Nonparametric Bootstrap Analysis Research Articles

Severe obstructive sleep apnea in children with syndromic craniosynostosis: analysis of pulse transit time.

We examined the association between pulse transit time (PTT) and obstructive sleep apnea (OSA) in children with syndromic craniosynostosis (SCS), where OSA is a common problem and may cause cardiorespiratory disturbance. Retrospective study of children (age <18 years) with SCS and moderate-to-severe OSA (i.e., obstructive apnea-hypopnea index [oAHI] ≥ 5), or no OSA (oAHI < 1) who underwent overnight polysomnography (PSG). Children without SCS and normal PSG were included as controls. Reference intervals (RIs) for PTT were computed by non-parametric bootstrap analysis. Based on RIs of controls, the sensitivity and specificity of PTT to detect OSA were determined. In a linear mixed-model the explanatory variables assessed were sex, age, sleep stage, and time after obstructive events. In all 68 included children (19 SCS with OSA, 30 SCS without OSA, 19 controls), obstructive events occurred throughout all sleep stages, most prominently during rapid eye movement sleep (REM) and non-REM sleep stages N1 and N2, with evident PTT changes. Greatest reductions were observed 4 - 8 s after an event (p < 0.05). In SCS with OSA, PTT RIs were lower during all sleep stages compared to SCS without OSA. The highest sensitivity was observed during N1 (55.5%), and the highest specificity during REM (76.5%). Lowest PTT values were identified during N1. Obstructive events occur throughout all sleep stages with transient reductions in PTT. However, PTT as a variable for OSA detection is limited by its sensitivity and specificity.

Cost-effectiveness of 2 Models of Pessary Care for Pelvic Organ Prolapse: Findings From the TOPSY Randomized Controlled Trial

ObjectivesPelvic organ prolapse is the descent of one or more reproductive organs from their normal position, causing associated negative symptoms. One conservative treatment option is pessary management. This study aimed to to investigate the cost-effectiveness of pessary self-management (SM) when compared with clinic-based care (CBC). A decision analytic model was developed to extend the economic evaluation. MethodsA randomized controlled trial with health economic evaluation. The SM group received a 30-minute SM teaching session, information leaflet, 2-week follow-up call, and a local helpline number. The CBC group received routine outpatient pessary appointments, determined by usual practice. The primary outcome for the cost-effectiveness analysis was incremental cost per quality-adjusted life year (QALY), 18 months post-randomization. Uncertainty was handled using nonparametric bootstrap analysis. In addition, a simple decision analytic model was developed using the trial data to extend the analysis over a 5-year period. ResultsThere was no significant difference in the mean number of QALYs gained between SM and CBC (1.241 vs 1.221), but mean cost was lower for SM (£578 vs £728). The incremental net benefit estimated at a willingness to pay of £20 000 per QALY gained was £564, with an 80.8% probability of cost-effectiveness. The modeling results were consistent with the trial analysis: the incremental net benefit was estimated as £4221, and the probability of SM being cost-effective at 5 years was 69.7%. ConclusionsResults suggest that pessary SM is likely to be cost-effective. The decision analytic model suggests that this result is likely to persist over longer durations.

Sex-specific reference values for total, central, and peripheral latency of motor evoked potentials from a large cohort.

Differentiating between physiologic and altered motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) is crucial in clinical practice. Some physical characteristics, such as height and age, introduce sources of variability unrelated to neural dysfunction. We provided new age- and height-adjusted normal values for cortical latency, central motor conduction time (CMCT), and peripheral motor conduction time (PMCT) from a large cohort of healthy subjects. Previously reported data from 587 participants were re-analyzed. Nervous system disorders were ruled out by clinical examination and magnetic resonance imaging. MEP latency was determined as stimulus-to-response latency through stimulation with a circular coil over the "hot spot" of the First Dorsal Interosseous and Tibialis Anterior muscles, during mild tonic contraction. CMCT was estimated as the difference between MEP cortical latency and PMCT by radicular magnetic stimulation. Additionally, right-to-left differences were calculated. For each parameter, multiple linear regression models of increasing complexity were fitted using height, age, and sex as regressors. Motor evoked potential cortical latency, PMCT, and CMCT were shown to be age- and height-dependent, although age had only a small effect on CMCT. Relying on Bayesian information criterion for model selection, MEP cortical latency and PMCT were explained best by linear models indicating a positive correlation with both height and age. Also, CMCT to lower limbs positively correlated with height and age. CMCT to upper limbs positively correlated to height, but slightly inversely correlated to age, as supported by non-parametric bootstrap analysis. Males had longer cortical latencies and CMCT to lower limbs, as well as longer PMCT and cortical latencies to upper limbs, even when accounting for differences in body height. Right-to-left-differences were independent of height, age, and sex. Based on the selected regression models, sex-specific reference values were obtained for all TMS-related latencies and inter-side differences, with adjustments for height and age, where warranted. A significant relationship was observed between height and age and all MEP latency values, in both upper and lower limbs. These set of reference values facilitate the evaluation of MEPs in clinical studies and research settings. Unlike previous reports, we also highlighted the contribution of sex.

