Multi-Echelon Inventory Optimization Using Deep Reinforcement Learning

In this chapter, we provide an overview of inventory management within the pharmaceutical industry and how to model and optimize it. Inventory management is a highly relevant topic, as it causes high costs such as holding, shortage, and reordering costs. Especially the event of a stock-out can cause damage that goes beyond monetary damage in the form of lost sales. To minimize those costs is the task of an optimized reorder policy. A reorder policy is optimal when it minimizes the accumulated cost in every situation. However, finding an optimal policy is not trivial. First, the problem is highly stochastic as we need to consider variable demands and lead times. Second, the supply chain consists of several warehouses incl. the factory, global distribution warehouses, and local affiliate warehouses, whereby the reorder policy of each warehouse has an impact on the optimal reorder policy of related warehouses. In this context, we discuss the concept of multi-echelon inventory optimization and a methodology that is capable of capturing both, the stochastic behavior of the environment and how it is impacted by the reorder policy: Markov decision processes (MDPs). On this basis, we introduce the concept, its related benefits and weaknesses of a methodology named Reinforcement Learning (RL). RL is capable of finding (near-) optimal (reorder) policies for MDPs. Furthermore, some simulation-based results and current research directions are presented

Cancer phase I trial design using drug combinations when a fraction of dose limiting toxicities is attributable to one or more agents

Drug combination trials are increasingly common nowadays in clinical research. However, very few methods have been developed to consider toxicity attributions in the dose escalation process. We are motivated by a trial in which the clinician is able to identify certain toxicities that can be attributed to one of the agents. We present a Bayesian adaptive design in which toxicity attributions are modeled via Copula regression and the maximum tolerated dose (MTD) curve is estimated as a function of model parameters. The dose escalation algorithm uses cohorts of two patients, following the continual reassessment method (CRM) scheme, where at each stage of the trial, we search for the dose of one agent given the current dose of the other agent. The performance of the design is studied by evaluating its operating characteristics when the underlying model is either correctly specified or misspecified. We show that this method can be extended to accommodate discrete dose combinations

Simulation of Nitrous Oxide Emissions in Zoysia Turfgrass Using DAYCENT and DNDC Ecosystem Models

Nitrous oxide (N2O) is an important greenhouse gas (GHG) implicated in global climate change. Process-based ecosystem models, such as DAYCENT and DNDC, have been widely used to predict GHG fluxes in agricultural systems. However, neither model has yet been applied to warm-season turfgrasses such as zoysiagrass. This study parameterized, calibrated, and validated the DAYCENT and DNDC models for N2O emissions from Meyer zoysiagrass (Zoysia japonica Steud.) using Bayes’ theorem and field data from Braun and Bremer (2018a, 2019) and Lewis and Bremer (2013). Results indicated DAYCENT, but not DNDC, reasonably simulated the impacts of irrigation and N-fertilization practices on biweekly and annual N2O emissions in zoysia turfgrass. When assuming no further climate change, the validated DAYCENT model predicted that typical recommendations for N-fertilization and irrigation in zoysiagrass (a low-input turfgrass) would reduce its cumulative global warming potential (GWP) for the first 45 years after establishment by encouraging soil carbon sequestration. Thereafter, soils would become saturated with carbon and hence, reductions of N inputs would be beneficial for mitigating further increases in N2O emissions and GWP

