Journal articles: 'Mobile population and Disease-free Steady state' – Grafiati (2024)

Abstract:

The propagation of infectious diseases and its impact on individuals play a major role in disease dynamics, and it is important to incorporate population heterogeneity into efforts to study diseases. As a simplistic but illustrative example, we examine interactions between urban and rural populations on the dynamics of disease spreading. Using a compartmental framework of susceptible–infected susceptible (SIS) dynamics with some level of immunity, we formulate a model that allows non linear reinfection. We investigate the effects of population movement in a simple scenario: a case with two patches, which allows us to model population movement between urban and rural areas. To study the dynamics of the system, we compute a basic reproduction number for each population (urban and rural). We also compute steady states, determine the local stability of the disease-free steady state, and identify conditions for the existence of endemic steady states. From our analysis and computational experiments, we illustrate that population movement plays an important role in disease dynamics. In some cases, it can be rather beneficial, as it can enlarge the region of stability of a disease-free steady state.

Abstract:

We use a model to study the dynamics of malaria in the human and mosquito population to explain the stability patterns of malaria. The model results show that the disease-free equilibrium is globally asymptotically stable and occurs whenever the basic reproduction number,R0is less than unity. We also note that whenR0>1, the disease-free equilibrium is unstable and the endemic equilibrium is stable. Numerical simulations show that recoveries and temporary immunity keep the populations at oscillation patterns and eventually converge to a steady state.

Abstract:

Pneumocccal pneumonia, a secondary bacterial infection that follows influenza A infection, is responsible for morbidity and mortality in children, elderly, and immunocomprised groups. A mathematical model to study the global stability of pneumococcal pneumonia with awareness and saturated treatment is presented. The basic reproduction number, R0, is computed using the next generation matrix method. The results show that if R0<1, the disease-free steady state is locally asymptotically stable; thus, pneumococcal pneumonia would be eradicated in the population. On the other hand, if R0>1 the endemic steady state is globally attractive; thus, the disease would persist in the population. The quadratic-linear and Goh–Voltera Lyapunov functionals approach are used to prove the global stabilities of the disease-free and endemic steady states, respectively. The sensitivity analysis of R0 on model parameters shows that, it is positively sensitive to the maximal effective rate before antibiotic resistance awareness, rate of relapse encountered in administering treatment, and loss of information by aware susceptible individuals. Contrarily, the sensitivity analysis of R0 on model parameters is negatively sensitive to recovery rate due to treatment and the rate at which unaware susceptible individuals become aware. The numerical analysis of the model shows that awareness about antibiotic resistance and treatment plays a significant role in the control of pneumococcal pneumonia.

Abstract:

We formulate an age-structured SIS epidemic model with periodic parameters, which includes host population and vector population. The host population is described by two partial differential equations, and the vector population is described by a single ordinary differential equation. The existence problem for endemic periodic solutions is reduced to a fixed point problem of a nonlinear integral operator acting on locally integrable periodic functions. We obtain that if the spectral radius of the Fréchet derivative of the fixed point operator at zero is greater than one, there exists a unique endemic periodic solution, and we investigate the global attractiveness of disease-free steady state of the normalized system.

Abstract:

In this paper, we introduce stochasticity into an SIR epidemic model with vaccination. The stochasticity in the model is a standard technique in stochastic population modeling. When the perturbations are small, by the method of stochastic Lyapunov functions, we carry out a detailed analysis on the dynamical behavior of the stochastic model regarding of the basic reproduction number [Formula: see text]. If [Formula: see text], the solution of the model is oscillating around a steady state, which is the disease-free equilibrium of the corresponding deterministic model. If [Formula: see text], there is a stationary distribution and the solution has the ergodic property, which means that the disease will prevail.

Abstract:

We introduce stochasticity into an SIS epidemic model with vaccination. The stochasticity in the model is a standard technique in stochastic population modeling. In the deterministic models, the basic reproduction numberR0is a threshold which determines the persistence or extinction of the disease. When the perturbation and the disease-related death rate are small, we carry out a detailed analysis on the dynamical behavior of the stochastic model, also regarding of the value ofR0. IfR0≤1, the solution of the model is oscillating around a steady state, which is the disease-free equilibrium of the corresponding deterministic model, whereas, ifR0>1, there is a stationary distribution, which means that the disease will prevail. The results are illustrated by computer simulations.

Abstract:

A continuous-time and deterministic model was used to characterize plant virus disease epidemics in relation to virus transmission mechanism and population dynamics of the insect vectors. The model can be written as a set of linked differential equations for healthy (virus-free), latently infected, infectious, and removed (postinfectious) plant categories, and virus-free, latent, and infective insects, with parameters based on the transmission classes, vector population dynamics, immigration/emigration rates, and virus-plant interactions. The rate of change in diseased plants is a function of the density of infective insects, the number of plants visited per time, and the probability of transmitting the virus per plant visit. The rate of change in infective insects is a function of the density of infectious plants, the number of plants visited per time by an insect, and the probability of acquiring the virus per plant visit. Numerical solutions of the differential equations were used to determine transitional and steady-state levels of disease incidence (d*); d* was also determined directly from the model parameters. Clear differences were found in disease development among the four transmission classes: nonpersistently transmitted (stylet-borne [NP]); semipersistently transmitted (foregut-borne [SP]); circulative, persistently transmitted (CP); and propagative, persistently transmitted (PP), with the highest disease incidence (d) for the SP and CP classes relative to the others, especially at low insect density when there was no insect migration or when the vector status of emigrating insects was the same as that of immigrating ones. The PP and CP viruses were most affected by changes in vector longevity, rates of acquisition, and inoculation of the virus by vectors, whereas the PP viruses were least affected by changes in insect mobility. When vector migration was explicitly considered, results depended on the fraction of infective insects in the immigration pool and the fraction of dying and emigrating vectors replaced by immigrants. The PP and CP viruses were most sensitive to changes in these factors. Based on model parameters, the basic reproductive number (R0)—number of new infected plants resulting, from an infected plant introduced into a susceptible plant population—was derived for some circ*mstances and used to determine the steady-state level of disease incidence and an approximate exponential rate of disease increase early in the epidemic. Results can be used to evaluate disease management strategies.

Abstract:

AbstractThe control of insect pests in agriculture is essential for food security. Chemical controls typically damage the environment and harm beneficial insects such as pollinators, so it is advantageous to identify targetted biological controls. Since predators are often generalists, pathogens or parasitoids are more likely to serve the purpose. Here, we model a fungal pathogen of aphids as a potential means to control of these important pests in cereal crops. Typical plant herbivore pathogen models are set up on two trophic levels, with dynamic variables the plant biomass and the uninfected and infected herbivore populations. Our model is unusual in that (i) it has to be set up on three trophic levels to take account of fungal spores in the environment, but (ii) the aphid feeding mechanism leads to the plant biomass equation becoming uncoupled from the system. The dynamical variables are therefore the uninfected and infected aphid population and the environmental fungal concentration. We carry out an analysis of the dynamics of the system. Assuming that the aphid population can survive in the absence of disease, the fungus can only persist (and control is only possible) if (i) the host grows sufficiently strongly in the absence of infection, and (ii) the pathogen transmission parameters are sufficiently large. If it does persist the fungus does not drive the aphid population to extinction, but controls it below its disease-free steady state value, either at a new coexistence steady state or through oscillations. Whether this control is sufficient for agricultural purposes will depend on the detailed parameter values for the system.

Abstract:

Abstract In this paper, a mathematical nonlinear model system of equations describing the dynamics of the co-interaction between malaria and filariasis epidemic affecting the susceptible host population of pregnant women in the tropics is formulated. The basic reproduction number Rmf of the coepidemic model is obtained, and we investigated that it is the threshold parameter between the extinction and persistence of the coepidemic disease. If Rmf < 1, then the disease-free steady state is both locally and globally asymptotically stable resulting in the disease dying out of the host. Also, if Rmf > 1, the disease lingers on. The center manifold theory is used to show that the unique endemic equilibrium is locally asymptotically stable. However, variations in the parameter values involved in the model build up will bring about appropriate control measures to curtail the spread of the coepidemic disease. Numerical simulations are carried out to confirm the theoretical results.

Abstract:

Background Diabetes mellitus is an established risk factor for cardiovascular diseases. Even impaired levels of glucose and insulin might harm organ function prior to diabetes onset. Whether serum glucose or insulin plays a direct role in cardiac dysfunction or lung volume reduction remains unclear. The aim was to investigate the relationship between glucose and insulin with the right ventricle and lung volumes within KORA-MRI FF4 study. Methods From the KORA-MRI FF4 cohort study 337 subjects (mean age 55.7 ± 9.1 years; 43% women) underwent a whole-body 3T MRI scan. Cardiac parameters derived from a cine-steady-state free precession sequence using cvi42. MRI-based lung volumes derived semi-automatically using an in-house algorithm. Fasting serum glucose, fasting insulin levels, and HOMA index were calculated in all study subjects. Linear regression analyses were performed to assess the relationships between glucose and insulin levels with right ventricle volumes and lung volumes adjusted for age, sex, BMI, and cardiovascular risk factors. Results In univariate and multivariate-adjusted models, high serum insulin was inversely associated with end-diastolic volume (β = −12.43, P < 0.001), end-systolic volume (β = −7.12, P < 0.001), stroke volume (β = −5.32, P < 0.001), but not with ejection fraction. The association remained significant after additional adjustment for lung volumes. Similarly, serum insulin was inversely associated with lung volume (β = −0.15, P = 0.04). Sensitivity analysis confirmed results after excluding subjects with known diabetes. Conclusions Serum insulin was inversely associated with right ventricle function and lung volumes in subjects from the general population free of cardiovascular disease, suggesting that increased insulin levels may contribute to subclinical cardiopulmonary circulation impairment.

Abstract:

In this research work, we have developed and analyzed a deterministic epidemiological model with a system of nonlinear differential equations for controlling the spread of Ebola virus disease (EVD) in a population with vital dynamics (where birth and death rates are not equal). The model examines the disease transmission dynamics with isolation from exposed and infected human class and effect of vaccination in susceptible human population through stability analysis and bifurcation analysis. The model exhibits two steady state equilibria, namely, disease-free and endemic equilibrium. Next generation matrix method is used to find the expression for [Formula: see text] (the basic reproduction number). Local and global stability of diseases-free equilibrium are shown using nonsingular M-matrix technique and Lyapunov’s theorem, respectively. The existence and local stability of endemic equilibrium are explored under certain conditions. All numerical data entries are supported by various authentic sources. The simulation study is done using MATLAB code 45 which uses Runge–Kutta method of fourth order and we plot the time series and bifurcation diagrams which support our analytical findings. Stability analysis of the model shows that the disease-free equilibrium is locally as well as globally asymptotically stable if [Formula: see text] and endemic equilibrium is locally asymptotically stable in absence of vaccination if [Formula: see text]. Using central manifold theorem, the presence of transcritical bifurcation for a threshold value of the transmission rate parameter [Formula: see text] when [Formula: see text] passes through unity and backward bifurcation (i.e. transcritical bifurcation in opposite direction) for some higher value of [Formula: see text] are established. Our simulation study shows that isolation of exposed and infected individuals can be used as a more effective tool to control the spreading of EVD than only vaccination.

Abstract:

Abstract Clinical teachers are increasingly challenged to find the time to provide point of care education for learners. To meet this challenge, an interprofessional team from competing health care systems created and sustained Geriatric Fast Facts (GFF): easily accessible, concise 1-2 page topic summaries for clinical teachers to use (in lieu of the mini-lecture) with learners at the point of care. Designed by geriatrics educators in consultation with IT experts, we launched a mobile enabled website that is indexed and searchable by free text or topic, organ system, ACGME competency, disease, and the “underlying science” for the disease/illness. GFF topics are authored by subject matter experts with peer review by senior geriatricians. Brief quizzes test learners’ knowledge with score reports. Our 4-year results reveal that: 1) “Geriatric Fast Facts” appear in the top Google 10 listing; 2) Search engines account for 39% of site traffic; 3) 60% of unique users (N=29,000) are via direct link; 4) 19% via referral from another site. Our “bounce rate” (55%) is ideal as users quickly gain the information sought - affirmed by our session duration which averages &lt; 2 minutes. Our Google Analytics results reflect steady growth and international reach: 73% of sessions are from the U.S., 5% from Canada, 22% international and growing! In summary with our population continuing to age and time for teaching being limited, GFFs are quick, accessible, evidence-based resources for point of care teaching.

Abstract:

e20536 Background: Osimertinib is an oral, potent, irreversible, CNS active EGFR-TKI, selective for sensitizing (EGFRm) and T790M resistance mutations, indicated for the treatment of patients with T790M positive advanced non-small cell lung cancer who have progressed on or after EGFR-TKI therapy. Osimertinib pharmaco*kinetics (PK) were evaluated using a population approach and pharmacodynamic (PD) relationships using appropriate modeling approaches. Methods: To understand the impact of covariates on osimertinib PK, a population PK analysis was performed using data from patients who received osimertinib (20–240 mg) during the AURA studies. Exposure metrics were derived from a PK model and used to assess the exposure-response (safety/efficacy) relationship. Efficacy analysis included patients who were T790M positive (n = 710) and safety analysis included all dosed patients (n = 1088). The impact of covariates on exposure-response was assessed. Models accounting for rare safety events were applied to quantify the association between events and exposure. Results: Population PK analyses supported dose- and time-independent PK of osimertinib with no clinically meaningful covariates identified. Patients in the highest exposure quartile (Q4) had a numerically shorter median progression-free survival (8.3 months [95% CI 6.9, 10.5]) compared with patients in Q1, Q2 and Q3 (all 11.2 months [95% CIs 9.7, 12.7; 8.5, 15.6 and 8.7, 13.7, respectively]). A model-based analysis indicated that this effect is likely due to a larger number of patients in Q4 with poor prognostic features, i.e. worse performance status (WHO 1 or 2) and lower baseline serum albumin compared with Q1, Q2 and Q3, rather than to osimertinib exposure. Model-predicted probability of a relationship between osimertinib exposure and LVEF changes was not evident. Model-based analysis predicted that, compared with the median probability (0.03), the probability of a patient experiencing interstitial lung disease may increase with increasing osimertinib exposure (Q1 probability 0.01 [steady-state AUC 6361 nM*h] vs Q4 0.06 [24460 nM*h]) at the 80 mg dose. Conclusions: Population PK and PK-PD analysis is supportive of 80 mg as an appropriate dose for osimertinib. Clinical trial information: NCT01802632; NCT01802632; NCT02094261; NCT02151981.

Abstract:

Abstract Aims Cardiovascular magnetic resonance (CMR) imaging is an important tool in the assessment of paediatric cardiac disease. Reported reference values of ventricular volumes and masses in the paediatric population are based on small cohorts and several methodologic differences between studies exist. We sought to create steady-state free precession (SSFP) CMR reference values for biventricular volumes and mass by combining data of previously published studies and re-analysing these data in a standardized manner. Methods and results A total of 141 healthy children (68 boys) from three European centres underwent cine-SSFP CMR imaging. Cardiac structures were manually contoured for end-diastolic and end-systolic phases in the short-axis orientation according to current standardized CMR post-processing guidelines. Volumes and masses were derived from these contours. Age-related reference curves were constructed using the lambda mu sigma method. Median age was 12.7 years (range 0.6–18.5). We report biventricular volumes and masses, unindexed and indexed for body surface area, stratified by age groups. In general, boys had approximately 15% higher biventricular volumes and masses compared with girls. Only in children aged &lt;6 years old no gender differences could be observed. Left ventricle ejection fraction was slightly higher in boys in this study population (median 67% vs. 65%, P = 0.016). Age-related reference curves showed non-linear relations between age and cardiac parameters. Conclusion We report volumetric SSFP CMR imaging reference values for children aged 0–18 years old in a relatively large multi-centre cohort. These references can be used in the follow-up of paediatric cardiac disease and for research purposes.

Abstract:

Abstract In chronic hemolytic states, hemoglobin is released in the bloodstream and free heme is formed upon hemoglobin oxidation. Free heme has been shown to trigger vaso-occlusion in animal models of sickle cell disease (SCD) by activating endothelial cells through toll-like receptor 4 (TLR4). Serum levels of glycoproteins specialized in clearing hemoglobin and heme, such as haptoglobin and hemopexin, are typically depleted in SCD plasma. High-density (HDL) and low-density lipoproteins (LDL) can also bind heme and work as the first line of defense against heme toxicity. Heme can react with LDL and generate oxidized LDL (ox-LDL), another TLR4 ligand.We aimed to investigate the importance of lipoproteins as heme scavengers by comparing SCD patients with hom*ozygous sickle cell anemia (SS) patients and double heterozygous hemoglobin SC disease (SC) patients, who present with higher and lower hemolytic rates, respectively. Eighty-three patients (aged 18-68 years old, 44 female) participated in this study: 43 SS (12 receiving hydroxyurea - HU) and 40 SC. Exclusion criteria were pregnancy, blood transfusion, pain crisis, or use of lipid lowering drugs in the past 3 months. Peripheral venous blood samples were collected in tubes with EDTA for complete blood counts and without antiocoagulant for serum separation after centrifugation at 500g for 20 min. Serum lactate dehydrogenase, total cholesterol and HDL were measured by conventional enzymatic-colorimetric methods on a Roche Hitachi Modular automation system (Roche, Germany). LDL was calculated by Friedewald equation. Serum oxidized LDL (ox-LDL), total and free heme were determined with commercially available ELISA assays (Mercodia Oxidized LDL ELISA, Heme QuantiChrom Assay, Bioassay Systems, USA). Statistical analysis was performed with SPSS v.22.0. LDH and reticulocyte count were significantly higher in SS patients than SC, and hemoglobin was significantly lower (P=0.001). Total heme was significantly higher in SS patients taking HU (SSHU) (90 ± 59 mM) compared with SC patients (66 ± 18 mM), P=0.01. Total cholesterol was higher in SC than in SS patients, 141 ± 28 vs. 107 ± 20 mg/dL, respectively, P =0.01). We found no significant differences between groups regarding LDL (P=0.08), HDL (P=0.10), ox-LDL (P=0.52). Total heme correlated negatively with total cholesterol (r=-0.33, P=0.037) and HDL (r=-0.49, P=0.001) in the whole population, regardless of genotype or treatment with HU. Surprisingly, free heme did not differ between SS, SSHU, or SC groups of patients (P=0.19), and did not correlate with cholesterol levels. The negative correlation between total heme and total cholesterol supports that lipoproteins contribute to defend the body against heme toxicity. Despite HDL, LDL, and ox-LDL not being significantly different among the groups, the stronger negative correlation between total heme and HDL suggests that this cholesterol fraction may be more important in heme scavenging. We hypothesize that more intense hemolysis may lead to the production of heme capable of oxidizing lipoproteins, which can then be rapidly cleared by macrophages, explaining hypocholesterolemia in SS patients. Similar concentrations of free heme and ox-LDL in all groups suggests that, in steady state, their concentrations are kept relatively constant regardless of hemolytic rate. Since circulating concentrations of these TLR4 ligands did not differ between SC and SS patients in our study, this might indicate that the contribution of hemolysis to endothelial dysfunction and to differences in severity and in the variety of complications between these genotypes may be better explained by TLR4 activation by bound heme rather than by activation by free heme or ox-LDL. Financial support: FAPESP/CAPES/CNPq Disclosures No relevant conflicts of interest to declare.