Development of population pharmacokinetics model and Bayesian estimation of rifampicin exposure in Indonesian patients with tuberculosis

BackgroundInterindividual variability in the pharmacokinetics (PK) of anti-tuberculosis (TB) drugs is the leading cause of treatment failure. Herein, we evaluated the influence of demographic, clinical, and genetic factors that cause variability in RIF PK parameters in Indonesian TB patients. MethodsIn total, 210 Indonesian patients with TB (300 plasma samples) were enrolled in this study. Clinical data, solute carrier organic anion transporter family member-1B1 (SLCO1B1) haplotypes *1a, *1b, and *15, and RIF concentrations were analyzed. The population PK model was developed using a non-linear mixed effect method. ResultsA one-compartment model with allometric scaling adequately described the PK of RIF. Age and SLCO1B1 haplotype *15 were significantly associated with variability in apparent clearance (CL/F). For patients in their 40s, each 10-year increase in age was associated with a 10% decrease in CL/F (7.85 L/h). Patients with the SLCO1B1 haplotype *15 had a 24% lower CL/F compared to those with the wild-type. Visual predictive checks and non-parametric bootstrap analysis indicated good model performance. ConclusionAge and SLCO1B1 haplotype *15 were significant covariates of RIF CL/F. Geriatric patients with haplotype *15 had significantly greater exposure to RIF. The model could optimize TB pharmacotherapy through its application in therapeutic drug monitoring (clinical trial no. NCT05280886).

The Parallel Mediation Effects of Depression, Well-Being, and Social Activity on Physical Performance and Frailty in Community-Dwelling Middle-Aged and Older People.

Frailty refers to a decline in an elderly person's physical, psychological, and social functioning, making them sensitive to stressors. Because frailty is caused by a variety of factors, including certain demographic characteristics, understanding the mediating factors that affect frailty in the elderly is critical. To provide evidence about the relationship between depression, well-being, social activity, physical performance, and frailty among older adults. The study used secondary data from Taiwan's Long-term Study of Aging (n = 7,622), excluding people with severe dementia. The chi-square test and Spearmen's coefficient correlation were used to assess the relationship between the demographic variables and frailty. Nonparametric bootstrapping analysis was used to test whether depression, well-being, and social activity are parallel mediators of the relationship between physical performance and frailty. This study was approved by Fu Jen Catholic University (FJU-IRB No. C110040). The overall frailty prevalence was 13.9%. We calculated a mean score and standard deviation for each measurement in this study. The correlation found low-to-moderate positive and negative statistically significant correlations between the variables. A significant, moderately negative relationship was found between physical performance and frailty that correlated with three potential mediating factors. The path indicated that lower physical performance scores and higher depression scores are more likely to be associated with frailty. Older adults who are depressed are more likely to become frail. Adults who are more socially active and report greater well-being are less likely to become frail. Therefore, further research should design and test a comprehensive intervention for older adults in community settings that addresses all three factors, aimed at increasing well-being and social activity while also treating depression.

Cost-effectiveness of single, high-dose, liposomal amphotericin regimen for HIV-associated cryptococcal meningitis in five countries in sub-Saharan Africa: an economic analysis of the AMBITION-cm trial

