Related Endpoints Research Articles

Pore-scale numerical modeling of coupled fluid flow and medium geometrical deformations in an unconsolidated porous medium

The interplay of fluid flow and medium grains' deformation/movement in unconsolidated porous media was numerically studied. The numerical simulations were done through coupling Cahn-Hilliard phase field and Navier-Stokes equations for fluid flow as well as stress-strain and Arbitrary Lagrangian/Eulerian mesh alteration equations for geomechanical effects, by the finite-element method. Single/two-phase flow through a real patterned micro-scale medium with/without grains' deformation and movements/rotation were studied. In single-phase models, the fluid velocity distribution was quite similar for the cases with rigid grains and that with only deformed grains. However, in an unconsolidated medium, the velocity magnitude and distribution were modified. The medium porosity had a linear trend with pressure, and was independent of the grains' movement/rotation. The models with deformed grains showed good agreement with Kozeny-Carman equation in permeability variation versus pressure. In the two-phase flow models, the velocity/displacement profiles, relative permeability end-points and capillary pressure were quantitatively compared in rigid and unconsolidated media versus medium wettability. The effect of the grains' deformation on the fluid distributions was negligible at low capillary numbers, especially in water-wet and neutral wetting conditions. However, the grains' movement/rotation considerably modified the flow regime at different grains' contact angles. At higher capillary numbers, the grains' deformation effect was more pronounced.

Numerical modeling of strongly coupled microscale multiphase flow and solid deformation

SummaryWhen fluid flows in porous media under subsurface conditions, significant deformation can occur. Such deformation is dependent on structural and phase characteristics. In this paper, we investigate the effect of multiphase flow on the deformation of porous media at the pore scale by implementing a strongly coupled partitioned solver discretized with finite volume (FV) technique. Specifically, the role of capillary forces on grain deformation in porous media is investigated. The fluid and solid subdomains are meshed using unstructured independent grids. The model is applied for solving multiphase coupled equations and is capable of capturing pore scale physics during primary drainage by solving the Navier‐Stokes equation and advecting fluid indicator function using volume of fluid (VOF) while the fluid is interacting with a nonlinear elastic solid matrix. The convergence of the coupled solver is accelerated by Aitken underrelaxation. We also reproduce geomechanical stress conditions, at the pore scale, by applying uniaxial stress on the solid while simultaneously solving the multiphase fluid‐solid interaction problem to investigate the effect of external stress on fluid occupancy, velocity‐field distribution, and relative permeability. We observe that the solid matrix exhibits elasto‐capillary behavior during the drainage sequence. Relative permeability endpoints are shifted on the basis of the external stress exerted.

CD34+ Cell Dose Influences Survival after Allogeneic Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide

Introduction: Higher infused total nucleated cell dose (TNC) in allogeneic bone marrow transplant (BMT) with post-transplant cyclophosphamide (PTCy) resulted in improved overall survival (OS) in a recent report (McCurdy, et al. BBMT. 2018). As many centers prefer peripheral blood stem cell grafts (PBSCT) with PTCy, the optimal cell dose with this platform requires elucidation. Methods: We retrospectively evaluated 144 consecutive adult patients with hematologic malignancies treated at the Moffitt Cancer Center between 2012-2018 with allogeneic T-cell replete PBSCT followed by PTCy-based graft-versus-host disease (GVHD) prophylaxis. Data were extracted from the Moffitt BMT Research & Analysis Information Network (BRAIN) database. Both myeloablative (n=87) and reduced intensity (n=57) conditioning regimens were included. For analyses, CD34+ cell dose was stratified into low (<5 x106/kg), intermediate (5-10 x 106/kg) and high (>10x106/kg). TNC was stratified as higher or lower than the median. CD3+ T cell dose was evaluated as a continuous, linear variable. Associations with transplant related survival outcomes were assessed using univariate and multivariate Cox proportional hazard survival models. Fine and Gray regression models were used to assess associations of transplant related endpoints with competing risks. Kaplan Meier curves and cumulative incidence function curves were also plotted. RESULTS: The median follow-up for the entire cohort was 24 months. The median age at PBSCT was 58 (range: 21-76) years. Donors were haploidentical (n=72, 50%), matched unrelated (n=39, 27%), matched related (n=18, 13%), and mismatched unrelated (n=15, 10%). Median CD34+ cell dose was 8.12 x 106/kg (range: 2.27 - 22.4 x 106/kg). Stratified CD34+ dose was low for 16 patients (11.1%), intermediate for 93 patients (64.6%), and high for 35 patients (24.3%). Median CD3+ dose was 2.89 x 108 (range: 2.33 x 105 - 6.54 x 108/kg). Median TNC was 9.66 x 108/kg (range: 3.82 x 108 - 1.04 x 109/kg). Overall, successful neutrophil engraftment by day 30 was achieved in 94% (95% CI 91-98%) and platelet engraftment (>20,000/mL) by day 100 in 87% (95% CI 81-93%) of all patients. The likelihood of neutrophil recovery was similar in the high and low CD34+ cell groups, while it was higher for the intermediate CD34+ cell group (HR=1.52, 95% CI 1.0-2.2; p=0.03). Platelet recovery was similar in the intermediate and high CD34+ cell groups, but significantly lower in low CD34+ cell group (HR=0.38, 95% CI 0.2-0.8; p=0.01). CuI of grade II-IV acute GVHD at day 100 was 39% (95% CI 32-48%) and of grade III-IV acute GVHD was 10% (95% CI 6-17%). CuI of chronic GVHD at 2 years was 50% (95% CI 41-59%). The CD34+ cell dose had no significant impact on either acute or chronic GVHD. Nonrelapse mortality (NRM) at 1 year was 19% (95% CI 13-27%). By CD34+ cell dose, the rates of NRM for low, intermediate, and high dose were 46% (95% CI 25-85%), 15% (95% CI 10-25%), and 15% (95% CI 7-34%), respectively (p=0.002). Relapse rate was 30% at 2 years with no differences across dose levels. Progression free survival (PFS) probability at 2 years was 47% (95% CI 39-57%) for the entire group, 0% (95% CI 0%) for the CD34+ low group, 53% (95% CI 42-65%) for the intermediate group and 51% (95% CI 35-73%) for the high dose group (p=0.0003). Two-year OS for the entire group was 57% (95% CI 49-67%), and was inferior in the low group (0%, 95% CI 0%) with no difference between the intermediate (61%, 95% CI 50-73%) and high (67%, 95% CI 52-87%) CD34+ cell dose groups (p=0.0002). In multivariable modeling, the low CD34+ cell dose group was associated with worse NRM (HR=4.1, 95% CI 1.2-14.5, p=0.03), PFS (HR=2.9, 95% CI 1.3-6.5, p=0.01), and OS (HR=3.2, 95% CI 1.4-7.6, p=0.01) compared with the high group, while there were no differences between the high and intermediate groups. Increasing CD3+ dose was also associated with improved NRM (HR=0.8, 95% CI 0.69-0.97, p=0.02), PFS (HR=0.7, 95% CI 0.5-0.9, p=0.02), and OS (HR=0.7, 95% CI 0.5-0.9, p=0.004). TNC had no impact on survival outcomes. CONCLUSION: In patients receiving allogeneic PBSCT with PTCy, CD34+ cell doses below 5 x 106 cells/kg yielded inferior OS and PFS, attributable to higher NRM. Doses of 5-10 x 106 cells/kg and >10 x 106 cells/kg resulted in comparable outcomes. Higher CD3+ dose/kg was also associated with improved survival outcomes. Overall, this study supports targeting a CD34+ dose of >5 x 106 cells/kg for allogeneic PBSCT with PTCy. Disclosures Nishihori: Novartis: Research Funding; Karyopharm: Research Funding. Bejanyan:Kiadis Pharma: Other: advisory board.

P797Association of office and ambulatory blood pressure with mortality and cardiovascular endpoints

Abstract Background Blood pressure (BP) is the strongest modifiable risk factor predicting death and cardiovascular complications. However, which BP index has greater clinical relevance is not established. Purpose To compare associations of adverse health outcomes with commonly used BP indexes. Methods Longitudinal population-based cohort study of 11,135 adults recruited in Europe, Asia and South America with baseline observations collected from 1985 until 2010 and last follow-up year ranging from 2006 to 2016. Multivariable-adjusted analyses addressed the associations of primary endpoints (total mortality and composite CV endpoints) and secondary endpoints (CV mortality, cardiac and coronary endpoints and stroke) with conventional BP, automated office BP and ambulatory BP indexes. Model performance was assessed by the integrated discrimination improvement (IDI) and change in the area under the curve (ΔAUC). Results The study included 49.3% women. Median age was 54.7 years. Over 13.8 years (median), 2836 participants died (18.5 per 1000 person-years) and 2049 (13.4 per 1000 person-years) experienced a cardiovascular endpoint. Both endpoints were related to all single systolic BP (SBP) indexes (P<0.001). In models that included both 24-h and nighttime SBP, the HRs for total mortality and the cardiovascular endpoint in relation to 24-h SBP were 0.98 (95% confidence interval, 0.92–1.06) and 1.17 (1.08–1.28) and HRs associated with nighttime SBP were 1.18 (1.11–1.27) and 1.12 (1.04–1.21), respectively. Otherwise, depending on the SBP index combined with 24-h or nighttime SBP, HRs for both endpoints associated with 24-h or nighttime SBP retained significance (P≤0.004), ranging from 1.12 (1.07–1.17) to 1.56 (1.41–1.74). In models that included either 24-h or nighttime SBP, HRs associated with other SBP indexes weakened, lost significance or reversed. IDI and ΔAUC for adding 24-h or nighttime SBP to other SBP indexes were consistently greater than unity except for combining 24-h and nighttime SBP. These findings were consistent for secondary endpoints, for systolic and diastolic BP, and in sensitivity analyses performed to evaluate the influence of antihypertensive drug treatment at baseline, various definitions of day and night, and the contribution of different cohorts to the overall results. Conclusions Associations of outcomes were strongest for 24-h and nighttime ambulatory BP, which outperformed all other BP indexes in predicting 10-year absolute risk and which should therefore be prioritised in clinical practice. Acknowledgement/Funding The European Union, the European Research Council, the European Research Area Net for Cardiovascular Diseases, et al.