Fluctuations in the quark-meson model for QCD with isospin chemical potential

We study the two-flavor quark-meson (QM) model with the functional renormalization group (FRG) to describe the effects of collective mesonic fluctuations on the phase diagram of QCD at finite baryon and isospin chemical potentials, $\mu_B$ and $\mu_I$. With only isospin chemical potential there is a precise equivalence between the competing dynamics of chiral versus pion condensation and that of collective mesonic and baryonic fluctuations in the quark-meson-diquark model for two-color QCD at finite baryon chemical potential. Here, finite $\mu_B=3\mu$ introduces an additional dimension to the phase diagram as compared to two-color QCD, however. At zero temperature, the ($\mu_I,\mu$)-plane of this phase diagram is strongly constrained by the "Silver Blaze problem." In particular, the onset of pion condensation must occur at $\mu_I= m_{\pi}/2$, independent of $\mu$ as long as $\mu + \mu_I$ stays below the constituent quark mass of the QM model or the liquid-gas transition line of nuclear matter in QCD. In order to maintain this relation beyond mean field it is crucial to compute the pion mass from its timelike correlator with the FRG in a consistent way.Comment: 10 pages, 11 figures; matches published versio

Generalized Parton Distributions and the Spin Structure of the Nucleon

Generalized parton distributions are a new type of hadronic observables which has recently stimulated great interest among theorists and experimentalists alike. Introduced to delineate the spin structure of the nucleon, the orbital angular momentum of quarks in particular, the new distributions contain vast information about the internal structure of the nucleon, with the usual electromagnetic form factors and Feynman parton distributions as their special limits. While new perturbative QCD processes, such as deeply virtual Compton scattering and exclusive meson production, have been found to measure the distributions directly in experiments, lattice QCD offers a great promise to provide the first-principle calculations of these interesting observables.Comment: 9 pages, plenary talk given at Lattice 2002, Cambridge, MA, US

Exploring community perceptions in preparation for a randomised controlled trial of biofortified flour in Pakistan

Background: Biofortification of staple food crops may be a cost-effective and sustainable approach to reducing micronutrient deficiencies in resource-poor settings with low dietary diversity. However, its success depends on uptake by the local population. This paper presents formative research conducted in a remote, rural community in North West Pakistan, prior to commencing a randomised controlled trial to test the effectiveness of consuming zinc-biofortified wheat flour for alleviating zinc deficiency. It explored local community members’ knowledge, understanding and attitudes towards biofortification and views on members of their community taking part in the trial. Methods: Four focus group discussions were conducted with male and female community members (separately for cultural reasons) and four in-depth interviews were conducted with Jirga members—respected male elders. Participation was limited to households that were ineligible for the trial so that we could explore the perspectives of community members who were not influenced by the incentives of the trial. Focus group participants were selected at community events for transparency. Data collection took place at the local school and homes of Jirga members. Thematic analysis was undertaken, using a combination of deductive and inductive approaches to identify key themes. Results: A total of 47 men and women participated in this study. Participants reported clear motivation to access and consume more nutritious flour, believing this would bring health benefits, particularly to women and children. Trusted members of the local community, including Jirga members and female health workers, should be involved in providing information on biofortified flour (and the trial) to increase levels of awareness and acceptance. Without their involvement, there is a risk that biofortified flour would be mistrusted. The cost of flour is the main factor affecting purchasing decisions, and biofortified flour will need to be cost-competitive to achieve widespread uptake in marginalised, rural communities. Conclusion: This formative study generated rich, qualitative data from a range of community stakeholders to improve the understanding of important barriers and facilitators to the widespread acceptability and adoption of biofortified wheat. Implementation research such as this will inform future decision-making in relation to scaling up biofortified wheat in Pakistan

Metrics for Differential Privacy in Concurrent Systems

Part 3: Security AnalysisInternational audienceOriginally proposed for privacy protection in the context of statistical databases, differential privacy is now widely adopted in various models of computation. In this paper we investigate techniques for proving differential privacy in the context of concurrent systems. Our motivation stems from the work of Tschantz et al., who proposed a verification method based on proving the existence of a stratified family between states, that can track the privacy leakage, ensuring that it does not exceed a given leakage budget. We improve this technique by investigating a state property which is more permissive and still implies differential privacy. We consider two pseudometrics on probabilistic automata: The first one is essentially a reformulation of the notion proposed by Tschantz et al. The second one is a more liberal variant, relaxing the relation between them by integrating the notion of amortisation, which results into a more parsimonious use of the privacy budget. We show that the metrical closeness of automata guarantees the preservation of differential privacy, which makes the two metrics suitable for verification. Moreover we show that process combinators are non-expansive in this pseudometric framework. We apply the pseudometric framework to reason about the degree of differential privacy of protocols by the example of the Dining Cryptographers Protocol with biased coins

