Constant Mortality Research Articles

Molecular Spectroscopy for the Biochemical Composition Analysis of Patient-Derived Pancreatic Cancer Organoids.

Pancreatic ductal adenocarcinoma (PDAC) continues to pose profound challenges within the field of oncology due to its notorious resistance to existing therapies and constant high mortality rates. The recent emergence of three-dimensional patient-derived organoid (PDO) models marks a significant advancement, opening new avenues for exploring cancer biology and assessing therapeutic approaches. The aim of this study focuses on the innovative use of Fourier-transform infrared (FT-IR) spectroscopy to analyze PDAC organoids, thus illuminating their biochemical intricacies. In this study, PDAC organoids, cultivated from specimens sourced from cancer patients, were subjected to FT-IR spectroscopic imaging. By examining the spectral data within the critical fingerprint region (950-1800 cm-1), and employing principal component analysis (PCA), biochemical disparities were detected and analyzed. The results revealed distinct spectral profiles corresponding to different sample preparation techniques, which in turn highlighted variations in protein content and structure. PCA revealed a high homogeneity within classes and minimal passage number influence on spectral profiles, with variations in lipid content and protein profiles. Significantly, the biochemical fingerprint of these PDOs closely mirrored that of the original human tissue samples. This investigation underscores the efficacy of molecular spectroscopy as a non-invasive method for profound characterization of PDAC organoids, enhancing our comprehension of tumor biochemistry. The capacity for swift and precise biochemical profiling of PDOs via molecular spectroscopy heralds a promising future for this technique in the realms of cancer diagnostics and personalized medicine.

A high-throughput assay identifies molecules with antimicrobial activity against persister cells.

Introduction. Persister cells are transiently non-growing antibiotic-tolerant bacteria that cause infection relapse, and there is no effective antibiotic therapy to tackle these infections.Gap statement. High-throughput assays in drug discovery are biased towards detecting drugs that inhibit bacterial growth rather than killing non-growing bacteria. A new and simple assay to discover such drugs is needed.Aim. This study aims to develop a simple and high-throughput assay to identify compounds with antimicrobial activity against persister cells and use it to identify molecular motifs with such activity.Methodology. We quantified Staphylococcus aureus persister cells by enumeration of colony forming units after 24 h ciprofloxacin treatment. We first quantified how the cell concentration, antibiotic concentration, growth phase and presence/absence of nutrients during antibiotic exposure affected the fraction of persister cells in a population. After optimizing these parameters, we screened the antimicrobial activity of compound fragments to identify molecular structures that have activity against persister cells.Results. Exponential- and stationary-phase cultures transferred to nutrient-rich media displayed a bi-phasic time-kill curve and contained 0.001-0.07% persister cells. A short rifampicin treatment resulted in 100% persister cells for 7 h, after which cells resumed activity and became susceptible. Stationary-phase cultures displayed a low but constant death rate but ultimately resulted in similarly low survival rates as the exponential-phase cultures after 24 h ciprofloxacin treatment. The persister phenotype was only maintained in most of the population for 24 h if cells were transferred to a carbon-free minimal medium before exposure to ciprofloxacin. Keeping cells starved enabled the generation of high concentrations of S. aureus cells that tolerate 50× MIC ciprofloxacin, and we used this protocol for rapid screening for biocidal antibiotics. We identified seven compounds from four structural clusters with activity against antibiotic-tolerant S. aureus. Two compounds were moderately cytotoxic, and the rest were highly cytotoxic.Conclusion. Transferring a stationary-phase culture to a carbon-free minimal medium for antimicrobial testing is a simple strategy for high-throughput screening for new antibiotics that kill persister cells. We identified molecule fragments with such activity, but further screening is needed to identify motifs with lower general cytotoxicity.

Probability Distribution of Tree Age for the Simple Birth-Death Process, with Applications to Distributions of Number of Ancestral Lineages and Divergence Times for Pairs of Taxa in a Yule Tree.