1578P - Does progress achieved in the treatment of patients with metastatic non-small cell lung cancer (NSCLC) reach the elderly population?

BackgroundAlthough treatment modalities for non-small cell lung cancer (NSCLC) are rapidly evolving, there is insufficient evidence that novel drugs reach elderly patients (aged ≥ 70 years) and improve their outcomes. The purpose of this study was to evaluate the access to treatment in the elderly population with stage IV NSCLC in a real life setting and its impact on survival (OS) over the past 10 years. MethodsWe compared elderly and younger patients with stage IV NSCLC treated at our tertiary cancer centre and its affiliated smaller hospitals. We collected patients and tumor characteristics such as age at diagnosis, gender, smoking history, histology, molecular subtyping, PDL1 expression status and data on treatment types as well as lines. We grouped the enrolled patients into four same size cohorts based on time and age at diagnosis: patients diagnosed 2005-2007 (elderly cohort-I) and 2015-2016 (elderly cohort-II) were compared to cohorts of patients <70 years old diagnosed during the same time periods (young cohorts-I and -II). The characteristics were analysed using Chi-square Test and survival related endpoints with Kaplan-Meier model. A log-rank test was used to test the equality of the survivor functions and a z-Test to assess the differences in survival proportions. Results499 NSCLC cases were retrospectively analysed. Median OS significantly improved in both, the elderly and the young cohorts, over time. OS in the elderly cohort-I and -II was slightly lower (3.7 months and 5.3 months) compared to the young cohorts-I and -II (7.8 and 12.1 months). In the young group 12-months OS was significantly improved over the last 10 years (34% [95%CI 27%-42%] and 52% [95%CI 43%-61%], p=0.049). There was no significant improvement in the elderly cohorts (18% [95%CI 11%-25% vs. 31% [95%CI 22%-39%], p=0.29). Therapy with any line of systemic treatment modalities remained lower in the elderly cohorts as compared to younger patients (53% versus 78%). ConclusionsWe observed a significant improvement in OS over the past 10 years in young patients, whereas a similar benefit was not found for the elderly. Our findings highlight a strong need in studying this growing population separately in elderly specific clinical trials. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureS. Schmidt: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: MSD; Research grant / Funding (institution): BMS; Research grant / Funding (institution): AstraZeneca; Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: TAKEDA; Travel / Accommodation / Expenses: Boehringer Ingelheim. M. Fruh: Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Roche; Advisory / Consultancy: Takeda. All other authors have declared no conflicts of interest.

LightGBM: An Effective and Scalable Algorithm for Prediction of Chemical Toxicity-Application to the Tox21 and Mutagenicity Data Sets.

Machine learning algorithms have attained widespread use in assessing the potential toxicities of pharmaceuticals and industrial chemicals because of their faster speed and lower cost compared to experimental bioassays. Gradient boosting is an effective algorithm that often achieves high predictivity, but historically the relative long computational time limited its applications in predicting large compound libraries or developing in silico predictive models that require frequent retraining. LightGBM, a recent improvement of the gradient boosting algorithm, inherited its high predictivity but resolved its scalability and long computational time by adopting a leaf-wise tree growth strategy and introducing novel techniques. In this study, we compared the predictive performance and the computational time of LightGBM to deep neural networks, random forests, support vector machines, and XGBoost. All algorithms were rigorously evaluated on publicly available Tox21 and mutagenicity data sets using a Bayesian optimization integrated nested 10-fold cross-validation scheme that performs hyperparameter optimization while examining model generalizability and transferability to new data. The evaluation results demonstrated that LightGBM is an effective and highly scalable algorithm offering the best predictive performance while consuming significantly shorter computational time than the other investigated algorithms across all Tox21 and mutagenicity data sets. We recommend LightGBM for applications of in silico safety assessment and also other areas of cheminformatics to fulfill the ever-growing demand for accurate and rapid prediction of various toxicity or activity related end points of large compound libraries present in the pharmaceutical and chemical industry.

Dietary reference values for sodium.

Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) derived dietary reference values (DRVs) for sodium. Evidence from balance studies on sodium and on the relationship between sodium intake and health outcomes, in particular cardiovascular disease (CVD)‐related endpoints and bone health, was reviewed. The data were not sufficient to enable an average requirement (AR) or population reference intake (PRI) to be derived. However, by integrating the available evidence and associated uncertainties, the Panel considers that a sodium intake of 2.0 g/day represents a level of sodium for which there is sufficient confidence in a reduced risk of CVD in the general adult population. In addition, a sodium intake of 2.0 g/day is likely to allow most of the general adult population to maintain sodium balance. Therefore, the Panel considers that 2.0 g sodium/day is a safe and adequate intake for the general EU population of adults. The same value applies to pregnant and lactating women. Sodium intakes that are considered safe and adequate for children are extrapolated from the value for adults, adjusting for their respective energy requirement and including a growth factor, and are as follows: 1.1 g/day for children aged 1–3 years, 1.3 g/day for children aged 4–6 years, 1.7 g/day for children aged 7–10 years and 2.0 g/day for children aged 11–17 years, respectively. For infants aged 7–11 months, an Adequate Intake (AI) of 0.2 g/day is proposed based on upwards extrapolation of the estimated sodium intake in exclusively breast‐fed infants aged 0–6 months.

