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1.  Relevance of Soft-Tissue Penetration by Levofloxacin for Target Site Bacterial Killing in Patients with Sepsis 
Antimicrobial Agents and Chemotherapy  2003;47(11):3548-3553.
Antimicrobial therapy of soft tissue infections in patients with sepsis sometimes lacks efficiency, despite the documented susceptibility of the causative pathogen to the administered antibiotic. In this context, impaired equilibration between the antibiotic concentrations in plasma and those in tissues in critically ill patients has been discussed. To characterize the impact of tissue penetration of anti-infective agents on antimicrobial killing, we used microdialysis to measure the concentration-versus-time profiles of levofloxacin in the interstitial space fluid of skeletal muscle in patients with sepsis. Subsequently, we applied an established dynamic in vivo pharmacokinetic-in vitro pharmacodynamic approach to simulate bacterial killing at the site of infection. The population mean areas under the concentration-time curves (AUCs) for levofloxacin showed that levofloxacin excellently penetrates soft tissues, as indicated by the ratio of the AUC from time zero to 8 h (AUC0-8) for muscle tissue (AUC0-8 muscle) to the AUC0-8 for free drug in plasma (AUC0-8 plasma free) (AUC0-8 muscle/AUC0-8 plasma free ratio) of 0.85. The individual values of tissue penetration and maximum concentration (Cmax) in muscle tissue were highly variable. No difference in bacterial killing of a select Staphylococcus aureus strain for which the MIC was 0.5 μg/ml was found between individuals after exposure to dynamically changing concentrations of levofloxacin in plasma and tissue in vitro. In contrast, the decrease in the bacterial counts of Pseudomonas aeruginosa (MIC = 2 μg/ml) varied extensively when the bacteria were exposed to levofloxacin at the concentrations determined from the individual concentration-versus-time profiles obtained in skeletal muscle. The extent of bacterial killing could be predicted by calculating individual Cmax/MIC and AUC0-8 muscle/AUC0-8 plasma free ratios (R = 0.96 and 0.93, respectively). We have therefore shown in the present study that individual differences in the tissue penetration of levofloxacin may markedly affect target site killing of bacteria for which MICs are close to 2 μg/ml.
doi:10.1128/AAC.47.11.3548-3553.2003
PMCID: PMC253769  PMID: 14576116
2.  The Relationship Between Fluticasone Furoate Systemic Exposure and Cortisol Suppression 
Clinical Pharmacokinetics  2013;52(10):885-896.
Introduction
The inhaled corticosteroid (ICS) fluticasone furoate is in development, in combination with the long-acting beta2-agonist vilanterol for the once-daily treatment of asthma and chronic obstructive pulmonary disease and as a monotherapy treatment for asthma. Corticosteroids, including ICSs, have the potential to induce dose-dependent systemic effects on the hypothalamic–pituitary–adrenal (HPA) axis. Cortisol suppression has been observed in asthma patients with normal HPA axis function at baseline on receiving high doses of ICSs, and is associated with adverse effects on a number of physiological processes. The measurement of 24-h serum cortisol and 24-h urinary cortisol excretion are sensitive methods for assessing adrenocortical activity, and can evaluate cortisol suppression in a dose-dependent manner.
Objective
The purpose of the meta-analysis presented here was to characterize the population pharmacokinetic/pharmacodynamic relationship between fluticasone furoate systemic exposure [as measured by area under the concentration–time curve over 24 h postdose (AUC24)] and both 24-h weighted mean serum cortisol (WM24) and 24-h urine cortisol excretion in healthy subjects and subjects with asthma.
Methods
The serum cortisol meta-analysis integrated eight studies; five Phase I studies in healthy subjects, two Phase IIa studies, and one Phase III study in subjects with asthma. Each study included serial blood sampling for estimation of WM24. The urine cortisol meta-analysis integrated three studies: one Phase I study in healthy subjects, and one Phase IIb and one Phase III study in subjects with asthma. Each study included complete 0–24 h urine collection for estimation of urine cortisol excretion. All studies included blood sampling for estimation of fluticasone furoate AUC24. A sigmoid maximum effect (Emax) model was fitted to fluticasone furoate AUC24 and serum cortisol and urine cortisol data using nonlinear mixed-effect modeling with the computer program NONMEM®.
Results
Over a wide range of systemic fluticasone furoate exposure representing the therapeutic and supratherapeutic range, the relationship between fluticasone furoate AUC24 and WM24 and 24-h urine cortisol excretion was well described by an Emax model. The average estimate of AUC producing 50 % of maximum effect (AUC50) was similar for the serum cortisol and urine cortisol models with values of 1,556 and 1,686 pg·h/mL, respectively. Although formulation/inhaler was shown to be a significant covariate on the estimates of both WM24 at zero concentration (C0) and AUC50 in the serum cortisol model, the differences were small and believed to be due to study variability. Age was shown to be a significant covariate on the estimates of both C0 and AUC50 in the urine cortisol model, and was considered to be a reflection of lower urine cortisol excretion in adolescents.
Conclusion
A pharmacokinetic/pharmacodynamic model has been established over a wide range of systemic fluticasone furoate exposure representing the therapeutic and supratherapeutic range to both WM24 and 24-h urine cortisol excretion. The values of AUC50 of 1,556 and 1,686 pg·h/mL, respectively, are several times higher than average fluticasone furoate AUC24 values observed at clinical doses of fluticasone furoate (≤200 μg). The models predict a fluticasone furoate AUC24 of 1,000 pg·h/mL would be required to reduce 24-h serum cortisol or 24-h urine cortisol excretion by 20 and 17 %, respectively.
doi:10.1007/s40262-013-0078-1
PMCID: PMC3779313  PMID: 23719680
3.  Pharmacodynamics of the New Fluoroquinolone Gatifloxacin in Murine Thigh and Lung Infection Models 
Gatifloxacin is a new 8-methoxy fluoroquinolone with enhanced activity against gram-positive cocci. We used the neutropenic murine thigh infection model to characterize the time course of antimicrobial activity of gatifloxacin and determine which pharmacokinetic (PK)-pharmacodynamic (PD) parameter best correlated with efficacy. The thighs of mice were infected with 106.5 to 107.4 CFU of strains of Staphylococcus aureus, Streptococcus pneumoniae, or Escherichia coli, and the mice were then treated for 24 h with 0.29 to 600 mg of gatifloxacin per kg of body weight per day, with the dose fractionated for dosing every 3, 6, 12, and 24 h. Levels in serum were measured by microbiologic assay. In vivo postantibiotic effects (PAEs) were calculated from serial values of the log10 numbers of CFU per thigh 2 to 4 h after the administration of doses of 8 and 32 mg/kg. Nonlinear regression analysis was used to determine which PK-PD parameter best correlated with the numbers of CFU per thigh at 24 h. Pharmacokinetic studies revealed peak/dose values of 0.23 to 0.32, area under the concentration-time curve (AUC)/dose values of 0.47 to 0.62, and half-lives of 0.6 to 1.1 h. Gatifloxacin produced in vivo PAEs of 0.2 to 3.1 h for S. pneumoniae and 0.4 to 2.3 h for S. aureus. The 24-h AUC/MIC was the PK-PD parameter that best correlated with efficacy (R2 = 90 to 94% for the three organisms, whereas R2 = 70 to 81% for peak level/MIC and R2 = 48 to 73% for the time that the concentration in serum was greater than the MIC). There was some reduced activity when dosing every 24 h was used due to the short half-life of gatifloxacin in mice. In subsequent studies we used the neutropenic and nonneutropenic murine thigh and lung infection models to determine if the magnitude of the AUC/MIC needed for the efficacy of gatifloxacin varied among pathogens (including resistant strains) and infection sites. The mice were infected with 106.5 to 107.4 CFU of four isolates of S. aureus (one methicillin resistant) per thigh, nine isolates of S. pneumoniae (two penicillin intermediate, four penicillin resistant, and two ciprofloxacin resistant) per thigh, four isolates of the family Enterobacteriaceae per thigh, a single isolate of Pseudomonas aeruginosa per thigh, and 108.3 CFU of Klebsiella pneumoniae per lung. The mice were then treated for 24 h with 0.29 to 600 mg of gatifloxacin per kg every 6 or 12 h. A sigmoid dose-response model was used to estimate the dose (in milligrams per kilogram per 24 h) required to achieve a net bacteriostatic effect over 24 h. MICs ranged from 0.015 to 8 μg/ml. The 24-h AUC/MICs for each static dose (1.7 to 592) varied from 16 to 72. Mean ± standard deviation 24-h AUC/MICs for isolates of the family Enterobacteriaceae, S. pneumoniae, and S. aureus were 41 ± 21, 52 ± 20, and 36 ± 9, respectively. Methicillin, penicillin, or ciprofloxacin resistance did not alter the magnitude of the AUC/MIC required for efficacy. The 24-h AUC/MICs required to achieve bacteriostatic effects against K. pneumoniae were quite similar in the thigh and lung (70 versus 56 in neutropenic mice and 32 versus 43 in nonneutropenic mice, respectively). The magnitude of the 24-h AUC/MIC of gatifloxacin required for efficacy against multiple pathogens varied only fourfold and was not significantly altered by drug resistance or site of infection.
doi:10.1128/AAC.46.6.1665-1670.2002
PMCID: PMC127205  PMID: 12019073
4.  Twenty-four-hour area under the concentration-time curve/MIC ratio as a generic predictor of fluoroquinolone antimicrobial effect by using three strains of Pseudomonas aeruginosa and an in vitro pharmacodynamic model. 
