Predicting the long-term impact of antiretroviral therapy scale-up on population incidence of tuberculosis.

OBJECTIVE: To investigate the impact of antiretroviral therapy (ART) on long-term population-level tuberculosis disease (TB) incidence in sub-Saharan Africa. METHODS: We used a mathematical model to consider the effect of different assumptions about life expectancy and TB risk during long-term ART under alternative scenarios for trends in population HIV incidence and ART coverage. RESULTS: All the scenarios we explored predicted that the widespread introduction of ART would initially reduce population-level TB incidence. However, many modelled scenarios projected a rebound in population-level TB incidence after around 20 years. This rebound was predicted to exceed the TB incidence present before ART scale-up if decreases in HIV incidence during the same period were not sufficiently rapid or if the protective effect of ART on TB was not sustained. Nevertheless, most scenarios predicted a reduction in the cumulative TB incidence when accompanied by a relative decline in HIV incidence of more than 10% each year. CONCLUSIONS: Despite short-term benefits of ART scale-up on population TB incidence in sub-Saharan Africa, longer-term projections raise the possibility of a rebound in TB incidence. This highlights the importance of sustaining good adherence and immunologic response to ART and, crucially, the need for effective HIV preventive interventions, including early widespread implementation of ART

Numerical solutions of random mean square Fisher-KPP models with advection

[EN] This paper deals with the construction of numerical stable solutions of random mean square Fisher-Kolmogorov-Petrosky-Piskunov (Fisher-KPP) models with advection. The construction of the numerical scheme is performed in two stages. Firstly, a semidiscretization technique transforms the original continuous problem into a nonlinear inhomogeneous system of random differential equations. Then, by extending to the random framework, the ideas of the exponential time differencing method, a full vector discretization of the problem addresses to a random vector difference scheme. A sample approach of the random vector difference scheme, the use of properties of Metzler matrices and the logarithmic norm allow the proof of stability of the numerical solutions in the mean square sense. In spite of the computational complexity, the results are illustrated by comparing the results with a test problem where the exact solution is known.Ministerio de Economia y Competitividad, Grant/Award Number: MTM2017-89664-PCasabán Bartual, MC.; Company Rossi, R.; Jódar Sánchez, LA. (2020). Numerical solutions of random mean square Fisher-KPP models with advection. Mathematical Methods in the Applied Sciences. 43(14):8015-8031. https://doi.org/10.1002/mma.5942S801580314314FISHER, R. A. (1937). THE WAVE OF ADVANCE OF ADVANTAGEOUS GENES. Annals of Eugenics, 7(4), 355-369. doi:10.1111/j.1469-1809.1937.tb02153.xBengfort, M., Malchow, H., & Hilker, F. M. (2016). The Fokker–Planck law of diffusion and pattern formation in heterogeneous environments. Journal of Mathematical Biology, 73(3), 683-704. doi:10.1007/s00285-016-0966-8Okubo, A., & Levin, S. A. (2001). Diffusion and Ecological Problems: Modern Perspectives. 