Managing technology risk in R&D project planning: Optimal timing and parallelization of R&D activities.

An inherent characteristic of R&D projects is technological uncertainty, which may result in project failure, and time and resources spent without any tangible return. In pharmaceutical projects, for instance, stringent scientific procedures have to be followed to ensure patient safety and drug efficacy in pre-clinical and clinical tests before a medicine can be approved for production. A project consists of several stages, and may have to be terminated in any of these stages, with typically a low likelihood of success. In project planning and scheduling, this technological uncertainty has typically been ignored, and project plans are developed only for scenarios in which the project succeeds. In this paper, we examine how to schedule projects in order to maximize their expected net present value, when the project activities have a probability of failure, and where an activity's failure leads to overall project termination. We formulate the problem, show that it is NP-hard and develop a branchand- bound algorithm that allows to obtain optimal solutions. We also present polynomial-time algorithms for special cases, and present a number of managerial insights for R&D project and planning, including the advantages and disadvantages of parallelization of R&D activities in different settings.Applications; Branch-and-bound; Computational complexity; Exact algorithms programming; Integer; Pharmaceutical; Project management; Project scheduling; R&D projects analysis of algorithms; Risk industries;

Study of the antimicrobial activities of Solanum indicum ssp. distichum (Schumach. and Thonning 1827) fruits (“gnangnan” berries) from a tropical humid zone (Côte d’Ivoire)

The antibacterial activity of both aqueous and ethanolic extracts of Solanum indicum ssp. distichum (Schumach. and Thonning, 1872) fruits was investigated. These extracts were evaluated for antibacterialactivity against two Gram positive (Listeria innocua LRGIA 01 and Staphylococcus aureus CNRZ3) and two Gram negative (Escherichia coli industrial strain and Pseudomonas aeruginosa ATCC 15742) strains. Thisevaluation was performed by following their growth by a spectrophotometric method in Brain Heart Infusion broth. L. innocua LRGIA01growth was completely inhibited by 0.04 g.mL-1 of aqueous extract of Solanumindicum berries, while a dose-dependent inhibition by 0.04 g.mL-1 and 0.1 g.mL-1 ethanolic extracts was observed. Conversely, the inhibitory activity of ethanolic extract on P. aeruginosa ATCC 15742 growth, was higher than that of aqueous extract. E. coli industrial strain and S. aureus CNRZ 3 growth were inhibited by 0.1 mg.mL-1 ethanolic extract but not by 0.04 mg.mL-1 ethanolic or aqueous extracts. These results suggest that different classes of compounds are likely responsible for the antibacterial activities. The high inhibitory activity of aqueous and ethanolic extracts on L. innocua LRGIA01 and P. aeruginosa ATCC 15742 strains, respectively calls for further studies to identify the antibacterial compounds present in Solanum indicum berriesand their mechanisms of action

Biopreservation of chocolate mousse with Lactobacillus helveticus 2/20: Microbial Challenge Test

Probiotic bacteria are used for food biopreservation because their metabolic products might contribute to ensuring food microbiological safety and/or increase its shelf life without the addition of chemical preservatives. Moreover, biopreserved foods are excellent vehicles for the delivery of probiotic bacteria. The aim of the study was to investigate the potential of chocolate mousse food matrix for the delivery of the probiotic strain Lactobacillus helveticus 2/20 (Lb. helveticus 2/20) and to investigate its capacity to inhibit the growth of two foodborne pathogenic bacteria (Staphylococcus aureus and Escherichia coli). Therefore, the populations of free or encapsulated in calcium alginate Lb. helveticus 2/20 cells and/or of each pathogen (used to voluntarily contaminate each sample) were monitored both in complex nutrient medium (MRS broth) and in chocolate mousse under refrigeration conditions and at room temperature. Lb. helveticus 2/20 alone in free or encapsulated state effectively inhibited the growth of Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC 25923 in chocolate mousse when stored at 20 ± 2 °C. Practically no viable unwanted bacteria were identified on the 7th day from the beginning of the process. High viable Lb. helveticus 2/20 cell populations were maintained during storage under refrigerated conditions (4 ± 2 °C) and at room temperature. Chocolate mousse is thus a promising food matrix to deliver probiotic Lb. helveticus 2/20 cells, which could also protect it from contamination by unwanted bacteria

Antimicrobial activity of camel milk casein and its hydrolysates

The aim of this study was to evaluate the antimicrobial activity of camel caseins and their hydrolysates by gastrointestinal proteolytic enzymes against 3 Gram-positive and 2 Gram-negative bacterial strains. Camel caseins (CN) were hydrolysed by successive action of pepsin and pancreatin. Hydrolysis of CN was checked by electrophoresis and gel filtration chromatography (GFC). Both techniques showed that CN was hydrolysed into peptides. Among the tested bacteria, a decrease of 19.3%±0.02 of E. coli XL1 blue cells growth was observed in the presence of undigested camel casein at a concentration of 20 mg ml−1. After successive hydrolyses by pepsin and pancreatin, camel milk casein hydrolysates still exhibited anti-bacterial activity against E. coli XL1 blue strain (19.73±0.01% growth inhibition under the same conditions). Gram-positive strain growth was not affected by intact camel CN, while, at the same concentration (20 mg ml–1), their hydrolysates slightly inhibited the growth of these bacteria. This suggests that antibacterial peptidic fragments of caseins were generated by pepsin and pancreatin