Several investigators have suggested that the 24-h area under the concentration-time curve (AUC)/MIC ratio (AUC/MIC24 or AUIC24) can be used to make comparisons of antimicrobial activity between fluoroquinolone antibiotics. Limited data exist regarding the generic predictive ability of AUC/MIC24 for the antimicrobial effects of fluoroquinolones. The purposes of the present investigation were to determine if the AUC/MIC24 can be used as a generic outcome predictor of fluoroquinolone antibacterial activity and to determine if a similar AUC/MIC24 breakpoint can be established for different fluoroquinolones. Using an in vitro pharmacodynamic model, 29 duplicate concentration time-kill curve experiments simulated AUC/MIC24s ranging from 52 to 508 SIT-1.h (inverse serum inhibitory titer integrated over time) with ciprofloxacin or ofloxacin against three strains of Pseudomonas aeruginosa. Each 24-h experiment was performed in cation-supplemented Mueller-Hinton broth with a starting inoculum of 10(6) CFU/ml. At timed intervals cation-supplemented Mueller-Hinton broth samples were collected for CFU and fluoroquinolone concentration determinations. Transformation of bacterial counts into the cumulative bacterial effect parameter of the 24-h area under the effect curve (AUEC24) was performed for each concentration time-kill curve. Multivariate regression analysis was used to compare pharmacodynamic predictors (AUC/MIC24, 24-h AUC, peak concentration [Cmax] to MIC ratios [Cmax:MIC], etc.) with ln AUEC24. To identify threshold breakpoint AUC/MIC24s, AUEC24s were stratified by the magnitude of AUC/MIC24 into subgroups, which were analyzed for differences in antibacterial effect. The Kruskal-Wallis test and subsequent Tukey's multiple comparison test were used to determine which AUC/MIC subgroups were significantly different. Multiple regression analysis revealed that only AUC/MIC24 (r2 = 0.65) and MIC (r2 = 0.03) were significantly correlated with antibacterial effect. At similar AUC/MIC24s, yet different MICs, Cmaxs, or elimination half-lives, the AUEC24s were similar for both fluoroquinolones. The relationship between AUC/MIC24 and ln AUEC24 was best described by a sigmoidal maximal antimicrobial effect (Emax) model (r2 = 0.72; Emax = 9.1; AUC/MIC50 = 119 SIT-1.h; S = 2.01 [S is an exponent that reflects the degree of sigmoidicity]). Ciprofloxacin-bacteria AUC/MIC24 values of < 100 SIT-1.h were significantly different (P < 0.05) from the AUC/MIC24 values of > 100 SIT-1.h. An ofloxacin AUC/MIC24 of > 100 SIT-1.h and an AUC/MIC24 of < 100 SIT-1.h exhibited a trend toward a significant difference (P > 0.05 but < 0.1). The inverse relationship between drug exposure and MIC increase postexposure was described by a sigmoidal fixed Emax model (AUC/MIC24, r2 = 0.40; AUC/MIC50 = 95 SIT-1.h; S = 1.97; Cmax:MIC, r2 = 0.41; Cmax:MIC50 = 7.3; S = 2.01). These data suggest that AUC/MIC24 may be the most descriptive measurement of fluoroquinolone antimicrobial activity against P. aeruginosa, that ofloxacin and ciprofloxacin have similar AUC/MIC24 threshold breakpoints at approximately 100 SIT-1.h, that the concentration-dependent selection of resistant organisms may parallel the threshold breakpoint of the antimicrobial effect, and that AUC/MIC24 generically describes the antibacterial effects of different fluoroquinolones.
PMCID: PMC163170  PMID: 8851583
5.  Population Pharmacokinetics and Pharmacodynamic Modeling of Abacavir (1592U89) from a Dose-Ranging, Double-Blind, Randomized Monotherapy Trial with Human Immunodeficiency Virus-Infected Subjects 
Abacavir (formerly 1592U89) is a carbocyclic nucleoside analog with potent anti-human immunodeficiency virus (anti-HIV) activity when administered alone or in combination with other antiretroviral agents. The population pharmacokinetics and pharmacodynamics of abacavir were investigated in 41 HIV type 1 (HIV-1)-infected, antiretroviral naive adults with baseline CD4+ cell counts of ≥100/mm3 and plasma HIV-1 RNA levels of >30,000 copies/ml. Data for analysis were obtained from patients who received randomized, blinded monotherapy with abacavir at 100, 300, or 600 mg twice-daily (BID) for up to 12 weeks. Plasma abacavir concentrations from sparse sampling were analyzed by standard population pharmacokinetic methods, and the effects of dose, combination therapy, gender, weight, and age on parameter estimates were investigated. Bayesian pharmacokinetic parameter estimates were calculated to determine the peak concentration of abacavir in plasma (Cmax) and the area under the concentration-time curve from time zero to infinity (AUC0–∞) for individual subjects. The pharmacokinetics of abacavir were dose proportional over the 100- to 600-mg dose range and were unaffected by any covariates. No significant correlations were observed between the incidence of the five most common adverse events (headache, nausea, diarrhea, vomiting, and malaise or fatigue) and AUC0–∞. A significant correlation was observed between Cmax and nausea by categorical analysis (P = 0.019), but this was of borderline significance by logistic regression (odds ratio, 1.45; 95% confidence interval, 0.95 to 2.32). The log10 time-averaged AUC0–∞ minus baseline (AAUCMB) values for HIV-1 RNA and CD4+ cell count correlated significantly with Cmax and AUC0–∞, but with better model fits for AUC0–∞. The increase in AAUCMB values for CD4+ cell count plateaued early for drug exposures that were associated with little change in AAUCMB values for plasma HIV-1 RNA. There was less than a 0.4 log10 difference over 12 weeks in the HIV-1 RNA levels with the doubling of the abacavir AUC0–∞ from 300 to 600 mg BID dosing. In conclusion, pharmacodynamic modeling supports the selection of abacavir 300 mg twice-daily dosing.
PMCID: PMC90013  PMID: 10898675
6.  Venous Thrombosis Risk after Cast Immobilization of the Lower Extremity: Derivation and Validation of a Clinical Prediction Score, L-TRiP(cast), in Three Population-Based Case–Control Studies 
PLoS Medicine  2015;12(11):e1001899.
Background
Guidelines and clinical practice vary considerably with respect to thrombosis prophylaxis during plaster cast immobilization of the lower extremity. Identifying patients at high risk for the development of venous thromboembolism (VTE) would provide a basis for considering individual thromboprophylaxis use and planning treatment studies.
The aims of this study were (1) to investigate the predictive value of genetic and environmental risk factors, levels of coagulation factors, and other biomarkers for the occurrence of VTE after cast immobilization of the lower extremity and (2) to develop a clinical prediction tool for the prediction of VTE in plaster cast patients.
Methods and Findings
We used data from a large population-based case–control study (MEGA study, 4,446 cases with VTE, 6,118 controls without) designed to identify risk factors for a first VTE. Cases were recruited from six anticoagulation clinics in the Netherlands between 1999 and 2004; controls were their partners or individuals identified via random digit dialing. Identification of predictor variables to be included in the model was based on reported associations in the literature or on a relative risk (odds ratio) > 1.2 and p ≤ 0.25 in the univariate analysis of all participants. Using multivariate logistic regression, a full prediction model was created. In addition to the full model (all variables), a restricted model (minimum number of predictors with a maximum predictive value) and a clinical model (environmental risk factors only, no blood draw or assays required) were created. To determine the discriminatory power in patients with cast immobilization (n = 230), the area under the curve (AUC) was calculated by means of a receiver operating characteristic. Validation was performed in two other case–control studies of the etiology of VTE: (1) the THE-VTE study, a two-center, population-based case–control study (conducted in Leiden, the Netherlands, and Cambridge, United Kingdom) with 784 cases and 523 controls included between March 2003 and December 2008 and (2) the Milan study, a population-based case–control study with 2,117 cases and 2,088 controls selected between December 1993 and December 2010 at the Thrombosis Center, Fondazione IRCCS Ca’ Granda–Ospedale Maggiore Policlinico, Milan, Italy.
The full model consisted of 32 predictors, including three genetic factors and six biomarkers. For this model, an AUC of 0.85 (95% CI 0.77–0.92) was found in individuals with plaster cast immobilization of the lower extremity. The AUC for the restricted model (containing 11 predictors, including two genetic factors and one biomarker) was 0.84 (95% CI 0.77–0.92). The clinical model (consisting of 14 environmental predictors) resulted in an AUC of 0.77 (95% CI 0.66–0.87). The clinical model was converted into a risk score, the L-TRiP(cast) score (Leiden–Thrombosis Risk Prediction for patients with cast immobilization score), which showed an AUC of 0.76 (95% CI 0.66–0.86). Validation in the THE-VTE study data resulted in an AUC of 0.77 (95% CI 0.58–0.96) for the L-TRiP(cast) score. Validation in the Milan study resulted in an AUC of 0.93 (95% CI 0.86–1.00) for the full model, an AUC of 0.92 (95% CI 0.76–0.87) for the restricted model, and an AUC of 0.96 (95% CI 0.92–0.99) for the clinical model. The L-TRiP(cast) score resulted in an AUC of 0.95 (95% CI 0.91–0.99).
Major limitations of this study were that information on thromboprophylaxis was not available for patients who had plaster cast immobilization of the lower extremity and that blood was drawn 3 mo after the thrombotic event.
Conclusions
These results show that information on environmental risk factors, coagulation factors, and genetic determinants in patients with plaster casts leads to high accuracy in the prediction of VTE risk. In daily practice, the clinical model may be the preferred model as its factors are most easy to determine, while the model still has good predictive performance. These results may provide guidance for thromboprophylaxis and form the basis for a management study.
Using three population-based case-control studies, Banne Nemeth and colleagues derive and validate a clinical prediction score (L-TRiP(cast)) for venous thrombosis risk.
Editors' Summary
Background
Blood normally flows smoothly around the human body, but when a cut or other injury occurs, proteins called clotting factors make the blood gel (coagulate) at the injury site. The resultant clot (thrombus) plugs the wound and prevents blood loss. Sometimes, however, a thrombus forms inside an uninjured blood vessel and partly or completely blocks the blood flow. Clot formation inside one of the veins deep in the body (usually in a leg) is called deep vein thrombosis (DVT). DVT, which can cause pain, swelling, and redness in the affected limb, is treated with anticoagulants, drugs that stop the clot growing. If left untreated, part of the clot can break off and travel to the lungs, where it can cause a life-threatening pulmonary embolism. DVT and pulmonary embolism are known collectively as venous thromboembolism (VTE). Risk factors for VTE include age, oral contraceptive use, having an inherited blood clotting disorder, and prolonged inactivity (for example, being bedridden). An individual’s lifetime risk of developing VTE is about 11%; 10%–30% of people die within 28 days of diagnosis of VTE.
Why Was This Study Done?
Clinicians cannot currently accurately predict who will develop VTE, but it would be very helpful to be able to identify individuals at high risk for VTE because the condition can be prevented by giving anticoagulants before a clot forms (thromboprophylaxis). The ability to predict VTE would be particularly useful in patients who have had a lower limb immobilized in a cast after, for example, breaking a bone. These patients have an increased risk of VTE compared to patients without cast immobilization. However, their absolute risk of VTE is not high enough to justify giving everyone with a leg cast thromboprophylaxis because this therapy increases the risk of major bleeds. Here, the researchers investigate the predictive value of genetic and environmental factors and levels of coagulation factors and other biomarkers on VTE occurrence after cast immobilization of the lower leg and develop a clinical tool for the prediction of VTE in patients with plaster casts.
What Did the Researchers Do and Find?
The researchers used data from the MEGA study, a study of risk factors for VTE, to build a prediction model for a first VTE in patients with a leg cast; the prediction model included 32 predictors (the full model). They also built a restricted model, which included only 11 predictors but had maximum predictive value, and a clinical model, which included 14 environmental predictors that can all be determined without drawing blood or undertaking any assays. They then determined the ability of each model to distinguish between patients with a leg cast who did and did not develop VTE using receiver operating characteristic (ROC) curve analysis. The area under the curve (AUC) for the full model was 0.85, for the restricted model it was 0.85, and for the clinical model it was 0.77. (A predictive test that discriminates perfectly between individuals who do and do not subsequently develop a specific condition has an AUC of 1.00; a test that is no better at predicting outcomes than flipping a coin has an AUC of 0.5.) Similar or higher AUCs were obtained for all the models using data collected in two independent studies. Finally, the researchers converted the clinical model into a risk score by giving each variable in the model a numerical score. The sum of these scores was used to stratify individuals into categories of low or high risk for VTE. With a cutoff of 9 points, the risk score correctly identified 80.8% of the patients in the MEGA study with a plaster cast who developed VTE and 60.8% of the patients who did not develop VTE.