In this contribution, a general expression is derived for the probability density of the time to the most recent common ancestor (TMRCA) of a simple birth-death tree, a widely used stochastic null-model of biological speciation and extinction, conditioned on the constant birth and death rates and number of extant lineages. This density is contrasted with a previous result which was obtained using a uniform prior for the time of origin. The new distribution is applied to two problems of phylogenetic interest. First, that of the probability of the number of taxa existing at any time in the past in a tree of a known number of extant species, and given birth and death rates, and second, that of determining the TMRCA of two randomly selected taxa in an unobserved tree that is produced by a simple birth-only, or Yule, process. In the latter case, it is assumed that only the rate of bifurcation (speciation) and the size, or number of tips, are known. This is shown to lead to a closed-form analytical expression for the probability distribution of this parameter, which is arrived at based on the known mathematical form of the age distribution of Yule trees of a given size and branching rate, which is derived here de novo, and a similar distribution which additionally is conditioned on tree age. The new distribution is the exact Yule prior for divergence times of pairs of taxa under the stated conditions and is potentially useful in statistical (Bayesian) inference studies of phylogenies.

Combinedly increased viability of Lactiplantibacillus plantarum grx16 by co‐encapsulation of cryoprotectants and porous starch within calcium alginate capsules

SummaryAlginate‐based encapsulation is an effective probiotics delivery system in the intestine. However, due to calcium ions and gastric juice damaging cell wall/membrane integrity during freeze‐drying and gastrointestinal ingestion, lots of cell lose their viability. This study, taking Lactiplantibacillus plantarum grx16 as an example, indicated that co‐encapsulation of cryoprotectants and porous starch within calcium alginate capsules (CAC) could combinedly improve the viability of probiotics encapsulated. Compared with calcium alginate‐protectant capsule (CAC‐Pro) (50.67%), the combination of porous starch increased the encapsulation rate of PS0.8‐CAC‐Pro to 82.68%. Meanwhile, the death rate constants of PS0.8‐CAC‐Pro decreased by 31.3% (−20 °C), 13.5% (4 °C) and 7.5% (25 °C), respectively. The survival rate of PS0.8‐CAC‐Pro was 81.94% after continuous simulated gastrointestinal digestion, which was significantly higher than that of CACs (69.46%) and CAC‐Pro (76.92%). This study provided an effective approach for modifying alginate capsule to reduce the loss of probiotics viability.

Evolution of smoking-attributable cardiovascular mortality in Germany 1992-2020

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Marga and Walter Boll Foundation, Kerpen, Germany. Background Despite comparatively weak tobacco control, smoking has steadily declined in Germany over the last 30 years. At the same time, while cardiovascular mortality rates have generally been decreasing in recent decades, population ageing leads to increasing numbers of deaths. Purpose To explore the impact of smoking prevalence on cardiovascular mortality against the background of these different trends at a population level, this study sought to quantify trends in smoking-attributable cardiovascular mortality (SACVM) in Germany over the past three decades. Methods Smoking and mortality statistics from 1992 to 2020 were obtained from the German Statistical Office, from which absolute and relative SACVM was calculated separately for each cardiovascular cause of death causally associated with smoking. The impact of population ageing was explored by comparing crude and age-standardized SACVM, respectively. To estimate the impact of population ageing on future SACVM, a forward projection until 2035 was modelled assuming constant mortality rates and a continuation of smoking trends. Results Results show that total absolute SACVM strongly declined over time, from about 71,900 cases in 1992 to about 42,000 cases in 2020, with a stronger drop in men (from about 51,200 to 26,400 cases) than in women (from about 20,700 to 15,600 cases). Somewhat stronger declines were seen for age-adjusted SACVM, with differences between crude and age-standardized SACVM being somewhat more distinct in men. Relative SACVM decreased overall, from 17.3% in 1992 to 14.6% in 2020. Sex-specific relative SACVM however showed differing trends: a strong decrease in men (from 29.3% to 18.8%) and a slight increase in women (8.6% to 10.6%). The forward projection of SACVM indicates a slight decline among men and a marked increase in women. Conclusions Results indicate that SACVM has strongly declined over the past three decades, even though being partly compensated by opposing trends in population ageing. The marked decrease in absolute SACVM seems to be mostly due to the general drop in cardiovascular mortality rates, and only partly due to declining smoking rates, particularly in women, where relative SACVM has even slightly increased. Over the next 15 years, population ageing and the increasing trend in relative SACVM among women might halt the recent declining trend in absolute SACVM. Hence, there is tremendous potential to curb the smoking-associated public health burden by implementing a comprehensive set of evidence-based tobacco control polices. Additionally, given still significant smoking rates in middle and old age, smoking cessation programs should be intensified.

