Abstract. The application of modeling and simulation techniques is increasingly common in preclinical stages of the drug discovery and development process. A survey focusing on preclinical pharmacokinetic/ pharmacodynamics (PK/PD) analysis was conducted across pharmaceutical companies that are members of the International Consortium for Quality and Innovation in Pharmaceutical Development. Based on survey responses,~68% of companies use preclinical PK/PD analysis in all therapeutic areas indicating its broad application. An important goal of preclinical PK/PD analysis in all pharmaceutical companies is for the selection/optimization of doses and/or dose regimens, including prediction of human efficacious doses. Oncology was the therapeutic area with the most PK/PD analysis support and where it showed the most impact. Consistent use of more complex systems pharmacology models and hybrid physiologically based pharmacokinetic models with PK/PD components was less common compared to traditional PK/PD models. Preclinical PK/PD analysis is increasingly being included in regulatory submissions with~73% of companies including these data to some degree. Most companies (~86%) have seen impact of preclinical PK/PD analyses in drug development. Finally,~59% of pharmaceutical companies have plans to expand their PK/PD modeling groups over the next 2 years indicating continued growth. The growth of preclinical PK/PD modeling groups in pharmaceutical industry is necessary to establish required resources and skills to further expand use of preclinical PK/PD modeling in a meaningful and impactful manner.
We consider the problem of a wait-free construction for a bounded-length queue, where D is a bound on the queue length, k is the size of a queue item, and n is the number of concurrent processes. The possibility of a wait-free queue is implied by the universal construction [1] in terms of atomic read/write and low-level consensus primitives, but the construction uses 0(Dkn3 ) space. This space requirement represents the fact that each of n3 cells represents a queue state and any queue operation copies the entire queue state from one cell to another. The space requirement for our construction is Dk + O(kn) (optimal for the case D = Q(n)).The problem is made difficult when the type of atomic operation is limited. Using Fetch&Increment and double word Comparef4Swap simplifies the construction task (for imtance, a space-efficient wait-free heap given in [z] uses a conditional atomic assignment to two words). Our work shows that a wait-free queue can be implemented using only a single word Compare&Swap (only Pg(Dn + 3n2 )1 bits are accessed by the CS operation). Our construction is not yet practical, since the bound on the number of steps for a process to complete an operation is 0(D2 n3 + n5 ).The baais for the construction is a linked list of cells, resembling the work [3]. Each cell can contain one queue item; a shared pool of D + O(n) cells contains the linked list representing the queue and other cells that are either available or at vaxious intermediate states between queue membership and availabilityy for recycling into the queue.A dequeue operation either returns an item from the queue or an empt~indication in case the queue had no items at the time (modulo Iinearizabllit y) of the operation. An enqueue operation may fail if the queue contsins D items at the time (modulo linearizability) of the enqueue.The primary technical difficulties with a link list representation derive from the helping method and the unreliabllit y of the CS operation in following a pointer chain, as explained in [3]. We resolve these difficulties by three techniques: (i) instead of using addresses as pointers, cells are given unique id fields and all next pointera rely only on cell ids; (ii) cell recycling and id recycling is carefully controlled and synchronized with publication (and subsequent retraction) of cell ids that are currently scanned by any process; and (iii) the deq ueue operation is split into several parts: a deqplace sub-operation, a dechai n sub-operation, and remaining steps that return an item to the operation's invoker. All CS operations refer to a word containing an id or a word of status bits: no CS operation is used to manipulate an address or the combination of an address and a counter [3, 4]. We use the helping technique [1], so that each process attempts to perform part of the announced operation of another process.F&mission 10 make digitolflwrd copies of~ll or porl of this omteriol ibr personal or ckmsroom use is gmnted without fee provided tlml the copies iwe not mode or distrihoted for profit or connwerci~l...
Discusses computational challenges in air quality modelling (as viewed by the authors). The focus of the paper will be on Di, thè`c urrent'' state-of-affairs. Owing to limitation of space the discussion will focus on only a few aspects of air quality modelling: i.e. chemical integration, sensitivity analysis and computational framework, with particular emphasis on aerosol issues.
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