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(2006). Asymptotic speeds of spread and traveling waves for monotone semiflows with applications. Communications on Pure and Applied Mathematics, 60(1), 1-40. doi:10.1002/cpa.20154E. Fitzgibbon, W., Parrott, M. E., & Webb, G. (1995). Diffusive epidemic models with spatial and age dependent heterogeneity. Discrete & Continuous Dynamical Systems - A, 1(1), 35-57. doi:10.3934/dcds.1995.1.35Kinezaki, N., Kawasaki, K., & Shigesada, N. (2006). Spatial dynamics of invasion in sinusoidally varying environments. Population Ecology, 48(4), 263-270. doi:10.1007/s10144-006-0263-2Jin, Y., Hilker, F. M., Steffler, P. M., & Lewis, M. A. (2014). Seasonal Invasion Dynamics in a Spatially Heterogeneous River with Fluctuating Flows. Bulletin of Mathematical Biology, 76(7), 1522-1565. doi:10.1007/s11538-014-9957-3Faou, E. (2009). Analysis of splitting methods for reaction-diffusion problems using stochastic calculus. Mathematics of Computation, 78(267), 1467-1483. doi:10.1090/s0025-5718-08-02185-6Doering, C. R., Mueller, C., & Smereka, P. (2003). Interacting particles, the stochastic Fisher–Kolmogorov–Petrovsky–Piscounov equation, and duality. Physica A: Statistical Mechanics and its Applications, 325(1-2), 243-259. doi:10.1016/s0378-4371(03)00203-6Siekmann, I., Bengfort, M., & Malchow, H. (2017). Coexistence of competitors mediated by nonlinear noise. The European Physical Journal Special Topics, 226(9), 2157-2170. doi:10.1140/epjst/e2017-70038-6McKean, H. P. (1975). Application of brownian motion to the equation of kolmogorov-petrovskii-piskunov. Communications on Pure and Applied Mathematics, 28(3), 323-331. doi:10.1002/cpa.3160280302Berestycki, H., & Nadin, G. (2012). Spreading speeds for one-dimensional monostable reaction-diffusion equations. Journal of Mathematical Physics, 53(11), 115619. doi:10.1063/1.4764932Cortés, J. C., Jódar, L., Villafuerte, L., & Villanueva, R. J. (2007). Computing mean square approximations of random diffusion models with source term. Mathematics and Computers in Simulation, 76(1-3), 44-48. doi:10.1016/j.matcom.2007.01.020Villafuerte, L., Braumann, C. A., Cortés, J.-C., & Jódar, L. (2010). Random differential operational calculus: Theory and applications. Computers & Mathematics with Applications, 59(1), 115-125. doi:10.1016/j.camwa.2009.08.061Casabán, M.-C., Cortés, J.-C., & Jódar, L. (2016). Solving linear and quadratic random matrix differential equations: A mean square approach. Applied Mathematical Modelling, 40(21-22), 9362-9377. doi:10.1016/j.apm.2016.06.017Sarmin, E. N., & Chudov, L. A. (1963). On the stability of the numerical integration of systems of ordinary differential equations arising in the use of the straight line method. USSR Computational Mathematics and Mathematical Physics, 3(6), 1537-1543. doi:10.1016/0041-5553(63)90256-8Sanz-Serna, J. M., & Verwer, J. G. (1989). Convergence analysis of one-step schemes in the method of lines. Applied Mathematics and Computation, 31, 183-196. doi:10.1016/0096-3003(89)90118-5Calvo, M. P., de Frutos, J., & Novo, J. (2001). Linearly implicit Runge–Kutta methods for advection–reaction–diffusion equations. Applied Numerical Mathematics, 37(4), 535-549. doi:10.1016/s0168-9274(00)00061-1Cox, S. M., & Matthews, P. C. (2002). Exponential Time Differencing for Stiff Systems. Journal of Computational Physics, 176(2), 430-455. doi:10.1006/jcph.2002.6995De la Hoz, F., & Vadillo, F. (2016). Numerical simulations of time-dependent partial differential equations. Journal of Computational and Applied Mathematics, 295, 175-184. doi:10.1016/j.cam.2014.10.006Company, R., Egorova, V. N., & Jódar, L. (2018). Conditional full stability of positivity-preserving finite difference scheme for diffusion–advection-reaction models. Journal of Computational and Applied Mathematics, 341, 157-168. doi:10.1016/j.cam.2018.02.031Kaczorek, T. 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A boosting method for maximizing the partial area under the ROC curve