Influence of combined temperature and food availability on Peruvian anchovy (Engraulis ringens) early life stages in the northern Humboldt Current system: A modelling approach

In the northern Humboldt Current system (NHCS), the Peruvian anchovy (Engraulis ringens) constitutes the bulk of landings and has a significant socioeconomic contribution. Understanding the impact of environment on the early-life stages of anchovy and further population dynamics remains challenging. Climate variability at a variety of scales modulates currents velocity, temperature and food availability, impacting early-life stages drift, growth and survival. In order to investigate these impacts, we developed Ichthyop-DEB, an individual-based model including larval retention processes and a Dynamic Energy Budget (DEB) bioenergetic module for larval growth. First, we assessed the effect of hydrodynamic simulations horizontal resolution on simulated larval retention patterns using a recruitment age-criterion of 30 days. Then, we evaluated the impact of the following biological processes on simulated larval recruitment patterns: (i) a minimum size-criterion (2 cm), as opposed to a minimum age-criterion (30 days), to be considered as recruited, (ii) the upper larval thermal limit tolerance of the species, for which lab experiments are lacking, and (iii) a constant larval mortality rate. We found that using different resolutions of the hydrodynamic model (10 and 2 km) led to similar simulated larval retention patterns. Retention was highest when spawning occurred in the superficial layer (0–15 m) in austral winter and in the deepest considered layer (30–45 m) in summer. Coupling with the DEB model produced contrasted growth patterns on the continental shelf with a strong month-latitude interaction. Larval recruitment was strongest from 6° to 10° S in austral summer, largely contributing to the average seasonal pattern. Depending on the temperature correction function tested with the bioenergetic module, simulated larval recruitment could also be strong in the northernmost zone (2°–4°S), an area not known for abundant anchovy populations, which suggests a possible thermal growth limitation. Finally, sensitivity tests performed on larval growth limitation by food suggested a deficiency in food supply in the southernmost zone (18°–20°S).

Discretising Keyfitz' entropy for studies of actuarial senescence and comparative demography

Abstract Keyfitz' entropy is a widely used metric to quantify the shape of the survivorship curve of populations, from plants to animals and microbes. Keyfitz' entropy values <1 correspond to life histories with an increasing mortality rate with age (i.e. actuarial senescence), whereas values >1 correspond to species with a decreasing mortality rate with age (negative senescence), and a Keyfitz entropy of exactly 1 corresponds to a constant mortality rate with age. Keyfitz' entropy was originally defined using a continuous‐time model, and has since been discretised to facilitate its calculation from discrete‐time demographic data. Here, we show that the previously used discretisation of the continuous‐time metric does not preserve the relationship with increasing, decreasing or constant mortality rates. To resolve this discrepancy, we propose a new discrete‐time formula for Keyfitz' entropy for age‐classified life histories. We show that this new method of discretisation preserves the relationship with increasing, decreasing, or constant mortality rates. We analyse the relationship between the original and the new discretisation, and we find that the existing metric tends to underestimate Keyfitz' entropy for both short‐lived species and long‐lived species, thereby introducing a consistent bias. To conclude, to avoid biases when classifying life histories as (non‐)senescent, we suggest researchers use either the new metric proposed here, or one of the many previously suggested survivorship shape metrics applicable to discrete‐time demographic data such as Gini coefficient or Hayley's median.