Abstract:

Abstract Abstract 2574 Poster Board II-551 Background: Morphine is frequently used to treat pain associated with sickle cell disease (SCD) however many patients report inadequate analgesia after receiving standard doses of morphine. Little information is available on the pharmaco*kinetics (PK) of morphine in SCD. Morphine is metabolized in the liver by glucuronidation by the enzyme uridine diphosphate glycosyltransferase 2B7 (UGT2B7) into two major metabolites, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G). These metabolites are excreted by glomerular filtration. Morphine and M6G contribute to the analgesia by binding to the μ-opioid receptors. We studied morphine PK in young adults with SCD who did not have biochemical evidence of hepatic or renal involvement and were free of any acute complication of SCD. Methods: The study was approved by the Howard University Institutional Review Board. Twenty-one individuals over 18 years of age with SCD underwent 24-hour PK study of morphine. Subjects were in steady state of health and had normal serum creatinine and transaminases. All subjects reported not taking any opioid for at least one week prior to the study and were screened by urine drug screen. All participants received a single infusion of morphine sulfate (0.1 mg/kg dose, maximum 10 mg) over 30 minutes. Timed blood samples for PK parameters were drawn from an indwelling catheter and plasma was analyzed for morphine, M3G, and M6G by liquid chromatography with electrospray ionization tandem mass spectrometry. The limit of quantitation of the assay was 0.25 ng/mL for all analytes. The USCPACK software collection (http://www.lapk.org) was used to fit candidate pharmaco*kinetic models to the time-concentration data for morphine and each of its metabolites. Morphine pharmaco*kinetic parameters including AUC0-∞ (area under the time-concentration curve from dose time extrapolated to time infinity), CL (clearance), Vd (volume of distribution) and t½ (half life) were calculated in SCD subjects while non-SCD PK parameters for the general population were derived from the Duramorph® package insert. Results: Data from 3 participants was excluded from the analysis (dosing error in one and presence of opiates in the baseline urine sample in two others). Of the remaining 18, 83% had SS phenotype and 44% were females. The mean ± SD age was 20.5 ± 3.4 years. A 3-compartment model best described disposition of morphine, while a 2-compartment model and a single compartment model were best fit for M3G, and M6G respectively. PK parameters for SCD and non-SCD population are summarized in Table 1. None of the estimated or calculated PK parameters were significantly associated with age, sex, hemoglobin concentration, serum bilirubin levels, and creatinine clearance. Conclusions: Clearance of morphine in this cohort of young SCD adults was approximately 3-fold higher compared the non-SCD population. The mean half-life of morphine was correspondingly 3- to 10-fold shorter while the volume of distribution was within the range of the non-SCD individuals. The clearance of morphine was higher in SCD, regardless of UGT2B7 −840G>A variant status which has been shown to affect metabolism of morphine in SCD. In the absence of overt renal and hepatic involvement and acute complications of SCD, the cause for this rapid clearance is unclear but probably is due to increased metabolism/elimination of the drug since the volume of distribution in SCD was comparable to non-SCD population. While there is variability in PK parameters, increased clearance found in our study implies that in order to achieve comparable plasma levels of morphine, SCD individuals will need higher and more frequent dosing of morphine. Further investigations are needed to determine the etiology of increased clearance of morphine in SCD which may have implications in the selection of appropriate doses and frequency of morphine administration. Disclosures: No relevant conflicts of interest to declare.

Abstract:

Vascular diseases are becoming an epidemic with an increasing aging population and increases in obesity and type II diabetes. Point-of-care (POC) diagnosis and monitoring of vascular diseases is an unmet medical need. Photoacoustic imaging (PAI) provides label-free multiparametric information of deep vasculature based on strong absorption of light photons by hemoglobin molecules. However, conventional PAI systems use bulky nanosecond lasers which hinders POC applications. Recently, light-emitting diodes (LEDs) have emerged as cost-effective and portable optical sources for the PAI of living subjects. However, state-of-art LED arrays carry significantly lower optical energy (<0.5 mJ/pulse) and high pulse repetition frequencies (PRFs) (4 KHz) compared to the high-power laser sources (100 mJ/pulse) with low PRFs of 10 Hz. Given these tradeoffs between portability, cost, optical energy and frame rate, this work systematically studies the deep tissue PAI performance of LED and laser illuminations to help select a suitable source for a given biomedical application. To draw a fair comparison, we developed a fiberoptic array that delivers laser illumination similar to the LED array and uses the same ultrasound transducer and data acquisition platform for PAI with these two illuminations. Several controlled studies on tissue phantoms demonstrated that portable LED arrays with high frame averaging show higher signal-to-noise ratios (SNRs) of up to 30 mm depth, and the high-energy laser source was found to be more effective for imaging depths greater than 30 mm at similar frame rates. Label-free in vivo imaging of human hand vasculature studies further confirmed that the vascular contrast from LED-PAI is similar to laser-PAI for up to 2 cm depths. Therefore, LED-PAI systems have strong potential to be a mobile health care technology for diagnosing vascular diseases such as peripheral arterial disease and stroke in POC and resource poor settings.

Abstract:

Vascular diseases are becoming an epidemic with an increasing aging population and increases in obesity and type II diabetes. Point-of-care (POC) diagnosis and monitoring of vascular diseases is an unmet medical need. Photoacoustic imaging (PAI) provides label-free multiparametric information of deep vasculature based on strong absorption of light photons by hemoglobin molecules. However, conventional PAI systems use bulky nanosecond lasers which hinders POC applications. Recently, light-emitting diodes (LEDs) have emerged as cost-effective and portable optical sources for the PAI of living subjects. However, state-of-art LED arrays carry significantly lower optical energy (<0.5 mJ/pulse) and high pulse repetition frequencies (PRFs) (4 KHz) compared to the high-power laser sources (100 mJ/pulse) with low PRFs of 10 Hz. Given these tradeoffs between portability, cost, optical energy and frame rate, this work systematically studies the deep tissue PAI performance of LED and laser illuminations to help select a suitable source for a given biomedical application. To draw a fair comparison, we developed a fiberoptic array that delivers laser illumination similar to the LED array and uses the same ultrasound transducer and data acquisition platform for PAI with these two illuminations. Several controlled studies on tissue phantoms demonstrated that portable LED arrays with high frame averaging show higher signal-to-noise ratios (SNRs) of up to 30 mm depth, and the high-energy laser source was found to be more effective for imaging depths greater than 30 mm at similar frame rates. Label-free in vivo imaging of human hand vasculature studies further confirmed that the vascular contrast from LED-PAI is similar to laser-PAI for up to 2 cm depths. Therefore, LED-PAI systems have strong potential to be a mobile health care technology for diagnosing vascular diseases such as peripheral arterial disease and stroke in POC and resource poor settings.

Abstract:

8021 Background: Elotuzumab is a humanized monoclonal antibody directed against SLAMF7 that is approved for use in relapsed multiple myeloma. We initiated a single-center, open label, phase 1 trial based on the hypothesis that the addition of elotuzumab and autologous peripheral blood mononuclear cell (PBMC) reconstitution to standard-of-care autologous hematopoietic stem cell transplantation (auto-SCT) and lenalidomide maintenance for consolidation therapy in myeloma patients will be safe and feasible. Methods: This is a Phase 1b, open-label, trial investigating elotuzumab and autologous PBMC reconstitution with auto-SCT consolidation therapy and lenalidomide maintenance. The primary objective of this study is to assess the safety and tolerability of elotuzumab and autologous PBMC reconstitution in the setting of auto-SCT and lenalidomide maintenance. The secondary objectives are to assess myeloma disease status and progression-free survival (PFS) after one year of treatment. Subjects must be eligible for auto-SCT, and meet inclusion/exclusion criteria. Fifteen subjects participated in this study. The treatment plan is: In addition to PBSC harvest, subjects undergo steady-state leukopheresis for PBMC collection. Subjects receive standard melphalan (day -1) and autologous stem cell rescue (day 0). Autologous PBMC are reinfused on day +3 and cycle 1 of elotuzumab 20 mg/kg IV is given on day +4. Subjects receive elotuzumab every 28 days up to cycle 12. Lenalidomide maintenance at 10 mg orally daily begins with cycle 4 of elotuzumab. The evaluable population constitutes all subjects who received at least four of the first five planned doses of elotuzumab. Results: 15 subjects have been enrolled in the study. All of these subjects are included in the safety population, having received at least 1 dose of elotuzumab. Nine of 15 subjects have completed 4 of the first 5 planned elotuzumab infusions.. The majority of adverse events, including infusion reactions attributable to elotuzumab, have been grade 2 or lower. There were no delays in hematopoietic reconstitution. No AEs were attributed to PBMC reconstitution. Conclusions: The combination of elotuzumab and PBMC reconstitution with standard auto-SCT and lenalidomide maintenance for consolidation therapy appears to be safe and feasible. The trial is ongoing and has completed accrual. The clinical results will be updated for presentation.

Abstract:

66 Background: AMG 386, a first-in-class investigational peptide-Fc fusion protein (peptibody), blocks angiogenesis via inhibiting the interaction between angiopoietins-1 and -2 and the Tie2 receptor. We evaluated the efficacy and tolerability of AMG 386 or placebo plus CX in the first-line treatment of metastatic gastroesophageal adenocarcinoma. Methods: Pts with confirmed metastatic adenocarcinoma of the stomach, gastroesophageal junction or distal esophagus were randomized 1:1:1 to receive CX (cisplatin, 80 mg/m2 IV Q3W; capecitabine, 1,000 mg/m2 orally BID for 14 days Q3W) plus AMG 386 10 mg/kg (Arm A), 3 mg/kg (Arm B), or placebo (Arm C) IV QW. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR; in pts with measurable disease), adverse events (AEs), and pharmaco*kinetics (PK). Results: 171 pts were randomized (Arm A/B/C, n = 56/59/56). Efficacy results are summarized in the table. The incidence of grade ≥ 3 AEs in Arms A/B/C was 80/84/75%. Serious AEs occurred in 73/60/47% and serious AEs grade ≥ 3 in 66/60/43% of pts. AEs in Arms A/B/C included abdominal pain (30/40/17%; grade ≥ 3, 18/3/4%), peripheral edema (13/29/6%; grade ≥ 3, 0/2/0%), venous thromboembolic events (20/22/19%; grade ≥ 3, 20/19/17%), and pulmonary embolism (9/3/15%; grade ≥ 3, 9/2/13%). Median AMG 386 Cmax and Cmin values at steady state after CX coadministration were dose-proportional. Coadministration with CX did not markedly affect AMG 386 exposure. Conclusions: In this study, AMG 386 plus CX did not significantly improve PFS or ORR over placebo plus CX in this patient population. The toxicity of the combination of AMG 386 plus CX, compared with placebo, was greater but manageable. No unexpected AEs occurred. [Table: see text] [Table: see text]

Abstract:

Abstract Sickling disorders have long been suspected of decreasing physiologic thresholds for thrombosis, and the sickling process in tissue of being abetted by elements of the hemostatic system. The landscape of the presumed hypercoagulable state, however, has been ill-defined and differences among sickling disorders with regard to its characteristics, if any, undelineated. Learning how this landscape may reflect the pathophysiology of the sickling process may help guide further study of the interactions among the vasculature and the varieties of abnormal erythrocytes resulting from these hemoglobinopathies and define new opportunities to ameliorate the clinical manifestations of "sickle cell disease." Methods: Using laboratory strategies developed to characterize thrombophilia in non-sickling patients with thrombosis, modified for a largely non-European population, 144 patients with sickling disorders were prospectively evaluated for predisposition to thrombosis. A standard group of hemostatic studies was performed using patient samples obtained during steady-state "non-sickling" conditions, by skilled venepuncturists working consistently with this patient group. Genotypes included: HbSS 96/144 (67%); Hb SC 26/144 (18%;) Hb SSTh; 14/144 (9.5%); Hb S/AThal 8/144 (5.5%). 49/144 (34%) patients (pts) received regular automated erythrocytapheresis for prior stroke, recurrent acute chest syndrome or severe pain episodes &gt; 6/yr. Results: As expected, 2/144 (1.4%) of pts were heterozygous for the Factor V Leiden mutation, 0/144 for the Prothrombin 20210 mutation, and 20/144 (14%) heterozygous, 1/144 (&lt;1%) hom*ozygous for the MTHFR C677T mutation despite hom*ocysteine levels &gt; 12 ng/dL in 38/144 patients (26%). Protein S activity levels were &lt;65% in 83/144 (58%) pts with commensurate free Protein S levels. Total Protein S levels varied widely with no correlation to sickling genotypes, suggesting -as with hom*ocysteine levels -dietary variation. Hb SC genotype was strongly associated with von Willebrand antigen (vWA) levels &gt; 175%, frequently with lesser vWFactor activity (vWF) levels, whereas Hb SSt and SThal more frequently exhibited normal vWA/vWF profiles. Factor VIII activity varied widely, exhibiting no correlation to vWF antigen or activity levels in any of the Hb genotypes. Other thrombophilic conditioners, e.g. antithrombin III activity/Ag, Factor VIII activity, plasmnogen activator inhibitor, and b2-glycoprotein I antibodies were either normal or varied as expected in a " normal," e.g European population, with no correlation to Hb genotype. Conclusions: Thrombophilia in patients with sickling disorders appears to have varied contributors: Hb SC appears most thrombophilic with levels of vWF antigen suggestive of vascular dysfunction and supportive of intravscular platelet adhesion a aggregation. Other genotypes exhibit variable phenotypes, with Hb SThal exhibiting the least thrombogenic phenotype from a aboratory assessment perspective. vWF antigen and Protein S abnormalities emphasize the likely role of inflammation and vascular dysfunction but the dysjunction of vWF and Factor VIII activity hint at greater complexity. Further study of these phenomena and the inclusion of platelet function studies may yield additional insights as to the interaction of sickling erythrocytes, their products and vascular/hemostatic interactions. For now, routine thromboprophylaxis in patients with SC disease appears essential, and likely important in all other genotypes except Hb SThal.

Abstract:

10542 Background: We conducted a Phase II study of alisertib, small-molecule inhibitor of Aurora A kinase, as single-agent treatment in patients < 22 y with recurrent or progressive atypical teratoid rhabdoid tumors (ATRT) (NCT02114229). Methods: Patients received alisertib once daily [80 mg/m2 (enteric-coated tablets) or 60 mg/m2 (liquid)] on Days 1–7 of a 21-day cycle for 2 y or until progressive disease (PD). Therapy was considered promising if ≥10 patients were without PD by MR imaging at 12 wk. Molecular groups were determined using Infinium Methylation EPIC BeadChips and the Heidelberg classifier. Alisertib plasma concentrations were measured in cycle 1, on Days 1 (single dose) and 7 (steady state) and analyzed using population-based modeling. Results: Data from 30 patients representing all 3 molecular groups [SHH (10/26), MYC (10/26), TYR (6/26), unknown (4/26)] was analyzed. One patient remains on therapy. The study did not meet the efficacy end point as only 8/29 patients were without PD after 12 wk, including 1 with partial response. Progression-free survival (PFS) was 31%±8.2% at 6 months and 15.8%±6.5% at 1 y. One- year overall survival (OS) was 42.1%±9.2%. One patient remained on treatment for > 12 months, and another for > 18 months. The median treatment duration was 44 days (range, 2–653 days). There was no difference in OS (p = 0.096) or PFS (p = 0.98) by molecular groups. Neutropenia was the most common adverse effect (77%). After single-dose alisertib, we observed higher mean maximum concentration (Cmax) 10.1±3.0 µM and faster time to Cmax (Tmax = 1.2±0.7 h) in the 22 patients who received liquid formulation than those who received tablets (Cmax = 5.7±2.4 µM, Tmax = 3.4±1.4 h). Drug exposure did not differ between the formulations (AUC0-∞ = 58.6±25 h·µM). Average apparent oral clearance was 2.32 L/h per m2, which was about half that reported in adults. Serial CSF samples were collected in 2 patients; the CSF/plasma AUC ratios were 1.2%-2.7%. Conclusions: Although the study did not meet the efficacy end point, alisertib was well tolerated as a single agent in children with recurrent ATRT. A third of the patients demonstrated disease stabilization for > 6 months. Treatment response beyond 1 y was seen in 2 patients Clinical trial information: NCT02114229.

Abstract:

Abstract Abstract 2369 Poster Board II-346 Background: The prognosis of fludarabine-refractory patients is poor and the current salvage regimens produce low CR rates and are unlikely to improve long-term survival in this patient population. Forodesine, an analog inhibitor of the enzyme purine nucleoside phosphorylase (PNP), leads to rise in plasma dGuo levels followed by accumulation of dGTP in T-cells,that results in DNA breakdown and cell apoptosis. Forodesine has exhibited promising clinical activity in T cell leukemia with complete inhibition of PNP during therapy (Gandhi et al, Blood 106:4253, 2005). Previous in-vitro studies conducted by our group demonstrated that forodesine induces caspase dependent cell death in primary CLL cells by accumulating high intracellular dGTP in CLL cells (Balakrishnan et al, Blood 108:2392, 2006). This provided the rationale to test forodesine in B-CLL. Aims: i) to investigate the efficacy (CR + PR) of forodesine in treating patients with advanced, fludarabine-treated CLL, ii) to evaluate the toxicity, duration of response, disease-free survival and overall survival associated with treatment with forodesine, and iii) to correlate PK/PD data of forodesine in CLL with its clinical activity. Methods: Patients with primary resistance to fludarabine-based therapy (no CR or PR) or with progressive disease after response to prior fludarabine based regimen were eligible. The forodesine dose was 200 mg oral once daily, administered continuously up to a maximum of 24 weeks. Blood samples were collected on days 1-5 and day 28 and pharmaco*kinetic and pharmacodynamic parameters were determined. Ex vivo incubation with forodesine and dGuo were also performed in CLL lymphocytes to compare the treatment effects in vivo and ex vivo investigations. Results: 8 patients were treated, the median age was 62 years (range 51-68), 7 males, median absolute lymphocyte count 35.85 (range 1.4-156.66) × 109/L, median serum beta 2 microglobulin level was 6.45 (range 3.6-16.3) mg/L. Six patients had Rai stage III-IV disease, the, median number of prior therapy was 5 (range 1-10), 5 patients were fludarabine refractory, 5 were ZAP-70 positive. Seven patients are evaluable for response and toxicity. Two patients had a transient decrease in their absolute lymphocyte count to normal level after the first 4 weeks, but it was short lasting. In the other 5 patients, the WBC counts increased progressively and in 3 patients there was also progression in lymphadenopathies. The toxicities observed were mild and included fatigue, bronchitis, diarrhea and low grade fever. Myelosuppression was transient and included neutropenia thrombocytopenia in 3 patients. One patient had pneumonia. The steady-state level of forodesine, measured on day 2, 3, 4, and 5, ranged between 200-1300 nM (n=8). At these concentrations, PNP inhibition in circulating RBCs, ranged between 57 and 89% (n=8). With this extent of PNP inhibition, steady-state dGuo concentration was a median 1.8 μM (range, 0.56 – 4.4 μM, n=8). The starting level of intracellular dGTP was a median 5 μM (range, 0.9 - 7.8 μM, n = 7) which increased to a median 12.5 μM (range 1.9 - 65 μM, n = 7). The circulating lymphocytes did not show annexin positivity above 10% during the first five days of treatment. To determine if CLL lymphocytes accumulate dGTP at high dGuo (10 and 20 μM) levels, we performed ex vivo incubations. Compared to in vivo, higher levels of dGTP were achieved ex vivo with a 10-50% increase in apoptosis. Conclusion: Oral forodesine showed activity with decrease in peripheral lymphocyte counts in 2 of 7 evaluable patients. However, all patients ultimately progressed while on treatment. Side effects were mild. The ex vivo biologic data and in vivo pharmacodynamic and clinical data suggest that forodesine has biological activity, and that alternative dosing schedules should be explored in future CLL trials. Disclosures: Off Label Use: Forodesine is not approved by FDA for treatment of CLL. Bantia:BioCryst: Employment. Gandhi:Mundipharma: Honoraria, Research Funding; Biocryst: Honoraria, Research Funding. Ravandi:Biocryst: Research Funding.

