24T, and ABCC2 G1249A were detected. A total of 46 recipients were enrolled in the pharmacokinetics study at day 30 after kidney transplantation. Differences in the MPA pharmacokinetic profiles confirmed large inter-patient variation of MPA exposure. A statistical significant increase in the dose-adjusted AUC6–12 level of MPA was found in patients bearing the -118(dT)10 allele of the UGT1A9 gene (T9 = 7.34 ± 4.11 mg h ml−1 g−1; T9/T10 = 11.54 ± 7.62 mg h ml−1 g−1; and T10 = 11.89 ±8.76 mg h ml−1 g−1, p = 0.041). A similar trend was also observed for the dose-adjusted AUC0–12 and AUC6–12 of MPAG. Patients carrying the heterozygous mutant alleles of ABCC2 G1249A exhibited higher AUC6–12/D of AcMPAG than those with wild-type genotype (p = 0.016). The other SNPs that were genotyped did not cause any significant variation in MPA and MPAG pharmacokinetic parameters. In conclusion, the enterohepatic recirculation of MPA in the patients seems to be more extensive in UGT1A9-118(dT)10 allele carriers, and the exposure of AcMPAG is higher in patients carrying ABCC2 G1249A genotype than those with wild-type genotype.

A dose finding and pharmacokinetic study of capecitabine in combination with oxaliplatin and irinotecan in metastatic colorectal cancer

The GONO-FOLFOXIRI regimen demonstrated higher activity and efficacy than FOLFIRI in metastatic colorectal cancer patients. The aim of this study was to determine the maximum tolerated dose of capecitabine, in substitution of 5-fluorouracil, combined with oxaliplatin and irinotecan and to evaluate the pharmacokinetics of the drugs. We treated 15 patients with escalating doses of capecitabine (from day 1 to 7) and fixed doses of oxaliplatin (85 mg/m(2)) plus irinotecan (165 mg/m(2)) (both administered on day 1), repeated every 2 weeks. Pharmacokinetic analysis was performed on plasma samples collected at the first cycle of treatment. The maximum tolerated dose of capecitabine resulted 2,000 mg/m(2)/day, with diarrhea being the only dose-limiting toxicity. Large interpatient variability in the pharmacokinetic parameters of investigated drugs was observed. Results in terms of activity are promising. At the maximum tolerated dose of capecitabine of 2,000 mg/m(2)/day the combination is feasible with promising activity and deserves further investigations.