The Rosenzweig–MacArthur Graphical Criterion for a Predator-Prey Model with Variable Mortality Rate

We consider a general modified Gause type model of predation, for which the predator mortality rate can depend on the densities of both species, prey and predator. We give a graphical criterion for the stability of positive hyperbolic equilibria, which is an extension of the well-known Rosenzweig–MacArthur graphical criterion for the case of a constant predator mortality rate. We examine the occurrence of a Poincaré–Andronov–Hopf bifurcation and give an expression for the first Lyapunov coefficient. Our model generalizes several models appearing in the literature. The relevance of our results, i.e. the use of the graphical criterion and the expression for the first Lyapunov coefficient, is tested on these models. The global behavior of the system is illustrated by numerical simulations which confirm the local properties of the models near the equilibria.

Immunoexpression of E-cadherin, CD44 and Claudin 7 in gastric adenocarcinomas.

Gastric adenocarcinomas represent frequent malignant tumors in the digestive tract, with a high and constant mortality rate in last decades. The disturbance of the adhesion molecules expression, which normally is essential in maintaining epithelial homeostasis, has a critical role in the initiation and progression of tumors. In this study, we analyzed the immunoexpression of E-cadherin, cluster of differentiation 44 (CD44), and Claudin 7 in 58 cases of gastric adenocarcinomas, in relation to the histopathological parameters of the lesions' aggressiveness. Increased E-cadherin immunoexpression was observed in tubular adenocarcinomas, those of low grade and in stages I-III. CD44 presented high scores in discohesive, hepatoid, tubular, and tubulopapillary adenocarcinomas, those of high grade and in advanced stages. Claudin 7 associated increased scores for tubular, tubulopapillary and micropapillary tumors, those of low grade and mainly in stage I. The markers used in the study can be useful for assessing the aggressiveness of gastric adenocarcinomas, in the context of specific adapted therapy.

Learning mitigates genetic drift

Genetic drift is a basic evolutionary principle describing random changes in allelic frequencies, with far-reaching consequences in various topics ranging from species conservation efforts to speciation. The conventional approach assumes that genetic drift has the same effect on all populations undergoing the same changes in size, regardless of different non-reproductive behaviors and history of the populations. However, here we reason that processes leading to a systematic increase of individuals` chances of survival, such as learning or immunological memory, can mitigate loss of genetic diversity caused by genetic drift even if the overall mortality rate in the population does not change. We further test this notion in an agent-based model with overlapping generations, monitoring allele numbers in a population of prey, either able or not able to learn from successfully escaping predators’ attacks. Importantly, both these populations start with the same effective size and have the same and constant overall mortality rates. Our results demonstrate that even under these conditions, learning can mitigate loss of genetic diversity caused by drift, by creating a pool of harder-to-die individuals that protect alleles they carry from extinction. Furthermore, this effect holds regardless if the population is haploid or diploid or whether it reproduces sexually or asexually. These findings may be of importance not only for basic evolutionary theory but also for other fields using the concept of genetic drift.

Inactivation kinetics and thermodynamics assessments of Geobacillus stearothermophilus during thermal sterilization for products safety

