Modelling imperfect adherence to HIV induction therapy

Abstract Background Induction-maintenance therapy is a treatment regime where patients are prescribed an intense course of treatment for a short period of time (the induction phase), followed by a simplified long-term regimen (maintenance). Since induction therapy has a significantly higher chance of pill fatigue than maintenance therapy, patients might take drug holidays during this period. Without guidance, patients who choose to stop therapy will each be making individual decisions, with no scientific basis. Methods We use mathematical modelling to investigate the effect of imperfect adherence during the inductive phase. We address the following research questions: 1. Can we theoretically determine the maximal length of a possible drug holiday and the minimal number of doses that must subsequently be taken while still avoiding resistance? 2. How many drug holidays can be taken during the induction phase? Results For a 180 day therapeutic program, a patient can take several drug holidays, but then has to follow each drug holiday with a strict, but fairly straightforward, drug-taking regimen. Since the results are dependent upon the drug regimen, we calculated the length and number of drug holidays for all fifteen protease-sparing triple-drug cocktails that have been approved by the US Food and Drug Administration. Conclusions Induction therapy with partial adherence is tolerable, but the outcome depends on the drug cocktail. Our theoretical predictions are in line with recent results from pilot studies of short-cycle treatment interruption strategies and may be useful in guiding the design of future clinical trials

A Stochastic Model of Latently Infected Cell Reactivation and Viral Blip Generation in Treated HIV Patients

Motivated by viral persistence in HIV+ patients on long-term anti-retroviral treatment (ART), we present a stochastic model of HIV viral dynamics in the blood stream. We consider the hypothesis that the residual viremia in patients on ART can be explained principally by the activation of cells latently infected by HIV before the initiation of ART and that viral blips (clinically-observed short periods of detectable viral load) represent large deviations from the mean. We model the system as a continuous-time, multi-type branching process. Deriving equations for the probability generating function we use a novel numerical approach to extract the probability distributions for latent reservoir sizes and viral loads. We find that latent reservoir extinction-time distributions underscore the importance of considering reservoir dynamics beyond simply the half-life. We calculate blip amplitudes and frequencies by computing complete viral load probability distributions, and study the duration of viral blips via direct numerical simulation. We find that our model qualitatively reproduces short small-amplitude blips detected in clinical studies of treated HIV infection. Stochastic models of this type provide insight into treatment-outcome variability that cannot be found from deterministic models

Models of general circulation of the atmosphere and oceans in forecasting changes in the regional climate of Ukraine in the 21st century.

For the first time quantitative characteristics of probable climate changes in Ukraine during the 21st century for three SRES emission scenarios B1, A1B and A2 have been obtained from an analysis of 84 runs of 10 Atmosphere-Ocean General Circulation Models (AOGCM) used for AR4 IPCC-2007. The analysis of AOGCM’s results has shown that projected differences of the averaged over the territory of Ukraine surface temperatures of the ending and the first decades of the 21st century will be in limits: B1 - from 0,7 to 3,0 °С with ensemble mean 2,0±0,8 °С; А1В - from 2,4 to 4,2 °С with mean 3,1±0,7 °С; and А2 - from 2,6 to 4,6 °С with mean 3,8±0,8 °С. There is not such an agreement for precipitation variations during the 21st century between AOGCMs, and precipita-tion changes vary from -23,4 to +11,6 % up to the end of the 21st century comparing to 2001-2010. Therefore, more detailed precipitation change projections for the territory of Ukraine could be made only with regional climate models. The most rapid changes of surface temperature and precipita-tion have been obtained in AOGCMs for А2 scenario, the slowest - for В1 respectively. The model ECHAM5/MPI-OM has been determined as the most successful AOGCM in simulation of climate of Ukraine because statistical analysis has shown that differences of its results with ensemble mean were minimal. Results of this model could be recommended as initial and boundary conditions for simulation of climate of Ukraine with regional climate models

Characterization of the Molecular Mechanisms Underlying the Chronic Phase of Stroke in a Cynomolgus Monkey Model of Induced Cerebral Ischemia

Stroke is one of the main causes of mortality and long-term disability worldwide. The pathophysiological mechanisms underlying this disease are not well understood, particularly in the chronic phase after the initial ischemic episode. In this study, a Macaca fascicularis stroke model consisting of two sample groups, as determined by MRI-quantified infarct volumes as a measure of the stroke severity 28 days after the ischemic episode, was evaluated using qualitative and quantitative proteomics analyses. By using multiple online multidimensional liquid chromatography platforms, 8790 nonredundant proteins were identified that condensed to 5223 protein groups at 1% global false discovery rate (FDR). After the application of a conservative criterion (5% local FDR), 4906 protein groups were identified from the analysis of cerebral cortex. Of the 2068 quantified proteins, differential proteomic analyses revealed that 31 and 23 were dysregulated in the elevated- and low-infarct-volume groups, respectively. Neurogenesis, synaptogenesis, and inflammation featured prominently as the cellular processes associated with these dysregulated proteins. Protein interaction network analysis revealed that the dysregulated proteins for inflammation and neurogenesis were highly connected, suggesting potential cross-talk between these processes in modulating the cytoskeletal structure and dynamics in the chronic phase poststroke. Elucidating the long-term consequences of brain tissue injuries from a cellular prospective, as well as the molecular mechanisms that are involved, would provide a basis for the development of new potentially neurorestorative therapies

Comparative analysis of the cost of manufacturing and restoring the details as "Shaft"

Проведено дослідження доцільності виконання відновлювальних робіт для деталей типу «Вал» блока ділильного транспортера, що використовується в сільськогосподарської промисловості при виробництві продукції. Проведено порівняння собівартості виготовлення нової деталі та відновлення спрацьованих поверхонь деталей при забезпеченні всіх показників якості.Проведены исследования возможности выполнения восстановительных робот для деталей типу «Вал» блока дилительного транспортера ,который используеться в сельскохозяйственной промышленности при изготовлении продукции. Проведены сравнения себестоимости изготовления новой детали и восстановления изношенных поверхностей деталей обеспечивающих все показатели качества.Study of expediency of implementation of repair works is undertaken for details as "Shaft" of block of dividing conveyer that is used at agricultural industry at the production of goods. Comparison of prime price of making of new detail and proceeding in the worked surfaces of details is conducted at providing of all indexes of qualit