What Do These Findings Mean?
Some aspects of this study may limit the accuracy of its findings. For example, no information was available about which patients with a plaster cast received thromboprophylaxis. Nevertheless, these findings suggest that information on environmental risk factors, coagulation factors, and genetic determinants can be used to predict VTE risk in patients with a leg cast with high accuracy. Importantly, the risk score derived and validated by the researchers, which includes only predictors that can be easily determined in clinical practice, may help clinicians decide which patients with a leg cast should receive thromboprophylaxis and which should not be exposed to the risk of anticoagulant therapy, until an unambiguous guideline for these patients becomes available.
Additional Information
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001899.
The US National Heart, Lung, and Blood Institute provides information on deep vein thrombosis (including an animation about how DVT causes pulmonary embolisms) and on pulmonary embolism
The UK National Health Service Choices website has information on deep vein thrombosis (including personal stories) and on pulmonary embolism
The US non-profit organization National Blood Clot Alliance provides detailed information about deep vein thrombosis and pulmonary embolism for patients and professionals and includes a selection of personal stories about these conditions
MedlinePlus has links to further information about deep vein thrombosis and pulmonary embolism (in English and Spanish)
Wikipedia has a page on ROC curve analysis (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
More information about the MEGA study is available
doi:10.1371/journal.pmed.1001899
PMCID: PMC4640574  PMID: 26554832
7.  Safety, Pharmacokinetics, and Pharmacodynamics of Cyclodextrin Itraconazole in Pediatric Patients with Oropharyngeal Candidiasis 
The safety, pharmacokinetics, and pharmacodynamics of cyclodextrin itraconazole (CD-ITRA) oral suspension were investigated in an open sequential dose escalation study with 26 human immunodeficiency virus (HIV)-infected children and adolescents (5 to 18 years old; mean CD4+-cell count, 128/μl) with oropharyngeal candidiasis (OPC). Patients received CD-ITRA at either 2.5 mg/kg of body weight once a day (QD) or 2.5 mg/kg twice a day (BID) for a total of 15 days. Pharmacokinetic sampling was performed after the first dose and for up to 120 h after the last dose, and antifungal efficacy was evaluated by standardized scoring of the oropharynx. Apart from mild to moderate gastrointestinal disturbances in three patients (11.5%), CD-ITRA was well tolerated. Two patients (7.6%) discontinued treatment prematurely due to study drug-related adverse events. After 15 days of treatment, the peak concentration of drug in plasma (Cmax), the area under the plasma concentration-time curve (AUC) from 0 to 24 h (AUC0-24), the concentration in plasma at the end of the dosing interval (predose) (Cmin), and the terminal half-life of itraconazole (ITRA) were (means and standard deviations) 0.604 ± 0.53 μg/ml, 6.80 ± 7.4 μg · h/ml, 0.192 ± 0.06 μg/ml, and 56.48 ± 44 h, respectively, for the QD regimen and 1.340 ± 0.75 μg/ml, 23.04 ± 14.5 μg · h/ml, 0.782 ± 0.19 μg/ml, and 104.22 ± 94 h, respectively, for the BID regimen. The mean AUC-based accumulation factors for ITRA on day 15 were 4.14 ± 0.9 and 3.53 ± 0.6, respectively. A comparison of the dose-normalized median AUC of the two dosage regimens revealed a trend toward nonlinear drug disposition (P = 0.05). The mean metabolic ratios (AUC of hydroxyitraconazole/AUC of ITRA) at day 15 were 1.96 ± 0.1 for the QD regimen and 1.29 ± 0.2 for the BID regimen, respectively (P < 0.05). The OPC score (range, 0 to 13) for all 26 patients decreased from a mean of 7.46 ± 0.8 at baseline to 2.8 ± 0.7 at the end of therapy (P < 0.001), demonstrating antifungal efficacy in this setting. The relationships among Cmax, Cmin, AUC0-12, Cmax/MIC, Cmin/MIC, AUC0-12/MIC, time during the dosing interval when the plasma drug concentrations were above the MIC for the infecting isolate, and the residual OPC score at day 15 for the entire study population fit inhibitory effect pharmacodynamic models (r, 0.595 to 0.421; P, <0.01 to <0.05). All patients with fluconazole-resistant isolates responded to treatment with CD-ITRA; however, there was no clear correlation between the MIC of ITRA and response to therapy. In conclusion, CD-ITRA was well tolerated and efficacious for the treatment of OPC in HIV-infected pediatric patients. Pharmacodynamic modeling revealed significant correlations between plasma drug concentrations and antifungal efficacy. Based on this documented safety and efficacy, a dosage of 2.5 mg/kg BID can be recommended for the treatment of OPC in pediatric patients ≥5 years old.
doi:10.1128/AAC.46.8.2554-2563.2002
PMCID: PMC127364  PMID: 12121932
8.  Underestimation of the Calculated Area Under the Concentration-Time Curve Based on Serum Creatinine for Vancomycin Dosing 
Infection & Chemotherapy  2014;46(1):21-29.
Background
The ratio of the steady-state 24-hour area under the concentration-time curve (ssAUC24) to the MIC (AUC24/MIC) for vancomycin has been recommended as the preferred pharmacodynamic index. The aim of this study was to assess whether the calculated AUC24 (cAUC24) using the creatinine clearance (CLcr) differs from the ssAUC24 based on the individual pharmacokinetic data estimated by a commercial software.
Materials and Methods
The cAUC24 was compared with the ssAUC24 with respect to age, body mass index, and trough concentration of vancomycin and the results were expressed as median and interquartile ranges. A correlation between the cAUC24 and ssAUC24 and the trough concentration of vancomycin was evaluated. The probability of reaching an AUC24/MIC of 400 or higher was compared between the cAUC24 and ssAUC24 for different MICs of vancomycin and different daily doses by simulation in a subgroup with a trough concentration of 10 mg/L and higher.
Results
The cAUC24 was significantly lower than the ssAUC24 (392.38 vs. 418.32 mg·hr/L, P < 0.0001) and correlated weakly with the trough concentration (r = 0.649 vs. r = 0.964). Assuming a MIC of 1.0 mg/L, the probability of reaching the value of 400 or higher was 77.5% for the cAUC24/MIC and 100% for the ssAUC24/MIC in patients with a trough concentration of 10 mg/L and higher. If the MIC increased to 2.0 mg/L, the probability was 57.7% for the cAUC24/MIC and 71.8% for the ssAUC24/MIC at a daily vancomycin dose of 4,000 mg.
Conclusions
The cAUC24 using the calculated CLcr is usually underestimated compared with the ssAUC24 based on individual pharmacokinetic data. Therefore, to obtain a more accurate AUC24, therapeutic monitoring of vancomycin rather than a simple calculation based on the CLcr should be performed, and a more accurate biomarker for renal function is needed.
doi:10.3947/ic.2014.46.1.21
PMCID: PMC3970305  PMID: 24693466
Vancomycin; Pharmacodynamics; Area under curve; Drug monitoring, Therapeutic
9.  Pharmacokinetics and pharmacodynamics of two multiple-dose piperacillin-tazobactam regimens. 
Antimicrobial Agents and Chemotherapy  1997;41(11):2511-2517.
The pharmacokinetics and pharmacodynamics of two multiple-dose regimens of piperacillin-tazobactam (3.375 g every 6 h and 4.5 g every 8 h) were evaluated at steady state for 12 healthy adult volunteers. Inhibitory and bactericidal activities for the two regimens were determined with five American Type Culture Collection (ATCC) organisms (Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Bacteroides fragilis). The percentage of time that plasma concentrations remained above the MIC (T > MIC) for each organism and dosage regimen was calculated. Areas under the inhibitory (AUIC0-24) and bactericidal activity (AUBC0-24) curves were calculated with the trapezoidal rule by using the reciprocal of the inhibitory and bactericidal titers determined for each dosage regimen. In order to assess the validity of predicted measures of bactericidal (AUC0-24/MBC) and inhibitory (AUC0-24/MIC) activity to determine bacteriological response to beta-lactam antimicrobial agents, AUC0-24/MBC and AUC0-24/MIC values were compared with measured AUBC0-24 and AUIC0-24 values. Total body clearance values were equivalent for piperacillin (183.96 +/- 22.66 versus 181.72 +/- 19.54 ml/min/1.73 m2, P > 0.05) and tazobactam (184.71 +/- 19.89 versus 184.87 +/- 18.35 ml/min/1.73 m2, P > 0.05) following the administration of the 3.375-g-every-6-h and 4.5-g-every-8-h dosages, respectively. Comparison of area under the plasma concentration-time curve (AUC0-24) for piperacillin (967.74 +/- 135.56 microg x h/ml versus 978.88 +/- 140.96 microg x h/ml) and tazobactam (120.14 +/- 15.78 microg x h/ml versus 120.01 +/- 16.22 microg x h/ml) revealed no significant differences (P > 0.05) between the 3.375-g-every-6-h and 4.5-g-every-8-h regimens, respectively. Both regimens provided T > MIC values of > 60% for all organisms tested. Measured values of bactericidal (AUBC) and inhibitory (AUIC) activity were significantly different (P < 0.05) from predicted values (AUC0-24/MBC and AUC0-24/MIC) for all organisms studied with the exception of the bactericidal activity for P. aeruginosa and S. aureus. Additionally, ATCC organisms possessing the same MICs and MBCs exhibited great differences in measured AUBC0-24 and AUIC0-24 values. Reasons for this difference may be inherent differences in organism specific susceptibility.
PMCID: PMC164153  PMID: 9371358
10.  On the analysis of glycomics mass spectrometry data via the regularized area under the ROC curve 
BMC Bioinformatics  2007;8:477.
Background
Novel molecular and statistical methods are in rising demand for disease diagnosis and prognosis with the help of recent advanced biotechnology. High-resolution mass spectrometry (MS) is one of those biotechnologies that are highly promising to improve health outcome. Previous literatures have identified some proteomics biomarkers that can distinguish healthy patients from cancer patients using MS data. In this paper, an MS study is demonstrated which uses glycomics to identify ovarian cancer. Glycomics is the study of glycans and glycoproteins. The glycans on the proteins may deviate between a cancer cell and a normal cell and may be visible in the blood. High-resolution MS has been applied to measure relative abundances of potential glycan biomarkers in human serum. Multiple potential glycan biomarkers are measured in MS spectra. With the objection of maximizing the empirical area under the ROC curve (AUC), an analysis method was considered which combines potential glycan biomarkers for the diagnosis of cancer.