HIV-associated cryptococcal meningitis is a leading cause of AIDS-related mortality. The AMBITION-cm trial showed that a regimen based on a single high dose of liposomal amphotericin B deoxycholate (AmBisome group) was non-inferior to the WHO-recommended treatment of seven daily doses of amphotericin B deoxycholate (control group) and was associated with fewer adverse events. We present a five-country cost-effectiveness analysis. The AMBITION-cm trial enrolled patients with HIV-associated cryptococcal meningitis from eight hospitals in Botswana, Malawi, South Africa, Uganda, and Zimbabwe. Taking a health service perspective, we collected country-specific unit costs and individual resource-use data per participant over the 10-week trial period, calculating mean cost per participant by group, mean cost-difference between groups, and incremental cost-effectiveness ratio per life-year saved. Non-parametric bootstrapping and scenarios analyses were performed including hypothetical real-world resource use. The trial registration number is ISRCTN72509687, and the trial has been completed. The AMBITION-cm trial enrolled 844 participants, and 814 were included in the intention-to-treat analysis (327 from Uganda, 225 from Malawi, 107 from South Africa, 84 from Botswana, and 71 from Zimbabwe) with 407 in each group, between Jan 31, 2018, and Feb 17, 2021. Using Malawi as a representative example, mean total costs per participant were US$1369 (95% CI 1314-1424) in the AmBisome group and $1237 (1181-1293) in the control group. The incremental cost-effectiveness ratio was $128 (59-257) per life-year saved. Excluding study protocol-driven cost, using a real-world toxicity monitoring schedule, the cost per life-year saved reduced to $80 (15-275). Changes in the duration of the hospital stay and antifungal medication cost showed the greatest effect in sensitivity analyses. Results were similar across countries, with the cost per life-year saved in the real-world scenario ranging from $71 in Botswana to $121 in Uganda. The AmBisome regimen was cost-effective at a low incremental cost-effectiveness ratio. The regimen might be even less costly and potentially cost-saving in real-world implementation given the lower drug-related toxicity and the potential for shorter hospital stays. European Developing Countries Clinical Trials Partnership, Swedish International Development Cooperation Agency, Wellcome Trust and Medical Research Council, UKAID Joint Global Health Trials, and the National Institute for Health Research. For the Chichewa, Isixhosa, Luganda, Setswana and Shona translations of the abstract see Supplementary Materials section.

Precision and accuracy assessment of single and multicamera three-dimensional photogrammetry compared with direct anthropometry.

To assess the precision and accuracy of single-camera photogrammetry (SCP) and multicamera photogrammetry (MCP) compared with direct anthropometry (DA). A total of 30 participants were recruited, and 17 soft tissue landmarks were identified and used to complete a total of 16 measurements. Using SCP and MCP, two three-dimensional (3D) images were acquired from each participant. All 3D measurements and direct measurements were measured twice by the same operator to assess intraexaminer repeatability. Intraclass coefficients (ICCs) were used to evaluate intraexaminer repeatability and interexaminer agreement of the methods. Nonparametric bootstrap analyses were used to compare the means of the measurements among the three methods. All three methods showed excellent intraexaminer repeatability (ICCs > 0.90), except interpupillary distance (ICC = 0.86) measured by SCP. Both SCP and MCP showed excellent interexaminer agreement (ICCs > 0.90), except interpupillary distance (ICC = 0.79), left gonion-pogonion (ICC = 0.74), and columella-subnasale-labrale superior angle (ICC = 0.86) measured by SCP. Overall, there was good agreement between methods, except for columella-subnasale-labrale superior angle (ICC = 0.40) between SCP and MCP. Both SCP and MCP techniques were found to be reliable and valid options for 3D facial imaging. SCP produced slightly larger mean values for several measurements, but the differences were within a clinically acceptable range. Because of the larger margin of errors, measurements including the gonial area and subnasale should be assessed with caution.

The relationship between ecological executive function and stigma among patients with epilepsy: The mediating effect of social support

ObjectiveStigma is a key determinant of mental health among patients with epilepsy (PWE). In prior work, many PWE have been found to exhibit impaired executive function (EF) and to lack sufficient social support. This study was developed to explore factors that may influence stigma in PWE with a focus on the associations among EF, social support, and stigma in this patient population. MethodsA questionnaire was administered to 121 patients with primary epilepsy as a means of collecting clinical and demographic details. The severity of EF impairment, social support levels, and stigma were analyzed using the Behavior Rating Inventory of Executive Function-Adult (BRIEF-A), the Social Support Rating Scale, and the Kilifi Stigma Scale for Epilepsy-Chinese (KSSE-C). Descriptive analyses were used to evaluate demographic details, and parameters associated with stigma were identified through multiple linear stepwise analyses. Spearman’s correlation analyses and moderated mediation analyses were utilized to examine relationships between impaired EF, social support, and stigma. Significant mediation effects were identified using the SPSS PROCESS macro via a bootstrap approach. ResultsUp to 95.9% of the 121 PWE in this study were affected by stigma, with differneces in stigma being associated with long-term residence (urban or rural), family monthly income, disease control status (controlled or uncontrolled), and medication types. Multiple stepwise linear regression analyses revealed that the number of years of education (t = - 4.58, P < 0.001), family monthly income per capita (t = −3.43, P = 0.001), and age of first episode (t = −2.71, P = 0.008) for PWE were negatively correlated with stigma scores, while long-term residence (t = 2.79, P = 0.006), course of disease (t = 3.65, P < 0.001), disease control (t = 2.79, P = 0.006), and types of medication (t = 2.73, P = 0.007) were positively correlated with stigma scores. Impaired EF was found to be significantly associated with stigma (β = 0.64, P < 0.001), and social support was able to mediate the association between stigma and impaired EF (β = 0.64, P < 0.001). Non-parametric bootstrap analysis results revealed the indirect impact of EF through social support (95% bootstrap CI = 0.11, 0.22), with the indirect influence of social support accounting for 44.3% of the overall effect of stigma. ConclusionsThese results offer new insight into the interactive mechanisms that underlie stigma and EF, in addition to clarifying the ability of social support to mediate this relationship. These data thus highlight valuable theoretical and methodological approaches to preventing stigma in PWE, suggesting that stigma in PWE can be effectively reduced by bolstering EF, and social support plays a mediating effect in this context.

