Size and Usage Patterns of Private TB Drug Markets in the High Burden Countries

BACKGROUND: Tuberculosis (TB) control is considered primarily a public health concern, and private sector TB treatment has attracted less attention. Thus, the size and characteristics of private sector TB drug sales remain largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: We used IMS Health data to analyze private TB drug consumption in 10 high burden countries (HBCs), after first mapping how well IMS data coverage overlapped with private markets. We defined private markets as any channels not used or influenced by national TB programs. Private markets in four countries--Pakistan, the Philippines, Indonesia and India--had the largest relative sales volumes; annually, they sold enough first line TB drugs to provide 65-117% of the respective countries' estimated annual incident cases with a standard 6-8 month regimen. First line drug volumes in five countries were predominantly fixed dose combinations (FDCs), but predominantly loose drugs in the other five. Across 10 countries, these drugs were available in 37 (loose drug) plus 74 (FDCs) distinct strengths. There were 54 distinct, significant first line manufacturers (range 2-11 per country), and most companies sold TB drugs in only a single study country. FDC markets were, however, more concentrated, with 4 companies capturing 69% of FDC volume across the ten countries. Among second line drugs, fluoroquinolones were widely available, with significant volumes used for TB in India, Pakistan and Indonesia. However, certain WHO-recommended drugs were not available and in general there were insufficient drug volumes to cover the majority of the expected burden of multidrug-resistant TB (MDR-TB). CONCLUSIONS/SIGNIFICANCE: Private TB drug markets in several HBCs are substantial, stable, and complicated. This calls for appropriate policy and market responses, including expansion of Public-Private Mix (PPM) programs, greater reach, flexibility and appeal of public programs, regulatory and quality enforcement, and expansion of public MDR-TB treatment programs

The Zeroth Law of Thermodynamics and Volume-Preserving Conservative Dynamics with Equilibrium Stochastic Damping

We propose a mathematical formulation of the zeroth law of thermodynamics and develop a stochastic dynamical theory, with a consistent irreversible thermodynamics, for systems possessing sustained conservative stationary current in phase space while in equilibrium with a heat bath. The theory generalizes underdamped mechanical equilibrium: $dx=gdt+\{-D\nabla\phi dt+\sqrt{2D}dB(t)\}$, with $\nabla\cdot g=0$ and $\{\cdots\}$ respectively representing phase-volume preserving dynamics and stochastic damping. The zeroth law implies stationary distribution $u^{ss}(x)=e^{-\phi(x)}$. We find an orthogonality $\nabla\phi\cdot g=0$ as a hallmark of the system. Stochastic thermodynamics based on time reversal $\big(t,\phi,g\big)\rightarrow\big(-t,\phi,-g\big)$ is formulated: entropy production $e_p^{\#}(t)=-dF(t)/dt$; generalized "heat" $h_d^{\#}(t)=-dU(t)/dt$, $U(t)=\int_{\mathbb{R}^n} \phi(x)u(x,t)dx$ being "internal energy", and "free energy" $F(t)=U(t)+\int_{\mathbb{R}^n} u(x,t)\ln u(x,t)dx$ never increases. Entropy follows $\frac{dS}{dt}=e_p^{\#}-h_d^{\#}$. Our formulation is shown to be consistent with an earlier theory of P. Ao. Its contradistinctions to other theories, potential-flux decomposition, stochastic Hamiltonian system with even and odd variables, Klein-Kramers equation, Freidlin-Wentzell's theory, and GENERIC, are discussed.Comment: 25 page

Deformed versus undeformed cat states encoding qubit

We study the possibility of exploiting superpositions of coherent states to encode qubit. A comparison between the use of deformed and undeformed bosonic algebra is made in connection with the amplitude damping errors.Comment: 6 pages, 2 eps figures, to appear in J. Opt.