Diets containing naturally occurring iron or naturally occurring iron plus supplemental ferrous sulfate both maintain normal hematological status in adult dogs

Iron is an essential mineral for dogs due to its roles in physiological processes. The NRC recommends the adequate intake for iron in adult dogs is 0.5 mg/kg of body weight. While iron should be present in high enough concentrations in the diet to maintain normal hematological status and prevent iron deficiency anemia, too much dietary iron can increase lipid oxidation in the food during preparation and storage, subsequently reducing shelf life, palatability, and nutritional content of foods. In general, iron is supplemented to diets to ensure that no dogs are deficient. The primary objective of this study was to investigate the ability of a diet containing either 0 mg/kg or 80 mg/kg supplemental iron to support normal hematological parameters in adult dogs. Twenty-two adult dogs were randomly assigned to one of two treatment diets: Test Diet 1, Experimental maintenance formula with 115 mg/kg endogenous iron + 0 mg/kg supplemental iron; and Test Diet 2, Experimental maintenance formula with 115 mg/kg endogenous iron + 80 mg/kg supplemental iron (ferrous sulfate). Dogs consumed treatment diets for 26 weeks, with clinical assessments (e.g., hemoglobin concentration/total iron binding capacity) assessed throughout the trial (0, 2, 4, and 6 months). Baseline iron related endpoints were not different between diet treatments (P &gt; 0.50), except for mean corpuscular hemoglobin concentrations (P = 0.046). No differences were found for iron related end points between the two diet treatments (P&gt;0.05) at any time point. In some diets no supplemental iron will be needed, based on the diet matrix, whereas others may require some supplemental iron. By reducing iron inclusion in the formulations of canine diets, food stability and shelf life may be improved. This reduction in supplemental iron can also reduce cost of formulation, benefiting food manufacturers, consumers, and adult dogs.

Condensate blockage remediation in a gas reservoir through wettability alteration using natural CaCO3 nanoparticles

Wettability alteration of near-wellbore region from liquid-wetting to gas-wetting has been known as a feasible method for eliminating condensate blockage in gas condensate reservoirs. In this research, the natural CaCO3 (Bio-Ca) nanoparticles containing chitin were used as environmentally friendly and cost-effective agents which can act as nanocomposite for wettability alteration. For this purpose, their performance was evaluated on wettability alteration of the gas/oil systems by conducting contact angle measurements and sand pack flooding tests. In addition, for evaluating the stability of nanofluids, zeta potential measurement was conducted. The Bio-Ca nanoparticles were produced using cuttlebone (Sepia Pharaonis) taken from the Persian Gulf. Also, silica nanoparticle was used as a scale for comparison of its performance with the newly synthesized nanoparticle. Four influencing factors including nanofluid concentration, gas flow rate, oil type, and nanoparticle type were investigated and the optimum conditions for improving oil recovery and gas/oil relative permeabilities were also obtained using Taguchi method. The values of zeta potential implied that both nanofluids are stable at the given pH. The results of the contact angle measurement indicated that the contact angles of condensate droplet raised from 0° to 105° after treating the rock surface by Bio-Ca nanofluid with a concentration of 0.05 wt. %. This is happened because of the increase in roughness with reduction of surface free energy of rock surface along with disjointing pressure mechanism. Analysis of variance showed the importance of considering the simultaneous effect of these parameters on oil recovery and relative permeabilities for wettability alteration purposes. Results show that the optimum conditions for increasing oil recovery using Bio-Ca nanoparticles include the nanofluid concentration of 0.05 wt. %, using normal heptane as a liquid phase, and a gas flow rate of 100 cc/min. Besides, for gas and oil relative permeability endpoints as a second response parameter, the most effective parameter is gas flow rate of 55 cc/min. Results of this work are confirmed that the Bio-Ca nanoparticles play a vital role in wettability alteration, which can alter the wettability of the medium from strongly oleophilic to oleophobic due to their biostructure.

Randomized controlled trials of pharmacological treatments to prevent COPD exacerbations: applicability to real-life patients

BackgroundIn patients with chronic obstructive pulmonary disease, all efforts should be made to prevent exacerbations because each event modifies the trajectory of the disease. Treatment recommendations are mostly built on results from randomized controlled trials (RCTs) whose methodology ensure internal validity. However, their relevance may be compromised by the lack of generalizability, due to poor representability of study populations compared to real-life patients.In order to delimit to whom the results of studies on current and future treatments apply, we sought to identify and characterize the fraction of COPD population that would be eligible for inclusion into RCTs aiming at decreasing exacerbation risk.MethodsWe used the Initiatives-BPCO database, a French cohort of 1309 real-life COPD patients monitored in academic centers. We identified industry-sponsored phase III and IV trials that enrolled more than 500 patients, lasted at least one year and used exacerbations related endpoints. Eligibility criteria were extracted from each trial and applied to the patients.ResultsThe eligibility criteria of 16 RCTs were applied to the 1309 patients. The most discriminating eligibility criteria were FEV1, minimum exacerbation rate in the previous year and smoking history, responsible for the exclusion of 39.9, 36.7 and 16.8% of patients, respectively. Altogether, 2.3 to 46.7% of our patients would have satisfied all eligibility criteria.ConclusionThese analyses confirm that an important gap exists between real-life patients and clinical trials populations in COPD, which limits the relevance of results and therefore should be considered when grading levels of evidence and designing future studies.