Cost-utility of a web-based intervention to promote maternal mental health among postpartum women presenting low risk for postpartum depression.

Web-based interventions for the promotion of maternal mental health could represent a cost-effective strategy to reduce the burden associated with perinatal mental illness. This study aimed to evaluate the cost-utility of Be a Mom, a self-guided web-based cognitive behavioral therapy intervention, compared with a waiting-list control. The economic evaluation alongside a randomized controlled trial was conducted from a societal perspective over a 14-month time frame. Postpartum women presenting low risk for postpartum depression were randomized to the intervention (n=191) or control (n=176) group and assessed at baseline, postintervention and 4 and 12months after postintervention. Data regarding healthcare use, productive losses and quality-adjusted life years (QALYs) were collected and used to calculate incremental cost-effectiveness ratios (ICERs). Uncertainty was accounted for with nonparametric bootstrapping and sensitivity analyses. At 14months, and after accounting for a 3.5 percent discount rate, the intervention resulted in a yearly cost-saving of EUR 165.47 (-361.77, 28.51) and a QALY gain of 0.0064 (-0.0116, 0.0244). Bootstrapping results revealed a dominant ICER for the intervention group. Although results were statistically nonsignificant, cost-effectiveness acceptability curves showed that at a EUR 0 willingness to pay threshold, there is a 96 percent probability that the intervention is cost-effective when compared with the control group. The sensitivity analyses generally supported the acceptable likelihood of the intervention being more cost-effective than the control group. From a societal perspective, the implementation of Be a Mom among low-risk postpartum women could be a cost-effective way to improve perinatal mental health.

Cost Effectiveness of a Cultural Physical Activity Intervention to Reduce Blood Pressure Among Native Hawaiians with Hypertension.

ObjectiveThe aim of this study was to calculate the costs and assess whether a culturally grounded physical activity intervention offered through community-based organizations is cost effective in reducing blood pressure among Native Hawaiian adults with hypertension.MethodsSix community-based organizations in Hawai‘i completed a randomized controlled trial between 2015 and 2019. Overall, 263 Native Hawaiian adults with uncontrolled hypertension (≥ 140 mmHg systolic, ≥ 90 mmHg diastolic) were randomized to either a 12-month intervention group of hula (traditional Hawaiian dance) lessons and self-regulation classes, or to an education-only waitlist control group. The primary outcome was change in systolic blood pressure collected at baseline and 3, 6, and 12 months for the intervention compared with the control group. Incremental cost-effectiveness ratios (ICERs) were calculated for primary and secondary outcomes. Non-parametric bootstrapping and sensitivity analyses evaluated uncertainty in parameters and outcomes.ResultsThe mean intervention cost was US$361/person, and the 6-month ICER was US$103/mmHg reduction in systolic blood pressure and US$95/mmHg in diastolic blood pressure. At 12 months, the intervention group maintained reductions in blood pressure, which exceeded reductions for usual care based on blood pressure outcomes. The change in blood pressure at 12 months resulted in ICERs of US$100/mmHg reduction in systolic blood pressure and US$93/mmHg in diastolic blood pressure. Sensitivity analyses suggested that at the estimated intervention cost, the probability that the program would lower systolic blood pressure by 5 mmHg was 67 and 2.5% at 6 and 12 months, respectively.ConclusionThe 6-month Ola Hou program may be cost effective for low-resource community-based organizations. Maintenance of blood pressure reductions at 6 and 12 months in the intervention group contributed to potential cost effectiveness. Future studies should further evaluate the cost effectiveness of indigenous physical activity programs in similar settings and by modeling lifetime costs and quality-adjusted life-years.Trial Registration NumberNCT02620709.Supplementary InformationThe online version contains supplementary material available at 10.1007/s41669-021-00291-6.

Economic Evaluation of Web- versus Telephone-based Interventions to Simultaneously Increase Colorectal and Breast Cancer Screening Among Women.