Results
Maximizing the empirical AUC of glycomics MS data is a large-dimensional optimization problem. The technical difficulty is that the empirical AUC function is not continuous. Instead, it is in fact an empirical 0–1 loss function with a large number of linear predictors. An approach was investigated that regularizes the area under the ROC curve while replacing the 0–1 loss function with a smooth surrogate function. The constrained threshold gradient descent regularization algorithm was applied, where the regularization parameters were chosen by the cross-validation method, and the confidence intervals of the regression parameters were estimated by the bootstrap method. The method is called TGDR-AUC algorithm. The properties of the approach were studied through a numerical simulation study, which incorporates the positive values of mass spectrometry data with the correlations between measurements within person. The simulation proved asymptotic properties that estimated AUC approaches the true AUC. Finally, mass spectrometry data of serum glycan for ovarian cancer diagnosis was analyzed. The optimal combination based on TGDR-AUC algorithm yields plausible result and the detected biomarkers are confirmed based on biological evidence.
Conclusion
The TGDR-AUC algorithm relaxes the normality and independence assumptions from previous literatures. In addition to its flexibility and easy interpretability, the algorithm yields good performance in combining potential biomarkers and is computationally feasible. Thus, the approach of TGDR-AUC is a plausible algorithm to classify disease status on the basis of multiple biomarkers.
doi:10.1186/1471-2105-8-477
PMCID: PMC2211327  PMID: 18076765
11.  A boosting method for maximizing the partial area under the ROC curve 
BMC Bioinformatics  2010;11:314.
Background
The receiver operating characteristic (ROC) curve is a fundamental tool to assess the discriminant performance for not only a single marker but also a score function combining multiple markers. The area under the ROC curve (AUC) for a score function measures the intrinsic ability for the score function to discriminate between the controls and cases. Recently, the partial AUC (pAUC) has been paid more attention than the AUC, because a suitable range of the false positive rate can be focused according to various clinical situations. However, existing pAUC-based methods only handle a few markers and do not take nonlinear combination of markers into consideration.
Results
We have developed a new statistical method that focuses on the pAUC based on a boosting technique. The markers are combined componentially for maximizing the pAUC in the boosting algorithm using natural cubic splines or decision stumps (single-level decision trees), according to the values of markers (continuous or discrete). We show that the resulting score plots are useful for understanding how each marker is associated with the outcome variable. We compare the performance of the proposed boosting method with those of other existing methods, and demonstrate the utility using real data sets. As a result, we have much better discrimination performances in the sense of the pAUC in both simulation studies and real data analysis.
Conclusions
The proposed method addresses how to combine the markers after a pAUC-based filtering procedure in high dimensional setting. Hence, it provides a consistent way of analyzing data based on the pAUC from maker selection to marker combination for discrimination problems. The method can capture not only linear but also nonlinear association between the outcome variable and the markers, about which the nonlinearity is known to be necessary in general for the maximization of the pAUC. The method also puts importance on the accuracy of classification performance as well as interpretability of the association, by offering simple and smooth resultant score plots for each marker.
doi:10.1186/1471-2105-11-314
PMCID: PMC2898798  PMID: 20537139
12.  Pharmacodynamic Target Evaluation of a Novel Oral Glucan Synthase Inhibitor, SCY-078 (MK-3118), Using an In Vivo Murine Invasive Candidiasis Model 
Echinocandins inhibit the synthesis of β-1,3-d-glucan in Candida and are the first-line therapy in numerous clinical settings. Their use is limited by poor oral bioavailability, and they are available only as intravenous therapies. Derivatives of enfumafungin are novel orally bioavailable glucan synthase inhibitors. We performed an in vivo pharmacodynamic (PD) evaluation with a novel enfumafungin derivative, SCY-078 (formerly MK-3118), in a well-established neutropenic murine model of invasive candidiasis against C. albicans, C. glabrata, and C. parapsilosis. The SCY-078 MICs varied 8-fold. Oral doses of 3.125 to 200 mg/kg SCY-078 salt in sterile water produced peak levels of 0.04 to 2.66 μg/ml, elimination half-lives of 5.8 to 8.5 h, areas under the concentration-time curve from 0 to 24 h (AUC0–24 h) of 0.61 to 41.10 μg · h/ml, and AUC from 0 to infinity (AUC0—∞) values of 0.68 to 40.31 μg · h/ml. The pharmacokinetics (PK) were approximately linear over the dose range studied. Maximum response (Emax) and PK/PD target identification studies were performed with 4 C. albicans, 4 C. glabrata, and 3 C. parapsilosis isolates. The PD index AUC/MIC was explored by using total (tAUC) and free (fAUC) drug concentrations. The maximum responses were 4.0, 4.0, and 4.3 log10 CFU/kidney reductions for C. albicans, C. glabrata, and C. parapsilosis, respectively. The AUC/MIC was a robust predictor of efficacy (R2, 0.53 to 0.91). The 24-h PD targets were a static dose of 63.5 mg/kg, a tAUC/MIC of 500, and an fAUC/MIC of 1.0 for C. albicans; a static dose of 58.4 mg/kg, a tAUC/MIC of 315, and an fAUC/MIC of 0.63 for C. glabrata; and a static dose of 84.4 mg/kg, a tAUC/MIC of 198, and an fAUC/MIC of 0.40 for C. parapsilosis. The mean fAUC/MIC values associated with a 1-log kill endpoint against these species were 1.42, 1.26, and 0.91 for C. albicans, C. glabrata, and C. parapsilosis, respectively. The static and 1-log kill endpoints were measured relative to the burden at the start of therapy. The static and 1-log kill doses, as well as the total and free drug AUC/MIC PD targets, were not statistically different between species but were numerically lower than those observed for echinocandins. SCY-078 is a promising novel oral glucan synthase inhibitor against Candida species, and further investigation is warranted.
doi:10.1128/AAC.04445-14
PMCID: PMC4335824  PMID: 25512406
13.  Parameters of bacterial killing and regrowth kinetics and antimicrobial effect examined in terms of area under the concentration-time curve relationships: action of ciprofloxacin against Escherichia coli in an in vitro dynamic model. 
Although many parameters have been described to quantitate the killing and regrowth of bacteria, substantial shortcomings are inherent in most of them, such as low sensitivity to pharmacokinetic determinants of the antimicrobial effect, an inability to predict a total effect, insufficient robustness, and uncertain interrelations between the parameters that prevent an ultimate determination of the effect. To examine different parameters, the kinetics of killing and regrowth of Escherichia coli (MIC, 0.013 microg/ml) were studied in vitro by simulating a series of ciprofloxacin monoexponential pharmacokinetic profiles. Initial ciprofloxacin concentrations varied from 0.02 to 19.2 microg/ml, whereas the half-life of 4 h was the same in all experiments. The following parameters were calculated and estimated: the time to reduce the initial inoculum (N0) 10-, 100-, and 1,000-fold (T90%, T99%, and T99.9%, respectively), the rate constant of bacterial elimination (k(elb)), the nadir level (Nmin) in the viable count (N)-versus-time (t) curve, the time to reach Nmin (t(min)), the numbers of bacteria that survived (Ntau) by the end of the observation period (tau), the area under the bacterial killing and regrowth curve (log N(A)-t curve) from the zero point (time zero) to tau (AUBC), the area above this curve (AAC), the area between the control growth curve (log N(C)-t curve) and the bacterial killing and regrowth curve (log N(A)-t curve) from the zero point to tau (ABBC) or to the time point when log N(A) reaches the maximal values observed in the log N(C)-t curve (I(E); intensity of the effect), and the time shift between the control growth and regrowth curves (T(E); duration of the effect). Being highly sensitive to the AUC, I(E), and T(E) showed the most regular AUC relationships: the effect expressed by I(E) or T(E) increased systematically when the AUC or initial concentration of ciprofloxacin rose. Other parameters, especially T90%, T99%, T99.9%, t(min), and log N0 - log Nmin = delta log Nmin, related to the AUC less regularly and were poorly sensitive to the AUC. T(E) proved to be the best predictor and t(min) proved to be the worst predictor of the total antimicrobial effect reflected by I(E). Distinct feedback relationships between the effect determination and the experimental design were demonstrated. It was shown that unjustified shortening of the observation period, i.e., cutting off the log N(A)-t curves, may lead to the degeneration of the AUC-response relationships, as expressed by log N0 - log Ntau = delta log Ntau, AUBC, AAC, or ABBC, to a point where it gives rise to the false idea of an AUC- or concentration-independent effect. Thus, use of I(E) and T(E) provides the most unbiased, robust, and comprehensive means of determining the antimicrobial effect.
PMCID: PMC163900  PMID: 9174184
14.  Pharmacodynamics of a Novel Des-F(6)-Quinolone, BMS-284756, against Streptococcus pneumoniae in the Thigh Infection Model 
BMS-284756 is a novel quinolone that lacks the six-position fluorine typical of existing compounds. Despite this structural change, BMS-284756 maintains potent antibacterial activity against gram-negative and gram-positive aerobic and anaerobic pathogens. The objective of this study was to define the pharmacodynamic profile of BMS-284756 against Streptococcus pneumoniae. Protein binding in mice was assessed by the ultrafiltration method. For pharmacodynamic studies, neutropenic ICR mice were used, as well as an immunocompetent mouse species, CBA/J, in order to evaluate the impact of white blood cells on infection outcome. Mice were infected with 105 to 106 CFU per thigh, and therapy was initiated after 2 h. Animals received BMS-284756 orally over a range of 1.25 to 100 mg/kg/day divided into one to four doses. At 0 and 24 h postinfection, thighs were harvested for bacterial density measurement. Survival was assessed during 96 h of therapy and again at 3 days after therapy. Pharmacokinetic studies were also conducted with infected mice. Protein binding was determined to be 80%. The MICs for clinical isolates (n = 8) ranged from 0.03 to 2 μg/ml. The change in bacterial density and survival was correlated with the pharmacodynamic parameters percentage of time that the drug concentration in serum remains above the MIC, AUC (area under the concentration-time curve)/MIC ratio, and peak/MIC ratio, and the best predictor of response was the AUC/MIC ratio for both outcome measures. Total AUC/MIC ratios of 100 to 200 appear to result in maximal bactericidal effects. While a total AUC/MIC ratio exposure value of 100 (free AUC/MIC ratio, ∼20) resulted in nearly 100% survival at the conclusion of therapy, a total AUC/MIC ratio of 200 (free AUC/MIC ratio, ∼40) was required to ensure survival at 3 days posttherapy. These data demonstrate (i) the in vivo bactericidal activity of BMS-284756 against S. pneumoniae, (ii) that protein binding has a profound impact on the in vivo pharmacodynamic assessment of BMS-284756, and (iii) that an AUC/MIC ratio of 200 (free AUC/MIC ratio, ∼40) appears to best characterize the required dynamic exposure for optimization of bactericidal activity and maximal survival.
doi:10.1128/AAC.47.5.1630-1635.2003
PMCID: PMC153298  PMID: 12709332
15.  AKT1 G205T Genotype Influences Obesity-Related Metabolic Phenotypes and Their Responses to Aerobic Exercise Training in Older Caucasians 
Experimental physiology  2010;96(3):338-347.