Abstract:

Abstract Introduction: Elotuzumab is a humanized monoclonal antibody directed against SLAMF7 that is approved for use in relapsed multiple myeloma patients in combination with lenalidomide and dexamethasone. This agent appears to have several modes of action, including facilitation of antibody-dependent, cell-mediated cytotoxicity (ADCC) through binding to SLAMF7 on myeloma cells and activation of natural killer (NK) cells to kill tumor cells through ligation of the target. We initiated a single-center, open label, phase 1 trial based on the hypothesis that the addition of elotuzumab and autologous peripheral blood mononuclear cell (PBMC) reconstitution to standard-of-care autologous hematopoietic stem cell transplantation (auto-SCT) and lenalidomide maintenance for consolidation therapy in myeloma patients after induction therapy will be safe and feasible. We hypothesize that early PBMC reconstitution post-auto-SCT will restore a viable NK cell population for activation by elotuzumab, which may target residual myeloma cells and promote tumor-specific humoral and cellular immune responses against myeloma cells. Subsequent maintenance therapy with elotuzumab and lenalidomide may amplify this response, resulting in long-term maintenance of the minimal residual disease state. Methods. This is a Phase 1b, open-label, trial investigating elotuzumab and autologous PBMC reconstitution with auto-SCT consolidation therapy and lenalidomide maintenance. The primary objective of this study is to assess the safety and tolerability of elotuzumab and autologous PBMC reconstitution in the setting of auto-SCT and lenalidomide maintenance in multiple myeloma patients. The secondary objectives are to assess myeloma disease status and progression-free survival (PFS) after one year of treatment. Subjects must achieve partial response or better by IMWG criteria with induction chemotherapy, be eligible for auto-SCT by institutional standards, and meet inclusion/exclusion criteria. Fifteen subjects are planned in this pilot study. The treatment plan is as follows: In addition to standard peripheral blood stem cell mobilization and harvest, subjects undergo steady-state leukopheresis for PBMC collection. Subjects receive standard melphalan conditioning (day -1) and autologous stem cell rescue (day 0). Autologous PBMC are reinfused on day +3 post-stem cell infusion and cycle 1 of elotuzumab 20 mg/kg IV is given on day +4. Subjects receive subsequent cycles of elotuzumab every 28 days up to cycle 12. Lenalidomide maintenance at 10 mg orally daily days 1-21 of every 28-day cycle begins with cycle 4 of elotuzumab, and may continue off study beyond cycle 12 at the investigator's discretion. Bone marrow aspirates and peripheral blood are collected for correlative studies at screening, cycle 2, cycle 4, and at the end of study after cycle 12. For the primary endpoint analysis, the safety population includes all subjects who received at least one dose of study treatment. The evaluable population constitutes all subjects who received at least four of the first five planned doses of elotuzumab. Results: Fourteen of the planned 15 subjects have been enrolled in the study. Demographic and staging data reflect the general transplant-eligible myeloma patient population at our institution. All 14 of these subjects are included in the safety population, having received at least 1 dose of elotuzumab. Nine of 14 subjects have completed at least 4 of the first 5 planned elotuzumab infusions and are evaluable. The majority of adverse events, including infusion reactions attributable to elotuzumab, have been grade 2 or lower. Grade 3 or higher hematologic AEs, including anemia, neutropenia, lymphopenia, thrombocytopenia, and non-hematologic AEs including nausea, vomiting, and dehydration, were attributable to the auto-SCT procedure. There were no delays in hematopoietic reconstitution observed. One episode of grade 3 hypertension was attributed to elotuzumab infusion and resolved with supportive care. No AEs were attributed to PBMC reconstitution. Conclusions: The combination of elotuzumab and PBMC reconstitution with standard auto-SCT and lenalidomide maintenance for consolidation therapy of multiple myeloma appears to be safe and feasible. One subject withdrew for personal reasons. The trial is ongoing and is expected to complete accrual and the clinical results will be updated for presentation. Disclosures Chari: Celgene: Consultancy, Research Funding; Array Biopharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pharmacyclics: Research Funding; Janssen: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Takeda: Consultancy, Research Funding. Geerlof:Bristol-Myers Squibb: Employment. Jagannath:Novartis: Consultancy; Janssen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Merck: Consultancy. Cho:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agenus, Inc.: Research Funding; Genentech Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Research Funding; Ludwig Institute for Cancer Research: Membership on an entity's Board of Directors or advisory committees.

Abstract:

Abstract Pulmonary hypertension (PHT) has emerged as a frequent cause of increased morbidity and mortality in adults with sickle cell disease (SCD). However, the incidence, prevalence and etiology of PHT in children with SCD are currently unknown. An elevated tricuspid regurgitant jet velocity (TRJV) ≥ 2.5 m/sec on Doppler echocardiogram (ECHO) in adults may predict PHT usually diagnosed by traditional cardiac catheterization. We hypothesized that routinely measuring TRJV in children and young adults with SCD was feasible and that TRJV correlated with degree of baseline hemolysis. Methods Using a standard protocol, we prospectively measured steady state TRJV in a convenience, cross-sectional sample of 43 patients (mean age 14.2±2.8 years, range 10 to 20) with hemoglobin (Hb) SS, SC or S-β0 thalassemia at our institution as part of a PHT screening initiative beginning December 2005. Patients on chronic transfusions were excluded. The relationship between TRJV and same day laboratory studies and clinical data obtained from patient charts was examined. Results TRJV was not measurable in 5 of 43 (12%) patients, due presumably to normal pulmonary artery systolic pressures. Neither right ventricular hypertrophy nor decreased septal wall motion, both suggestive of PHT, was present when TRJV could not be determined. In the remaining 38 studies in which TRJV could be quantified (mean 2.34 m/sec±0.44), TRJV was ≥ 2.5 m/sec in 13 patients. Using Pearson’s correlation coefficient, we found a significant correlation between TRJV and LDH (r=0.54, p=0.01), with higher TRJV associated with higher LDH. There were also significant, though more modest, positive correlations between TRJV and WBC (r=0.37, p=0.05) and reticulocyte count (r=0.40, p=0.05) and a significant negative correlation between TRJV and Hb (r= -0.46, p=0.01). Using t-test for independent samples, we found a significant difference in mean LDH (458 IU/L±192 vs. 338 IU/L±144, p=0.037), Hb (8.7 g/dL±1.3 vs. 10.2 g/dL±1.6, p=0.008) and reticulocyte count (17.3%±10.3 vs. 10.7%±6.9, p=0.027) between patients with TRJV ≥ 2.5 and &lt;2.5 m/sec. A difference approaching significance in total WBC (11.4 x103/μL±5.3 vs. 8.3 x103/μL ±3.2, p=0.075) was also observed between the two groups. We found neither a significant difference in mean values between the two groups nor significant relationships with TRJV when we examined platelet count, plasma free Hb, percent fetal Hb or total bilirubin. Using Fisher’s Exact Test, we did not demonstrate in our small cohort a difference in the proportion of patients with TRJV ≥ 2.5 or &lt; 2.5 m/sec who had a history of hydroxyurea use, acute chest syndrome, frequent pain, asthma, splenectomy, gallstones, priapism, exchange transfusion, heart disease or tonsilloadenoidectomy. Conclusions We conclude that TRJV by ECHO is quantifiable in most children and young adults being evaluated for PHT and that a higher LDH and reticulocyte count and a lower Hb at baseline are observed more frequently with elevated TRJV. Larger cohort studies are needed to test the predictive value of one or more of these markers of hemolysis. Although long term outcomes associated with elevated TRJV, as an indication of PHT, in children with SCD remains unclear, decreasing hemolysis in this population may represent an early therapeutic target in the prevention of future clinically significant PHT.

Abstract:

Abstract Ischemic injuries and subsequent degenerative myocardial and conduction system abnormalities occur in patients with sickle cell disease (SCD). This may lead to conduction and repolarization delays reflected as QTc prolongation. Patients with SCD have increased risk of cardiac death, the basis of which remains uncertain. QTc prolongation may be a contributing factor. We decided to examine factors that can potentiate QTc prolongation in this population. In particular, we studied effect of iron overload estimated by serum Ferritin level on QTc. We performed a cross-sectional study in SCD patients older than 18 years, in steady state, followed in our clinic. Patients with acute illness or vaso-occlusive crisis in prior 2 weeks, patients with bundle branch block, pacemaker or arrhythmia and patients unable to give consent were excluded. Prolonged QTC was defined as >450 and >460 ms in men and women respectively. Patients were divided into 3 groups corresponding to mild, moderate and severe iron overload with Ferritin < 1000, between 1000 and 3000 and > 3000 ng/mL respectively. QTc was prolonged in 25/177 patients (14%). Those were older (p=0.041), had lower hemoglobin (Hb) (p<0.001) and higher Ferritin (p=0.019). Their mean age was 33.8 years, Hb 8.26 g/dL and Ferritin 3167 ng/mL compared to 29.2, 9.58 and 1735 respectively in patients with normal QTc. Twenty eight % of patients with prolonged QTc had comorbidities compared to 9% of patients with normal QTc (p=0.004). There was no difference between the 2 groups regarding gender, weight, blood pressure, Lactate dehydrogenase, electrolytes, Reticulocytes count or use of medications known to prolong QTc. Mean QTC was 429, 438 and 440 ms in groups 1,2 and 3 respectively (p=0.013). Linear regression analysis showed that QTc is expected to be longer in groups 2 and 3 compared to group 1. We also estimated QTc prolongation corresponding to 500 unit increment in Ferritin. QTc is expected to get prolonged by 0.83 ms for each 500 unit increment of Ferritin with p value of 0.028 in unadjusted model and by 0.79 ms with p value of 0.035 and 0.67 ms with p value of 0.085 in models where age and comorbidities were adjusted for respectively. Hb was found to be inversely correlated with Ferritin. Correlation coefficient was -0.39 with p value < 0.001. Although there was no significant correlation between Ferritin and JTc, analysis showed that QRS is expected to increase by 0.33 ms for each 500 unit increment in Ferritin with p value of 0.022. Comorbidities including diabetes mellitus, kidney and heart disease are known independent factors that can cause QTC prolongation. QTc increases with age. However, this mainly applies to people older than 50 years (J Geriatric Cardiol 2016 Sep;13(9):740-8). We don't believe age is an independent QTc prolonging factor in our patients especially that mean age of patients with prolonged QTc was 33.87 years. Probably older patients had longer exposure to iron toxicity which may be the true contributing factor to QTc prolongation. Patients with prolonged QTc had lower Hb. However, no correlation was found between Hb and QTc in patients with anemia caused by conditions other than SCD (Chin Med J 2015 Dec 20;128(24):3385-6). In addition, major cause of tissue injury in SCD patients is intracellular polymerization of HbS. However, there is no correlation between Hb concentration and intracellular HbS polymer content (Blood 1998 Mar 1;91(5):1777-83). Thus, we don't think Hb is an independent QTc prolonging factor. Probably patients with lower Hb received more transfusions and subsequently had more pronounced iron overload which may be the direct contributing factor to QTc prolongation. The negative correlation between Hb and Ferritin supports our hypothesis. Thus, we think that the model where just comorbidities were adjusted for is the best to reflect the association between Ferritin and QTc. Iron overload reduces overshoot ( Circulation 1999 Aug 10;100(6):675-83) which will compromise propagation of cardiac impulse and result in conduction delay. Iron also leads to production of free radicals. That will cause chronic inflammation and fibrosis. We showed that QRS is expected to get prolonged with iron overload in SCD patients which is consistent with the physiology of iron toxicity. QTc prolongation seems to be associated with iron overload in SCD patients. Conduction delay manifested by prolonged QRS may be the main contributor rather than repolarization delay. Disclosures Bader: NIMHD: Research Funding. Majumdar:NIMHD: Research Funding. Maher:NIMHD: Research Funding.

Abstract:

Abstract <Introduction> Hematogones are lymphoblast-like cells that increase transiently in the bone marrow and have a characteristic profile of normal B cell precursors co-expressing CD10 and CD19. A cluster of hematogones is often found in the region of low side scatter and dimmer CD45 expression (SSC low CD45 dim), which also includes lymphoid and myeloid precursors, basophils, and partial components of natural killer cells. However, in steady state healthy adult bone marrow, SSC low CD45 dim populations are hardly detectable. In the bone marrow of patients recovering from chemotherapy or bone marrow transplantation, SSC low CD45 dim populations occasionally appear, with the majority of the population consisting of hematogones, especially in patients in complete remission (CR). Studies have shown that increased hematogones in patients with high-risk hematological malignancies after allogeneic hematopoietic stem cell transplantation (HSCT) improved survival. The specific detection of hematogones is difficult because multicolor flow cytometry is necessary to exclude myeloid/lymphoid blasts in active leukemia patients. However, after allogeneic HSCT in patients with leukemia and confirmed CR or malignant lymphoma without bone marrow invasion, hematogones can be easily detected as cells with SSC low CD45 dim populations. <Patients and methods> This retrospective case analysis included 88 patients treated with allogeneic HSCT at our hospitals from October 2010 to November 2014. The cases included acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) in CR at the time of allogeneic HSCT, chemo-naïve or azacitidine-treated myelodysplastic syndrome (MDS) and malignant lymphoma (ML) or adult T cell leukemia/lymphoma (ATL) with marrow CR or without bone marrow invasion. We excluded 8 patients without engraftment. The remaining 80 patients underwent bone marrow aspiration around 28 days after HSCT and were confirmed to be in CR. Bone marrow cells were stained with APC-Cy7-conjugated CD45 and analyzed using FACSCanto. Patients were defined as being simply detected hematogones (SHG)-positive if 0.6%, which is the median proportion of SSC low CD45 dim cells in this study, or more of total nuclear cells were SSC low CD45 dim; the others were defined as SHG-negative. <Results> The median follow-up of survivors of our cohort was 773 (81-1593) days. Primary diagnoses were AML (n=36), ALL (n=21), MDS (n=8), and ML or ATL (n=15). They were treated with bone marrow transplantation (n=51), peripheral blood stem cell transplantation (n=6), and cord blood transplantation (n=23). Among them, 40 were SHG-positive and 40 were SHG-negative. Overall survivals (OS) at 2 years was 94.8% and 58.2% (p<0.001), event free survival (EFS) at 2 years was 94.9% and 46.5% (p<0.001). Cumulative incidence of relapse at 2 years was 5.1% and 34.0% (p<0.001), and cumulative incidence of treatment related mortality (TRM) at 2 years was 0% and 20.6% (p=0.0059) in SHG-positive and SHG-negative groups, respectively. Cumulative incidence of acute graft-versus-host disease (aGVHD) at day 100 was 68.3% and 65.5% (p=0.31) and for severe aGVHD (grade II-IV) was 31.8% and 36.3% (p=0.87) in SHG-positive and SHG-negative groups, respectively. Age ≥50 years, sex, hematopoietic cell transplant-comorbidity index over 2, disease risk index (DRI), myeloablative conditioning regimen and donor source were entered into multivariate analysis, which identified SHG-positive and a low or intermediate DRI as independently associated with a good prognosis. <Conclusion> Thus, the presence of SHG at day 28 predicts improved OS and EFS, and a lower incidence of relapse and TRM. This population of cells is easily detectable, providing useful information for outcome predictions. Patients without SSC low CD45 dim populations should be carefully observed after allogeneic HSCT. Disclosures No relevant conflicts of interest to declare.

Abstract:

Abstract Abstract 506 Background: In a majority of chronic myeloid leukemia patients treatment with imatinib (IM) induces durable hematologic, cytogenetic, and molecular responses, which in turn results in a dramatic improvement of progression-free survival. A new challenge for further optimizing the management of CML is to determine if treatment with TKIs such as IM could eventually cure the patients, particularly those with sustained undetectable disease, by reducing or eliminating the leukemic self-renewing cell (LSC) population thought to drive the disease. Given the challenges in directly assessing LSC burden in patients, we have applied mathematical modeling to molecular response data from patients on IM therapy to infer whether LSC levels can be reduced during IM treatment. Methods: To conduct our study we have utilized 281 patients on the IM arm of the International Randomized Study of Interferon Versus STI571 (IRIS) trial (Drucker et al., NEJM, 2006; 355, 2408). The 281 patients maintained a 90% dose intensity over the course of treatment (up to 7 years) and had a sufficient number of PCR samples above the quantitation limit to support parameter estimation. We have modeled the Bcr-Abl/Bcr transcript ratio time course R(t) as a biexponential (R(t) = Aeαt + Beβt ) and estimated the model parameters for each patient using maximum likelihood methods. The parameter α < 0 describes the rapid initial decline in log10(R) upon treatment start while β describes the shallower slope of the subsequent log10(R) kinetics (figure 1a). Results: nearly every patient response trajectory (93%-263/281) was well-described by the bi-exponential model. The key parameter β, corresponding to the steady-state per-year reduction in log10 transcript levels, ranged from a minimum = -9.2, lower quartile = -1.1, median = -0.6, upper quartile = -0.2, maximum = 10.5 (see figure 1b). Approximately 21% (54/263) of patients had β>0, suggestive of molecular relapse, while 79% (209/263) have β<0, corresponding to continued transcript decline. Discussion: The durable reduction in Bcr-Abl transcripts in the majority of patients has two possible interpretations: either LSCs are depleted at a rate β, or LSCs are not depleted but leukemic progenitor cells in the bone marrow have a median half-life of over one year in many patients. However, leukemic progenitor dynamics appear to occur at a time scale of months (Abe et al, Int J Hematol. 2008; 88, 471); thus a durable reduction in transcript level must correspond to a depletion of LSCs. Our hypothesis that IM induces LSC depletion is also consistent with the observation that 50% of patients maintain undetectable Bcr-Abl transcript levels upon treatment discontinuation (Guastafierro et al, Leukemia Res. 2009; 33, 1079). Conclusions: Mathematical modeling which combines pathophysiologic principles of CML with 7-year molecular response data in individual patients predicts that most patients (∼79%) experience reduction in LSC burden while on sustained IM treatment. In the future, this modeling approach can be used to analyze data from patients who stop IM after achieving CMR in the context of carefully conducted clinical trials, with the goal of assessing (a) the potential impact of IM interruption on LSC levels, particularly in those patients who relapse upon stopping IM and then are re-induced, and (b) whether the probability of achieving cure depends on duration of CMR, the steepness of response prior to achieving CMR (β), and/or additional factors. Disclosures: Stein: Novartis: Employment. Kalebic:Novartis: Employment. Bottino:Novartis: Employment.