Screening for colorectal and breast cancer is considered cost effective, but limited evidence exists on cost-effectiveness of screening promotion interventions that simultaneously target both cancers. Increasing Colorectal and Breast Cancer Screening (Project COBRA), a randomized controlled trial conducted in the community, examined the cost-effectiveness of an innovative tailored web-based intervention compared with tailored telephone counseling and usual care. Screening status at 6 months was obtained by participant surveys plus medical record reviews. Cost was prospectively measured from the patient and provider perspectives using time logs and project invoices. Relative efficiency of the interventions was quantified by the incremental cost-effectiveness ratios. Nonparametric bootstrapping and net benefit regression analysis were used to assess statistical uncertainty of the results. The average cost per participant to implement the Phone counseling, Web-based, and Web + Phone counseling interventions were $277, $314, and $337, respectively. Comparing Phone counseling with usual care resulted in an additional cost of $300 (95% confidence interval [CI]: $283-$320) per cancer screening test and $421 (95% CI: $400-$441) per additional person screened in the target population. Phone counseling alone was more cost-effective than the Web + Phone intervention. Web-based intervention alone was more costly but less effective than the Phone counseling. When simultaneously promoting screening for both colorectal and breast cancer the Web-based intervention was less cost-effective compared with Phone and Web + Phone strategies. The results suggest that targeting multiple cancer screening may improve the cost-effectiveness of cancer screening interventions. PREVENTION RELEVANCE: This study informs researchers, decision makers, healthcare providers, and payers about the improved cost-effectiveness of targeting multiple cancer screenings for cancer early detection programs.

Cost-Utility Analysis of Continuation Versus Discontinuation of First-Line Chemotherapy in Patients With Metastatic Squamous-Cell Esophageal Cancer: Economic Evaluation Alongside the E-DIS Trial

ObjectivesContinuous chemotherapy has been used to treat patients with metastatic esophageal squamous cell carcinoma (mESCC), despite weak evidence supporting a clinical benefit, associated side effects for the patients, and unjustified medical costs. In the French setting, we conducted a cost-utility analysis alongside the randomized E-DIS trial (NCT01248299), which compared first-line fluorouracil/platinum-based chemotherapy continuation (CT-CONT) to CT discontinuation (CT-DISC) in progressive-free patients after an initial 6-week treatment phase. MethodsA partitioned survival analysis was performed using patient-level data collected during the trial for survival outcomes, quality of life (EQ-5D-3L), and medical costs. The mean quality-adjusted life-years (QALYs) and medical costs were estimated over an 18-month period to assess the incremental net monetary benefit and incremental cost-effectiveness ratio. Uncertainty was handled using the nonparametric bootstrap and univariate analysis. Sixty-seven patients with mESCC were randomized and included in the cost-utility analysis. ResultsOn average, CT-CONT slightly decreased the number of QALYs (-0.038) and increased the cost per patient (+ €1177). At a willingness-to-pay threshold of €50 000/QALY, the incremental net monetary benefit was negative (-€3077 [95% confidence interval: -6564; 4359]), and the incremental cost-effectiveness ratio was -30 958€/QALY (CT-CONT dominated). The probability of the CT-CONT treatment option being cost-effective at a willingness-to-pay threshold of €50 000/QALY, compared to CT-DISC, was 29%. ConclusionsCT-DISC may be considered as an alternative therapeutic option to CT-CONT in patients with mESCC who have stable disease after an initial chemotherapy treatment phase. A continuous chemotherapy could indeed reduce the number of QALYs because of the disutility associated with the continuous treatment.

Clinical outcomes and healthcare expenditures in the real world with left ventricular assist devices – The CLEAR-LVAD study

Several distinctly engineered left ventricular assist devices (LVADs) are in clinical use. However, contemporaneous real world comparisons have not been conducted, and clinical trials were not powered to evaluate differential survival outcomes across devices. Determine real world survival outcomes and healthcare expenditures for commercially available durable LVADs. Using a retrospective observational cohort design, Medicare claims files were linked to manufacturer device registration data to identify de-novo, durable LVAD implants performed between January 2014 and December 2018, with follow-up through December 2019. Survival outcomes were compared using a Cox proportional hazards model stratified by LVAD type and validated using propensity score matching. Healthcare resource utilization was analyzed across device types by using nonparametric bootstrap analysis methodology. Primary outcome was survival at 1-year and total Part A Medicare payments. A total of 4,195 de-novo LVAD implants were identified in fee-for-service Medicare beneficiaries (821 HeartMate 3; 1,840 HeartMate II; and 1,534 Other-VADs). The adjusted hazard ratio for mortality at 1-year (confirmed in a propensity score matched analysis) for the HeartMate 3 vs HeartMate II was 0.64 (95% CI; 0.52-0.79, p< 0.001) and for the HeartMate 3 vs Other-VADs was 0.51 (95% CI; 0.42-0.63, p < 0.001). The HeartMate 3 cohort experienced fewer hospitalizations per patient-year vs Other-VADs (respectively, 2.8 vs 3.2 EPPY hospitalizations, p < 0.01) and 6.1 fewer hospital days on average (respectively, 25.2 vs 31.3 days, p < 0.01). The difference in Medicare expenditures, conditional on survival, for HeartMate 3 vs HeartMate II was -$10,722, p < 0.001 (17.4% reduction) and for HeartMate 3 vs Other-VADs was -$17,947, p < 0.001 (26.1% reduction). In this analysis of a large, real world, United States. administrative dataset of durable LVADs, we observed that the HeartMate 3 had superior survival, reduced healthcare resource use, and lower healthcare expenditure compared to other contemporary commercially available LVADs.