Chemical kinetics and thermodynamics provide modes and mechanisms for the thermal death of microbial spores. In this study, the effect of thermal inactivation on Geobacillus stearothermophilus, a highly heat-resistant bacterial species, was studied over the temperature range of 95, 100, 105, and 110 °C and holding sterilization periods of 10, 15, 20, 25, 30, and 45 min by the application of mathematical analysis of kinetic and thermodynamic properties. Thermal death rate constant, k, for the best kinetic order of sterilization ranged between 0.0431 to 0.1581 min−1 with the energy of activation, Ea, estimated to be 115.96 kJ/mol. Two primary thermal death kinetic models were applied (log-linear first order and the nonlinear Weibull). Weibull's model provided more reliable kinetic parameters to predict the effect of thermal treatments. Concave curves (α >1) were predicted with the Weibull's model for 100, 105, and 110 °C (1.57, 1.26, and 1.22 respectively), indicating the susceptibility of spores to lethal treatment. The rate parameter, ɸ (first reduction time) decreased with increasing thermal heating (28.80 min (95 °C), 21.08 min (100 °C), 14.61 min (105 °C), and 9.65 min (110 °C)) following the paths of the D-values (about 7 min to attain 88% spores’ destruction after 110 °C heating) of the log-linear kinetic model. Thermal death time (TDT) for the complete destruction of spores was predicted to be after 40 min at 110 °C. The z-value was 23.31 °C, indicating the sterilization temperature that must be attained for one log destruction of spores. The heat of activation showed endothermic reactions for all temperatures (∆H ranged 112.90 – 112.78 kJ/mol), Gibb's free energy of activation, ∆G, ranged from 325 – 333.74 kJ/mol (indicating a non-spontaneous reaction), and the entropy of activation (∆S) showed reversibility of reaction (∆S < 1) for all the thermal temperatures.

A systematic map of demographic data from elephant populations throughout Africa: implications for poaching and population analyses

Abstract The crisis facing Africa’s elephant populations is a notorious example of ongoing wildlife declines caused by illegal harvesting. Targeted conservation interventions require detailed knowledge about changes in population sizes and the effect of illegal activities. However, accurately quantifying poaching intensity is a difficult task: commonly calculated from ranger‐based carcass‐encounter data, the proportion of illegally killed elephants (PIKE) is a function of poaching and background mortality. Hence, at constant poaching intensity, PIKE decreases with increasing natural mortality and also with hunting, management interventions, and other anthropogenically induced deaths. Natural mortality is often more difficult to quantify with accuracy than mortality due to illegal killing, as elephants that die naturally are more likely to be missed than those taken by poachers. In recent analyses, constant background mortality rates were assumed. Yet, for example climate‐driven fluctuations in natural mortality, if not quantified and accounted for, may lead to biased estimates of poaching intensity. Varying background mortality rates can be accounted for in the analysis of PIKE, but this requires near‐complete counts of natural and management‐related deaths and hunting records. Carefully developed population models, which simulate population dynamics and demographic changes while accounting for variation in environmental conditions and management strategies, are alternatives. However, successful calibration of such models requires integrating comprehensive demographic data. We systematically review the scientific and ‘grey’ literature on African elephant demography with the objective of facilitating poaching and population analysis possibilities through an inventory of information relevant to demography. Our screening of 10900 publications resulted in the review of relevant information provided by 431 studies from 420 study sites throughout Africa. From these, we extracted demographic data collected between 1900 and 2017, and collated them in the newly created African Elephant Demographic Database (AEDD; 10.6084/m9.figshare.19387085). We found 37 natural mortality estimates from five different study sites. Other mortality data, demographic rates, and age‐ and sex‐structured population data were substantially more abundant, both temporally and spatially. This new collection of demographic rates, age‐ and sex‐structured population data, and cause‐partitioned mortality estimates identifies spatial and temporal data gaps and provides prior information needed for African elephant population models. Closing these data gaps and subsequent analyses of realistic population models may aid elephant conservation via improved policies, legislation, and protection.