Abstract:

Abstract Introduction Novel approaches are needed to treat pediatric relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Blinatumomab is a bispecific T-cell engager (BiTE®) antibody that has shown remission in an exploratory study of 36 adult patients with relapsed/refractory ALL. Primary toxicities in adults have been cytokine release syndrome (CRS) and central nervous system (CNS) related toxicity. We initiated a phase 1/2 multicenter study to identify, in the phase 1 part, the optimal dose of blinatumomab in pediatric patients with relapsed/refractory BCP-ALL. Methods In this ongoing study, eligible patients are <18 years old and must have BCP-ALL that is refractory, in second or later bone marrow relapse, or in any marrow relapse after allogeneic hematopoietic stem cell transplantation (HSCT). Blinatumomab is administered by continuous intravenous infusion over 28 days, followed by a 14-day treatment-free interval (up to five cycles). Data from the five doses that have been explored to date are presented. Maximum tolerated dose (MTD), defined as the highest dose level with less than two of six patients experiencing dose-limiting toxicity (DLT) within the first treatment cycle, is the primary endpoint in the phase 1 part of the study (rolling 6 design). Serum samples were collected for pharmaco*kinetics evaluation and cytokine measurement. Results In the phase 1 part of the study, 34 patients received a total of 56 cycles. Six (18%) patients had refractory disease and 6 (18%) had experienced at least two bone marrow relapses. Twenty-two (65%) patients had relapsed following HSCT. DLTs for dose levels 1 through 4 are summarized in the Table. The MTD for this patient population was established at 15 µg/m²/day. In order to reduce the risk of CRS, a dose of 5 µg/m²/day for 7 days escalating to 15 µg/m²/day for the remainder of the first cycle and all following cycles (5→15 µg/m²/day; dose level 5) was evaluated as recommended dose. None of the 11 patients treated at this dose level developed CRS and no grade 3 CNS-related adverse events (AEs) occurred. Across dose levels, the most common AEs regardless of causality were pyrexia (62% of patients), headache (35%), anemia (29%), and hypertension (29%). One patient treated at 5 µg/m²/day had a grade 3 seizure at the beginning of the second treatment cycle, which resolved clinically and showed no changes on MRI. Across all dose levels, 11 (32%) patients had complete remission (CR), one (3%) had hypocellular blast-free bone marrow, and two (6%) had partial remission within the first two treatment cycles, for an overall response rate of 41%. Some efficacy assessments are still ongoing, and full response data for the phase 1 part of the study will be available at the time of presentation. Two patients experienced hematologic relapse (one each at dose levels 2 and 3, during the fifth and third cycles, respectively). Pharmaco*kinetic parameters, such as steady-state concentration (Css) and clearance, appeared to be similar to those from adult patients with relapsed/refractory BCP-ALL who received body surface area-based blinatumomab dosing. Transient elevations of serum cytokines were observed mainly in the first two days after infusion start, in particular IL-6, IFN-gamma, IL-10, and, to a lesser extent, IL-2 and TNF-α. Conclusions In the ongoing phase 1 part of this study in pediatric patients with relapsed/refractory BCP-ALL, a dose of 15 µg/m²/day was established as MTD. Cytokine-release syndrome has been dose-limiting. Pharmaco*kinetic analysis at the recommended dose of 5→15 µg/m²/day is ongoing. This dose de-escalation strategy has been successful in ameliorating severe CRS to date. Blinatumomab treatment has shown promising antitumor activity in this relapsed/refractory patient population. Disclosures: von Stackelberg: Amgen Inc.: Honoraria. Zugmaier:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Rheingold:Novartis: Research Funding. Holland:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership. Mergen:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Fischer:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Zhu:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership. Hijazi:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Gore:Amgen Inc.: Travel expenses paid for DSMC meeting (Feb 2013) Other.

Abstract:

Background Presently, acute myeloid leukemia (AML) risk stratification is estimated prior to treatment by incorporating patient and disease characteristics. However, apart from the limited use of minimal residual disease measurement, few methodologies assess AML relapse risk post-treatment. In attempts to correlate pre- and post-treatment blood cell counts with hematologic disease outcomes, the ratio, LNR, between absolute lymphocyte count (ALC) and neutrophils (ANC) has been utilized to approximate the relationship between the lymphoid system and the myeloid microenvironment (in particular myeloid-derived suppressor cells), and increased LNR is prognostic in myeloma and lymphoma. Similarly, increased LMR (lymphocyte to monocyte ratio), utilized as a crude marker of tumor-infiltrating lymphocytes and tumor-associated macrophages, predicts better outcomes in Hodgkin's disease (Romano et al. Ann Hematol2018). However, analyses correlating such ratios with AML outcomes have not been performed. Here we specifically investigate whether LNR, LMR, or neutrophil-monocyte (NMR) ratios, measured at multiple time-points, correlate with outcomes. Methods We identified patients &gt;18 yrs receiving induction chemotherapy at our institution between 1/1/2005 - 12/31/2019. Data collected included demographics, comorbidities (Charlson Comorbidity Index [CCI]), AML subtype, cytogenetics/molecular data, ELN risk stratification, and response to therapy. We recorded patients' total WBC, ANC, ALC and AMC both prior to treatment, at first ANC recovery (ANC &gt; 1.0 x 109/L with ALC and AMC &gt; 0), and just prior to next therapy. We also identified a subset of patients who received consolidation chemotherapies with curative intent and collected their first WBC counts ~100 days post-therapy completion (range 50-150 days). The calculated LNR, LMR, and NMR at these time-points were correlated with Event-Free Survival (EFS), defined as time to relapse, death from any cause, or last follow-up. Data was censored on 6/1/2020. WBC ratios were categorized into tertiles. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards models, survivor functions estimated using Kaplan-Meier and the equality of survivor functions tested using stratified log-rank tests. Outcomes were adjusted for CCI, age, sex, race, subtype, presence of inflammation/infection, and ELN risk. Results 145 patients met eligibility criteria, however 23 with primary refractory AML were excluded from EFS analysis. Using WBC ratios at first ANC recovery, both intermediate and high LNR trended towards a lower HR for EFS: HR 0.54 (95% CI 0.24-1.23,p= 0.142) and 0.68 (95% CI 0.32-1.33,p= 0.329), respectively, however differences were not statistically significant (Table 1 and Figure 1). A high NMR also trended towards a worse EFS: HR 1.71 (95% CI 0.74-3.99,p= 0.212), though it was also not statistically significant. LMR did not correlate with improved EFS. Notably, pre-induction ratios and the ratios measured just prior to next treatment were not associated with any differences in EFS. In a subset of patients who received curative intent consolidation chemotherapies (generally ELN favorable risk), a t-test correlating for relapse was performed, though limited by small numbers (16 without, 8 with relapse). Patients in this group who did not relapse trended toward a numerically higher LNR and LMR, 0.57 vs 0.50 (p =0.36) and 4.33 vs 3.97 (p= 0.39), respectively. Discussion In our patient population, high LNR after induction chemotherapy trended towards predicting an improved EFS. Thus, recovery WBC ratios, although crude approximations of the immune system and the tumor microenvironment, may predict patients at higher risk of relapse, however, more patients are clearly needed to show whether a statistically significant association exists. The optimal time to evaluate these counts is also not clear. Nonetheless, as blood counts are obtained routinely post-treatment, these ratios may represent a low-cost strategy to predict relapse risk, potentially allowing for earlier treatment and donor searches for allogeneic transplantation. We propose to repeat these analyses using a multi-center approach - we are especially interested in ratios measured at the 100 days post-therapy mark, as we suspect these may better reflect the immune system at steady state and, potentially, risk of relapse. Disclosures Arain: Astellas:Other: Spouse is employed.Calip:Flatiron Health:Current Employment.Khan:Takeda:Research Funding;Celgene:Consultancy;Incyte:Honoraria;Amgen:Consultancy.Patel:Amgen:Consultancy;Janssen:Consultancy;Celgene:Consultancy.Quigley:Amgen:Other: Advisory board;Agios:Speakers Bureau;Alnylam:Speakers Bureau.

Abstract:

Abstract Multiple myeloma remains one of the best indication for intensive chemotherapy followed by autologous hematopoietic stem cell transplantation (autoT). Intensive therapy followed by autologous transplantation is superior to conventional chemotherapy and it was demonstrated that two autoT were superior to one except for patients in very good partial response or in complete response after the first autotransplant. Peripheral blood stem cells (PBSC) can be used as well as bone marrow as HSC source with the same efficacy but very few data have been reported regarding PBSC recruitment. The main goal of our work was to study the impact on overall and event-free survival (OS and EFS) of PBSC recruitment using either growth factors (GF) alone (steady state) or chemotherapy followed by GF. Secondly, we performed a multivariate analysis studying influence on OS and EFS of sex, age, lines of therapy, pretransplant status, TBI, PBSC recruitment and number of autoT. We have analyzed 193 PBSC autoT (1 autoT=160, 2 autoT=33) performed for 160 MM patients [81 males and 71 females, mean age: 55 years (39–71)]. At diagnosis, 88 patients presented a MM Ig G (70k and 18l), 28 Ig A (16k and 12l), 3 Ig D (1k and 2l), 21 light chains k and 13 light chains l, 3 non secreting and 4 with plasmocyte leukemias. According to Durie and Salmon classification 75% of patients were in stage III, 15% in stage II and 10% in progressive I. Before transplantation, patients have received 1 line of poly-chemotherapy (n=141), 2 lines (n=15) or 3 lines (n=4) and 154 were evaluated for the response with 11 complete remission, 113 partial remission and 30 stable or evolutive disease just before transplant. As HSC (n=189), patients received PBSC which were recruited by GF alone (n=105) or cyclophosphamide+GF (n= 84). Conditioning (n=189),consisted in melphalan and TBI (n=51), melphalan alone (n=132), melphalan associated to cyclophosphamide or busulfan (n=6). We divided the population into 4 groups : group 1 who received one autoT of PBSC recruited by GF (n=76), group 2 one autoT of PBSC recruited by chemotherapy+GF (n=50), group 3 two autoT of PBSC recruited by GF (n=16) and group 4 two autoT of PBSC recruited by chemotherapy+GF (n=17). The median follow-up (FU) of the 4 groups were different with shorter FU (group 3: 9.9 months, group 4: 13 months) for patients who received tandem autoT because of the recent character of this strategy as compared to a long term follow-up for patients who received only one transplant (group 1: 35months, group 2: 55.3 months). Probabilities of OS and EFS at 2 years were 76% (95%CI 67–87) and 60% (95%CI 49.5–73) for group 1, 77% (95%CI 65–90.5) and 70% (95%CI 57.5–85) for group 2, 87.5% (95%CI 73–100) and 72.9% (95%CI 49–100) for group 3, 100% and 66.7% (95%CI 36–100) for group 4. The difference was not significant because of follow-up differences between the 4 groups and small number of patients in groups 3 and 4. In addition, multivariate analysis did not show any significant influence of the different studied parameters on OS and EFS. Nevertheless, because of these interesting preliminary results, a longer follow-up is warranted for definitive conclusions.

Abstract:

Abstract This analysis studied 197 autologous HSCT performed in 132 patients treated for multiple myeloma (MM) in our center between 2000 and 2007. There were 53 females and 79 males with a median age of 56.8 years (34–72). At diagnosis there were 71 IgG (49κ, 22λ), 26 IgA (15κ,11λ), 2 IgD (1κ, 1λ), 27 light chain (18κ,9λ), 2 plasma cell leukemia, 3 non secretory, 1 non secretory/non excretory. There were 11 stage I (10A and 1B), 12 IIA, 96 III(75A and 21B) and 13 not classified. At diagnosis, 24/98pts had a del(13), and 65/179 had high levels of β2microglobulin. Before 2004, 50% of transplants were done and the median interval between diagnosis and HSCT was 7.8 months (3.5–131). We divided the population into 2 groups (I = 65: double-auto, II = 67 simple auto). The disease status pre-transplant according to the number of apheresis were: 1 apheresis (group I: 3CR, 29PR, 3SD, 1PD; group II: 2CR, 24PR, 3PD), 2 apheresis (group I: 16PR, 1SD, 1PD; group II: 3CR, 9PR, 1PD), 3 apheresis (group I: 1CR, 4PR; group II: 10PR, 1unknown), 4 apheresis (group I: 4PR, 1PD; group II: 1CR, 10PR, 2SD), 6 apheresis (group II: 1PR) and 8 apheresis (group: 1PR). PBSC were mobilized in steady state in 135 cases, 53 after cyclophosphamide alone, 9 cyclophosphamide with other drugs. During mobilization, we used GCSF in 179cases, GM-CSF in 5cases, SCF in 4 cases and associations of GM-CSF+ GCSF in 2(1%) cases and SCF+GCSF in 7(3.5%) cases. The median number of infused cells were: TNC 5×107/kg (1–59), CFU-GM 70.5×104/kg (0–2616) and CD34+cells 3×106/kg (0–27). Of these, 115 (58%) had a number of CD34+cells&lt;4×106/kg and 82 (42%) ≥4×106/kg. As conditioning regimens, all pts received melphalan alone with a median total dose of 304mg [130–440]. After transplantation, 156(79%) have received growth factors [1(0.5%) GM-CSF, 148 (95%) G-CSF and 7 (4.5%) SCF] and 195 pts well engrafted (99%). Concerning red blood cell (RBC) transfusions, 60% of pts did not received any RBC transfusions, 30% received between 1 and 4 transfusions, 7% between 5 and 8 and 3% 10 or more and concerning platelet (Pt) transfusions, 35,5% did not received any Pt transfusions, 53% received between 1 and 3, 9% between 4 and 7 and 2.5% 10 or more. The median number of RBC and Pt transfusions were 0 [0–23] and 1 [0–20] respectively. The median number of days with neutrophils &lt;0.5G/L was 6 (0–33) and with Pt&lt;50G/L 17 (2–104) and the median length of hospitalization for auto transplantation was 18 days (14–54). The probability of 5-year overall and event-free survival (OS and EFS) were 64.3% (56.3–73.4%) and 32.4% (24.9–42.2%) and the median OS was not reached. Among all pts, 25 received an allogeneic HSCT as further treatment. Statistical analysis studied age disease status at transplant infused TNC, CD34+cell and CFU-GM, growth factors during mobilization and after transplantation, mobilization chemotherapy, interval Diag-T and transplantation period in a conditional logistic-regression model to analyze associations between these variables and length of hospitalization, number of RBC and Pt transfusions; a multivariate analysis using Cox model to analyze the impact of these variables on length of aplasia (&lt;0.5G/L neutrophils and &lt;50G/L Pt). We observed no significant impact of all studied variables on length of hospitalization and RBC transfusions and a significant negative impact of long interval diagnosis-T (p=0.05) and of the period &gt; 2004 on Pt transfusion number (p=0.03). We showed a significant positive impact of CFU-GM number [HR=1 (1000–1.002) (p=0.03)] and growth factor use after transplantation [HR=0.55 (0.36–0.85) (p=0.005)] on days &lt;0.5 G/L neutrophils and a significant negative impact of CD34+cell&lt;4 ×106/kg on the number of days &lt;50G/L Pt ([HR=1.65 (1.09–2.50) (p=0.01)]. A more refined analysis of the groups, as well as a medico-economic analysis are ongoing and will be presented. In conclusion, this retrospective analysis showed an interesting long-term overall survival probability for this high risk MM population. We demonstrated no apparent impact of the pre-transplant, mobilization, and graft variables on number of transfusions and the length of hospitalization in this global analysis. However, we did show a significant influence of the diagnosis-T interval on platelet transfusions and of the CD34+ cell number, GCSF post-transplant and CFU-GM number on the length of aplasia.

Abstract:

Abstract Background: RG7388 is a new, potent, oral, nutlin-class MDM2 antagonist. This trial evaluated its use in AML to determine the recommended phase 2 dose (RP2D), dose-limiting toxicities (DLTs), pharmaco*kinetics (PK), pharmacodynamics and clinical responses. Methods: This multicenter, open-label phase 1/1b dose escalation (DE) study evaluated RG7388 as monotherapy (daily ´ 5 d q28d) (Part 1 DE) and in combination with cytarabine (ara-C 1 g/m2 IV x 6 d q28d) (Part 2 DE). Extensions (Ex) were initiated at the RP2D. Part 1Ex (RG7388) included pts > 70 y or > 60 y with comorbidities. Part 2Ex pts (RG7388 ± ara-C) had relapsed/refractory (R/R) AML, ≤ 2 regimens and no antecedent hematologic disorders (AHD) or transplant (ASCT). Blood and marrow analyses included PK, TP53 mutations (mt) by AmpliChip, serum MIC-1 and MDM2gene expression. Results: To date, 86 pts have been treated. DE is complete, Part 1Ex was discontinued after 9 pts and 34 of 40 planned pts are enrolled in Part 2Ex. One DLT of prolonged myelosuppression was reported. RP2D is 1200 mg/d (600 mg bid) x 5 d q28d for both mono- and combination therapy due to diarrhea not formally a DLT but felt to be dose-limiting. The most common adverse events were GI (diarrhea reported by > 85% of pts) or infection-related (> 70% of pts). Twenty pts received monotherapy during Part 1 DE at 400 (n = 2), 800 (n = 6) and 1600 mg (n = 12) daily x 5 d. Median age was 68.5 y (range 28-83 y), median prior therapies = 2 (range 0-4), 1 pt had ASCT and 8 had AHD. Four pts died in the first 30 days. Five pts achieved either a CR (n = 2) or CRi/MLFS (n = 3). In Part 1Ex, 9 pts were treated with RG7388 at the RP2D. Median age was 75 y (range 66-83), 8 pts had AHD (6 prior hypomethylators, 3 pts lower intensity therapy) and 1 had prior solid tumor. Best responses reported were 1 CRi/MLFS, 1 PR, 1HI, 3 PD. Three pts died in the first 30 days. Further enrollment in this arm was discontinued as induction of prolonged myelosuppression increased the risks of infection and early deaths. Combination treatment with lower RG7388 doses may be better tolerated in this fragile elderly population. Twenty-three pts were enrolled in Part 2 DE (RG7388 + ara-C) at daily doses of 400 (n = 10), 800 (n = 7), and 1200 mg (n = 6); median age 64 y (range 32-76); median prior therapies = 1.5 (range 0-5); prior ASCT 2; AHD 4; 5 had prior malignancies. Four pts died in the first 30 days. Six relapsed AML pts achieved CRs (4 received prior ara-C and 2 had prior hypomethylators). To date, 34 of 40 planned pts with R/R AML have been enrolled to Part 2Ex (RG7388 ± ara-C); 23 pts have responses reported, with 4 CRs, 1 CRi, 1 PR, 1 HI, 16 PD. Three pts died in the first 30 days. T1/2 is ≈ 1 d, irrespective of age, concomitant azoles or ara-C. Bone marrow levels are ≈ 70% of plasma drug levels at steady state. CRs were seen in diverse pts, including varied risk groups, prior AHD, therapy-related AML (t-AML), p53 mt, R/R and de novo AML. All pts who achieved a CR during DE were relapse free for > 60 d. One pt on monotherapy and 2 on combination therapy remained relapse free for > 400 d and > 200 d from start of study, respectively. A potential predictive gene expression signature correlated with RG7388 therapy (AUC = 0.73, p = 0.021). Conclusions: We report the Ph1/1b PK, safety and clinical activity of a new, potent MDM2 antagonist in AML. CRs occur rapidly and are durable (> 60 d) in elderly AML pts with RG7388 monotherapy and in R/R pts with combination therapy. Table Patient characteristics by response to treatment Part 1 DE (N = 20) 16 responses Best response 2 CR; 3CRi/MLFS 3 PR 4 HI 4 PD TP53 status WT WT 1 MT, 3 WT 1 V ELN* AHD(responders) 4 I, 1 A 3 (MDS, MF, CMML) 3 I 2 (MDS, CMML) Part 1Ex (N = 9) 6 responses Best response 1 CRi/MLFS 0 PR 2 HI 3 PD TP53 status WT WT, MT 2 WT, 1 U ELN* AHD(responders) I ET Part 2 DE (N = 23) 20 responses Best response 6 CR 2 PR 2 HI 10 PD TP53 status 1 MT WT WT 1 MT, 1 V ELN* AHD(responders) 1 F, 3 I, 2 A 1 t-AML 1 I, 1 A Part 2Ex (N = 34) 23 responses Best response 4 CR; 1 CRi/MLFS 1 PR 1 HI 16 PD TP53 status 4 WT, 1 U WT WT 1 MT, 5 WT, 10 U ELN*(responders) 1 F, 3 I, 1 A A CR, complete remission; CRi, complete remission with incomplete recovery; HI, hematologic improvement; MLFS, morphologic leukemia-free state; PD, progressive disease; PR, partial response; WT, wild type; V, splice variant; U, unknown/pending; AHD, includes myelodysplastic syndrome (MDS), essential thrombocythemia (ET), chronic myelomonocytic leukemia (CMML), myelofibrosis(MF) *ELN: Risk by European Leukemia Net: favorable (F), Intermediate I and II (I), or adverse (A) Disclosures Yee: Roche: Research Funding. Martinelli:Pfizer: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; ARIAD: Consultancy, Speakers Bureau. Vey:Roche: Honoraria. Assouline:Roche: Honoraria, Research Funding; Janssen: Honoraria. Drummond:Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Blotner:Roche: Employment. Higgins:Roche: Employment. Middleton:Roche: Employment. Nichols:Roche: Employment. Chen:Roche: Employment. Zhong:Roche: Employment. Pierceall:Roche: Employment. Zhi:Roche: Employment. Chen:Roche: Employment.