As part of the insulin signaling pathway, AKT influences growth and metabolism. The AKT1 gene G205T (rs1130214) polymorphism has potential functional effects. Thus, we determined whether the G205T polymorphism influences metabolic variables and their responses to aerobic exercise training. Following dietary stabilization, healthy, sedentary, 50-75 yr old Caucasian men (n = 51) and women (n = 58) underwent 6 months of aerobic exercise training. Before and after completing the intervention, dual-energy x-ray absorptiometry measured percent body fat, computed tomography measured visceral and subcutaneous fat, and oral glucose tolerance testing measured glucose total area under the curve (AUC), insulin AUC, and insulin sensitivity. Taqman assay determined AKT1 G205T genotypes. At baseline, men with the GG genotype (n = 29) had lower VO2max values (p = 0.026), and higher percent body fat (p = 0.046), subcutaneous fat (p = 0.021), and insulin AUC (p = 0.003) values than T allele carriers (n = 22). Despite their rather disadvantageous starting values, men with the GG genotype seemed to respond to exercise training more robustly than men with the T allele, highlighted by significantly greater fold change improvements in insulin AUC (p = 0.012) and glucose AUC (p = 0.035). Although the GG group also significantly improved VO2max with training, the change in VO2max was not as great as that of the T allele carriers (p = 0.037). In contrast, after accounting for hormone replacement therapy use, none of the variables differed in the women at baseline. As a result of exercise training, women with the T allele (n = 20) had greater fold change improvements in fasting glucose (p = 0.011), glucose AUC (p = 0.017), and insulin sensitivity (p = 0.044) than GG genotype women (n = 38). Our results suggest that the AKT1 G205T polymorphism influences metabolic variables and their responses to aerobic exercise training in older previously sedentary individuals.
doi:10.1113/expphysiol.2010.055400
PMCID: PMC3075436  PMID: 21097644
polymorphism; exercise; glucose
16.  Evaluation of Glycemic Variability in Well-Controlled Type 2 Diabetes Mellitus 
Abstract
Aims
It is necessary to evaluate glucose variability and postprandial hyperglycemia in patients with well-controlled type 2 diabetes mellitus because of the limitations associated with hemoglobin A1c (HbA1c) measurements. We evaluated parameters reflecting postprandial hyperglycemia and glycemic variability in patients with optimal HbA1c.
Patients and Methods
Thirty-nine patients with HbA1c levels below 7% were recruited to the study. A continuous glucose monitoring system (CGMS) was applied for two 72-h periods. 1,5-Anhydroglucitol (1,5-AG) and fructosamine (FA) were measured as parameters for postprandial hyperglycemia and glucose variability. Using CGMS data, the following postprandial hyperglycemia parameters were calculated: mean postprandial maximum glucose (MPMG) and area under the curve for glucose above 180 mg/dL (AUC-180). To measure glycemic variability, we calculated mean amplitude of glucose excursion (MAGE) using a classical (MAGEc) and new method (MAGE group of sign [MAGEgos]).
Results
The baseline HbA1c level was 6.3±0.3%. The mean MPMG was 10.34±1.84 mmol/L, and the mean AUC-180 was 0.17±0.23 mmol/L/day. The mean MAGEgos was 3.27±1.29 mmol/L, and MAGEc was 4.30±1.43 mmol/L, indicating glycemic variability in our patients. The mean levels of 1,5-AG and FA were 16.7±7.4 μg/mL and 273.0±22.5 μmol/L, respectively. In a correlation analysis, FA was significantly correlated with MPMG, AUC-180, MAGEgos, and MAGEc. In contrast, 1,5-AG was only correlated with AUC-180.
Conclusions
This study demonstrated postprandial hyperglycemia and glycemic variability in subjects with well-controlled diabetes. FA may reflect postprandial hyperglycemia and glycemic variability, but 1,5-AG may be of limited value for assessing glucose variability in patients with well-controlled type 2 diabetes mellitus.
doi:10.1089/dia.2012.0315
PMCID: PMC3671661  PMID: 23617251
17.  Continuous Subcutaneous Insulin Infusion (CSII) Pumps for Type 1 and Type 2 Adult Diabetic Populations 
Executive Summary
In June 2008, the Medical Advisory Secretariat began work on the Diabetes Strategy Evidence Project, an evidence-based review of the literature surrounding strategies for successful management and treatment of diabetes. This project came about when the Health System Strategy Division at the Ministry of Health and Long-Term Care subsequently asked the secretariat to provide an evidentiary platform for the Ministry’s newly released Diabetes Strategy.
After an initial review of the strategy and consultation with experts, the secretariat identified five key areas in which evidence was needed. Evidence-based analyses have been prepared for each of these five areas: insulin pumps, behavioural interventions, bariatric surgery, home telemonitoring, and community based care. For each area, an economic analysis was completed where appropriate and is described in a separate report.
To review these titles within the Diabetes Strategy Evidence series, please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/mas_about.html,
Diabetes Strategy Evidence Platform: Summary of Evidence-Based Analyses
Continuous Subcutaneous Insulin Infusion Pumps for Type 1 and Type 2 Adult Diabetics: An Evidence-Based Analysis
Behavioural Interventions for Type 2 Diabetes: An Evidence-Based Analysis
Bariatric Surgery for People with Diabetes and Morbid Obesity: An Evidence-Based Summary
Community-Based Care for the Management of Type 2 Diabetes: An Evidence-Based Analysis
Home Telemonitoring for Type 2 Diabetes: An Evidence-Based Analysis
Application of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario
Objective
The objective of this analysis is to review the efficacy of continuous subcutaneous insulin infusion (CSII) pumps as compared to multiple daily injections (MDI) for the type 1 and type 2 adult diabetics.
Clinical Need and Target Population
Insulin therapy is an integral component of the treatment of many individuals with diabetes. Type 1, or juvenile-onset diabetes, is a life-long disorder that commonly manifests in children and adolescents, but onset can occur at any age. It represents about 10% of the total diabetes population and involves immune-mediated destruction of insulin producing cells in the pancreas. The loss of these cells results in a decrease in insulin production, which in turn necessitates exogenous insulin therapy.
Type 2, or ‘maturity-onset’ diabetes represents about 90% of the total diabetes population and is marked by a resistance to insulin or insufficient insulin secretion. The risk of developing type 2 diabetes increases with age, obesity, and lack of physical activity. The condition tends to develop gradually and may remain undiagnosed for many years. Approximately 30% of patients with type 2 diabetes eventually require insulin therapy.
CSII Pumps
In conventional therapy programs for diabetes, insulin is injected once or twice a day in some combination of short- and long-acting insulin preparations. Some patients require intensive therapy regimes known as multiple daily injection (MDI) programs, in which insulin is injected three or more times a day. It’s a time consuming process and usually requires an injection of slow acting basal insulin in the morning or evening and frequent doses of short-acting insulin prior to eating. The most common form of slower acting insulin used is neutral protamine gagedorn (NPH), which reaches peak activity 3 to 5 hours after injection. There are some concerns surrounding the use of NPH at night-time as, if injected immediately before bed, nocturnal hypoglycemia may occur. To combat nocturnal hypoglycemia and other issues related to absorption, alternative insulins have been developed, such as the slow-acting insulin glargine. Glargine has no peak action time and instead acts consistently over a twenty-four hour period, helping reduce the frequency of hypoglycemic episodes.
Alternatively, intensive therapy regimes can be administered by continuous insulin infusion (CSII) pumps. These devices attempt to closely mimic the behaviour of the pancreas, continuously providing a basal level insulin to the body with additional boluses at meal times. Modern CSII pumps are comprised of a small battery-driven pump that is designed to administer insulin subcutaneously through the abdominal wall via butterfly needle. The insulin dose is adjusted in response to measured capillary glucose values in a fashion similar to MDI and is thus often seen as a preferred method to multiple injection therapy. There are, however, still risks associated with the use of CSII pumps. Despite the increased use of CSII pumps, there is uncertainty around their effectiveness as compared to MDI for improving glycemic control.
Part A: Type 1 Diabetic Adults (≥19 years)
An evidence-based analysis on the efficacy of CSII pumps compared to MDI was carried out on both type 1 and type 2 adult diabetic populations.
Research Questions
Are CSII pumps more effective than MDI for improving glycemic control in adults (≥19 years) with type 1 diabetes?
Are CSII pumps more effective than MDI for improving additional outcomes related to diabetes such as quality of life (QoL)?
Literature Search
Inclusion Criteria
Randomized controlled trials, systematic reviews, meta-analysis and/or health technology assessments from MEDLINE, EMBASE, CINAHL
Adults (≥ 19 years)
Type 1 diabetes
Study evaluates CSII vs. MDI
Published between January 1, 2002 – March 24, 2009
Patient currently on intensive insulin therapy
Exclusion Criteria
Studies with <20 patients
Studies <5 weeks in duration
CSII applied only at night time and not 24 hours/day
Mixed group of diabetes patients (children, adults, type 1, type 2)
Pregnancy studies
Outcomes of Interest
The primary outcomes of interest were glycosylated hemoglobin (HbA1c) levels, mean daily blood glucose, glucose variability, and frequency of hypoglycaemic events. Other outcomes of interest were insulin requirements, adverse events, and quality of life.
Search Strategy
The literature search strategy employed keywords and subject headings to capture the concepts of:
1) insulin pumps, and
2) type 1 diabetes.
The search was run on July 6, 2008 in the following databases: Ovid MEDLINE (1996 to June Week 4 2008), OVID MEDLINE In-Process and Other Non-Indexed Citations, EMBASE (1980 to 2008 Week 26), OVID CINAHL (1982 to June Week 4 2008) the Cochrane Library, and the Centre for Reviews and Dissemination/International Agency for Health Technology Assessment. A search update was run on March 24, 2009 and studies published prior to 2002 were also examined for inclusion into the review. Parallel search strategies were developed for the remaining databases. Search results were limited to human and English-language published between January 2002 and March 24, 2009. Abstracts were reviewed, and studies meeting the inclusion criteria outlined above were obtained. Reference lists were also checked for relevant studies.
Summary of Findings
The database search identified 519 relevant citations published between 1996 and March 24, 2009. Of the 519 abstracts reviewed, four RCTs and one abstract met the inclusion criteria outlined above. While efficacy outcomes were reported in each of the trials, a meta-analysis was not possible due to missing data around standard deviations of change values as well as missing data for the first period of the crossover arm of the trial. Meta-analysis was not possible on other outcomes (quality of life, insulin requirements, frequency of hypoglycemia) due to differences in reporting.
HbA1c
In studies where no baseline data was reported, the final values were used. Two studies (Hanaire-Broutin et al. 2000, Hoogma et al. 2005) reported a slight reduction in HbA1c of 0.35% and 0.22% respectively for CSII pumps in comparison to MDI. A slightly larger reduction in HbA1c of 0.84% was reported by DeVries et al.; however, this study was the only study to include patients with poor glycemic control marked by higher baseline HbA1c levels. One study (Bruttomesso et al. 2008) showed no difference between CSII pumps and MDI on Hba1c levels and was the only study using insulin glargine (consistent with results of parallel RCT in abstract by Bolli 2004). While there is statistically significant reduction in HbA1c in three of four trials, there is no evidence to suggest these results are clinically significant.