The statistical reliability of 267-GHz JCMT observations of Venus: no significant evidence for phosphine absorption

ABSTRACT In the light of the recent announcement of the discovery of the potential biosignature phosphine in the atmosphere of Venus, I present an independent reanalysis of the original James Clerk Maxwell Telescope (JCMT) data to assess the statistical reliability of the detection. Two line detection methods are explored: low-order polynomial fits and higher order multiple polynomial fits. A non-parametric bootstrap analysis reveals that neither line detection method is able to recover a statistically significant detection. Similar to the results of other reanalyses of ALMA(Atacama Large Millimetre Array) Venus spectra, the polynomial fitting process results in false positive detections in the JCMT spectrum. There is thus no significant evidence for phosphine absorption in the JCMT Venus spectra.

Population Pharmacokinetics of Eryaspase in Patients with Acute Lymphoblastic Leukemia or Pancreatic Adenocarcinoma

L-asparaginase (ASNase) is a microbial enzyme and a chemotherapeutic agent that has been a standard component of multi-agent chemotherapy for the treatment of acute lymphoblastic leukemia (ALL). Eryaspase, ASNase encapsulated in red blood cells, is being developed with an improved pharmacokinetic profile compared to some other ASNase products. The purpose of the present analysis was to describe the population pharmacokinetics (Pop PK) of eryaspase and sources of variability in two patient populations - ALL or pancreatic adenocarcinoma (PAC). Eryaspase was administered intravenously at doses of 50, 100, and 150 U/kg to patients enrolled in Phase 1-3 clinical trials in combination with chemotherapy. Either serial or sparse pharmacokinetic sampling was performed in each study. A Pop PK model was fit to the data using Nonlinear Mixed Effects Modeling (NONMEM®) software, and included an assessment of covariates, e.g., demography, disease type, formulation, and immunogenicity. The adequacy of the final Pop PK model and parameter estimates was investigated with a visual predictive check (VPC) and non-parametric bootstrap analysis. Using the final Pop PK model, a simulation was performed for eryaspase 100 U/kg every 2 weeks and included a target trough reference ASNase level of 100 U/L. The Pop PK analysis included 162 patients (94 ALL and 68 PAC) with median age of 56.5 years (range of 2-84 years). Eryaspase concentration-time data were best described by a one compartment model with first order elimination. Population clearance and volume of distribution were 0.29 L/day and 6.12 L, respectively. That equates to a terminal half-life of approximately 15 days. Both clearance and volume of distribution were found to increase with increasing body weight. No other covariate tested was found to influence eryaspase pharmacokinetics, including patient age and gender, patient population (ALL vs PAC), and formulation (native vs recombinant ASNase). VPC showed the final model well captured the data; furthermore, the final model parameters and bootstrap results were in accordance. The effect of positive presence of neutralizing antibodies on eryaspase clearance was inconclusive because of variability within and across studies. The figure below displays the median (solid line) and 95% prediction interval (blue shaded region) of simulated ASNase concentrations with a reference line of 100 U/L. The simulation shows that approximately 95% of patients would exceed the target trough level of 100 U/L following the first and subsequent infusions following administration of 100 U/kg every 2 weeks. In conclusion, the Pop PK analysis provided valuable information in the characterization of eryaspase and factors that influence its variability. As expected for an RBC-type product, the clearance was low, and the volume of distribution was consistent with blood volume. Terminal phase t1/2 was approximately 15 days, and body weight was a significant covariate for both clearance and volume of distribution. Based on simulation, an eryaspase dosing regimen of 100 U/kg every 2 weeks would provide trough ASNase activity levels above 100 U/L for approximately 95% of patients. Eryaspase is currently being investigated in ALL patients with hypersensitivity reactions, as well as a phase 3 clinical study in PAC (Trybeca-1) and a phase 2 study in Triple Negative Breast Cancer (Trybeca-2). Figure Disclosures Hoke: Erytech: Current Employment. Lorenzi:Precision Pathways: Consultancy. El-Hariry:Erytech: Current Employment.