Abstract:

Seven spot ladybird beetle, (Coccinella septempunctata) is a widely distributed natural enemy of soft-bodied insect pests especially aphids worldwide. Both the adult and larvae of this coccinellid beetle are voracious feeders and serve as a commercially available biological control agent around the globe. Different techniques are adopted to enhance the mass rearing and storage of this natural enemy by taking advantage of its natural ability to withstand under extremely low temperatures and entering diapause under unfavorable low temperature conditions. The key objective of this study was to develop a cost effective technique for enhancing the storage life and predatory potential of the larvae of C. septempunctata through cold storage in conjunction with the use of nuclear techniques, gamma radiations. Results showed that the host eating potential of larvae was enhanced as the cold storage duration was increased. Gamma irradiation further enhanced the feeding potential of larvae that were kept under cold storage. Different irradiation doses also affected the development time of C. septempuntata larvae significantly. Without cold storage, the lower radiation doses (10 and 25 GY) prolonged the developmental time as compared to un-irradiated larvae. Furthermore, the higher dose of radiation (50GY) increased the developmental time after removal from cold storage. This study first time paves the way to use radiation in conjunction with cold storage as an effective technique in implementation of different biological control approaches as a part of any IPM programs.Key wordGamma irradiations; cold storage, Coccinella septempunctata larvae; predatory potential; integrated pest management programme.INTRODUCTIONNuclear techniques such as gamma radiations have a vast application in different programmes of biological control including continuous supply of sterilized host and improved rearing techniques (Greany and Carpenter, 2000; Cai et al., 2017). Similarly irradiation can be used for sentinel-host eggs and larvae for monitoring survival and distribution of parasitoids (Jordão-paranhos et al., 2003; Hendrichs et al., 2009; Tunçbilek et al., 2009; Zapater et al., 2009; Van Lenteren, 2012). Also, at the production level, such technique may facilitate the management of host rearing, improve quality and expedite transport of product (Fatima et al., 2009; Hamed et al., 2009; Wang et al., 2009). Gamma irradiations can also be used to stop insect’s development to enhance host suitability for their use in different mass rearing programs (Celmer-Warda, 2004; Hendrichs et al., 2009; Seth et al., 2009). Development and survival of all insects have a direct connection with temperatures which in turn affect the physical, functional and behavioral adaptations (Ramløy, 2000). Many insects living in moderate regions can survive at low temperature by process of diapause. A temperature between 0 to 10oC may cause some insects to become sluggish and they only become active when the temperature is suitable. Such insects show greater adaptations to flexible temperature regimes for better survival. Many studies have reported this concept of cold-hardiness in insects in general (Bale, 2002; Danks, 2006) and specifically in coccinellid beetles over past years (Watanabe, 2002; Koch et al., 2004; Pervez and Omkar, 2006; Labrie et al., 2008; Berkvens et al., 2010). Using this cold hardiness phenomenon, many coccinellids have been studied for the effect of cold storage such as Coccinella undecimpunctata (Abdel‐Salam and Abdel‐Baky, 2000), Coleomegilla maculata (Gagné and Coderre, 2001) and Harmonia axyridis (Watanabe, 2002). This natural phenomenon, therefore, can be a helpful tool in developing low temperature stockpiling for improving mass-rearing procedures (Mousapour et al., 2014). It may provide a significant output in terms of providing natural enemies as and when required during pest infestation peaks (Venkatesan et al., 2000). Use of irradiation in conjunction with cold storage proves to be an effective technique in implementation of different biological control approaches as a part of any IPM programme. A study reported that the pupate of house fly, Musca domestica irradiated at dose of 500 Gy and can stored up to 2 months at 6°C for future use for a parasitoid wasp Spalangia endius rearing (Zapater et al., 2009). Similarly, when irradiated at 20 GY, parasitic wasps Cotesia flavipes were stored safely up to two months without deterioration of their parasitic potential (Fatima et al., 2009). Similarly, bio-control program of sugarcane shoot borer Chilo infescatellus proved successful through the use of irradiation combined with cold storage of its egg and larval parasitoids Trichogramma chilonis and C. flavipes (Fatima et al., 2009). Less mobile life stages such as larvae are of significance in any IPM strategy because they remain on target site for more time period as compared to adults. Therefore, use of predatory larvae is very promising in different biological control approaches because of their immediate attack on pests and more resistance to unfavorable environmental conditions than delicate egg stage. In addition, with their augmentation into fields, larval stage shows their presence for longer time than adult stage and their feeding potential is also satisfactory as that of adults. For the best utilization of these predators in the field and maximum impact of 3rd and 4th larval instars on prey, we should encourage late 2nd second instar larvae of predatory beetles in the fields as these instars have more feeding capacity due to increased size and ability to handle larger preys.In spite of higher significance, there is little information available about the effect of cold storage on the survival of larval instars of different ladybird beetles and its effect on their predatory potential. Very few studies report the use of cold storage for non-diapausing larval stage like for Semiadalia undecimnotata and only one study reported the short-term storage (up to two weeks) of 2nd and 3rd instar coccinellid, C. maculate, without any loss in feeding voracity of larvae after storage (Gagné and Coderre, 2001). The survival of 3rd and 4th larval instars of C. undecimpunctata for 7 days after storage at 5oC was reported in a study but the survival rate declined after 15-60 days of storage (Abdel‐Salam and Abdel‐Baky, 2000). As C. septempunctata is considered one of the voracious predators (Afroz, 2001; Jandial and Malik, 2006; Bilashini and Singh, 2009; Xia et al., 2018) and diapause is a prominent feature of this beetle and it may undergo facultative diapause under suitable laboratory conditions (Suleman, 2015). No information is available to date about the combined effect of cold storage and irradiation on the larval instars of this species.OBJECTIVES The objective of this study was to devise a cost effective technique for the cold storage and its effect on the subsequent predatory potential of the seven spotted ladybird beetle larvae in conjunction with the use of gamma radiations. Hypothesis of the study was that an optimum length of low temperature treatment for storage purpose would not affect the predation capacity of C. septempunctata larvae and their developmental parameters including survival and pupation will remain unaffected. Furthermore, use of gamma irradiation will have some additional effects on survival and feeding capacity of irradiated C. septempunctata larvae. Such techniques can be utilized in different biocontrol programs where short term storage is required. So these larvae can be successfully imparted in different IPM programs against sucking complex of insect pests as a component of biological control strategyMATERIALS AND METHODSPlant materials: Collection and rearing of C. septempunctata: Adult C. septempunctata were collected from the wheat crop (in NIAB vicinity and farm area) in the month of March during late winter and early in spring season 2016-2017. They were kept in plastic jars and were fed with brassica aphids. Under controlled laboratory conditions (25+2oC, 16h: 8h L:D and 65+5% R.H.), eggs of C. septempuctata were obtained and after hatching, larvae were also given brassica aphids as dietary source. Larvae of second instar were selected for this experiment (as the first instar is generally very weak and vulnerable to mortality under low temperatures). As the larvae approached second instar, they were separated for the experimentation. Irradiation of larvae at different doses: Irradiation of larvae was carried out by the irradiation source 137CS at Radiation laboratory, and the larvae were then brought back to the IPM laboratory, Plant Protection Division, Nuclear Institute for Agriculture and Biology (NIAB) Faisalabad. Radiation doses of 10 GY (Grey), 25 GY and 50 GY were used to treat the second instar larvae. There were three replicates for each treatment and five larvae per replicate were used. Control treatment was left un-irradiated.Cold storage of irradiated larvae: In present work, second instar C. septempunctata larvae were studied for storage at low temperature of 8oC. The larvae were kept at 8oC for 0, I and II weeks where week 0 depicts no cold treatment and this set of larvae was left under laboratory conditions for feeding and to complete their development. For larvae that were kept under cold storage for one week at 8°C, the term week I was devised. Similarly, week II denotes the larvae that remained under cold conditions (8°C) for two continuous weeks. Larvae were removed from cold storage in their respective week i.e., after week I and week II and were left under laboratory conditions to complete their development by feeding on aphids. Data collection: For recording the predatory potential of C. septempunctata larvae, 100 aphids were provided per larva per replicate on a daily basis until pupation as this number was more than their feeding capacity to make sure that they were not starved (personal observation). Observations were recorded for survival rate, developmental time and feeding potential. Data analysis: Data were statistically analysed by Statistical Software SPSS (Version 16.0). The data were subjected to normality check through the One-sample Kolmogorov-Smirnov test. Non normal data were transformed to normal data which were then used for all parametric variance tests. One-way and two-way analyses of variance were used. For comparison between variables, LSD test at α 0.05 was applied.RESULTSFeeding potential of irradiated larvae after removal from cold storage: Results showed an increase in the feeding potential of C. septempunctata larvae with increased cold storage duration. The feeding potential was significantly higher for the larvae that spent maximum length of time (week II) under cold storage conditions followed by week I and week 0. Gamma irradiations further enhanced the feeding potential of larvae that were kept under cold storage. When larvae were irradiated at 10 GY, the eating capacity of larvae increased significantly with the duration of cold storage. Similarly, larvae that were irradiated at 25 GY, showed increase in feeding potential on aphids as the time period of cold storage increased. The feeding potential of larvae that were irradiated at 50 GY, was again significantly increased with increase of cold storage duration. When different radiation doses were compared to week 0 of storage, there was a significant difference in feeding potential and larvae irradiated at 50 GY consumed the maximum numbers of aphids when no cold storage was done followed by larvae irradiated at 10 and 25 GY. With the other treatment, where larvae were kept under cold storage for one week (week I) the larvae irradiated at 50GY again showed the highest feeding potential. The feeding potential of irradiated larvae was again significantly higher than the un-irradiated larvae that were kept for two weeks (week II) under cold storage (table 1).Two-way ANOVA was performed to check the interaction between the different radiation doses and different lengths of storage durations for feeding potential of C. septempunctata larvae on aphids. The feeding potential of larvae irradiated at different doses and subjected to variable durations of cold storage were significantly different for both the radiation doses and cold storage intervals. Furthermore, the interaction between the radiation doses and storage duration was also significant meaning that the larvae irradiated at different doses with different length of cold storage were having significant variations in feeding levels (table 2).Developmental time of irradiated larvae after removal from cold storage: Significant difference was found in the development time of the larvae of C. septempunctata when irradiated at different doses at week 0 (without cold storage). The larvae irradiated at 10 GY took the maximum time for development and with the increase in irradiation dosage, from 25 to 50 GY, the time of development was shortened. The larvae irradiated at 50 GY had the same development time as the un-irradiated ones. When, the irradiated larvae were subjected to cold storage of one week duration (week I), their development time after removal from storage condition varied significantly. The larvae irradiated at 25 GY took the maximum time for development followed by larvae irradiated at 50 GY and 10 GY. There was an indication that the development time was extended for irradiated larvae as compared to un-irradiated larvae.Results also depicted a significant difference in the time taken by irradiated larvae to complete their development after taken out from cold storage of two weeks duration (week II). As the storage time of irradiated larvae increased, the development time was prolonged. Results showed that the larvae that were irradiated at 25 and 50 GY, took the maximum time to complete their development. With the prolonged duration of cold storage up to two weeks (week II), this difference of development time was less evident at lower doses (10 GY). The larvae irradiated at 10 GY showed a significant difference in their developmental duration after being taken out of cold storage conditions of the week 0, I and II. There was no difference in the developmental duration of larvae that were un-irradiated and subjected to different regimes of storage. Un-irradiated larvae were least affected by the duration of storage. With the increase in the storage time, a decrease in the developmental time was recorded. Larvae that were irradiated at 10 GY, took the maximum period to complete their development when no cold storage was done (week 0) followed by week I and II of cold storage. When the larvae irradiated at 25 GY were compared for their development time, there was again significant difference for week 0, I and II of storage duration. Maximum time was taken by the larvae for their complete development when removed from cold storage after one week (week I). With the increase in storage duration the time taken by larvae to complete their development after removal from cold storage reduced.When the larvae were removed after different lengths of cold storage duration i.e., week 0, week I and week II, there was a significant difference in the developmental time afterwards. Results have shown that the higher dose of radiation, increased the developmental time after removal from cold storage. The larvae irradiated at 50 GY took the longest time to complete their development after removal from cold storage (week I and week II) as compared the larvae that were not kept under cold storage conditions (week 0) (table 3).Interaction between the different radiation doses and different lengths of storage durations for development time of larvae were checked by two-way ANOVA. The development time of larvae irradiated at different doses and subjected to variable durations of cold storage were significantly different for both the doses and cold storage intervals. Furthermore, the interaction between the radiation doses and storage duration was also significant meaning that the larvae irradiated at different doses with different length of cold storage were having significant variations in development times (table 4). DISCUSSIONThe present research work indicates the possibility of keeping the larval instars of C. septempunctata under cold storage conditions of 8oC for a short duration of around 14 days without affecting its further development and feeding potential. Furthermore, irradiation can enhance the feeding potential and increase the development time of larval instars. This in turn could be a useful technique in mass rearing and field release programmes for biological control through larval instars. Usually temperature range of 8-10oC is an optimal selection of low temperature for storage as reported earlier for eggs two spotted ladybird beetle, Adalia bipunctata and the eggs of C. septempunctata (Hamalainen and Markkula, 1977), Trichogramma species (Jalali and Singh, 1992) and fairyfly, Gonatocerus ashmeadi (Hymenoptra; Mymaridae) (Leopold and Chen, 2007). However, a study reported more than 80% survival rate for the coccinellid beetle, Harmonia axyridis for up to 150 days at moderately low temperature of 3-6oC (Ruan et al., 2012). So there is great flexibility in coccinellid adults and larvae for tolerating low temperature conditions. After removal from cold storage, larvae showed better feeding potential with consumption of more aphids when compared to normal larvae that were not placed under low temperature conditions. This indicates that when the adult or immature insect stages are subjected to low temperature environment, they tend to reduce their metabolic activity for keeping them alive on the reserves of their body fats and sustain themselves for a substantial length of time under such cold environment. Hereafter, the larval instars that were in cold storage were behaving as if starved for a certain length of time and showed more hunger. This behavior of improved or higher feeding potential of stored larvae has been reported previously (Chapman, 1998). Hence, the feeding potential of C. septempunctata larvae significantly increased after cold storage. Gagné and Coderre (2001) reported higher predatory efficacy in larvae of C. maculata when stored at the same temperature as in the present study i.e., 8oC. Similarly, Ruan et al. (2012) showed that the multicolored Asian ladybug, H. axyridis, when stored under cold conditions, had more eating capacity towards aphids Aphis craccivora Koch than the individuals that were not stored. Such studies indicate that the higher feeding potential in insects after being subjected to low temperature environmental conditions could be due to the maintenance of their metabolism rate to a certain level while utilizing their energy reserves to the maximum extent (Watanabe, 2002).The individuals coming out from cold storage are therefore capable of consuming more pray as they were in a condition of starvation and they have to regain their energy loss through enhanced consumption. Furthermore, the starvation in C. septempunctata has previously been reported to affect their feeding potential (Suleman et al., 2017). In the present study, the larval development was delayed after returning to normal laboratory conditions. Cold storage affects the life cycle of many insects other than coccinellids. The cold storage of green bug aphid parasitoid, Lysiphlebus testaceipes Cresson (Hymenoptra; Braconidae) mummies increased the life cycle 3-4 times. Nevertheless, in current study the development process of stored larvae resumed quickly after taking them out and larvae completed their development up to adult stage. Similar kinds of results were reported for resumption of larval development after removal from cold storage conditions. Such studies only report satisfactory survival rates and development for a short duration of cold storage but as the length of storage is increased, it could become harmful to certain insects. Gagné and Coderre (2001) reported that cold storage for longer period (three weeks) proved fatal for almost 40% of larvae of C. maculata. Furthermore, in the same study, the feeding potential of C. maculata larvae was also affected beyond two weeks of cold storage due to the loss of mobility after a long storage period. Many studies have reported that longer durations of low temperature conditions can either damage the metabolic pathways of body cells or may increase the levels of toxins within the bodies of insects. Also, low temperature exposure for longer duration may cause specific interruptions in the insect body especially neuro-hormones responsible for insect development, which could be dangerous or even life threatening.Chen et al. (2004) also reported that the biological qualities of parasitized Bemisia tabaci pupae on population quality of Encarsia formosa were affected negatively with increase in cold storage duration. Similarly, the egg hatchability of green lacewing Chrysoperla carnea Stephen was lost completely beyond 18 days of cold storage (Sohail et al., 2019). However, in the present study the cold storage was done for maximum two weeks and it is to be regarded as a short term storage hence the survival rate was satisfactory. Longer periods of cold storage for larvae are not considered safe due to their vulnerable state as compared to adults which are hardier. Also 2nd instar larvae used in the present study for cold storage for being bigger in size and physical stronger than 1st instar. Abdel‐Salam and Abdel‐Baky (2000) reported that in C. undecimpunctata the cold storage of 3rd and 4th larval instars was higher and considered safer than early larval instars. The same study showed sharp decline in survival rate after two weeks and there was no survival beyond 30-60 days of cold storage. The present study showed that short term storage of the larvae of C. septempunctata could be done without any loss of their feeding potential or development so the quality of predator remained unaffected. Similar kind of work for many other insects had been reported previously where cold storage technique proved useful without deteriorating the fitness of stored insects. For example, the flight ability of reared codling moth Cydia pomonella Linnaeus remained unaffected after removal from cold storage (Matveev et al., 2017). Moreover, a sturdy reported that pupae of a parasitoid wasp Trichogramma nerudai (Hymenoptera; Trichogrammatidae) could be safely put in cold storage for above than 50 days (Tezze and Botto, 2004). Similarly, a technique of cold storage of non-diapausing eggs of black fly Simulium ornaturm Meigen was developed at 1oC. Another study reported safe storage of a predatory bug insidious flower bug Orius insidiosus for more than 10 days at 8°C (Bueno et al., 2014).In present study without cold storage, the lower doses of 10 and 25 GY prolonged the developmental time as compared to un-irradiated larvae and higher doses of irradiations in conjunction with cold storage again significantly prolonged the developmental time of larvae when returned to the laboratory conditions. Salem et al. (2014) also reported that Gamma irradiations significantly increased the duration of developmental stages (larvae and pupae) in cutworm, Agrotis ipsilon (Hufnagel). In another study, where endoparasitic wasps Glyptapanteles liparidis were evaluated with irradiated and non-irradiated gypsy moth Lymantria dispar larvae for oviposition, it was found that non-irradiated larvae had a shorter time to reach the adult stage as compared to irradiated larvae (Novotny et al., 2003). Both for higher doses with cold storage and lower doses without cold storage extended the larval duration of C. septempunctata. In another study when the parasitoid wasp Habrobracon hebetor was irradiated at the dose of 10 GY, it resulted in prolonged longevity (Genchev et al., 2008). In the same study, when another parasitoid Ventruria canescens was irradiated at lower doses of 4GY and 3 GY, it resulted in increased emergence from the host larvae, while gamma irradiations at the dose of 1 GY and 2 GY significantly stimulated the rate of parasitism (Genchev et al., 2008). The current study also indicated higher rates of predation in the form of increased feeding potential of larvae as a result of irradiations at lower doses.CONCLUSIONThe outcome of the current study shows that storage of 2nd instar C. septempunctata at low temperature of 8oC for a short duration of about 14 days is completely safe and could have broader application in different biocontrol programs. Such flexibility in storage duration can also assist in different mass rearing techniques and commercial uses. The combination of gamma radiation with low temperature cold storage could be a useful tool in developing different biological pest management programs against sucking insect pests. Incidence of periodic occurrence of both the target insect pests with their predatory ladybird beetles in synchrony is an important aspect that could be further strengthened by cold storage techniques. Therefore, short or long term bulk cold storage of useful commercial biocontrol agents and then reactivating them at appropriate time of pest infestation is a simple but an advantageous method in mass rearing programs. Increased feeding capacity of stored larvae is another edge and hence such larvae may prove more beneficial as compared to unstored larvae. Both cold storage and improved feeding of the C. septempuctata larvae can be utilized for implementation of IPM for many sucking insect pests of various crops, fruits and vegetables. Due to some constraints this study could not be continued beyond two weeks but for future directions, higher doses and longer duration periods could further elaborate the understanding and better application of such useful techniques in future IPM programmes on a wider scale. Also, some other predatory coccinellid beetle species can be tested with similar doses and cold storage treatments to see how effective this technique is on other species as well.ACKNOWLEDGMENTS We acknowledge the Sugarcane Research and Development Board for providing a research grant (No. SRDB/P/4/16) to carry out this research work. This paper is a part of research thesis entitled “Effect of gamma irradiation on storage and predatory potential of seven spotted lady bird beetle larvae” submitted to Higher Education Commission, Pakistan for the degree of M.Phil. Biological Sciences.CONFLICT OF INTERESTAuthors have no conflict of interest.REFERENCESAbdel‐Salam, A. and N. J. J. o. A. E. Abdel‐Baky, 2000. Possible storage of Coccinella undecimpunctata (Col., coccinellidae) under low temperature and its effect on some biological characteristics. 124(3‐4): 169-176.Afroz, S., 2001. Relative abundance of aphids and their coccinellid predators. Journal of aphidology, 15: 113-118.Bale, J., 2002. Insects and low temperatures: From molecular biology to distributions and abundance. Biological sciences, 357(1423): 849-862.Berkvens, N., J. S. Bale, D. Berkvens, L. Tirry and P. De Clercq, 2010. Cold tolerance of the harlequin ladybird Harmonia axyridis in europe. Journal of insect physiology, 56(4): 438-444.Bilashini, Y. and T. J. I. J. A. E. Singh, 2009. Studies on population dynamics and feeding potential of Coccinella septempunctata linnaeus in relation to Lipaphis erysimi (kaltenbach) on cabbage. Indian journal of applied entomology, 23: 99-103.Bueno, V. H. P., L. M. Carvalho and J. Van Lenteren, 2014. Performance of Orius insidiosus after storage, exposure to dispersal material, handling and shipment processes. Bulletin of insectology, 67(2): 175-183.Cai, P., X. Gu, M. Yao, H. Zhang, J. Huang, A. Idress, Q. Ji, J. Chen and J. Yang, 2017. The optimal age and radiation dose for Bactrocera dorsalis (Hendel)(Diptera: Tephritidae) eggs as hosts for mass-reared Fopius arisanus (Sonan)(Hymenoptera: Braconidae). Biological control, 108: 89-97.Celmer-Warda, K., 2004. Preliminary studies suitability and acceptability of irradiated host larvae Plodia interpunctella (Hubner) on larval parasitoids Venturia canescens (gravenhorst). Annals of warsaw agricultural university, horticulture (Landscape Architecture), 25: 67-73.Chapman, R. F., 1998. The insects: Structure and function. Cambridge university press.Chen, Q., L.-f. Xiao, G.-r. Zhu, Y.-s. LIU, Y.-j. ZHANG, Q.-j. WU and B.-y. XU, 2004. Effect of cold storage on the quality of Encarsia formosa Gahan. Chinese journal of biological control, 20(2): 107-109.Danks, H., 2006. Insect adaptations to cold and changing environments. The Canadian entomologist, 138(1): 1-23.Fatima, B., N. Ahmad, R. M. Memon, M. Bux and Q. Ahmad, 2009. Enhancing biological control of sugarcane shoot borer, Chilo infuscatellus (Lepidoptera: Pyralidae), through use of radiation to improve laboratory rearing and field augmentation of egg and larval parasitoids. Biocontrol science technology, 19(sup1): 277-290.Gagné, I. and D. Coderre, 2001. Cold storage of Coleomegilla maculata larvae. Biocontrol science technology, 11(3): 361-369.Genchev, N., N. Balevski, D. Obretenchev and A. Obretencheva, 2008. Stimulation effects of low gamma radiation doses on perasitoids Habrobracon hebetor and Ventruria canescens. Journal of Balkan ecology, 11: 99-102.Greany, P. D. and J. E. Carpenter, 2000. Årea-ide control of fruit flies and other insect pests: Importance. Joint proceedings of the International Conference on Årea-Wide Control of insect pests, May 28–June 2, 1998 and the Fifth International symposium on fruit flies of economi, June 1-5.Hamalainen, M. and M. Markkula, 1977. Cool storage of Coccinella septempunctata and Adalia bipunctata (Col., coccinellidae) eggs for use in the biological control in greenhouses. Annales agricultural fennicae, 16: 132-136.Hamed, M., S. Nadeem and A. Riaz, 2009. Use of gamma radiation for improving the mass production of Trichogramma chilonis and Chrysoperla carnea. Biocontrol science technology, 19(sup1): 43-48.Hendrichs, J., K. Bloem, G. Hoch, J. E. Carpenter, P. Greany and A. S. Robinson, 2009. Improving the cost-effectiveness, trade and safety of biological control for agricultural insect pests using nuclear techniques. Biocontrol science technology, 19(sup1): 3-22.Jalali, S. and S. Singh, 1992. Differential response of four Trichogramma species to low temperatures for short term storage. Entomophaga, 37(1): 159-165.Jandial, V. K. and K. Malik, 2006. Feeding potential of Coccinella septempunctata Linn. (Coccinellidae: Coleoptera) on mustard aphid, lipaphis erysimi kalt. And potato peach aphid, Myzus persicae sulzer. Journal of entomological research, 30(4): 291-293.Jordão-paranhos, B. A., J. M. Walder and N. T. Papadopoulos, 2003. A simple method to study parasitism and field biology of the parasitoid Diachasmimorpha longicaudata (Hymenoptera: Braconidae) on Ceratitis capitata (Diptera: Tephritidae). Biocontrol science technology, 13(6): 631-639.Koch, R. L., M. Carrillo, R. Venette, C. Cannon and W. D. Hutchison, 2004. Cold hardiness of the multicolored asian lady beetle (Coleoptera: Coccinellidae). Environmental entomology, 33(4): 815-822.Labrie, G., D. Coderre and E. Lucas, 2008. Overwintering strategy of multicolored asian lady beetle (Coleoptera: Coccinellidae): Cold-free space as a factor of invasive success. Annals of the entomological society of America, 101(5): 860-866.Leopold, R. and W.-l. Chen, 2007. Cold storage of the adult stage of Gonatocerus ashmeadi girault: The impact on maternal and progeny quality. In: Proceedings of the 2007 pierce’s disease research symposium, San Diego, CA. pp: 42-46.Matveev, E., J. Kwon, G. Judd and M. J. T. C. E. Evenden, 2017. The effect of cold storage of mass-reared codling moths (Lepidoptera: Tortricidae) on subsequent flight capacity. The Canadian entomologist, 149(3): 391-398.Mousapour, Z., A. Askarianzadeh and H. Abbasipour, 2014. Effect of cold storage of pupae parasitoid wasp, Habrobracon hebetor (say)(Hymenoptera: Braconidae), on its efficiency. Archives of phytopathology plant protection, 47(8): 966-972.Novotny, J., M. Zúbrik, M. L. McManus and A. M. Liebhold, 2003. Sterile insect technique as a tool for increasing the efficacy of gypsy moth biocontrol. Proceedings: Ecology, survey and management of forest insects GTR-NE-311, 311.Pervez, A. and Omkar, 2006. Ecology and biological control application of multicoloured asian ladybird, Harmonia axyridis: A review. Biocontrol science technology, 16(2): 111-128.Ramløy, U.-B., 2000. Aspects of natural cold tolerance in ectothermic animals. Human reproduction, 15(suppl_5): 26-46.Ruan, C.-C., W.-M. Du, X.-M. Wang, J.-J. Zhang and L.-S. Zang, 2012. Effect of long-term cold storage on the fitness of pre-wintering Harmonia axyridis (pallas). BioControl, 57(1): 95-102.Salem, H., M. Fouda, A. Abas, W. Ali and A. Gabarty, 2014. Effects of gamma irradiation on the development and reproduction of the greasy cutworm, Agrotis ipsilon (Hufn.). Journal of radiation research applied sciences, 7(1): 110-115.Seth, R. K., T. K. Barik and S. Chauhan, 2009. Interaction of entomopathogenic nematodes, Steinernema glaseri (Rhabditida: Steinernematidae), cultured in irradiated hosts, with ‘f1 sterility’: Towards management of a tropical pest, Spodoptera litura (fabr.)(Lepidoptera: Noctuidae). Biocontrol science technology, 19(sup1): 139-155.Sohail, M., S. S. Khan, R. Muhammad, Q. A. Soomro, M. U. Asif and B. K. Solangi, 2019. Impact of insect growth regulators on biology and behavior of Chrysoperla carnea (stephens)(Neuroptera: Chrysopidae). Ecotoxicology, 28(9): 1115-1125.Suleman, N., 2015. Heterodynamic processes in Coccinella septempunctata L. (Coccinellidae: Coleoptera): A mini review. Entomological science, 18(2): 141-146.Suleman, N., M. Hamed and A. Riaz, 2017. Feeding potential of the predatory ladybird beetle Coccinella septempunctata (Coleoptera; Coccinellidae) as affected by the hunger levels on natural host species. Journal of phytopathology pest management, 4: 38-47.Tezze, A. A. and E. N. Botto, 2004. Effect of cold storage on the quality of Trichogramma nerudai (Hymenoptera: Trichogrammatidae). Biological control, 30(1): 11-16.Tunçbilek, A. S., U. Canpolat and F. Sumer, 2009. Suitability of irradiated and cold-stored eggs of Ephestia kuehniella (Pyralidae: Lepidoptera) and Sitotroga cerealella (Gelechidae: Lepidoptera) for stockpiling the egg-parasitoid Trichogramma evanescens (Trichogrammatidae: Hymenoptera) in diapause. Biocontrol science technology, 19(sup1): 127-138.Van Lenteren, J. C., 2012. The state of commercial augmentative biological control: Plenty of natural enemies, but a frustrating lack of uptake. BioControl, 57(1): 1-20.Venkatesan, T., S. Singh and S. Jalali, 2000. Effect of cold storage on cocoons of Goniozus nephantidis muesebeck (Hymenoptera: Bethylidae) stored for varying periods at different temperature regimes. Journal of entomological research, 24(1): 43-47.Wang, E., D. Lu, X. Liu and Y. Li, 2009. Evaluating the use of nuclear techniques for colonization and production of Trichogramma chilonis in combination with releasing irradiated moths for control of cotton bollworm, Helicoverpa armigera. Biocontrol science technology, 19(sup1): 235-242.Watanabe, M., 2002. Cold tolerance and myo-inositol accumulation in overwintering adults of a lady beetle, Harmonia axyridis (Coleoptera: Coccinellidae). European journal of entomology, 99(1): 5-10.Xia, J., J. Wang, J. Cui, P. Leffelaar, R. Rabbinge and W. Van Der Werf, 2018. Development of a stage-structured process-based predator–prey model to analyse biological control of cotton aphid, Aphis gossypii, by the sevenspot ladybeetle, Coccinella septempunctata, in cotton. Ecological complexity, 33: 11-30.Zapater, M. C., C. E. Andiarena, G. P. Camargo and N. Bartoloni, 2009. Use of irradiated musca domestica pupae to optimize mass rearing and commercial shipment of the parasitoid spalangia endius (Hymenoptera: Pteromalidae). Biocontrol science technology, 19(sup1): 261-270.