Protein binding kinetics quantification via coupled plasmonic-photonic resonance nanosensors in generic microplate reader

Almost no analytical assays, either colorimetric or fluorescence assays, for generic microplate readers is capable of dynamic measurements of protein-protein binding or the quantification of kinetic association and dissociation constants of protein interactions. On the other hand, protein binding kinetics quantification can be uniquely done on special expensive surface plasmon resonance (SPR) sensing equipment. Here we report the integration of coupled plasmonic-photonic resonance nanosensors in standard 96-well plate format and by using which, for the very first time, the demonstration of label-free dynamic SPR-like protein binding measurement and kinetics quantification in a generic microplate reader. Our low-cost label-free nanosensor plate enables very sensitive detection of immobilized protein interactions based on the transmission optical density (OD) value changes at specific wavelengths measured in a generic microplate reader. The relative end-point OD value changes show a good linear response with protein concentrations (from 0.05 to 50 μg/ml). And the protein quantification in serum results are consistent with the concurrent hospital lab tests. Most importantly, the kinetic association and dissociation constants of protein interactions in our sensor plate wells are determined by time-lapse dynamic OD value measurement in the generic microplate reader. Enabled by our unique nanosensor plate, SPR-like measurement of protein binding kinetics is now available using generic microplate reader ubiquitous in many chemistry and biomedical research labs.

Characterization of multiple biomarker responses using flow cytometry to improve environmental hazard assessment with the green microalgae Raphidocelis subcapitata

Microalgal toxicity tests using integrative endpoints as algal growth are regularly required to analyse the toxicity of potentially hazardous substances in the aquatic environment. However, these do not provide mechanistic information on the toxic mode of action by which contaminants may affect algae. Bottled waters can be used as a substitute for culturing media and should not impose any stress to the cultured organisms. However, certain chemical components can interfere with specific cell targets which are not revealed by general toxicity assays. The present study investigated the sensitivity of flow cytometry (FCM) to analyse sub-lethal effects of different bottled waters to the freshwater microalgae Raphidocelis subcapitata. Several endpoints were analysed including growth rate, natural pigments content, cell size, complexity, viability and cycle, Reactive Oxygen Species (ROS) formation, mitochondrial membrane potential and Lipid Peroxidation (LPO). Additionally, photosystem II (PSII) performance was analysed by PAM fluorometry, to provide further information on the absorption, distribution and use of energy in photosynthesis. Results indicated that the most sensitive endpoints were the oxidative stress related endpoints ROS formation and LPO, pigment content, morphological endpoints as cell size, complexity and cycle, with growth rate being one of the least sensitive. Although being essential macronutrients for algal growth, the chemical elements Ca, Na, Mg, and NH4 were identified as being primarily responsible for the observed toxicological effects to exposed algae. The applied methodology proved to be of high throughput, simultaneously assembling information on morphological, biochemical, and physiological status of algal cells. FCM also showed potential to reveal mechanistic information on the toxic mode of action of the bottled waters before any effects on algal growth was observed. The used approach demonstrated its potential for being integrated into future microalgal toxicity bioassays for testing chemicals to improve the hazard information obtained from currently approved internationally accepted test guidelines.

A study protocol for the N-ICE trial: A randomised double-blind placebo-controlled study of the safety and efficacy of N-acetyl-cysteine (NAC) as a pharmacotherapy for methamphetamine (\u201cice\u201d) dependence

BackgroundThere are currently no approved pharmacotherapies for managing methamphetamine dependence. N-acetylcysteine (NAC) has been found to reduce the craving for methamphetamine and other drugs, but its effect on methamphetamine use and other clinically related endpoints are uncertain. The N-ICE trial is evaluating the safety and efficacy of NAC as a take-home pharmacotherapy for methamphetamine dependence.Methods/designThis is a two-arm parallel double-blind placebo-controlled three-site randomised trial (ratio 1:1) using permuted block randomisation, with variable block sizes. It is stratified by site, sex and whether the methamphetamine is injected or not. Participants (N = 180; 60 per site) need to be dependent on methamphetamine, interested in reducing their methamphetamine use and not currently receiving treatment for substance use disorders. The trial is being conducted in outpatient settings in Melbourne, Geelong and Wollongong, Australia. Participants will receive either 2400 mg oral NAC or a matched placebo, delivered as a take-home medication for 12 weeks. Two 600 mg capsules are self-administered in the morning and two more in the evening. Adherence is being monitored using eCAP™ medication bottle lids, which record the date and time of each occasion the bottle is opened. The primary outcome is methamphetamine use during the 12-week trial medication period, measured as (a) days of use, assessed using the timeline followback, and (b) methamphetamine-positive saliva tests, taken weekly. Secondary measures include weekly assessment of methamphetamine craving, severity of methamphetamine dependence, methamphetamine withdrawal symptoms and psychiatric symptoms (depression, suicidality, psychotic symptoms and hostility). Adverse events are monitored at each weekly assessment. Tolerability is assessed using the Treatment Satisfaction Questionnaire for Medication.DiscussionThe N-ICE trial is the first clinical trial to assess whether NAC can reduce methamphetamine use. This trial will improve our understanding of the potential utility of NAC in managing methamphetamine dependence and clinically related outcomes. If found to be effective, take-home NAC could be a potentially scalable and affordable pharmacotherapy option for treating methamphetamine dependence.Trial registrationAustralian and New Zealand Clinical Trials Registry, ACTRN12618000366257. Registered on 29 May 2018.