Outpatient and self-referred participants: Adherence to treatment components and outcome in an internet intervention targeting anxiety disorders

ObjectiveWhile adherence is an important factor influencing the effectiveness of internet interventions, many studies operationalize adherence only by the number of sessions and do not report adherence to specific treatment components. The goal of this study was to investigate adherence to treatment components as well as outcome in outpatients and self-referred participants who participated in an internet intervention targeting anxiety. MethodOutpatients (N = 50) were compared to self-referred (N = 37) participants and a matched outpatient waitlist sample (based on nearest neighbor matching): Using t-test and χ2 tests adherence to treatment components based on the number of completed exercises was compared between participant groups. A 2 × 2 repeated measures ANOVA was used to compare pre-to post symptom change between participant groups. Primary measures included the Generalized Anxiety Disorder Scale-7 (GAD-7) and the Mini Social Phobia Inventory (Mini-SPIN). Using nonparametric bootstrap analyses number of sessions and adherence to treatment components were investigated as potential mediators of the relationship between participant group and outcome. Finally, predictors of adherence to treatment components in outpatient participants were investigated using LASSO and logistic regression. ResultsSelf-referred participants were more adherent than outpatient participants, however the groups did not differ significantly in outcome. Outpatient participants who adhered to relaxation showed greater improvement during the waiting period than the matched outpatient waitlist sample. The effect of participant group on outcome was mediated via adherence to exposure and number of sessions. ConclusionsIn internet interventions adherence to treatment components differs between participant groups and has a mediating effect on treatment outcome. Therefore, it should be fostered, especially when participants are not self-referred. In line with these findings more studies should investigate relevant participant characteristics in more depth.

Cardiac risk assessment based on early Phase I data and PK-QTc analysis is concordant with the outcome of thorough QTc trials: an assessment based on eleven drug candidates.

Cardiac safety assessment is a key regulatory requirement for almost all new drugs. Until recently, one evaluation aspect was via a specifically designated, expensive, and resource intensive thorough QTc study, and a by-time-point analysis using an intersection-union test (IUT). ICH E14 Q&A (R3) (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_Q_As_R3__Step4.pdf) allows for analysis of the PK-QTc relationship using early Phase I data to assess QTc liability. In this paper, we compared the cardiac risk assessment based on the early Phase I analysis with that from a thorough QTc study across eleven drug candidate programs, and demonstrate that the conclusions are largely the same. The early Phase I analysis is based upon a linear mixed effect model with known covariance structure (Dosne et al. in Stat Med 36(24):3844-3857, 2017). The treatment effect was evaluated at the supratherapeutic Cmax as observed in the thorough QTc study using a non-parametric bootstrap analysis to generate 90% confidence intervals for the treatment effect, and implementation of the standardized methodology in R and SAS software yielded consistent results. The risk assessment based on the concentration-response analysis on the early Phase I data was concordant with that based on the standard analysis of the thorough QTc study for nine out of the eleven drug candidates. This retrospective analysis is consistent with and supportive of the conclusion of a previous prospective analysis by Darpo et al. (Clin Pharmacol Ther 97(4):326-335, 2015) to evaluate whether C-QTc analysis can detect QTc effects in a small study with healthy subjects.

Cost-effectiveness of an intervention to reduce fear of cancer recurrence: The ConquerFear randomized controlled trial.

Alongside a randomized controlled trial (RCT) evaluating the efficacy of the ConquerFear intervention for reducing fear of cancer recurrence in cancer survivors, the cost-effectiveness of this novel intervention was assessed, primarily from the health sector perspective, with broader societal productivity impacts assessed. Health care resource use was collected by a tailored cost diary. Incremental costs were calculated as the difference in total costs between the intervention and control groups. Incremental cost-effectiveness ratios (ICERs) were estimated by cost-effectiveness and cost-utility analyses, comparing incremental costs with incremental outcomes measured. Nonparametric bootstrap analysis was performed to evaluate uncertainty in costs and outcomes. Cancer survivors were randomized into ConquerFear (n=121), or an active control group receiving relaxation training (n=101). Participants received on average 3.69 sessions, incurring an average cost of $297 per person, with no group difference. The ITT analysis results indicated a mean ICER $34300 per quality-adjusted life year (QALY) with average incremental cost $488 and health gain of 0.0142 QALYs, from the health care sector perspective. Bootstrap analysis showed 30% of iterations were dominant and overall 53% ICERs were cost-effective as judged by the commonly used $50000/QALY threshold. The ConquerFear intervention is associated with a modest cost and may provide good value for money, but further evidence is needed. Long-term cost-effectiveness needs further investigation to capture full benefits from the intervention beyond the trial follow-up.