Abstract:

International audience We consider a mathematical SIL model for the spread of a directly transmitted infectious disease in an age-structured population; taking into account the demographic process and the vertical transmission of the disease. First we establish the mathematical well-posedness of the time evolution problem by using the semigroup approach. Next we prove that the basic reproduction ratio R0 is given as the spectral radius of a positive operator, and an endemic state exist if and only if the basic reproduction ratio R0 is greater than unity, while the disease-free equilibrium is locally asymptotically stable if R0<1. We also show that the endemic steady states are forwardly bifurcated from the disease-free steady state when R0 cross the unity. Finally we examine the conditions for the local stability of the endemic steady states.

Abstract:

This study aims to use Lyapunov function method to build a SEIR model in the analysis of early detection and treatment. The SEIR model is a system of ordinary differential equations of six dimension developed from our compartment then building a mathematical theorem which guarantees the existence of a case of TB, the disease free-equilibrium and the total eradication of the disease from its host community that is disease endemic TB. Three theorems were proved using Lyapunov function method. With these, we concluded that in this research work have given a complete stability analysis of a tuberculosis model with two differential infectivity classes of early detected infected individual and late detected infected individual. By analysing this model, we found that it is locally asymptotically stable and possesses the only locally stable equilibrium state depending on the basic reproductive ratio R0 this steady state is either the endemic or the disease-free. The local stability of the infection-free equilibrium state implies that for an initial level of infection the disease will eventually fade out from the population when the condition for the stability, number R0 ≤1, hold. The condition R0>1, implies that the disease will persist in a population.

Abstract:

Background: Data are conflicting regarding the extent to which insulin resistance or dysglycemia contribute to the development of elevated blood pressure (BP). Therefore, we examined whether these metabolic abnormalities are associated with distinct BP components, including measures of pulsatile versus steady state load (surrogates for large and small artery disease) in a large community-based cohort. Methods: We studied 10,720 non-diabetic participants from 4 U.S. sites in the Hispanic Community Health Study / Study of Latinos who were free of cardiovascular disease and not on any anti-hypertensive medications. We used linear regression for complex survey sampling and non-parametric spline models to examine the relation of insulin resistance (HOMA-IR) and dysglycemia (HbA1c) with components of BP (systolic, diastolic, pulse pressure [PP, reflecting pulsatile load], and mean arterial pressure [MAP, reflecting steady state load]) while adjusting for established clinical correlates of BP. Results: The target population mean age was 38 years (s.e. 0.22) and included 52% women, 38% with pre-diabetes, 35% obese, and 9% with untreated hypertension. All BP component measures were higher in pre-diabetes than non-diabetes. In multivariable analyses, HOMA-IR was significantly associated with increase in all BP components (P<0.01 for all), including both PP and MAP, in the setting of both pre-diabetes and particularly non-diabetes (Figure). By contrast, HbA1c was not significantly associated with increase in any BP component. Conclusion: In a large population of non-diabetic Hispanic/Latino adults, insulin resistance (rather than dysglycemia per se) is related to increase in all BP components including measures of both pulsatile load (representing large artery disease) and steady state load (representing small artery disease). These findings may have implications for interventions aimed at preventing large and small vessel disease in the community.

Abstract:

AbstractThe Middle East and North Africa (MENA) region has witnessed a slow but steady increase in the harm reduction response since 2016. It is likely that such gains are threatened by the impact of COVID-19. Very little is known about the health response and situation of people who use drugs (PWUD) during the pandemic in the region. A mixed method study was conducted by the MENA Harm Reduction Association (MENAHRA) to assess the situation of PWUD and impacts on harm reduction services during COVID-19. Twelve countries and two regional viewpoints responded to the survey. A virtual focus group was held with the MENA Network of People who Use Drugs (MENANPUD) focal points (n = 11). The study highlights how COVID-19 aggravated existing marginalization and stigmatization of PWUD and other key populations in the MENA region, with government level resourcing severely impacted by COVID-19. It further illustrates the commitment by harm reduction non-governmental organizations (NGOs) in diversifying their response, particularly through mobile outreach to drug hot spots, and the reliance of technology to support awareness raising, telemedicine, and medicine supplies. Positive shifts are observed in harm reduction policy by governments in some MENA countries and the continued commitment to support PWUD communities by existing harm reduction NGOs. Continued advocacy for and implementation of harm reduction responses at the domestic and regional levels should be underpinned by inclusion in state health emergency planning and disease control efforts, awareness raising around innovation and telemedicine to support health and NGO support systems and medicine supply chains, resourcing of NGOs, and provision of economic support for PWUD, disease surveillance, and research.