Stochastic computing based on volatile GeSe ovonic threshold switching selectors

Stochastic computing (SC) is a special type of digital compute strategy where values are represented by the probability of 1 and 0 in stochastic bit streams, which leads to superior hardware simplicity and error-tolerance. In this paper, we propose and demonstrate SC with GeSe based Ovonic Threshold Switching (OTS) selector devices by exploiting their probabilistic switching behavior. The stochastic bit streams generated by OTS are demonstrated with good computation accuracy in both multiplication operation and image processing circuit. Moreover, the bit distribution has been statistically studied and linked to the collective defect de/localization behavior in the chalcogenide material. Weibull distribution of the delay time supports the origin of such probabilistic switching, facilitates further optimization of the operation condition, and lays the foundation for device modelling and circuit design. Considering its other advantages such as simple structure, fast speed, and volatile nature, OTS is a promising material for implementing SC in a wide range of novel applications, such as image processors, neural networks, control systems and reliability analysis

GeSe-based Ovonic Threshold Switching Volatile True Random Number Generator

In this paper, we propose and demonstrate a novel technique for true random number generator (TRNG) application using GeSe-based Ovonic threshold switching (OTS) selector devices. The inherent variability in OTS threshold voltage results in a bimodal distribution of on/off states which can be easily converted into digital bits. The experimental evaluation shows that the proposed TRNG enables the generation of high-quality random bits that passed 12 tests in the National Institute of Standards and Technology statistical test suite without complex external circuits for post-processing. The randomness is further evidenced by the prediction rate of ∼50% using machine learning algorithm. Compared with the TRNGs based on non-volatile memories, the volatile nature of OTS avoids the reset operation, thus further simplifying the operation and improving the generation frequency

Treatment patterns and clinical outcomes

BACKGROUND: Treatment resistant depression (TRD) characterizes a subgroup of 10-30% of patients with major depressive disorder, and is associated with considerable morbidity and mortality. A consensus treatment for TRD does not exist, which often leads to wide variations in treatment strategies. Real-world studies on treatment patterns and outcomes in TRD patients in Europe are lacking and could help elucidate current treatment strategies and their efficacy. METHODS: This non-interventional cohort study of patients with TRD (defined as treatment failure on ≥2 oral antidepressants given at adequate dose and duration) with moderate to severe depression collected real-world data on treatment patterns and outcomes in several European countries. Patients were started on a new treatment for depression according to routine clinical practice. RESULTS: Among 411 patients enrolled, after 6 months, only 16.7% achieved remission and 73.5% showed no response. At Month 12, while 19.2% achieved remission and 69.2% showed no response, 33.3% of those in remission at Month 6 were no longer in remission. Pharmacological treatments employed were heterogenous; 54 different drugs were recorded at baseline, and the top 5 treatment types according to drug classes accounted for 40.0% of patients. Even though remission rates were very low, at Month 12, 60.0% of patients had not changed treatment since enrolment. CONCLUSIONS: The heterogeneity of treatments highlights a lack of consensus. Moreover, despite low response rates, patients often remained on treatments for substantial periods of time. These data further support existence of an unmet treatment need for TRD patients in Europe.publishersversionpublishe

Healthcare resource utilization

Background: Treatment resistant depression (TRD) is diagnosed when patients experiencing a major depressive episode fail to respond to ≥2 treatments. Along with substantial indirect costs, patients with TRD have higher healthcare resource utilization (HCRU) than other patients with depression. However, research on the economic impact of this HCRU, and differences according to response to treatment, is lacking. Methods: This multicenter, observational study documented HCRU among patients with TRD in European clinical practice initiating new antidepressant treatments. Data regarding access to outpatient consultations and other healthcare resources for the first 6 months, collected using a questionnaire, were analyzed qualitatively according to response and remission status. The economic impact of HCRU, estimated using European costing data, was analyzed quantitatively. Results: Among 411 patients, average HCRU was higher in non-responders, attending five times more general practitioner (GP) consultations and spending longer in hospital (1.7 versus 1.1 days) than responders. Greater differences were observed according to remission status, with non-remitters attending seven times more GP consultations and spending approximately three times longer in hospital (1.7 versus 0.6 days) than remitters. Consequently, the estimated economic impacts of non-responders and non-remitters were significantly greater than those of responders and remitters, respectively. Limitations: Key limitations are small cohort size, absence of control groups and generalizability to different healthcare systems. Conclusion: Patients with TRD, particularly those not achieving remission, have considerable HCRU, with associated economic impact. The costs of unmet TRD treatment needs are thus substantial, and treatment success is fundamental to reduce individual needs and societal costs.publishersversionpublishe

Dependence of switching probability on operation conditions in GexSe1-x ovonic threshold switching selectors

Ovonic threshold switching (OTS) selector is a promising candidate to suppress the sneak current paths in resistive switching memory (RRAM) arrays. Variations in the threshold voltage (Vth), and the hold voltage (Vhd) have been reported, but a quantitative analysis of the switching probability dependence on the OTS operation conditions is still missing. A novel characterization method is developed in this work, and the time-to-switch-on/off (ton/toff) at a constant VOTS is found following the Weibull distribution, based on which the dependence of switching probability on pulse bias and time can be extracted and extrapolated, and the switching probability can be ensured with appropriately chosen operation conditions. The difference between square and triangle switching pulses is also explained. This provides a practical guidance for predicting the switching probability under different operation conditions and for designing reliable one-selector-one-RRAM (1S1R) arrays