Positive taxis and sustained responsiveness to water motions in larval zebrafish

Larval zebrafish (Danio rerio) have become favored subjects for studying the neural bases of behavior. Here, we report a highly stereotyped response of zebrafish larvae to hydrodynamic stimuli. It involves positive taxis, motion damping and sustained responsiveness to flows derived from local, non-stressful water motions. The response depends on the lateral line and has a high sensitivity to stimulus frequency and strength, sensory background and rearing conditions—also encompassing increased threshold levels of response to parallel input. The results show that zebrafish larvae can use near-field detection to locate sources of minute water motions, and offer a unique handle for analyses of hydrodynamic sensing, sensory responsiveness and arousal with accurate control of stimulus properties

Theory of Pseudomodes in Quantum Optical Processes

This paper deals with non-Markovian behaviour in atomic systems coupled to a structured reservoir of quantum EM field modes, with particular relevance to atoms interacting with the field in high Q cavities or photonic band gap materials. In cases such as the former, we show that the pseudo mode theory for single quantum reservoir excitations can be obtained by applying the Fano diagonalisation method to a system in which the atomic transitions are coupled to a discrete set of (cavity) quasimodes, which in turn are coupled to a continuum set of (external) quasimodes with slowly varying coupling constants and continuum mode density. Each pseudomode can be identified with a discrete quasimode, which gives structure to the actual reservoir of true modes via the expressions for the equivalent atom-true mode coupling constants. The quasimode theory enables cases of multiple excitation of the reservoir to now be treated via Markovian master equations for the atom-discrete quasimode system. Applications of the theory to one, two and many discrete quasimodes are made. For a simple photonic band gap model, where the reservoir structure is associated with the true mode density rather than the coupling constants, the single quantum excitation case appears to be equivalent to a case with two discrete quasimodes

Fatigue, quality of life and physical fitness following an exercise intervention in multiple myeloma survivors (MASCOT): an exploratory randomised Phase 2 trial utilising a modified Zelen design

Background: Exercise may improve fatigue in multiple myeloma survivors, but trial evidence is limited, and exercise may be perceived as risky in this older patient group with osteolytic bone destruction. Methods: In this Phase 2 Zelen trial, multiple myeloma survivors who had completed treatment at least 6 weeks ago, or were on maintenance only, were enrolled in a cohort study and randomly assigned to usual care or a 6-month exercise programme of tailored aerobic and resistance training. Outcome assessors and usual care participants were masked. The primary outcome was the FACIT-F fatigue score with higher scores denoting less fatigue. Results: During 2014–2016, 131 participants were randomised 3:1 to intervention (n = 89) or usual care (n = 42) to allow for patients declining allocation to the exercise arm. There was no difference between groups in fatigue at 3 months (between-group mean difference: 1.6 [95% CI: −1.1–4.3]) or 6 months (0.3 [95% CI: −2.6–3.1]). Muscle strength improved at 3 months (8.4 kg [95% CI: 0.5–16.3]) and 6 months (10.8 kg [95% CI: 1.2–20.5]). Using per-protocol analysis, cardiovascular fitness improved at 3 months (+1.2 ml/kg/min [95% CI: 0.3–3.7]). In participants with clinical fatigue (n = 17), there was a trend towards less fatigue with exercise over 6 months (6.3 [95% CI: −0.6–13.3]). There were no serious adverse events. Conclusions: Exercise appeared safe and improved muscle strength and cardiovascular fitness, but benefits in fatigue appeared limited to participants with clinical fatigue at baseline. Future studies should focus on patients with clinical fatigue. Clinical trial registration: The study was registered with ISRCTN (38480455) and is completed