Abstract:

ObjectiveWe report the findings of Andhra Pradesh state’s mobile medical service programme and how It is currently used to strengthen the disease surveillance mechanisms at the village level.IntroductionIndia has an Integrated Disease Surveillance project that reports key communicable and infectious diseases at the district and sub-district level. However, recent reviews suggest structural and functional deficiencies resulting in poor data quality (1). Hence evidence-based actions are often delayed. Piramal Swasthya in collaboration with Government of Andhra Pradesh launched a mobile medical unit (MMU) programme in 2016. This Mobile medical service delivers primary care services to rural population besides reporting and alerting unusual health events to district and state health authorities for timely and appropriate action.The MMU service in the Indian state of Andhra Pradesh is one of the oldest and largest public-private initiatives in India. Two hundred and ninety-two MMUs provide fixed-day services to nearly 20,000 patients a day across 14,000 villages in rural Andhra Pradesh. Every day an MMU equipped with medical ( a doctor) and non-medical (1 nurse, 1 registration officer, 1 driver, 1 pharmacist, 1 lab technician, 1 driver) staff visit 2 service points (villages) as per prefixed route map. Each MMU also has its own mobile tablet operated by registration officer for capturing patient details. The core services delivered through MMUs are the diagnosis, treatment, counseling, and free drug distribution to the beneficiaries suffering from common ailments ranging from seasonal diseases to acute communicable and common chronic non-communicable diseases. The routinely collected patient data is daily synchronized on a centrally managed data servers.MethodsFor this analysis, we used aggregated and pooled data that were routinely collected from August 2016-March 2018. Patient details such as socio-demographic variables (age, sex etc.) medical history and key vitals (random blood sugar, blood pressure, pulse rate etc.) and disease diagnosis variables were analyzed. Besides, communication and action taken reports shared with Government of Andhra Pradesh were also analyzed. We report the findings of the programme with reference to strengthing the village level communicable disease surveillance. Unusual health events were defined as more than 3 patients reporting the epidemiologically linked and similar conditions clustered in the same village.ResultsWe observed 4,352,859 unique beneficiaries registrations and 9,122,349 patient visits. Of all unique beneficiaries, 79.3% had complete diagnosis details (53% non-communicable disease, 39% communicable and 8% others conditions). A total of 7 unusual health events related to specific and suspected conditions (3 vector-borne diseases related, 4 diarrhea-related) were reported to district health authorities, of which 3 were confirmed outbreaks (1 dengue, 1 malaria, and 1 typhoid) as investigated by local health authorities.ConclusionsMobile medical services are useful to detect unusual health events in areas with limited resources. It increases accountability and response from the Government authorities if the timely information is shared with competent health authorities. Careful evaluation of the mobile health interventions is needed before scaling-up such services in other remote rural areas.References1. Kumar A, Goel MK, Jain RB, Khanna P. Tracking the Implementation to identify gaps in Integrated Disease Surveillance Program in a Block of District Jhajjar (Haryana). Journal of Family Medicine and Primary Care. 2014;3(3):213-215.2. Raut D, Bhola A. Integrated disease surveillance in India: Way forward. Global Journal of Medicine and Public Health.2014;3(4):1-10

Abstract:

ObjectiveAutomated syndromic surveillance using mobile devices is an emerging public health focus that has a high potential for enhanced disease tracking and prevention in areas with poor infrastructure. Pacific Northwest National Laboratory sought to develop an Android mobile application for syndromic biosurveillance that would i) use the phone camera to take images of human faces to detect individuals that are sick through a machine learning (ML) model and ii) collect image data to increase training data available for ML models. The initial prototype use case is for screening and tracking the health of soldiers for use by the Department of Defense’s Disease Threat Reduction Agency.IntroductionInfectious diseases present with multifarious factors requiring several efforts to detect, prevent, and break the chain of transmission. Recently, machine learning has shown to be promising for automated surveillance leading to rapid and early interventions, and extraction of phenotypic features of human faces [3, 5]. In addition, mobile devices have become a promising tool to provide on-the-ground surveillance, especially in remote areas and geolocation mapping [4].Pacific Northwest National Laboratory (PNNL) combines machine learning with mobile technology to provide a groundbreaking prototype of disease surveillance without the need for internet, just a camera. In this android application, VisionDx, a machine learning algorithm analyses human face images and within milliseconds notifies the user with confidence level whether or not the person is sick. VisionDx comes with two modes, photo and video, and additional features of history, map, and statistics. This application is the first of its kind and provides a new way to think about the future of syndromic surveillance.MethodsData. Human healthy (n = 1096) and non-healthy (n = 1269) facial images met the criteria for training the Machine Learning model after preprocessing them. The healthy images were obtained from the Chicago face database [6] and California Institute of Technology [2]. There are no known collections of disease facial images. Using open source image collection/curation services, images were identified by a variety of keywords, including specific infectious diseases. The criteria for image inclusion was 1. a frontal face was identified using OpenCV library [1], and 2. the image contained signs of disease through visual inspection (e.g., abnormal color, texture, swelling).Model. To identify a sick face from a healthy one, we used transfer machine learning and experimented with various pretrained Convolutional Neural Networks (CNN) from Google for mobile and embedded vision applications. Using MobileNet, we trained the final model with our data and deployed it to our prototype mobile app. Google Mobile Vision API and TensorFlow mobile were used to detect human faces and run predictions in the mobile app.Mobile Application. The Android app was built using Android Studio to provide an easily navigable interface that connects every action between tabbed features. The app features (i.e., Map, Camera, History, and Statistics) are in tab view format. The custom-made camera is the main feature of the app, and it contains face detection capability. A real-time health status detection function gives a level of confidence based the algorithm results found on detected faces in the camera image.ResultsPNNL's prototype Android application, VisionDx, was built with user-friendly tab views and functions to take camera images of human faces and classify them as sick or healthy through an inbuilt ML model. The major functions of the app are the camera, map, history, and statistics pages. The camera tab has a custom-made camera with face detection algorithm and classification model of sick or healthy. The camera has image or video mode and results of the algorithm are updated in milliseconds. The Statistics view provides a simple pie chart on sick/healthy images based on user selected time and location. The Map shows pins representing all labeled images stored, and the History displays all the labeled images. Clicking on an image in either view shows the image with metadata, i.e., model confidence levels, geolocation, and datetime.The CNN model prediction accuracy has ~98% validation accuracy and ~96% test accuracy. High model performance shows the possibility that deep learning could be a powerful tool to detect sickness. However, given the limited dataset, this high accuracy also means the model is most likely overfit to the data. The training set is limited: a. the number of training images is small compared to the variability in facial expressions and skin coloring, and b. the sick images only contained overt clinical signs. If trained on a larger, diverse set of data, this prototype app could prove extremely useful in surveillance efforts of individual to large groups of people in remote areas, e.g., to identify individuals in need of medical attention or get an overview of population health. In effort to improve the model, VisionDx was developed as a data collection tool to build a more comprehensive dataset. Within the tool, users can override the model prediction, i.e., false positive or false negative, with a simple toggle button. Lastly, the app was built to protect privacy so that other phone aps can't access the images unless shared by a user.ConclusionsDeveloped at PNNL for the Defense Threat Reduction Agency, VisionDx is a novel, camera-based mobile application for real-time biosurveillance and early warning in the field without internet dependency. The prototype mobile app takes pictures of faces and analyzes them using a state-of-the-art machine learning model to give two confidence levels of likelihood of being sick and healthy. With further development of a labeled dataset, such as by using the app as a data collection too, the results of the algorithm will quickly improve leading to a ground-breaking approach to public health surveillance.References1. Bradski G. (n.d.) The OpenCV Library. Retrieved Sept 30, 2018 at http://www.drdobbs.com/open-source/the-opencv-library/1844043192. Computational Vision: Archive. (1999). Retrieved Sept 22, 2018 at http://www.vision.caltech.edu/html-files/archive.html3. Ferry Q, Steinberg J, Webber C, et al (2014). Diagnostically relevant facial gestalt information from ordinary photos. ELife, 3, e02020.4. Fornace KM, Surendra H, Abidin TR, et al (2018). Use of mobile technology-based participatory mapping approaches to geolocate health facility attendees for disease surveillance in low resource settings. International Journal of Health Geographics, 17(1), 21. https://doi.org/10.1186/s12942-018-0141-05. Lopez DM, de Mello FL, G Dias, CM, et al (2017). Evaluating the Surveillance System for Spotted Fever in Brazil Using Machine-Learning Techniques. Frontiers in Public Health, 5. https://doi.org/10.3389/fpubh.2017.003236. Ma DS, Correll J, Wittenbrink B. (2015) The Chicago face database: A free stimulus set of faces and norming data. Behavior Research Methods, 47(4), 1122–1135. https://doi.org/10.3758/s13428-014-0532-5

Abstract:

Diabetes mellitus can independently contribute to cardiovascular disease and represents a severe risk factor for premature development of cardiovascular disease. A three-fold higher mortality than the general population has been observed in type 1 diabetes mellitus whereas a two- to four-fold increased probability to develop cardiovascular disease has been observed in type 2 diabetes mellitus. Cardiovascular magnetic resonance, a non-radiative modality, is superior to all other modalities in detecting myocardial infarction. The main cardiovascular magnetic resonance sequences used include a) balanced steady-state free precession (bSSFP) for function evaluation; b) T2-W for oedema detection; c) T1 W for ischemia detection during adenosine stress; and d) late gadolinium enhanced T1-W images (LGE), evaluated 15 min after injection of paramagnetic contrast agent gadolinium, which permit the diagnosis of replacement fibrosis, which appears white in the middle of suppressed, nulled myocardium. Although LGE is the technique of choice for diagnosis of replacement fibrosis, it cannot assess diffuse myocardial fibrosis. The application of T1 mapping (native or pre contrast and post contrast) allows identification of diffuse myocardial fibrosis, which is not detectable my other means. Native T1 and Contrast-enhanced T1 mapping are involved in the extracellular volume fraction (ECV) calculation. Recently, 1H-cardiovascular magnetic resonance spectroscopy has been applied to calculate the amount of myocardial triglycerides, but at the moment it is not part of the routine assessment of diabetes mellitus. The multifaceted nature of cardiovascular magnetic resonance has the great potential of concurrent evaluation of function and myocardial ischemia/fibrosis in the same examination and represents an indispensable tool for accurate diagnosis of cardiovascular disease in diabetes mellitus.

Abstract:

Background Heart disease has been and continues to be the number one cause of death in New York City and New York State. In 2009, an estimated 19,715 deaths were associated with heart disease in New York City alone. Health awareness has played a key role in the steady decline of this number. NYU Langone Medical Center has been receiving funding from a grant to support free health fairs that have provided basic testing to any individual willing to enroll since 2008. To date, nearly a hundred of these fairs have been conducted across New York City in places of worship, community centers, and Bellevue Hospital Center. Methods Health fairs were conducted over a four-year period targeting lower income communities in the New York City Metro area. The target population included any individual over the age of 18. When consented, they provided their demographics and filled a questionnaire. The patient then received a finger prick to examine blood glucose, total cholesterol, LDL, HDL, and triglyceride levels, along with their blood pressure. After receiving the results on-site, the patients were counseled by a qualified individual, often a NP or physician, and given an interpretation of their results accompanied with lifestyle advice and clinic referrals. The data from the fairs was compiled onto an online Electronic Data Capture system. Results A total of 4366 subjects were enrolled with a median age of 45. Analysis of the data showed significant numbers associated with risk factors of heart disease. 40.1% (1687 of 4204) of all subjects showed a total cholesterol level greater than or equal to 200 mg/dL with the highest risk group being African-Americans at 68.4% (661 of 966). A family history of coronary disease or sudden death before age 55 was noted by 23.33% (923 of 3966) of subjects. 24.07% (1051 of 4366) of the patients were referred to their primary care provider or Bellevue Hospital's clinic because of abnormal test results at the health fair. Conclusion The data values obtained provide a general outlook of the health within lower income communities in New York City. A significant portion of the enrolled subjects met at least one risk factor associated with heart disease. Many factors can be attributed to these statistics including lifestyle, genetics, and access to healthcare. These free health fairs have made dramatic impact in local communities by providing access to simple yet important tests.

Abstract:

Abstract Funding Acknowledgements Type of funding sources: None. Background Stress cardiovascular magnetic resonance (S-CMR) has been recognized as a reliable technique for the diagnosis and prognostic stratification of patients with known or suspected coronary artery disease (CAD). Recently, the novel technique of feature-tracking (FT) strain has been applied to S-CMR in order to improve the risk stratification of patients. However, no data are available on the prognostication role of FT strain in patients undergoing a S-CMR with dypiridamole. Aim of this study is to assess the additional role of FT strain in the long-term risk stratification of a large population of patients with known or suspected CAD undergoing a S-CMR with dypiridamole. Methods 731 consecutive patients (age: 63 ± 10 y, male 84%) with stable typical or atypical symptoms suggesting possible cardiac ischemia underwent dipyridamole S-CMR. The patients were followed up for 5.8 ± 1.2 years. CMR-FT analysis of steady state free precession (SSFP) short and long axis cine images obtained in rest and stress conditions was performed in each patient to obtain 2D global peak systolic rest and stress longitudinal (GLS), circumferential (GCS) and radial strains (GRS). Major adverse cardiac events (MACE) were defined as myocardial infarction and cardiac death. Results MACE occurred in 64 (8.7%) patients. Patients experiencing MACE showed higher indexed left ventricular (LV) end-diastolic (EDVi), end-systolic (ESVi) volumes and lower LV ejection fraction (LVEF), higher late-gadolinium enhancement (LGE) presence and reduced both rest and stress GLS, GCS and GRS. At multivariable analysis, LVEDVi (HR 1,01 [95% CI 1.001-1.022]) and LGE (HR 2.399 [95% CI 1.322-4.355] were independently associated with MACE (p = 0.027 and p = 0.04 respectively). By Kaplan-Meier analysis, patients with stress GLS ≥ -15.35% had significantly reduced event-free survival compared with those with stress GLS &lt; -15.35 (log-rank p = 0.001). A model based on stress GCS &gt; - 15.3% plus LVEDVi showed a similar prognostication value of a model made of LVEDVi plus LGE. Conclusions In patients with known or suspected CAD undergoing S-CMR with dypiridamole, a model based on LVEDVi plus stress GCS owns a prognostication value similar to LVEDVi plus LGE.

Abstract:

Abstract Background Mitral valve (MV) and tricuspid valve (TV) apparatus geometry are essential to define mechanisms and etiologies of regurgitation and to inform surgical or transcatheter interventions. Given the increasing use of cardiovascular magnetic resonance (CMR) for the evaluation of valvular heart disease, we aimed to establish CMR-derived age- and sex-specific reference values for mitral annular (MA) and tricuspid annular (TA) dimensions and tethering indices derived from truly healthy Caucasian adults. Methods 5065 consecutive UK Biobank participants underwent CMR using cine balanced steady-state free precession imaging at 1.5 T. Participants with non-Caucasian ethnicity, prevalent cardiovascular disease and other conditions known to affect cardiac chamber size and function were excluded. Absolute and indexed reference ranges for MA and TA diameters and tethering indices were stratified by gender and age (45–54, 55–64, 65–74 years). Results Overall, 721 (14.2%) truly healthy participants aged 45–74 years (54% women) formed the reference cohort. Absolute MA and TA diameters, MV tenting length and MV tenting area, were significantly larger in men. Mean ± standard deviation (SD) end-diastolic and end-systolic MA diameters in the 3-chamber view (anteroposterior diameter) were 2.9 ± 0.4 cm (1.5 ± 0.2 cm/m2) and 3.3 ± 0.4 cm (1.7 ± 0.2 cm/m2) in men, and 2.6 ± 0.4 cm (1.6 ± 0.2 cm/m2) and 3.0 ± 0.4 cm (1.8 ± 0.2 cm/m2) in women, respectively. Mean ± SD end-diastolic and end-systolic TA diameters in the 4-chamber view were 3.2 ± 0.5 cm (1.6 ± 0.3 cm/m2) and 3.2 ± 0.5 cm (1.7 ± 0.3 cm/m2) in men, and 2.9 ± 0.4 cm (1.7 ± 0.2 cm/m2) and 2.8 ± 0.4 cm (1.7 ± 0.3 cm/m2) in women, respectively. With advancing age, end-diastolic TA diameter became larger and posterior MV leaflet angle smaller in both sexes. Reproducibility of measurements was good to excellent with an inter-rater intraclass correlation coefficient (ICC) between 0.92 and 0.98 and an intra-rater ICC between 0.90 and 0.97. Conclusions We described age- and sex-specific reference ranges of MA and TA dimensions and tethering indices in the largest validated healthy Caucasian population. Reference ranges presented in this study may help to improve the distinction between normal and pathological states, prompting the identification of subjects that may benefit from advanced cardiac imaging for annular sizing and planning of valvular interventions.

Abstract:

Abstract Introduction Cardiovascular disease (CVD) is more common in women who have had pregnancy complications such as spontaneous pregnancy loss. We used cross-sectional data from the UK Biobank Imaging Enhancement Study to determine whether pregnancy loss is associated with cardiac or vascular remodelling in later life, which might contribute to this increased risk. Methods Pregnancy history was reported by women participating in UK Biobank between 2006 and 2010 at age 40–69 years using a self-completed touch-screen questionnaire. Self-reported pregnancy loss was related to cardiovascular measures collected in those women who had participated in the Imaging Enhancement Study up to the end of 2015. Cardiac structure and function were assessed by magnetic resonance (CMR) steady-state free precession imaging at 1.5 Tesla. Three long axes cines (horizontal, vertical and LV outflow tract) and a complete short axis stack were acquired, covering both ventricles. Tagging was used to measure myocardial strain in basal, midventricular and apical short axes views. Carotid intima-media thickness (CIMT) measurements were taken for both common carotid arteries using a CardioHealth Station. Statistical associations with CMR and carotid measures were adjusted for age, BMI and other cardiovascular risk factors. Results Data were available on 2660 women of whom 113 were excluded because of pre-existing CVD and 8 had no pregnancy information available. Of the remaining 2539, 466 were nulligravid and 2073 had a history of pregnancies, of whom 622 reported at least one pregnancy loss (92% miscarriages and 8% stillbirths) and 1451 reported no pregnancy loss. No significant differences in cardiac or carotid parameters were evident in women who reported pregnancy loss compared to other groups (Table 1). CMR cardiac geometry & CIMT measurements Variable Pregnancy History Adjusted Means ± SE Effect Size (%) 95% CI P LVEDV (ml) Pregnancy Loss 122.2±1.0 0 – – No Pregnancy 124.1±1.4 1.58 (−0.83, 4.05) 0.20 Pregnancy (no loss) 122.2±0.8 0.2 (−1.42, 1.48) 0.97 LVESV (ml) Pregnancy Loss 47.8±0.6 0 – – No Pregnancy 48.0±0.8 0.45 (−3.19, 4.22) 0.81 Pregnancy (no loss) 47.3±0.5 −1.01 (−3.19, 1.22) 0.37 VEF (%) Pregnancy Loss 60.6±0.3 0 – – No Pregnancy 61.0±0.4 0.42 (−0.50, 1.35) 0.37 Pregnancy (no loss) 61.0±0.2 0.43 (−0.14, 0.99) 0.14 LVM (g) Pregnancy Loss 70.6±0.6 0 – – No Pregnancy 70.5±0.8 −0.15 (−2.68, 2.44) 0.91 Pregnancy (no loss) 70.4±0.5 −0.26 (−1.81, 1.30) 0.74 CIMT (μm) Pregnancy Loss 633.3±6.5 0 – – No Pregnancy 619.3±8.4 −2.22 (−5.04, 0.68) 0.13 Pregnancy (no loss) 627.1±4.9 −0.99 (−2.75, 0.81) 0.28 Conclusion Women who self-report pregnancy loss do not have significant differences in cardiac or carotid structure in later life to explain past epidemiological findings of increased cardiovascular risk in this population. This may be because this risk operates through other disease mechanisms or that self-report is not a sufficiently reliable way to identify pregnancy loss, and thereby allocate women into risk groups.

Abstract:

Women with type 1 diabetes (T1D) lose the premenopausal protection from cardiovascular disease (CVD) that non-diabetic (non-DM) women have compared to men, and are also more insulin resistant than non-DM women. Standard CVD risk factors have not been found to adequately predict CVD in the T1D population, but insulin resistance is emerging as a potentially important risk factor. The aim of this study was to determine whether sex hormone levels such as estradiol (E2), total testosterone (TT), and sex-hormone binding globulin (SHBG) explained any of the decreased insulin sensitivity in women with T1D, which could be important in CVD prevention. This study included 25 premenopausal women 18-45 years of age with a mean ± SD age of 33 ± 8 years who completed a three stage (4, 8 and 40 mU/m2/min) hyperinsulinemic-euglycemic clamp during the luteal phase of the menstrual cycle (T1D n=12 and non-DM n=13). A steady state was achieved during the last 30 minutes of the high insulin infusion stage and mean glucose infusion rate (GIR [mg/kg/FFM/min]) during this time was used as an estimate of the skeletal muscle glucose disposal rate. Sex hormones were compared using unpaired Student t tests between T1D and non-DM participants during each phase of the menstrual cycle and during the morning of the clamp.. Significant differences were explored in multivariable linear regression in which stepwise model selection was used to determine the final model adjusting for age and diabetes status. In age-adjusted analysis, women with T1D were less than half as insulin sensitive as non-DM women (least squares mean ± SE: 7.5±2.2 vs. 19.0±2.1, respectively, p=0.0014). SHBG was significantly higher in the T1D than the non-DM subjects the morning of the clamp (p<0.0001) and during each phase of the menstrual cycle (p = 0.01). TT was significantly higher in T1D women during the early follicular phase of the menstrual cycle (p=0.02) and was negatively correlated with GIR (r = -0.54, p = 0.04). E2 during the early follicular phase was positively correlated with GIR (r = 0.83, p = 0.01). In multivariable analysis, the difference in the GIR was attenuated by 58%(1-(5.1/12.14)) (least squares mean ± SE: 10.9 ± 1.7 in T1D vs. 16.0 ± 1.5 in non-DM, p = 0.07) after adjusting for age, diabetes status, minutes of vigorous activity, average waist circumference, free estradiol index and testosterone during the early follicular phase of the menstrual cycle In conclusion, the decreased insulin sensitivity observed in premenopausal T1D women with regular menstrual cycles can be mostly explained by lower levels of physical activity, greater central adiposity and differences in sex hormone levels. Most of these factors are modifiable, and so could be important targets in the reduction of CVD.