Mean Blood Glucose
Three of four studies reported a statistically significant reduction in the mean daily blood glucose for patients using CSII pump, though these results were not clinically significant. One study (DeVries et al. 2002) did not report study data on mean blood glucose but noted that the differences were not statistically significant. There is difficulty with interpreting study findings as blood glucose was measured differently across studies. Three of four studies used a glucose diary, while one study used a memory meter. In addition, frequency of self monitoring of blood glucose (SMBG) varied from four to nine times per day. Measurements used to determine differences in mean daily blood glucose between the CSII pump group and MDI group at clinic visits were collected at varying time points. Two studies use measurements from the last day prior to the final visit (Hoogma et al. 2005, DeVries et al. 2002), while one study used measurements taken during the last 30 days and another study used measurements taken during the 14 days prior to the final visit of each treatment period.
Glucose Variability
All four studies showed a statistically significant reduction in glucose variability for patients using CSII pumps compared to those using MDI, though one, Bruttomesso et al. 2008, only showed a significant reduction at the morning time point. Brutomesso et al. also used alternate measures of glucose variability and found that both the Lability index and mean amplitude of glycemic excursions (MAGE) were in concordance with the findings using the standard deviation (SD) values of mean blood glucose, but the average daily risk range (ADRR) showed no difference between the CSII pump and MDI groups.
Hypoglycemic Events
There is conflicting evidence concerning the efficacy of CSII pumps in decreasing both mild and severe hypoglycemic events. For mild hypoglycemic events, DeVries et al. observed a higher number of events per patient week in the CSII pump group than the MDI group, while Hoogma et al. observed a higher number of events per patient year in the MDI group. The remaining two studies found no differences between the two groups in the frequency of mild hypoglycemic events. For severe hypoglycemic events, Hoogma et al. found an increase in events per patient year among MDI patients, however, all of the other RCTs showed no difference between the patient groups in this aspect.
Insulin Requirements and Adverse Events
In all four studies, insulin requirements were significantly lower in patients receiving CSII pump treatment in comparison to MDI. This difference was statistically significant in all studies. Adverse events were reported in three studies. Devries et al. found no difference in ketoacidotic episodes between CSII pump and MDI users. Bruttomesso et al. reported no adverse events during the study. Hanaire-Broutin et al. found that 30 patients experienced 58 serious adverse events (SAEs) during MDI and 23 patients had 33 SAEs during treatment out of a total of 256 patients. Most events were related to severe hypoglycemia and diabetic ketoacidosis.
Quality of Life and Patient Preference
QoL was measured in three studies and patient preference was measured in one. All three studies found an improvement in QoL for CSII users compared to those using MDI, although various instruments were used among the studies and possible reporting bias was evident as non-positive outcomes were not consistently reported. Moreover, there was also conflicting results in two of the studies using the Diabetes Treatment Satisfaction Questionnaire (DTSQ). DeVries et al. reported no difference in treatment satisfaction between CSII pump users and MDI users while Brutomesso et al. reported that treatment satisfaction improved among CSII pump users.
Patient preference for CSII pumps was demonstrated in just one study (Hanaire-Broutin et al. 2000) and there are considerable limitations with interpreting this data as it was gathered through interview and 72% of patients that preferred CSII pumps were previously on CSII pump therapy prior to the study. As all studies were industry sponsored, findings on QoL and patient preference must be interpreted with caution.
Quality of Evidence
Overall, the body of evidence was downgraded from high to low due to study quality and issues with directness as identified using the GRADE quality assessment tool (see Table 1) While blinding of patient to intervention/control was not feasible in these studies, blinding of study personnel during outcome assessment and allocation concealment were generally lacking. Trials reported consistent results for the outcomes HbA1c, mean blood glucose and glucose variability, but the directness or generalizability of studies, particularly with respect to the generalizability of the diabetic population, was questionable as most trials used highly motivated populations with fairly good glycemic control. In addition, the populations in each of the studies varied with respect to prior treatment regimens, which may not be generalizable to the population eligible for pumps in Ontario. For the outcome of hypoglycaemic events the evidence was further downgraded to very low since there was conflicting evidence between studies with respect to the frequency of mild and severe hypoglycaemic events in patients using CSII pumps as compared to CSII (see Table 2). The GRADE quality of evidence for the use of CSII in adults with type 1 diabetes is therefore low to very low and any estimate of effect is, therefore, uncertain.
GRADE Quality Assessment for CSII pumps vs. MDI on HbA1c, Mean Blood Glucose, and Glucose Variability for Adults with Type 1 Diabetes
Inadequate or unknown allocation concealment (3/4 studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; No ITT analysis (2/4 studies); possible bias SMBG (all studies)
HbA1c: 3/4 studies show consistency however magnitude of effect varies greatly; Single study uses insulin glargine instead of NPH; Mean Blood Glucose: 3/4 studies show consistency however magnitude of effect varies between studies; Glucose Variability: All studies show consistency but 1 study only showed a significant effect in the morning
Generalizability in question due to varying populations: highly motivated populations, educational component of interventions/ run-in phases, insulin pen use in 2/4 studies and varying levels of baseline glycemic control and experience with intensified insulin therapy, pumps and MDI.
GRADE Quality Assessment for CSII pumps vs. MDI on Frequency of Hypoglycemic
Inadequate or unknown allocation concealment (3/4 studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; No ITT analysis (2/4 studies); possible bias SMBG (all studies)
Conflicting evidence with respect to mild and severe hypoglycemic events reported in studies
Generalizability in question due to varying populations: highly motivated populations, educational component of interventions/ run-in phases, insulin pen use in 2/4 studies and varying levels of baseline glycemic control and experience with intensified insulin therapy, pumps and MDI.
Economic Analysis
One article was included in the analysis from the economic literature scan. Four other economic evaluations were identified but did not meet our inclusion criteria. Two of these articles did not compare CSII with MDI and the other two articles used summary estimates from a mixed population with Type 1 and 2 diabetes in their economic microsimulation to estimate costs and effects over time. Included were English articles that conducted comparisons between CSII and MDI with the outcome of Quality Adjusted Life Years (QALY) in an adult population with type 1 diabetes.
From one study, a subset of the population with type 1 diabetes was identified that may be suitable and benefit from using insulin pumps. There is, however, limited data in the literature addressing the cost-effectiveness of insulin pumps versus MDI in type 1 diabetes. Longer term models are required to estimate the long term costs and effects of pumps compared to MDI in this population.
Conclusions
CSII pumps for the treatment of adults with type 1 diabetes
Based on low-quality evidence, CSII pumps confer a statistically significant but not clinically significant reduction in HbA1c and mean daily blood glucose as compared to MDI in adults with type 1 diabetes (>19 years).
CSII pumps also confer a statistically significant reduction in glucose variability as compared to MDI in adults with type 1 diabetes (>19 years) however the clinical significance is unknown.
There is indirect evidence that the use of newer long-acting insulins (e.g. insulin glargine) in MDI regimens result in less of a difference between MDI and CSII compared to differences between MDI and CSII in which older insulins are used.
There is conflicting evidence regarding both mild and severe hypoglycemic events in this population when using CSII pumps as compared to MDI. These findings are based on very low-quality evidence.
There is an improved quality of life for patients using CSII pumps as compared to MDI however, limitations exist with this evidence.
Significant limitations of the literature exist specifically:
All studies sponsored by insulin pump manufacturers
All studies used crossover design
Prior treatment regimens varied
Types of insulins used in study varied (NPH vs. glargine)
Generalizability of studies in question as populations were highly motivated and half of studies used insulin pens as the mode of delivery for MDI
One short-term study concluded that pumps are cost-effective, although this was based on limited data and longer term models are required to estimate the long-term costs and effects of pumps compared to MDI in adults with type 1 diabetes.
Part B: Type 2 Diabetic Adults
Research Questions
Are CSII pumps more effective than MDI for improving glycemic control in adults (≥19 years) with type 2 diabetes?
Are CSII pumps more effective than MDI for improving other outcomes related to diabetes such as quality of life?
Literature Search
Inclusion Criteria
Randomized controlled trials, systematic reviews, meta-analysis and/or health technology assessments from MEDLINE, Excerpta Medica Database (EMBASE), Cumulative Index to Nursing & Allied Health Literature (CINAHL)
Any person with type 2 diabetes requiring insulin treatment intensive
Published between January 1, 2000 – August 2008
Exclusion Criteria
Studies with <10 patients
Studies <5 weeks in duration
CSII applied only at night time and not 24 hours/day
Mixed group of diabetes patients (children, adults, type 1, type 2)
Pregnancy studies
Outcomes of Interest
The primary outcome of interest was a reduction in glycosylated hemoglobin (HbA1c) levels. Other outcomes of interest were mean blood glucose level, glucose variability, insulin requirements, frequency of hypoglycemic events, adverse events, and quality of life.
Search Strategy
A comprehensive literature search was performed in OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, CINAHL, The Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published between January 1, 2000 and August 15, 2008. Studies meeting the inclusion criteria were selected from the search results. Data on the study characteristics, patient characteristics, primary and secondary treatment outcomes, and adverse events were abstracted. Reference lists of selected articles were also checked for relevant studies. The quality of the evidence was assessed as high, moderate, low, or very low according to the GRADE methodology.
Summary of Findings
The database search identified 286 relevant citations published between 1996 and August 2008. Of the 286 abstracts reviewed, four RCTs met the inclusion criteria outlined above. Upon examination, two studies were subsequently excluded from the meta-analysis due to small sample size and missing data (Berthe et al.), as well as outlier status and high drop out rate (Wainstein et al) which is consistent with previously reported meta-analyses on this topic (Jeitler et al 2008, and Fatourechi M et al. 2009).
HbA1c
The primary outcome in this analysis was reduction in HbA1c. Both studies demonstrated that both CSII pumps and MDI reduce HbA1c, but neither treatment modality was found to be superior to the other. The results of a random effects model meta-analysis showed a mean difference in HbA1c of -0.14 (-0.40, 0.13) between the two groups, which was found not to be statistically or clinically significant. There was no statistical heterogeneity observed between the two studies (I2=0%).
Forrest plot of two parallel, RCTs comparing CSII to MDI in type 2 diabetes
Secondary Outcomes
Mean Blood Glucose and Glucose Variability
Mean blood glucose was only used as an efficacy outcome in one study (Raskin et al. 2003). The authors found that the only time point in which there were consistently lower blood glucose values for the CSII group compared to the MDI group was 90 minutes after breakfast. Glucose variability was not examined in either study and the authors reported no difference in weight gain between the CSII pump group and MDI groups at the end of study. Conflicting results were reported regarding injection site reactions between the two studies. Herman et al. reported no difference in the number of subjects experiencing site problems between the two groups, while Raskin et al. reported that there were no injection site reactions in the MDI group but 15 such episodes among 8 participants in the CSII pump group.