455-P: Levels of Plasma Prekallikrein Predict Myocardial Infarction in Non-Hispanic White Participants of the Veterans Affairs Diabetes Trial (VADT)

We hypothesize in diabetes that augmented activity of the plasma kallikrein-kinin system reflect and contribute to vascular damage and inflammations. Our objective was to determine the role of plasma PK as a predictor of cardiovascular events in type 2 diabetes in the VADT cohort. Levels of plasma total prekallikrein (PK) were measured in 604 VADT patients, a median of 1.5 years after entry into the study. Participants were followed an average of 4.1 years. Hazard ratios (HRs) for CV endpoints in relation to PK tertiles and having a non-zero versus zero value for plasma active kallikrein (PAK) were calculated by Cox proportional hazard models. During follow-up, 4.9% had an MI and 7.4% had an MI or cardiovascular death. Because there was evidence that minority status modified the associations between PK and outcomes of interest, but there was very limited power in minorities, results are presented in the total population adjusting for minority status and limited to the non-Hispanic white (NHW) population (Table). After adjustments by conventional risk factors, in NHW individuals the hazard ratio comparing the middle to lowest tertile of PK levels was 3.94 (95% CI: 1.09, 14.2) for MI and 3.45 (95% CI: 1.25, 9.48) for MI combined with cardiovascular death. Our study indicates that plasma PK levels predict MI and cardiovascular death in NHW patients with type 2 diabetes. Disclosure K.J. Hunt: None. M.A. Jaffa: None. M. Sohn: None. M.F. Lopes-Virella: None. A.A. Jaffa: None. Funding National Heart, Lung, and Blood Institute

Randomized phase II CLIO study on olaparib monotherapy versus chemotherapy in platinum-resistant ovarian cancer.

5507 Background: The CLIO trial (NCT02822157) evaluated olaparib single-agent therapy versus standard of care chemotherapy in platinum-resistant (recurrence within 6 months after last platin) ovarian cancer (PROC). Methods: Eligible patients with measurable disease and ≥1 prior line of chemotherapy were randomized 2:1 to Olaparib (OLA) monotherapy (300 mg tablets, BID) or physician’s choice chemotherapy (CT; PLD 40 mg/m2 q 4 wks; Topotecan 1.25 mg/m2 day 1—5 q 3 wks; Paclitaxel 80 mg/m2 day 1, 8,15 q 3 wks; Gemcitabine 1000 mg/m2 day 1, 8 and 15 q 4 wks). Primary endpoint was objective overall response (ORR) per RECIST v1.1. Germline BRCA status was available for all patients. Disease control rate (DCR) was defined as response for at least 12 wks. Results: 100 patients with PROC were randomized 2:1 to OLA (N = 67) or CT (N = 33). Median prior lines of treatment was 3 (range: 1—8). ORR (unconfirmed) was 18% (12/67) for OLA and 6% (2/33) for CT. ORR for OLA was 38% (5/13) in gBRCAm and 13% (7/54) in gBRCAwt patients. Of note, 2 patients with gBRIP1 mutation had no response under OLA. DCR was 35.8% (24/67) for OLA and 42% (14/33) for CT. DCR under OLA in gBRCAm was 62% (8/13) compared to 30% (16/54) in gBRCAwt disease. The median duration of response (DOR) and the median progression-free survival (PFS) was similar: 5.4 months vs 4.5 months (DOR) and 2.9 vs 3.4 months (PFS) for OLA and CT, respectively. Grade ≥3 treatment-related AEs occurred in 60% vs 52% for OLA and CT, respectively. Somatic HRR mutation analysis is ongoing and will be presented. Conclusions: Olaparib monotherapy showed a favorable response rate in PROC compared with chemotherapy also in gBRCAwt patients. Analysis of clinical endpoints in relation to HRR is ongoing and will be presented. Clinical trial information: NCT02822157.