Kinetics and Performance of Biological Activated Carbon Reactor for Advanced Treatment of Textile Dye Wastewater

The kinetics and performance of a biological activated carbon (BAC) reactor were evaluated to validate the proposed kinetic model. The Freundlich adsorption capacity (Ka) and adsorption intensity constants (n) obtained from the batch experiments were 1.023 ± 0.134 (mg/g) (L/mg)1/n and 2.036 ± 0.785, respectively. The effective diffusivity (Ds) of the substrate within the activated carbon was determined by comparing the adsorption model value with the experimental data to find the best fit value (4.3 × 10–4 cm2/d). The batch tests revealed that the yield coefficient (Y) was 0.18 mg VSS/mg COD. Monod and Haldane kinetics were applied to fit the experimental data and determine the biokinetic constants, such as the maximum specific utilization rate (k), half-saturation constant (KS), inhibition constant (Ki), and biomass death rate coefficient (kd). The results revealed that the Haldane kinetics fit the experimental data better than the Monod kinetics. The values of k, KS, Ki, and kd were 3.52 mg COD/mg VSS-d, 71.7 mg COD/L, 81.63 mg COD/L, and 4.9 × 10−3 1/d, respectively. The BAC reactor had a high COD removal efficiency of 94.45% at a steady state. The average influent color was found to be 62 ± 22 ADMI color units, and the color removal efficiency was 73–100% (average 92.3 ± 10.2%). The removal efficiency for ammonium was 73.9 ± 24.4%, while the residual concentration of ammonium in the effluent was 1.91 ± 2.04 mg/L. The effluent quality from the BAC reactor could meet the discharge standard and satisfy the reuse requirements of textile dye wastewater.

The impact of smoking on mortality in the face of population ageing: the example of Germany

Abstract Background Despite weak tobacco control, smoking in Germany has steadily declined over the last 25 years. As policymakers often expect that this trend will also reflect in a declining associated public health burden, I sought to quantify trends in smoking-attributable mortality (SAM) and to explore the impact of population ageing. Methods Smoking and mortality statistics from 1992 to 2018 were obtained from the German Statistical Office, from which SAM was calculated separately for each cause of death causally associated with smoking using Levin's formula for population-attributable fractions. The impact of population ageing was explored by comparing crude and age-standardized SAM, respectively. To estimate the impact of population ageing on future SAM, a forward projection until 2040 was modelled assuming continuation of smoking trends and constant mortality rates. Results About 126.900 deaths were attributable to smoking in Germany in 2018. Since 1992, total SAM declined only slightly, while stronger decreases were seen in age-adjusted SAM. Differences between crude and age-standardized SAM seem to be particularly striking in men. The forward projection of SAM suggests that recent increases in smoking in the middle aged as well as population ageing dynamics will lead to further steady increases within the next two decades in both sexes to about 138.250. Conclusions Results indicate that past decreases in SAM due to declines in smoking were largely compensated by population ageing. In the next two decades, current smoking trends and population ageing will lead to a steady increase in SAM. Only by taking determined immediate policy action could significant inroads into reducing the smoking-associated disease burden be achieved. Also, given still significant smoking rates in middle and old age, there is tremendous potential to curb the associated public health burden by intensifying cessation programs. Key messages Contrary to common expectations among policymakers, the smoking-attributable public health burden will strongly increase in the next decades in Germany. Determined immediate policy action is required to halt or attenuate these trends.

Stochastic bifurcation in single-species model induced by α-stable Lévy noise

Bifurcation analysis has many applications in different scientific fields, such as electronics, biology, ecology, and economics. In population biology, deterministic methods of bifurcation are commonly used. In contrast, stochastic bifurcation techniques are infrequently employed. Here we establish stochastic P-bifurcation behavior of (i) a growth model with state dependent birth rate and constant death rate, and (ii) a logistic growth model with state dependent carrying capacity, both of which are driven by multiplicative symmetric stable Lévy noise. Transcritical bifurcation occurs in the deterministic counterpart of the first model, while saddle-node bifurcation takes place in the logistic growth model. We focus on the impact of the variations of the growth rate, the per capita daily adult mortality rate, the stability index, and the noise intensity on the stationary probability density functions of the associated non-local Fokker–Planck equation. Implications of these bifurcations in population dynamics are discussed. In the first model the bifurcation parameter is the ratio of the population birth rate to the population death rate. In the second model the bifurcation parameter corresponds to the sensitivity of carrying capacity to change in the size of the population near equilibrium. In each case we show that as the value of the bifurcation parameter increases, the shape of the steady-state probability density function changes and that both stochastic models exhibit stochastic P-bifurcation. The unimodal density functions become more peaked around deterministic equilibrium points as the stability index increases, while an increase in any one of the other parameter has an effect on the stationary probability density function. That means the geometry of the density function changes from unimodal to flat, and its peak appears in the middle of the domain, which means a transition occurs.