Frequency of Hypoglycemic Events and Insulin Requirements
All studies reported that there were no differences in the number of mild hypoglycemic events in patients on CSII pumps versus MDI. Herman et al. also reported no differences in the number of severe hypoglycemic events in patients using CSII pumps compared to those on MDI. Raskin et al. reported that there were no severe hypoglycemic events in either group throughout the study duration. Insulin requirements were only examined in Herman et al., who found that daily insulin requirements were equal between the CSII pump and MDI treatment groups.
Quality of Life
QoL was measured by Herman et al. using the Diabetes Quality of Life Clinical Trial Questionnaire (DQOLCTQ). There were no differences reported between CSII users and MDI users for treatment satisfaction, diabetes impact, and worry-related scores. Patient satisfaction was measured in Raskin et al. using a patient satisfaction questionnaire, whose results indicated that patients in the CSII pump group had significantly greater improvement in overall treatment satisfaction at the end of the study compared to the MDI group. Although patient preference was also reported, it was only examined in the CSII pump group, thus results indicating a greater preference for CSII pumps in this groups (as compared to prior injectable insulin regimens) are biased and must be interpreted with caution.
Quality of Evidence
Overall, the body of evidence was downgraded from high to low according to study quality and issues with directness as identified using the GRADE quality assessment tool (see Table 3). While blinding of patient to intervention/control is not feasible in these studies, blinding of study personnel during outcome assessment and allocation concealment were generally lacking. ITT was not clearly explained in one study and heterogeneity between study populations was evident from participants’ treatment regimens prior to study initiation. Although trials reported consistent results for HbA1c outcomes, the directness or generalizability of studies, particularly with respect to the generalizability of the diabetic population, was questionable as trials required patients to adhere to an intense SMBG regimen. This suggests that patients were highly motivated. In addition, since prior treatment regimens varied between participants (no requirement for patients to be on MDI), study findings may not be generalizable to the population eligible for a pump in Ontario. The GRADE quality of evidence for the use of CSII in adults with type 2 diabetes is, therefore, low and any estimate of effect is uncertain.
GRADE Quality Assessment for CSII pumps vs. MDI on HbA1c Adults with Type 2 Diabetes
Inadequate or unknown allocation concealment (all studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; ITT not well explained in 1 of 2 studies
Indirect due to lack of generalizability of findings since participants varied with respect to prior treatment regimens and intensive SMBG suggests highly motivated populations used in trials.
Economic Analysis
An economic analysis of CSII pumps was carried out using the Ontario Diabetes Economic Model (ODEM) and has been previously described in the report entitled “Application of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario”, part of the diabetes strategy evidence series. Based on the analysis, CSII pumps are not cost-effective for adults with type 2 diabetes, either for the age 65+ sub-group or for all patients in general. Details of the analysis can be found in the full report.
Conclusions
CSII pumps for the treatment of adults with type 2 diabetes
There is low quality evidence demonstrating that the efficacy of CSII pumps is not superior to MDI for adult type 2 diabetics.
There were no differences in the number of mild and severe hypoglycemic events in patients on CSII pumps versus MDI.
There are conflicting findings with respect to an improved quality of life for patients using CSII pumps as compared to MDI.
Significant limitations of the literature exist specifically:
All studies sponsored by insulin pump manufacturers
Prior treatment regimens varied
Types of insulins used in study varied (NPH vs. glargine)
Generalizability of studies in question as populations may not reflect eligible patient population in Ontario (participants not necessarily on MDI prior to study initiation, pen used in one study and frequency of SMBG required during study was high suggesting highly motivated participants)
Based on ODEM, insulin pumps are not cost-effective for adults with type 2 diabetes either for the age 65+ sub-group or for all patients in general.
PMCID: PMC3377523  PMID: 23074525
18.  Risk Models for Progression to Advanced Age-Related Macular Degeneration Using Demographic, Environmental, Genetic, and Ocular Factors 
Ophthalmology  2011;118(11):2203-2211.
Purpose
To expand our predictive models for progression to advanced stages of age-related macular degeneration (AMD) based on demographic, environmental, genetic, and ocular factors, using longer follow-up, time varying analyses, calculation of absolute risks, adjustment for competing risks, and detailed baseline AMD and drusen status.
Design
Prospective, longitudinal study.
Participants
We included 2937 individuals in the Age-Related Eye Disease Study, of which 819 subjects progressed to advanced AMD during 12 years of follow-up.
Methods
Cox proportional hazards regression analyses were performed to calculate hazard ratios for progression. Covariates included demographic and environmental factors, 6 variants in 5 genes, baseline macular drusen size, and presence and type of advanced AMD in 1 eye at baseline. To assess the ability of risk scores based on all covariates to discriminate between progressors and nonprogressors, an algorithm was developed and the area under the receiver operating characteristic curve (AUC) was calculated. To validate the overall model, the total sample was randomly subdivided into derivation and test samples. Another model was built based on the derivation sample and assessed for calibration and discrimination in the test sample. Sample sizes needed for testing new treatments in clinical trials were estimated based on models with and without genetic variables.
Main Outcome Measures
Progression to advanced AMD, including geographic atrophy and neovascular disease.
Results
In multivariate models, age, smoking, body mass index, single nucleotide polymorphisms in the CFH, ARMS2/HTRA1, C3, C2, and CFB genes, as well as presence of advanced AMD in 1 eye and drusen size in both eyes were all independently associated with progression. The AUC for progression at 10 years in the model with genetic factors, drusen size, and environmental covariates was 0.915 in the total sample. In the test sample, based on a model estimated from the derivation sample, the AUC was 0.908. The sample sizes needed for clinical trials were estimated to be lower when genetic susceptibility was considered.
Conclusions
Factors reflective of nature and nurture were incorporated into an expanded algorithm for risk prediction, which performed very well in both derivation and test samples. Risk scores and predicted progression rates will be useful for AMD surveillance and for designing clinical trials.
Financial Disclosure(s)
Proprietary or commercial disclosure may be found after the references.
doi:10.1016/j.ophtha.2011.04.029
PMCID: PMC4097877  PMID: 21959373
19.  Single- and Repeated-Dose Pharmacokinetics of Ceftaroline in Plasma and Soft Tissues of Healthy Volunteers for Two Different Dosing Regimens of Ceftaroline Fosamil 
Ceftaroline fosamil (CPT-F) is currently approved for use for the treatment of complicated skin and soft tissue infections and community-acquired pneumonia at 600 mg twice daily (q12h), but other dosing regimens are under evaluation. To date, very limited data on the soft tissue pharmacokinetics (PK) of the active compound, ceftaroline (CPT), are available. CPT concentrations in the plasma, muscle, and subcutis of 12 male healthy volunteers were measured by microdialysis after single and repeated intravenous administration of 600 mg CPT-F q12h or three times daily (q8h) in two groups of 6 subjects each. Relevant PK and PK/pharmacodynamic (PD) parameters were calculated and compared between groups. In plasma, the area under the concentration-time curve (AUC) from 0 to 24 h for total CPT and the cumulative percentage of the dosing interval during which the free drug concentrations exceeded the MIC (fTMIC) for unbound CPT for the currently established threshold of 1 mg/liter were significantly higher in the group receiving CPT-F q8h. Exposure to free drug in soft tissues was higher in the group receiving CPT-F q8h, but high interindividual variability in relevant PK parameters was observed. The mean ratios of the AUC from time zero to the end of the dosing interval (AUC0-τ) for free CPT in soft tissues and the AUC0-τ for the calculated free fraction in plasma at steady state ranged from 0.66 to 0.75. Administration of CPT-F q8h led to higher levels of drug exposure in all investigated compartments. When MIC values above 1 mg/liter were assumed, the calculated fTMIC after dosing q12h was markedly lower than that after dosing q8h. The clinical implications of these differences are discussed in light of recently completed clinical phase III and PK/PD studies.
doi:10.1128/AAC.00097-16
PMCID: PMC4879389  PMID: 27044549
20.  2015 Marshall Urist Young Investigator Award: Prognostication in Patients With Long Bone Metastases: Does a Boosting Algorithm Improve Survival Estimates? 
Background
Survival estimation guides surgical decision-making in metastatic bone disease. Traditionally, classic scoring systems, such as the Bauer score, provide survival estimates based on a summary score of prognostic factors. Identification of new factors might improve the accuracy of these models. Additionally, the use of different algorithms—nomograms or boosting algorithms—could further improve accuracy of prognostication relative to classic scoring systems. A nomogram is an extension of a classic scoring system and generates a more-individualized survival probability based on a patient’s set of characteristics using a figure. Boosting is a method that automatically trains to classify outcomes by applying classifiers (variables) in a sequential way and subsequently combines them. A boosting algorithm provides survival probabilities based on every possible combination of variables.
Questions/purposes
We wished to (1) assess factors independently associated with decreased survival in patients with metastatic long bone fractures and (2) compare the accuracy of a classic scoring system, nomogram, and boosting algorithms in predicting 30-, 90-, and 365-day survival.
Methods
We included all 927 patients in our retrospective study who underwent surgery for a metastatic long bone fracture at two institutions between January 1999 and December 2013. We included only the first procedure if patients underwent multiple surgical procedures or had more than one fracture. Median followup was 8 months (interquartile range, 3-25 months); 369 of 412 (90%) patients who where alive at 1 year were still in followup. Multivariable Cox regression analysis was used to identify clinical and laboratory factors independently associated with decreased survival. We created a classic scoring system, nomogram, and boosting algorithms based on identified variables. Accuracy of the algorithms was assessed using area under the curve analysis through fivefold cross validation.
Results
The following factors were associated with a decreased likelihood of survival after surgical treatment of a metastatic long bone fracture, after controlling for relevant confounding variables: older age (hazard ratio [HR], 1.0; 95% CI, 1.0–1.0; p < 0.001), additional comorbidity (HR, 1.2; 95% CI, 1.0–1.4; p = 0.034), BMI less than 18.5 kg/m2 (HR, 2.0; 95% CI, 1.2–3.5; p = 0.011), tumor type with poor prognosis (HR, 1.8; 95% CI, 1.6–2.2; p < 0.001), multiple bone metastases (HR, 1.3; 95% CI, 1.1–1.6; p = 0.008), visceral metastases (HR, 1.6; 95% CI, 1.4–1.9; p < 0.001), and lower hemoglobin level (HR, 0.91; 95% CI, 0.87–0.96; p < 0.001). The survival estimates by the nomogram were moderately accurate for predicting 30-day (area under the curve [AUC], 0.72), 90-day (AUC, 0.75), and 365-day (AUC, 0.73) survival and remained stable after correcting for optimism through fivefold cross validation. Boosting algorithms were better predictors of survival on the training datasets, but decreased to a performance level comparable to the nomogram when applied on testing datasets for 30-day (AUC, 0.69), 90-day (AUC, 0.75), and 365-day (AUC, 0.72) survival prediction. Performance of the classic scoring system was lowest for all prediction periods.