Impact and influence of PET on imaging related endpoints in patients with Lymphoma using IWG-NHL or Lugano classification.

e19061 Background: Positron Emission Tomography (PET) scans were applied to lymphoma as early as in 1990s. Revised criteria for lymphoma assessment was published in 2007 by International Working Group (IWG). The criteria for PET into response assessment were added due to better sensitivity and superiority of PET over CT and its ability to distinguish between viable tumor and necrosis or fibrosis in residual mass after treatment. PET was primarily recommended for patients with FDG avid curable lymphomas such as Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma (DLBCL) and later for the post-treatment assessment of DLBCL and HL. The Lugano Classification 2014 regarded FDG PET/CT to be the standard for staging and assessment of all FDG-avid histologies. Methods: A retrospective review of 10 Lymphoma studies with a total of 1,537 subjects and 17,394 time points was carried out using PET in addition to CT as per imaging schedule. There were 5 clinical trials with a total of 1,169 subjects with 15,480 time points using IWG-NHL classification 2007 while 5 clinical trials with a total of 729 subjects and 1,914 time points using Lugano classification 2014. The number of subjects and time points with PET where PET had an impact on the overall assessment was calculated. Results: PET was available for a total of 1,159 subjects (out of 1,537) and 4,688 time points (out of 17,394) across all 10 studies. Out of 4,688 visits with PET, 956 (20.4%) visits had an impact on overall assessment due to additional metabolic findings. Out of 1,159 subjects with PET, 462 (39.9%) subjects had an impact on overall assessment and study endpoints due to additional uptake related findings. The impact across different studies was between 7% to 59% possibly due to difference in indication, line of therapy and blinded independent review design. The most common impact due to PET was related to complete response and disease progression. Conclusions: It can be concluded that PET significantly impacts assessments and imaging endpoints for lymphoma clinical trials using IWG-NHL classification or Lugano classification. Thus, addition of PET improves the outcome of the response not only in lymphoma treatment and diagnosis, but also clinical trial outcomes. [Table: see text]

Dynamics of HBV surface antigen related end points in chronic hepatitis B infection: a systematic review and meta-analysis.

In chronic hepatitis B (CHB) treatment, hepatitis B surface antigen (HBsAg) is regarded as a promising clinical end point associated with long-term clinical outcomes. We performed a meta-analysis to characterize the dynamics and influencing factors of HBsAg. Literature search was conducted through PubMed from January 1995 to May 2015 for papers reporting HBsAg in patients receiving various antiviral treatments. We conducted weighted linear regression to select for potential influencing factors on maximum HBsAg loss percentage, and subgroup analysis to calculate the pooled estimates of maximum HBsAg loss and seroconversion percentage following treatment of interferon (IFN), nucleoside analogue (NUC) or combination therapies (NUC+IFN), respectively. Study heterogeneity was assessed through sensitivity test and I-square statistics. We collected data from 24 papers involving 6,674 adult CHB patients. In most studies, average HBsAg level decreased during treatment but relapsed after treatment cessation, while HBsAg loss or seroconversion percentage continued to increase or remained stable after treatment cessation. No strong relationship was observed between maximum HBsAg change and its baseline level. The pooled estimates of maximum HBsAg loss percentage for IFN (5.3%, 2.7-7.9%) and NUC+IFN (5.2%, 3.1-7.4%) were significantly higher than that of NUC (0.93%, 0.29-1.6%). Higher maximum HBsAg loss percentage is associated with longer peak time. Pooled maximum HBsAg seroconversion percentage estimates were 1.6%, 0.56% and 6.2% for IFN, NUC and NUC+IFN. With respect to HBsAg lowering, this meta-analysis confirmed the importance of longer treatment duration and addition of IFN, which revealed the potential value of immune-based therapies.

MON-101 The LD Lync Study: Natural History Study of Lipodystrophy Syndromes: Early Lessons from the Pilot Data

Lipodystrophy syndromes are a heterogeneous cluster of rare diseases characterized by a paucity or abnormal distribution of fat which are also associated with insulin resistance and ectopic lipid deposition. Owing to the rarity of the syndromes, the natural history and exact evolution of clinical, and psychosocial aspects are largely unknown. In March, 2018 we launched a prospective data registry- the LD Lync. The registry will be expanded to multiple centers across the US to ensure maximum number of participants. Anticipated sample size is 500. The goal is to collect data on various aspects of lipodystrophy syndromes (LD) including demographic, morphometric, clinical, genetic, socioeconomic characteristics and novel patient related end points such as quality of life, hunger and pain scales, mood and anxiety, and eating habits. During the past 8 months, we initiated the pilot data collection at our center. As of this month, we collected data on 61 affected individuals (49F/12 M, mean±SD Age: 44±15, with 4 acquired generalized LD (AGL), 3 acquired partial LD (APL), 48 familial partial LD (FPLD), 1 congenital generalized LD (CGL), 5 atypical LD). The median (IQR) difference between symptoms onset and time of diagnosis was 14y (24). The prevalence (95%CI) of diabetes, hypertriglyceridemia, nonalcoholic fatty liver disease were 83% (71-92), 81% (69-90), and 78% (67-89) respectively. In terms of significant organ manifestations, 10% (95%CI:2-18) had myocardial infarction, 3% (0-8) had heart failure, 23% (14-35) had pancreatitis, and 8% (1-16) had malignancy. The (Median: IQR) age of diagnosis of these diseases was heterogeneous: diabetes 31y (26), hypercholesterolemia 27y (20), hypertriglyceridemia 25y (17), fatty liver disease 33y (31), and myocardial infarction 50y (16) . Out of 60 patients, 70% (58-82) are on lipid lowering drugs, 77% (66-87) on glucose lowering drugs, 37% (24-49) on hormones, and 68% (57-80) on anti-hypertensives. Out of the 61 who completed the GAD-7, IPAQ-2002, Modified 13 item binge eating scale, SF-36 scale, PHQ-9, and the perceived financial burden scale, 33% (95% CI, 21-45) had minimal anxiety, 28.3% (17-40) had mild anxiety, 20% (10-30) had moderate anxiety, and 18% (8-28) had severe anxiety. On quality of life, with 100% being the perfect score, our patients had low scores mean(95%CI): 37%(34-40) on emotional wellbeing, 49% (43-55) on social functioning, 55% (48-62) on pain level, and 32% (27-37) on general health. On the financial impact of lipodystrophy: 46% (33-58) reported moderate or higher levels of burden. We conclude that the lipodystrophy syndromes present with a large burden not only in terms of known medical complications but also in socioeconomic and psychosocial aspects of life. Expansion of this registry to include multiple sites in the US and across the globe will improve our understanding of all aspects of these diseases.