One-Dimensional Birth-Death Process and Delbr\"{u}ck-Gillespie Theory of Mesoscopic Nonlinear Chemical Reactions

As a mathematical theory for the stochasstic, nonlinear dynamics of individuals within a population, Delbr\"{u}ck-Gillespie process (DGP) $n(t)\in\mathbb{Z}^N$, is a birth-death system with state-dependent rates which contain the system size $V$ as a natural parameter. For large $V$, it is intimately related to an autonomous, nonlinear ordinary differential equation as well as a diffusion process. For nonlinear dynamical systems with multiple attractors, the quasi-stationary and stationary behavior of such a birth-death process can be underestood in terms of a separation of time scales by a $T^*\sim e^{\alpha V}$ $(\alpha>0)$: a relatively fast, intra-basin diffusion for $t\ll T^*$ and a much slower inter-basin Markov jump process for $t\gg T^*$. In the present paper for one-dimensional systems, we study both stationary behavior ($t=\infty$) in terms of invariant distribution $p_n^{ss}(V)$, and finite time dynamics in terms of the mean first passsage time (MFPT) $T_{n_1\rightarrow n_2}(V)$. We obtain an asymptotic expression of MFPT in terms of the "stochastic potential" $\Phi(x,V)=-(1/V)\ln p^{ss}_{xV}(V)$. We show in general no continuous diffusion process can provide asymptotically accurate representations for both the MFPT and the $p_n^{ss}(V)$ for a DGP. When $n_1$ and $n_2$ belong to two different basins of attraction, the MFPT yields the $T^*(V)$ in terms of $\Phi(x,V)\approx \phi_0(x)+(1/V)\phi_1(x)$. For systems with a saddle-node bifurcation and catastrophe, discontinuous "phase transition" emerges, which can be characterized by $\Phi(x,V)$ in the limit of $V\rightarrow\infty$. In terms of time scale separation, the relation between deterministic, local nonlinear bifurcations and stochastic global phase transition is discussed. The one-dimensional theory is a pedagogic first step toward a general theory of DGP.Comment: 32 pages, 3 figure

Boosting Long-term Memory via Wakeful Rest: Intentional Rehearsal is not Necessary, Automatic Consolidation is Sufficient.

<div><p>People perform better on tests of delayed free recall if learning is followed immediately by a short wakeful rest than by a short period of sensory stimulation. Animal and human work suggests that wakeful resting provides optimal conditions for the consolidation of recently acquired memories. However, an alternative account cannot be ruled out, namely that wakeful resting provides optimal conditions for intentional rehearsal of recently acquired memories, thus driving superior memory. Here we utilised non-recallable words to examine whether wakeful rest boosts long-term memory, even when new memories could not be rehearsed intentionally during the wakeful rest delay. The probing of non-recallable words requires a recognition paradigm. Therefore, we first established, via Experiment 1, that the rest-induced boost in memory observed via free recall can be replicated in a recognition paradigm, using concrete nouns. In Experiment 2, participants heard 30 non-recallable non-words, presented as ‘foreign names in a bridge club abroad’ and then either rested wakefully or played a visual spot-the-difference game for 10 minutes. Retention was probed via recognition at two time points, 15 minutes and 7 days after presentation. As in Experiment 1, wakeful rest boosted recognition significantly, and this boost was maintained for at least 7 days. Our results indicate that the enhancement of memory via wakeful rest is <i>not</i> dependent upon intentional rehearsal of learned material during the rest period. We thus conclude that consolidation is <i>sufficient</i> for this rest-induced memory boost to emerge. We propose that wakeful resting allows for superior memory consolidation, resulting in stronger and/or more veridical representations of experienced events which can be detected via tests of free recall and recognition.</p></div

Counter-Gradient Variation in Respiratory Performance of Coral Reef Fishes at Elevated Temperatures