Conclusions
Comorbidity status and BMI are newly identified factors associated with decreased survival and should be taken into account when estimating survival. Performance of the boosting algorithms and nomogram were comparable on the testing datasets. However, the nomogram is easier to apply and therefore more useful to aid surgical decision making in clinical practice.
Level of Evidence
Level III, prognostic study.
Electronic supplementary material
The online version of this article (doi:10.1007/s11999-015-4446-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s11999-015-4446-z
PMCID: PMC4562931  PMID: 26155769
21.  Repeated salivary daytime cortisol and onset of mood episodes in offspring of bipolar parents 
Background
Differences in cortisol secretion may differentiate individuals at high compared to low genetic risk for bipolar disorder (BD) and predict the onset or recurrence of mood episodes. The objectives of this study were to determine if salivary cortisol measures are: (1) different in high-risk offspring of parents with BD (HR) compared to control offspring of unaffected parents (C), (2) stable over time, (3) associated with the development of mood episode onset/recurrence, and (4) influenced by comorbid complications.
Methods
Fifty-three HR and 22 C completed salivary cortisol sampling annually for up to 4 years in conjunction with semi-structured clinical interviews. The cortisol awakening response (CAR), daytime cortisol [area under the curve (AUC)], and evening cortisol (8:00 p.m.) were calculated.
Results
There were no differences in baseline CAR, AUC and evening cortisol between HR and C (p = 0.38, p = 0.30 and p = 0.84), respectively. CAR, AUC and evening cortisol were stable over yearly assessments in HR, while in Cs, evening cortisol increased over time (p = 0.008), and CAR and AUC remained stable. In HR, AUC and evening cortisol increased the hazard of a new onset mood disorder/recurrence by 2.7 times (p = 0.01), and 3.5 times (p = 0.01), respectively, but this was no longer significant after accounting for multiple comparisons.
Conclusions
Salivary cortisol is stable over time within HR offspring. However, between individuals, basal salivary cortisol is highly variable. More research is needed, with larger samples of prospectively studied HR youth using a more reliable method of cortisol measurement, to determine the potential role of cortisol in the development of mood disorders.
Electronic supplementary material
The online version of this article (doi:10.1186/s40345-016-0053-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s40345-016-0053-5
PMCID: PMC4882311  PMID: 27230036
Hypothalamic pituitary adrenal axis; Cortisol; Mood disorders; Bipolar disorder; High-risk offspring; Pathophysiology
22.  Evaluation of a cumulative SUV-volume histogram method for parameterizing heterogeneous intratumoural FDG uptake in non-small cell lung cancer PET studies 
Purpose
Standardized uptake values (SUV) are commonly used for quantification of whole-body [18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) studies. Changes in SUV following therapy, however, only provide a proper measure of response in case of homogeneous FDG uptake in the tumour. The purpose of this study was therefore to implement and characterize a method that enables quantification of heterogeneity in tumour FDG uptake.
Methods
Cumulative SUV-volume histograms (CSH), describing % of total tumour volume above % threshold of maximum SUV (SUVmax), were calculated. The area under a CSH curve (AUC) is a quantitative index of tumour uptake heterogeneity, with lower AUC corresponding to higher degrees of heterogeneity. Simulations of homogeneous and heterogeneous responses were performed to assess the value of AUC-CSH for measuring uptake and/or response heterogeneity. In addition, partial volume correction and image denoising was applied prior to calculating AUC-CSH. Finally, the method was applied to a number of human FDG scans.
Results
Partial volume correction and noise reduction improved CSH curves. Both simulations and clinical examples showed that AUC-CSH values corresponded with level of tumour heterogeneity and/or heterogeneity in response. In contrast, this correspondence was not seen with SUVmax alone. The results indicate that the main advantage of AUC-CSH above other measures, such as 1/COV (coefficient of variation), is the possibility to measure or normalize AUC-CSH in different ways.
Conclusion
AUC-CSH might be used as a quantitative index of heterogeneity in tracer uptake. In response monitoring studies it can be used to address heterogeneity in response.
doi:10.1007/s00259-011-1845-6
PMCID: PMC3151405  PMID: 21617975
Positron emission tomography (PET); Standardized uptake value (SUV); Intratumoural heterogeneity; Cumulative SUV-volume histogram (CSH); Intensity-volume histograms (IVH)
23.  Comparison of Stress-Hemoconcentration Correction Techniques for Stress-Induced Coagulation 
BioMed Research International  2013;2013:480648.
When examining stress effects on coagulation, arithmetic correction is typically used to adjust for concomitant hemoconcentration but may be inappropriate for coagulation activity assays. We examined a new physiologically relevant method of correcting for stress-hemoconcentration. Blood was drawn from healthy men (N = 40) during baseline, mental stress, and recovery, and factor VII activity (FVII:C), factor VIII activity (FVIII:C), activated partial thromboplastin time (APTT), prothrombin time (PT%), fibrinogen, D-dimer, and plasma volume were determined. Three hemoconcentration correction techniques were assessed: arithmetic correction and two reconstitution techniques using baseline plasma or physiological saline. Area-under-the-curve (AUC) was computed for each technique. For FVII:C, uncorrected AUC was significantly greater than AUC corrected arithmetically. For PT%, uncorrected AUC was significantly greater than AUC corrected with saline or arithmetically. For APTT, uncorrected AUC was significantly less than AUC corrected with saline and greater than AUC corrected arithmetically. For fibrinogen, uncorrected AUC was significantly greater than AUC corrected with saline or arithmetically. For D-dimer, uncorrected AUC was significantly greater than AUC corrected arithmetically. No differences in AUC were observed for FVIII:C. Saline reconstitution seems most appropriate when adjusting for hemoconcentration effects on clotting time and activity. Stress-hemoconcentration accounted for the majority of coagulation changes.
doi:10.1155/2013/480648
PMCID: PMC3814105  PMID: 24222908
24.  Pharmacodynamics of the New Des-F(6)-Quinolone Garenoxacin in a Murine Thigh Infection Model 
Antimicrobial Agents and Chemotherapy  2003;47(12):3935-3941.
Garenoxacin is a new des-F(6)-quinolone with broad-spectrum activity against both gram-positive cocci and gram-negative bacilli. We used the neutropenic murine thigh infection model to characterize the time course of antimicrobial activity of garenoxacin and determine which pharmacokinetic-pharmacodynamic (PK-PD) parameter best correlated with efficacy. Serum drug levels following three fourfold-escalating single-dose levels of garenoxacin were measured by microbiologic assay. In vivo postantibiotic effects (PAEs) were determined after doses of 16 and 64 mg/kg of body weight. Mice had 106.5 to 106.7 CFU of Streptococcus pneumoniae strain ATCC 10813 or Staphylococcus aureus strain ATCC 33591 per thigh when they were treated for 24 h with garenoxacin at a dose of 4 to 128 mg/kg/day fractionated for 3-, 6-, 12-, and 24-hour dosing regimens. Nonlinear regression analysis was used to determine which PK-PD parameter best correlated with the measurement of CFU/thigh at 24 h. Pharmacokinetic studies yielded peak/dose values of 0.2 to 0.3, area under the concentration-time curve (AUC)/dose values of 0.1 to 0.5, and half-lives of 0.7 to 1.6 h. Garenoxacin produced in vivo PAEs of 1.4 to 8.2 h with S. pneumoniae ATCC 10813, 7.6 to >12.4 h with S. aureus ATCC 25923, and 0 to 1.5 h with Klebsiella pneumoniae ATCC 43816. The 24-h AUC/MIC ratio was the PK-PD parameter that best correlated with efficacy (R2 = 71 to 90% for the two organisms compared with 43 to 56% for the peak/MIC ratio and 47 to 75% for percent time above the MIC [% T>MIC]).In subsequent studies we used the neutropenic murine thigh infection model to determine if the magnitude of the AUC/MIC ratio needed for efficacy of garenoxacin varied among pathogens (including resistant strains). Mice had 105.9 to 107.2 CFU of 6 strains of S. aureus (2 methicillin resistant), 11 strains of S. pneumoniae (5 penicillin susceptible, 1 penicillin intermediate, and 5 penicillin resistant, and of the resistant strains, 3 were also ciprofloxacin resistant), and 4 gram-negative strains per thigh when treated for 24 h with 1 to 64 mg of garenoxacin per kg every 12 h. A sigmoid dose-response model was used to estimate the doses (mg/kg/24 h) required to achieve a net bacteriostatic effect over 24 h. MICs ranged from 0.008 to 4 μg/ml. The free drug 24-h AUC/MIC ratios for each static dose (2.8 to 128 mg/kg/day) varied from 8.2 to 145. The mean 24-h AUC/MIC ratios ± standard deviations for S. pneumoniae, S. aureus, and gram-negative strains were 33 ± 18, 81 ± 37, and 33 ± 30, respectively. Methicillin, penicillin, or ciprofloxacin resistance did not alter the magnitude of the AUC/MIC ratio required for efficacy.
doi:10.1128/AAC.47.12.3935-3941.2003
PMCID: PMC296207  PMID: 14638504
25.  Effects of Reusing Baseline Volumes of Interest by Applying (Non-)Rigid Image Registration on Positron Emission Tomography Response Assessments 
PLoS ONE  2014;9(1):e87167.
Objectives
Reusing baseline volumes of interest (VOI) by applying non-rigid and to some extent (local) rigid image registration showed good test-retest variability similar to delineating VOI on both scans individually. The aim of the present study was to compare response assessments and classifications based on various types of image registration with those based on (semi)-automatic tumour delineation.
Methods
Baseline (n = 13), early (n = 12) and late (n = 9) response (after one and three cycles of treatment, respectively) whole body [18F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (PET/CT) scans were acquired in subjects with advanced gastrointestinal malignancies. Lesions were identified for early and late response scans. VOI were drawn independently on all scans using an adaptive 50% threshold method (A50). In addition, various types of (non-)rigid image registration were applied to PET and/or CT images, after which baseline VOI were projected onto response scans. Response was classified using PET Response Criteria in Solid Tumors for maximum standardized uptake value (SUVmax), average SUV (SUVmean), peak SUV (SUVpeak), metabolically active tumour volume (MATV), total lesion glycolysis (TLG) and the area under a cumulative SUV-volume histogram curve (AUC).
Results
Non-rigid PET-based registration and non-rigid CT-based registration followed by non-rigid PET-based registration (CTPET) did not show differences in response classifications compared to A50 for SUVmax and SUVpeak,, however, differences were observed for MATV, SUVmean, TLG and AUC. For the latter, these registrations demonstrated a poorer performance for small lung lesions (<2.8 ml), whereas A50 showed a poorer performance when another area with high uptake was close to the target lesion. All methods were affected by lesions with very heterogeneous tracer uptake.
Conclusions
Non-rigid PET- and CTPET-based image registrations may be used to classify response based on SUVmax and SUVpeak. For other quantitative measures future studies should assess which method is valid for response evaluations by correlating with survival data.
doi:10.1371/journal.pone.0087167
PMCID: PMC3904976  PMID: 24489860

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