Fenugreek Saponins Lower HOMA‐IR Estimate in Insulin‐Resistant Subjects: A Randomized, Placebo‐Controlled, Study

BackgroundType 2 Diabetes Mellitus (T2DM) is growing at epidemic proportions worldwide. Insulin resistance, defined as an impaired responsiveness of the body to insulin, is a pre‐diabetic stage in the transition from obesity to full‐blown diabetes. Recent studies from our lab demonstrated that furostanolic saponins (FS) isolated from the spice fenugreek improved glucose tolerance and reduced hepatic steatosis in high‐fat diet‐fed, obese mice.ObjectiveThe objective of this study was to evaluate the effect of supplementation of fenugreek FS on cardiometabolic parameters in insulin resistant, obese subjects.MethodsThis was a single center, double‐blind, randomized, placebo‐controlled, parallel‐arm, pilot study in overweight/obese (body mass index&gt;25Kg/m2) young (mean age 27.1±6.1y), otherwise healthy, male and female subjects who satisfied any two of the following three inclusion criteria: i) hemoglobin A1c &gt;5.6% ii) a two‐hour post‐glucose challenge blood‐glucose level &gt; 125 mg/dL and iii) Homeostatic Model Assessment‐insulin resistance (HOMA‐IR) value of &gt;2.5 (fasting insulin (microU/L) x fasting glucose (nmol/L)/22.5). Following informed consent, health‐screening and satisfaction of the inclusion/exclusion criterial, 28‐participants were randomly assigned to receive either placebo (microcrystalline cellulose) or FS (500 mg twice daily) capsules for a period of 12‐weeks. Anthropometric measurements, blood pressure, fasting blood glucose, fasting serum insulin, hemoglobin A1c, lipids, ALT, AST, C‐reactive proteins were determined at baseline and following 12‐week intervention. Body fat composition was determined by dual energy X‐ray absorptiometry. Serum cytokine levels were determined by a Bio‐Plex Pro Human Cytokine 8‐Plex assay. Data were analyzed by a nonparametric bootstrap analysis and the difference of simulated data from treatment and placebo were compared to test for significance. All runs were included in the calculation of 95% confidence interval.ResultsOf the 28 recruited, 25 subjects completed the study. No adverse events were reported, except for one subject who dropped form the study complaining of mild stomach discomfort. No changes were observed between pre‐ and post‐intervention in mean body mass, systolic or diastolic blood pressure, fasting glucose, hemoglobin A1c, lipid‐panel, serum transaminases, and cytokine levels in subjects receiving either the placebo or FS. In contrast, a significant reduction in HOMA‐IR was observed in subjects who received FS compared to those who received the placebo. Additionally, a trend towards lowering of serum insulin levels was observed in the group that received FS.ConclusionTwelve‐week supplementation with fenugreek saponins resulted in reduction in markers of insulin resistance in obese, insulin‐resistant subjects, warranting future studies with FS in overt‐diabetic subjects.Support or Funding InformationSupported by the NIH through the National Institute of General Medical Sciences (NIGMS) #1U54GM104944‐01A1 under the Institutional Development Award (IDeA) program.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Population Pharmacokinetics and Dosing Optimization of Linezolid in Pediatric Patients.

Linezolid is a synthetic antibiotic very effective in the treatment of infections caused by Gram-positive pathogens. Although the clinical application of linezolid in children has increased progressively, data on linezolid pharmacokinetics in pediatric patients are very limited. The aim of this study was to develop a population pharmacokinetic model for linezolid in children and optimize the dosing strategy in order to improve therapeutic efficacy. We performed a prospective pharmacokinetic study of pediatric patients aged 0 to 12 years. The population pharmacokinetic model was developed using the NONMEM program. Goodness-of-fit plots, nonparametric bootstrap analysis, normalized prediction distribution errors, and a visual predictive check were employed to evaluate the final model. The dosing regimen was optimized based on the final model. The pharmacokinetic data from 112 pediatric patients ages 0.03 to 11.9 years were analyzed. The pharmacokinetics could best be described by a one-compartment model with first-order elimination along with body weight and the estimated glomerular filtration rate as significant covariates. Simulations demonstrated that the currently approved dosage of 10 mg/kg of body weight every 8 h (q8h) would lead to a high risk of underdosing for children in the presence of bacteria with MICs of ≥2 mg/liter. To reach the pharmacokinetic target, an elevated dosage of 15 or 20 mg/kg q8h may be required for them. The population pharmacokinetics of linezolid were characterized in pediatric patients, and simulations provide an evidence-based approach for linezolid dosage individualization.