The Sibling Distribution for Multivariate Life Time Data

AbstractA flexible class of multivariate distributions for continuous lifetimes is proposed. The distribution is defined in terms of the age-at-death of m siblings. The expression for the joint density is derived using classical results from mathematical demography. The parameters of the distribution are the age-specific birth and death rates, in addition to a vector of relative death times for the m siblings. For the case of constant birth and death rates we are able to derive an explicit expression for the bivariate sibling density, which is proven to be MTP2, and hence has positive dependence. Further, we show that a special case of the sibling distribution belongs to the Block-Basu class of multivariate distribution. In the general case, with age-dependent birth and death rates, evaluation of the density involves numerical integration, but is still feasible.

A Canadian Cost-Effectiveness Analysis for the Treatment of Immune Thrombocytopenia: Assessing the Relative Value of with Eltrombopag Versus Romiplostim

Background:Eltrombopag (EPAG) was evaluated as a second line treatment for adult chronic immune thrombocytopenia (ITP) in the 2005 Phase III RAISE randomized, placebo-controlled trial. More than 80% of patients reached satisfactory platelet counts within two weeks. However, the relative value of EPAG as a second line treatment for ITP remains to be formally assessed.Objective:This study aimed to estimate the cost-effectiveness of treating ITP with comparable thrombopoietin receptor agonists: EPAG versus Romiplostim (ROMI).Methods:A cost-effectiveness model was developed from a Canadian payer perspective. In the base case, Markov model was implemented to estimate the benefits and costs expected with each treatment over a lifetime time horizon. Three health states based on the clinical pathway and current guidelines for the treatment of ITP were included in the model: (1) on treatment, (2) treatment failure/discontinuation, and (3) mortality. As reducing bleeding is the therapeutic goal in ITP, bleeding rates were incorporated into the model. Pre-mortality, patients could experience three events: no bleeding, mild/moderate bleeding, or severe bleeding. Data on EPAG use were obtained from the EXTEND study, an open-label extension of four trials including RAISE. For ROMI, data were obtained from Phase III trials and a subsequent extension study. Lifetime overall survival was extrapolated by applying constant treatment-specific mortality rates derived from severe bleeding events and natural mortality rates. As no health-related quality of life data were collected during the RAISE clinical trial, EPAG health state utilities were obtained from other relevant studies (Szende, 2010; Leontiadis, 2010; ROM NICE submission TA221). The costs of drugs (primary and secondary therapy), rescue medications, routine care, bleeding episodes, adverse events, and mortality were incorporated into the model. Costs, in Canadian dollars, were derived from the relevant pricing databases. Costs and benefits were discounted at 1.5% per year according to CADTH guidelines.Results:EPAG-treated patients gained 22.53 life years (LY) and 18.81 quality-adjusted life years (QALY) while those treated with ROMI gained 22.45 LYs and 18.80 QALYs. The total cost for EPAG treatment was estimated at $513,301 versus $805,025 for ROMI treatment. EPAG was dominant (lower cost, greater benefit) in terms of both costs per LY and costs per QALY. Sensitivity analyses supported base case findings. Deterministic sensitivity analysis predicted the greatest sensitivity to variations in the rates of severe bleeding, discontinuation, and natural mortality. The probabilistic sensitivity analysis demonstrated the probability of cost-effectiveness was 55.7% at both $25,000 and $50,000 thresholds and EPAG was therefore a reasonably efficient use of resources. In a subsequent cost-consequence analysis, EPAG patients experienced fewer severe bleeding events (0.05 versus 0.08 for ROMI) and, overall, their annual costs were lower ($65,514 versus $96,914 for ROMI).Conclusion:Both EPAG and ROMI has demonstrated significant improved in bleeding versus the standard of care in the phase 3 clinical trial.s These results were applied in the economic analysis and EPAG proved to be more cost-effective as compared to ROMI. DisclosuresRoy:Novartis: Employment, Equity Ownership. Neyra:Novartis: Employment. El Ouagari:Novartis: Employment.