Long-Term Burden of Hemocompatibility Related Adverse Events in the MOMENTUM 3 Trial: Final Analysis of the 1028 Patient Cohort

Summary of Objectives The MOMENTUM 3 trial has demonstrated superiority of the centrifugal HeartMate 3 (HM3) device to the mechanical bearing axial HeartMate II (HMII) continuous-flow cardiac pump, in patients with advanced heart failure refractory to medical management. In this final analysis of the full trial cohort, we evaluate the net burden of hemocompatibility related adverse events between the two LVAS in the long-term and identified risk factors associated with the development of hemocompatibility related adverse events (HRAE's). Methods MOMENTUM 3 is a randomized controlled trial of the HM3 pump versus the HMII pump, irrespective of intended goal of support. This large adaptive trial is designed to have 3 prespecified end points of which the short term (n=294, 6-months) and long-term (n=366, 2-years) primary end points have been reported; we now present this analysis from the full of all 1028 randomized patients. To assess the aggregate of HRAEs, we evaluate the endpoint of 2-year survival free of any non-surgical bleeding, thromboembolic event, pump thrombosis or any neurological event. The net burden of HRAEs will be assessed using a previously defined and validated severity tiered hemocompatibility score, which separates clinical events into four escalating tiers of severity to derive a total score for HRAE events encountered during the entire experience for each patient to death, transplantation or study end. Furthermore, we will identify risk factors for the development of HRAEs. The analysis will be performed with the full cohort of MOMENTUM 3: n=1028 patients. The last patient completed 2 years of follow-up in August 2018; the data lock will be accomplished in November 2018 and final results will be analyzed and available by March 2019. Endpoints This will be the first comprehensive analysis of the long-term outcomes for an aggregate hemocompatibility related adverse endpoint and tiered severity score to evaluate the net burden of bleeding and thrombotic complications experienced by patients treated with either the HM3 or HMII LVAS in the pivotal MOMENTUM 3 trial. (Funded by Abbott; MOMENTUM 3 ClinicalTrials.gov number, NCT02224755.)

Multi-generational exposure to Pb in two monophyletic Daphnia species: Individual, functional and population related endpoints

To better evaluate chemical damage in chronically contaminated habitats, a nine-generational exposure to Lead (Pb) was done with two monophyletic Daphnia species, from temperate (Daphnia magna) and tropical (Daphnia similis) environments. The multi-generational test consisted generally of a continuous Pb exposed set of organisms, plus an extra control set running simultaneously. To assess daphnids recovery after Pb exposure, some organisms from the sixth generation were transferred to clean media for three extra generations (recovery period; F6 to F9), while others were keep Pb exposed. All setups (control, Pb exposure and recovery period) were submitted to two different dietary regimes, the standard (3 × 105 cells/mL) and restricted food (1.5 × 105 cells/mL) regimes. To evaluate the effects of generational Pb exposure and food regimes, individual, functional and population related endpoints were assessed (number of offspring, body length and rate of population increase (r) and feeding rate (FR)). The tests were conducted on the first (F0) and last generations (F9). No differences were shown on number of offspring and feeding among F9 control and continuous Pb exposed D. magna, although a higher r was shown for F9 Pb exposed organisms. F9 Pb exposed D. similis also presented a higher r than F9 control, however, lethality was induced at high Pb exposure levels. At food restriction the patterns were opposite and D. magna died at high Pb exposure while Pb exposed D. similis was the only setup (compared to control and recovery period) to survive at high Pb exposure levels. Regarding the recovery period, D. magna (standard food) did not cope well with the Pb re-exposure and lethality was induced, while D. similis indicate a decreased Pb sensitivity (only setup that survived high Pb exposure levels). Under food restriction, both species presented a decreased Pb sensitivity and consequent failed recovery (possibly due to epigenetic changes). Both species presented similar patterns regarding generations. Organisms from F0 presented enhanced reproductive outputs in comparison to F9 and the contrary occurred to the FR (even in control organisms). Data show an acclimation under a generational Pb exposure, which could increase the population of adapted organisms in natural habitats. And, since there was not a full recovery after three generations in clean media, an indication of epigenetic changes for both species may also be considered.