Abstract:

When historian Graeme Davison famously declared that “Australia was born urban and quickly grew suburban” (98), he was clearly referring to Melbourne or Sydney, but certainly not Brisbane. Although the Brisbane of 2011 might resemble a contemporary, thriving metropolis, its genealogy is not an urban one. For most of its history, as Gillian Whitlock has noted, Brisbane was “a place where urban industrial society is kept at bay” (80). What distinguishes Brisbane from Australia’s larger southern capital cities is its rapid morphology into a city from a provincial, suburban, town. Indeed it is Brisbane’s distinctive regionalism, with its sub-tropical climate, offering a steamy, fecund backdrop to narratives of the city that has produced a plethora of writing in literary accounts of the city, from author David Malouf through to contemporary writers such as Andrew McGahan, John Birmingham, Venero Armanno, Susan Johnson, and Nick Earls. Brisbane’s lack of urban tradition makes its transformation unique among Australian cities. Its rapid population growth and urban development have changed the way that many people now live in the city. Unlike the larger cities of Sydney or Melbourne, whose inner cities were established on the Victorian model of terrace-row housing on small lots, Brisbane’s early planners eschewed this approach. So, one of the features that gives the city its distinction is the languorous suburban quality of its inner-city areas, where many house blocks are the size of the suburban quarter-acre block, all within coo-ee of the city centre. Other allotments are medium to small in size, and, until recently, housed single dwellings of varying sizes and grandeur. Add to this a sub-tropical climate in which ‘green and growth’ is abundant and the pretty but flimsy timber vernacular housing, and it’s easy to imagine that you might be many kilometres from a major metropolitan centre as you walk around Brisbane’s inner city areas. It is partly this feature that prompted demographer Bernard Salt to declare Brisbane “Australia’s most suburban city” (Salt 5). Prior to urban renewal in the early 1990s, Brisbane was a low-density town with very few apartment blocks; most people lived in standalone houses.From the inception of the first Urban Renewal program in 1992, a joint initiative of the Federal government’s Building Better Cities Program and managed by the Brisbane City Council (BCC), Brisbane’s urban development has undergone significant change. In particular, the city’s Central Business District (CBD) and inner city have experienced intense development and densification with a sharp rise in medium- to high-density apartment dwellings to accommodate the city’s swelling population. Population growth has added to the demand for increased density, and from the period 1995–2006 Brisbane was Australia’s fastest growing city (ABS).Today, parts of Brisbane’s inner city resembles the density of the larger cities of Melbourne and Sydney. Apartment blocks have mushroomed along the riverfront and throughout inner and middle ring suburbs. Brisbane’s population has enthusiastically embraced apartment living, with “empty nesters” leaving their suburban family homes for the city, and apartments have become the affordable option for renters and first home purchasers. A significant increase in urban amenities such as large-scale parklands and river side boardwalks, and a growth in service industries such as cafes, restaurants and bars—a feature of cities the world over—have contributed to the appeal of the city and the changing way that people live in Brisbane.Urbanism demands specific techniques of living—life is different in medium- to high-density dwellings, in populous places, where people live in close proximity to one another. In many ways it’s the antithesis to suburban life, a way of living that, as Davison notes, was established around an ethos of privacy, health, and seclusion and is exemplified in the gated communities seen in the suburbs today. The suburbs are characterised by generosity of space and land, and developed as a refuge and escape from the city, a legacy of the nineteenth-century industrial city’s connection with overcrowding, disease, and disorder. Suburban living flourished in Australia from the eighteenth century and Davison notes how, when Governor Phillip drew up the first town plan for Sydney in 1789, it embodied the aspirations of “decency, good order, health and domestic privacy,” which lie at the heart of suburban ideals (100).The health and moral impetus underpinning the establishment of suburban life—that is, to remove people from overcrowding and the unhygienic conditions of slums—for Davison meant that the suburban ethos was based on a “logic of avoidance” (110). Attempting to banish anything deemed dangerous and offensive, the suburbs were seen to offer a more natural, orderly, and healthy environment. A virtuous and happy life required plenty of room—thus, a garden and the expectation of privacy was paramount.The suburbs as a site of lived experience and cultural meaning is significant for understanding the shift from suburban living to the adoption of medium- to high-density inner-city living in Brisbane. I suggest that the ways in which this shift is captured discursively, particularly in promotional material, are indicative of the suburbs' stronghold on the collective imagination. Reinforcing this perception of Brisbane as a suburban city is a history of literary narratives that have cast Brisbane in ways that set it apart from other Australian cities, and that are to do with its non-urban characteristics. Imaginative and symbolic discourses of place have real and material consequences (Lefebvre), as advertisers are only too well aware. Discursively, city life has been imagined oppositionally from life in the suburbs: the two sites embody different cultural meanings and values. In Australia, the suburbs are frequently a site of derision and satire, characterized as bastions of conformity and materialism (Horne), offering little of value in contrast to the city’s many enchantments and diverse pleasures. In the well-established tradition of satire, “suburban bashing is replete in literature, film and popular culture” (Felton et al xx). From Barry Humphries’s characterisation of Dame Edna Everage, housewife superstar, who first appeared in the 1960s, to the recent television comedy series Kath and Kim, suburbia and its inhabitants are represented as dull-witted, obsessed with trivia, and unworldly. This article does not intend to rehearse the tradition of suburban lampooning; rather, it seeks to illustrate how ideas about suburban living are hard held and how the suburban ethos maintains its grip, particularly in relation to notions of privacy and peace, despite the celebratory discourse around the emerging forms of urbanism in Brisbane.As Brisbane morphed rapidly from a provincial, suburban town to a metropolis throughout the 1990s and early 2000s, a set of metropolitan discourses developed in the local media that presented new ways of inhabiting and imagining the city and offered new affiliations and identifications with the city. In establishing Brisbane’s distinction as a city, marketing material relied heavily on the opposition between the city and the suburbs, implying that urban vitality and diversity rules triumphant over the suburbs’ apparent dullness and hom*ogeneity. In a billboard advertisem*nt for apartments in the urban renewal area of Newstead (2004), images of architectural renderings of the apartments were anchored by the words—“Urban living NOT suburban”—leaving little room for doubt. It is not the design qualities of the apartments or the building itself being promoted here, but a way of life that alludes to utopian ideas of urban life, of enchantment with the city, and implies, with the heavy emphasis of “NOT suburban,” the inferiority of suburban living.The cultural commodification of the late twentieth- and twenty-first-century city has been well documented (Evans; Dear; Zukin; Harvey) and its symbolic value as a commodity is expressed in marketing literature via familiar metropolitan tropes that are frequently amorphous and international. The malleability of such images makes them easily transportable and transposable, and they provided a useful stockpile for promoting a city such as Brisbane that lacked its own urban resources with which to construct a new identity. In the early days of urban renewal, the iconic images and references to powerhouse cities such as New York, London, and even Venice were heavily relied upon. In the latter example, an advertisem*nt promoting Brisbane appeared in the Sydney Morning Herald colour magazine (May 2005). This advertisem*nt represented Brisbane as an antipodean Venice, showing a large reach of the Brisbane river replete with gondolas flanked by the city’s only nineteenth-century riverside building, the Custom’s House. The allusion to traditional European culture is a departure from the usual tropes of “fun and sun” associated with promotions of Queensland, including Brisbane, while the new approach to promoting Brisbane is cognizant of the value of culture in the symbolic and economic hierarchy of the contemporary city. Perhaps equally, the advertisem*nt could be read as ironic, a postmodern self-parodying statement about the city in general. In a nod to the centrality of the spectacle, the advertisem*nt might be a salute to idea of the city as theme park, a pleasure playground and a collective fantasy of escape. Nonetheless, either interpretation presents Brisbane as somewhere else.In other promotional literature for apartment dwellings, suburban living maintains its imaginative grip, evident in a brochure advertising Petrie Point apartments in Brisbane’s urban renewal area of inner-city New Farm (2000). In the brochure, the promise of peace and calm—ideals that have their basis in suburban living—are imposed and promoted as a feature of inner-city living. Paradoxically, while suggesting that a wholesale evacuation and rejection of suburban life is occurring presumably because it is dull, the brochure simultaneously upholds the values of suburbia:Discerning baby boomers and generation X’ers who prefer lounging over latte rather than mowing the quarter acre block, are abandoning suburban living in droves. Instead, hankering after a more cosmopolitan lifestyle without the mind numbing drive to work, they are retreating to the residential mecca, the inner city, for chic shops and a lively dining, arts and theatre culture. (my italics)In the above extract, the rhetoric used to promote and uphold the virtues of a cosmopolitan inner-city life is sabotaged by a language that in many respects capitulates to the ideals of suburban living, and evokes the health and retreat ethos of suburbia. “Lounging” over lattes and “retreating to a residential mecca”[i] allude to precisely the type of suburban living the brochure purports to eschew. Privacy, relaxation, and health is a discourse and, more importantly, a way of living that is in many ways anathema to life in the city. It is a dream-wish that those features most valued about suburban life, can and should somehow be transplanted to the city. In its promotion of urban amenity, the brochure draws upon a somewhat bourgeois collection of cultural amenities and activities such as a (presumably traditional) arts and theatre culture, “lively dining,” and “chic” shops. The appeal to “discerning baby boomers and generation X’ers” has more than a whiff of status and class, an appeal that disavows the contemporary city’s attention to diversity and inclusivity, and frequently the source of promotion of many international cities. In contrast to the suburban sub-text of exclusivity and seclusion in the Petrie Point Apartment’s brochure, is a promotion of Sydney’s inner-city Newtown as a tourist site and spectacle, which makes an appeal to suburban antipathy clear from the outset. The brochure, distributed by NSW Tourism (2000) displays a strong emphasis on Newtown’s cultural and ethnic diversity, and the various forms of cultural consumption on offer. The inner-city suburb’s appeal is based on its re-framing as a site of tourist consumption of diversity and difference in which diversity is central to its performance as a tourist site. It relies on the distinction between “ordinary” suburbs and “cosmopolitan” places:Some cities are cursed with suburbs, but Sydney’s blessed with Newtown — a cosmopolitan neighbourhood of more than 600 stores, 70 restaurants, 42 cafes, theatres, pubs, and entertainment venues, all trading in two streets whose origins lie in the nineteenth century … Newtown is the Catwalk for those with more style than money … a parade where Yves St Laurent meets Saint Vincent de Paul, where Milano meets post-punk bohemia, where Max Mara meets Doc Marten, a stage where a petticoat is more likely to be your grandma’s than a Colette Dinnigan designer original (From Sydney Marketing brochure)Its opening oppositional gambit—“some cities are cursed with suburbs”—conveniently elides the fact that like all Australian cities, Sydney is largely suburban and many of Sydney’s suburbs are more ethnically diverse than its inner-city areas. Cabramatta, Fairfield, and most other suburbs have characteristically high numbers of ethnic groups such as Vietnamese, Korean, Lebanese, and so forth. Recent events, however, have helped to reframe these places as problem areas, rather than epicentres of diversity.The mingling of social groups invites the tourist-flâneur to a performance of difference, “a parade where Yves St Laurent meets Saint Vincent de Paul (my italics), where Milano meets post-punk bohemia,” and where “the upwardly mobile and down at heel” appear in what is presented as something of a theatrical extravaganza. Newtown is a product, its diversity a commodity. Consumed visually and corporeally via its divergent sights, sounds, smells and tastes (the brochure goes on to state that 70 restaurants offer cuisine from all over the globe), Newtown is a “successful neighbourhood experiment in the new globalism.” The area’s social inequities—which are implicit in the text, referred to as the “down at heel”—are vanquished and celebrated, incorporated into the rhetoric of difference.Brisbane’s lack of urban tradition and culture, as well as its lack of diversity in comparison to Sydney, reveals itself in the first brochure while the Newtown brochure appeals to the idea of a consumer-based cosmopolitanism. As a sociological concept, cosmopolitanism refers to a set of "subjective attitudes, outlooks and practices" broadly characterized as “disposition of openness towards others, people, things and experiences whose origin is non local” (Skrbis and Woodward 1). Clearly cosmopolitan attitudes do not have to be geographically located, but frequently the city is promoted as the site of these values, with the suburbs, apparently, forever looking inward.In the realm of marketing, appeals to the imagination are ubiquitous, but discursive practices can become embedded in everyday life. Despite the growth of urbanism, the increasing take up of metropolitan life and the enduring disdain among some for the suburbs, the hard-held suburban values of peace and privacy have pragmatic implications for the ways in which those values are embedded in people’s expectations of life in the inner city.The exponential growth in apartment living in Brisbane offers different ways of living to the suburban house. For a sub-tropical city where "life on the verandah" is a significant feature of the Queenslander house with its front and exterior verandahs, in the suburbs, a reasonable degree of privacy is assured. Much of Brisbane’s vernacular and contemporary housing is sensitive to this indoor-outdoor style of living, a distinct feature and appeal of everyday life in many suburbs. When "life on the verandah" is adapted to inner-city apartment buildings, expectations that indoor-outdoor living can be maintained in the same way can be problematic. In the inner city, life on the verandah may challenge expectations about privacy, noise and visual elements. While the Brisbane City Plan 2000 attempts to deal with privacy issues by mandating privacy screenings on verandahs, and the side screening of windows to prevent overlooking neighbours, there is ample evidence that attitudinal change is difficult. The exchange of a suburban lifestyle for an urban one, with the exposure to urbanity’s complexity, potential chaos and noise, can be confronting. In the Urban Renewal area and entertainment precinct of Fortitude Valley, during the late 1990s, several newly arrived residents mounted a vigorous campaign to the Brisbane City Council (BCC) and State government to have noise levels reduced from local nightclubs and bars. Fortitude Valley—the Valley, as it is known locally—had long been Brisbane’s main area for nightclubs, bars and brothels. A small precinct bounded by two major one-way roads, it was the locus of the infamous ABC 4 Corners “Moonlight State” report, which exposed the lines of corruption between politicians, police, and the judiciary of the former Bjelke-Petersen government (1974–1987) and who met in the Valley’s bars and brothels. The Valley was notorious for Brisbanites as the only place in a provincial, suburban town that resembled the seedy side of life associated with big cities. The BCC’s Urban Renewal Task Force and associated developers initially had a tough task convincing people that the area had been transformed. But as more amenity was established, and old buildings were converted to warehouse-style living in the pattern of gentrification the world over, people started moving in to the area from the suburbs and interstate (Felton). One of the resident campaigners against noise had purchased an apartment in the Sun Building, a former newspaper house and in which one of the apartment walls directly abutted the adjoining and popular nightclub, The Press Club. The Valley’s location as a music venue was supported by the BCC, who initially responded to residents’ noise complaints with its “loud and proud” campaign (Valley Metro). The focus of the campaign was to alert people moving into the newly converted apartments in the Valley to the existing use of the neighbourhood by musicians and music clubs. In another iteration of this campaign, the BCC worked with owners of music venues to ensure the area remains a viable music precinct while implementing restrictions on noise levels. Residents who objected to nightclub noise clearly failed to consider the impact of moving into an area that was already well known, even a decade ago, as the city’s premier precinct for music and entertainment venues. Since that time, the Valley has become Australia’s only regulated and promoted music precinct.The shift from suburban to urban living requires people to live in very different ways. Thrust into close proximity with strangers amongst a diverse population, residents can be confronted with a myriad of sensory inputs—to a cacophony of noise, sights, smells (Allon and Anderson). Expectations of order, retreat, and privacy inevitably come into conflict with urbanism’s inherent messiness. The contested nature of urban space is expressed in neighbour disputes, complaints about noise and visual amenity, and sometimes in eruptions of street violence. There is no shortage of examples in the Brisbane’s Urban Renewal areas such as Fortitude Valley, where acts of hom*ophobia, racism, and other less destructive conflicts continue to be a frequent occurrence. While the refashioned discursive Brisbane is re-presented as cool, cultured, and creative, the tensions of urbanism and tests to civility remain in a process of constant negotiation. This is the way the city’s past disrupts and resists its cool new surface.[i] The use of the word mecca in the brochure occurred prior to 11 September 2001.ReferencesAllon, Fiona, and Kay Anderson. "Sentient Sydney." In Passionate City: An International Symposium. Melbourne: RMIT, School of Media Communication, 2004. 89–97.Australian Bureau of Statistics (ABS). Regional Population Growth, Australia, 1996-2006.Birmingham, John. "The Lost City of Vegas: David Malouf’s Old Brisbane." Hot Iron Corrugated Sky. Ed. R. Sheahan-Bright and S. Glover. St Lucia: U of Queensland P, 2002. xx–xx.Davison, Graeme. "The Past and Future of the Australian Suburb." Suburban Dreaming: An Interdisciplinary Approach to Australian Cities. Ed. L. Johnson. Geelong: Deakin University Press, 1994. xx–xx.Dear, Michael. The Postmodern Urban Condition. Oxford: Blackwell, 2000.Evans, Graeme. “Hard-Branding the Cultural City—From Prado to Prada.” International Journal of Urban and Regional Research 27.2 (2003): 417–40.Evans, Raymond, and Carole Ferrier, eds. Radical Brisbane. Melbourne: The Vulgar Press, 2004.Felton, Emma, Christy Collis, and Phil Graham. “Making Connections: Creative Industries Networks in Outer Urban Locations.” Australian Geographer 14.1 (Mar. 2010): 57–70.Felton, Emma. Emerging Urbanism: A Social and Cultural Study of Urban Change in Brisbane. PhD thesis. Brisbane: Griffith University, 2007.Glover, Stuart, and Stuart Cunningham. "The New Brisbane." Artlink 23.2 (2003): 16–23. Harvey, David. The Condition of Postmodernity: An Enquiry into the Origins of Cultural Change. Cambridge, MA: Blackwell, 1990. Horne, Donald. The Lucky Country: Australia in the Sixties. Ringwood: Penguin, 1964.Lefebvre, Henri. The Production of Space. Oxford: Basil Blackwell, 1991.Malouf, David. Johnno. St Lucia: University of Queensland Press, 1975. ---. 12 Edmondstone Street. London: Penguin, 1986.NSW Tourism. Sydney City 2000. Sydney, 2000.Salt, Bernard. Cinderella City: A Vision of Brisbane’s Rise to Prominence. Sydney: Austcorp, 2005.Skrbis, Zlatko, and Ian Woodward. “The Ambivalence of Ordinary Cosmopolitanism: Investigating the Limits of Cosmopolitanism Openness.” Sociological Review (2007): 1-14.Valley Metro. 1 May 2011 < http://www.valleymetro.com.au/the_valley.aspx >.Whitlock, Gillian. “Queensland: The State of the Art on the 'Last Frontier.’" Westerly 29.2 (1984): 85–90.Zukin, Sharon. The Culture of Cities. Cambridge, MA: Basil Blackwell, 1995.