The response of species to global warming depends on how different populations are affected by increasing temperature throughout the species' geographic range. Local adaptation to thermal gradients could cause populations in different parts of the range to respond differently. In aquatic systems, keeping pace with increased oxygen demand is the key parameter affecting species' response to higher temperatures. Therefore, respiratory performance is expected to vary between populations at different latitudes because they experience different thermal environments. We tested for geographical variation in respiratory performance of tropical marine fishes by comparing thermal effects on resting and maximum rates of oxygen uptake for six species of coral reef fish at two locations on the Great Barrier Reef (GBR), Australia. The two locations, Heron Island and Lizard Island, are separated by approximately 1200 km along a latitudinal gradient. We found strong counter-gradient variation in aerobic scope between locations in four species from two families (Pomacentridae and Apogonidae). High-latitude populations (Heron Island, southern GBR) performed significantly better than low-latitude populations (Lizard Island, northern GBR) at temperatures up to 5°C above average summer surface-water temperature. The other two species showed no difference in aerobic scope between locations. Latitudinal variation in aerobic scope was primarily driven by up to 80% higher maximum rates of oxygen uptake in the higher latitude populations. Our findings suggest that compensatory mechanisms in high-latitude populations enhance their performance at extreme temperatures, and consequently, that high-latitude populations of reef fishes will be less impacted by ocean warming than will low-latitude populations

The Chemical Master Equation Approach to Nonequilibrium Steady-State of Open Biochemical Systems: Linear Single-Molecule Enzyme Kinetics and Nonlinear Biochemical Reaction Networks

We develop the stochastic, chemical master equation as a unifying approach to the dynamics of biochemical reaction systems in a mesoscopic volume under a living environment. A living environment provides a continuous chemical energy input that sustains the reaction system in a nonequilibrium steady state with concentration fluctuations. We discuss the linear, unimolecular single-molecule enzyme kinetics, phosphorylation-dephosphorylation cycle (PdPC) with bistability, and network exhibiting oscillations. Emphasis is paid to the comparison between the stochastic dynamics and the prediction based on the traditional approach based on the Law of Mass Action. We introduce the difference between nonlinear bistability and stochastic bistability, the latter has no deterministic counterpart. For systems with nonlinear bistability, there are three different time scales: (a) individual biochemical reactions, (b) nonlinear network dynamics approaching to attractors, and (c) cellular evolution. For mesoscopic systems with size of a living cell, dynamics in (a) and (c) are stochastic while that with (b) is dominantly deterministic. Both (b) and (c) are emergent properties of a dynamic biochemical network; We suggest that the (c) is most relevant to major cellular biochemical processes such as epi-genetic regulation, apoptosis, and cancer immunoediting. The cellular evolution proceeds with transitions among the attractors of (b) in a “punctuated equilibrium” manner

Survival of Lactobacillus sakei during heating, drying and storage in the dried state when growth has occurred in the presence of sucrose or monosodium glutamate

Spray-dried cells of Lactobacillus sakei CTC 494 survived ca. 60% longer in the spray dried state when cells were grown in the presence of 20 g sucrose l)1 or 12.5 g monosodium glutamate l)1. No significant differences were observed in viability during storage in the freeze dried state with the addition of these compounds to the growth medium, nor in survival during a heat treatment (55ºC). Both sucrose and glutamate in the growth medium suppressed intracellular accumulation of total amino acids and changed the overall pattern of the individual amino acids. Glutamate in the growth medium enhanced intracellular glutamate by ca. 38

Markovian Dynamics on Complex Reaction Networks

Complex networks, comprised of individual elements that interact with each other through reaction channels, are ubiquitous across many scientific and engineering disciplines. Examples include biochemical, pharmacokinetic, epidemiological, ecological, social, neural, and multi-agent networks. A common approach to modeling such networks is by a master equation that governs the dynamic evolution of the joint probability mass function of the underling population process and naturally leads to Markovian dynamics for such process. Due however to the nonlinear nature of most reactions, the computation and analysis of the resulting stochastic population dynamics is a difficult task. This review article provides a coherent and comprehensive coverage of recently developed approaches and methods to tackle this problem. After reviewing a general framework for modeling Markovian reaction networks and giving specific examples, the authors present numerical and computational techniques capable of evaluating or approximating the solution of the master equation, discuss a recently developed approach for studying the stationary behavior of Markovian reaction networks using a potential energy landscape perspective, and provide an introduction to the emerging theory of thermodynamic analysis of such networks. Three representative problems of opinion formation, transcription regulation, and neural network dynamics are used as illustrative examples.Comment: 52 pages, 11 figures, for freely available MATLAB software, see http://www.cis.jhu.edu/~goutsias/CSS%20lab/software.htm