A simplified model for simulating anaerobic digesters: Application to valorisation of bagasse and distillery spent wash

Current anaerobic digestion (AD) design methods rely on crude empirical models or sophisticated anaerobic digestion models (like ADM1) requiring a large number of parameters which are difficult to obtain experimentally. A simplified model for simulating AD was developed in this work. The model requires knowledge of CH4/CO2 ratio in biogas or indigestible fraction in substrate and batch biomethane potential (BMP) data for estimating three kinetic parameters (maximum specific growth rate, half velocity constant and cell death rate). Reported lab scale BMP data of sugarcane bagasse and spent wash were used to first estimate the kinetics and then to simulate corresponding largescale AD. Simulated results of specific methane yield and digester performance were consistent with available largescale AD data. The potential of the model to simulate single and multi-stage AD were illustrated. The presented approach and model will be useful for effectively valorising a variety of complex biomass substrates to biogas.

Parasite evolution in an age-structured population

Although mortality increases with age in most organisms, senescence is missing from models of parasite evolution. Since virulence evolves according to the host’s mortality, and since virulence influences the intensity of transmission, which determines the average age at infection and thus the mortality rate of a senescing host, we expected that epi-evolutionary feedbacks would underlie the evolution of virulence in a population of senescing hosts. We tested this idea by extending an age-structured model of epidemiological dynamics with the parasite’s evolution. A straightforward prediction of our model is that stronger senescence forces the evolution of higher virulence. However, the model also reveals that the evolved virulence depends on the average age at infection, giving an evolutionary feedback with the epidemiological situation, a prediction not found when assuming a constant mortality rate with age. Additionally, and in contrast to most models of parasite evolution, we found that the virulence at the evolutionary equilibrium is influenced by whether the force of infection depends on the density or on the frequency of infected hosts, due to changes in the average age at infection. Our findings suggest that ignoring age-specific effects, and in particular senescence, can give misleading predictions about parasite evolution.

Fabrication of zinc/silver binary nanoparticles, their enhanced microbial and adsorbing properties

Monometallic ZnO nanoparticles were prepared by hydrolysis of zinc acetate with ammonium hydroxide solution. Bimetallic zinc-silver nanoparticles (ZnO-AgNPs) were prepared using metal displacement galvanic cell reaction in presence of cetyltrimethylammonium bromide (CTAB). The optical and photo-physical properties of both NPs were determined. Surface plasmon resonance (SPR) intensity of ZnO-AgNPs depends on the ratio of metal salt precursors and other experimental conditions. The optical band gap (2.98 eV), agglomeration number (26819.92), and molar concentration (1.14 × 10−4 mol/liter) of ZnO-AgNPs were determined. Langmuir adsorption monolayer, Freundlich, intraparticles diffusion and multilayer adsorption isotherms used for the determination of maximum adsorption efficiency and adsorption isotherm parameters to the removal of safranin dye from an aqueous solution. The kinetics of safranin removal has also been discussed with pseudo-first order, pseudo-second order, intraparticle diffusion and multilayer kinetic models. The antibacterial and antifungal activities of ZnO, Ag and ZnO-AgNPs were determined against human pathogens using growth kinetic and disk diffusion methods. The concentrations of ZnO-AgNPs have significant effect on the bacterial growth kinetics. The death rate constants increase with increasing the NPs concentrations. It has been found that the ZnO-AgNPs hold higher microbial activities than that of monometallic counterpart, ZnO and AgNPs. Mechanism of bacterial growth and death was discussed.