<p>Abstract</p> <p>Background</p> <p>The receiver operating characteristic (ROC) curve is a fundamental tool to assess the discriminant performance for not only a single marker but also a score function combining multiple markers. The area under the ROC curve (AUC) for a score function measures the intrinsic ability for the score function to discriminate between the controls and cases. Recently, the partial AUC (pAUC) has been paid more attention than the AUC, because a suitable range of the false positive rate can be focused according to various clinical situations. However, existing pAUC-based methods only handle a few markers and do not take nonlinear combination of markers into consideration.</p> <p>Results</p> <p>We have developed a new statistical method that focuses on the pAUC based on a boosting technique. The markers are combined componentially for maximizing the pAUC in the boosting algorithm using natural cubic splines or decision stumps (single-level decision trees), according to the values of markers (continuous or discrete). We show that the resulting score plots are useful for understanding how each marker is associated with the outcome variable. We compare the performance of the proposed boosting method with those of other existing methods, and demonstrate the utility using real data sets. As a result, we have much better discrimination performances in the sense of the pAUC in both simulation studies and real data analysis.</p> <p>Conclusions</p> <p>The proposed method addresses how to combine the markers after a pAUC-based filtering procedure in high dimensional setting. Hence, it provides a consistent way of analyzing data based on the pAUC from maker selection to marker combination for discrimination problems. The method can capture not only linear but also nonlinear association between the outcome variable and the markers, about which the nonlinearity is known to be necessary in general for the maximization of the pAUC. The method also puts importance on the accuracy of classification performance as well as interpretability of the association, by offering simple and smooth resultant score plots for each marker.</p

Multilevel analysis of clinical parameters in chronic periodontitis after root planing/scaling, surgery, and systemic and local antibiotics: 2-year results

Aim: Find the periodontal treatment that best maintained clinical results over time evaluated by changes in pocket depth (PD) and clinical attachment level (CAL). Methods: 229 patients with chronic periodontitis from USA (n=134) and Sweden (n=95) were randomly assigned to eight groups receiving 1 scaling+root planing (SRP) alone or combined with 2 surgery (SURG)+systemic amoxicillin (AMOX)+systemic metronidazole (MET); 3 SURG+local tetracycline (TET); 4 SURG; 5 AMOX+MET+TET; 6 AMOX+MET; 7 TET; and 8 SURG+AMOX+MET+TET. Antibiotics were given immediately after SRP. Plaque, gingival redness, bleeding on probing, suppuration, PD, and CAL were recorded at baseline and after 3, 6, 12, 18, and 24 months. Treatment effects were evaluated by linear multilevel regression and logistic multilevel regression models. We considered only data from sites with a baseline PD of at least 5 mm of 187 patients completing the study. Results: Surgically treated patients experienced most CAL loss. Adjunctive therapy including SURG was most effective in reducing PD. Combining SURG with AMOX, MET, and TET gave significant clinical benefits. Past and current smoking habits were significant predictors of deeper PD. Only current smoking was a significant predictor of CAL loss. Bleeding, accumulation of plaque, gingival redness, and suppuration were significant predictors of further CAL loss and deeper PD. Conclusions: Both surgical and non-surgical therapies can be used to arrest chronic periodontitis. SURG+AMOX+MET+TET gave best maintenance of clinical results

How acceptable are antiretrovirals for the prevention of sexually transmitted HIV? A review of research on the acceptability of oral pre-exposure prophylaxis and treatment as prevention

Recent research has demonstrated how antiretrovirals (ARVs) could be effective in the prevention of sexually transmitted HIV. We review research on the acceptability of oral pre-exposure prophylaxis (PrEP) and treatment as prevention (TasP) for HIV prevention amongst potential users. We consider with whom, where and in what context this research has been conducted, how acceptability has been approached, and what research gaps remain. Findings from 33 studies show a lack of TasP research, PrEP studies which have focused largely on men who have sex with men (MSM) in a US context, and varied measures of acceptability. In order to identify when, where and for whom PrEP and TasP would be most appropriate and effective, research is needed in five areas: acceptability of TasP to people living with HIV; motivation for PrEP use and adherence; current perceptions and management of risk; the impact of broader social and structural factors; and consistent definition and operationalisation of acceptability which moves beyond adherence

Increased RPA1 gene dosage affects genomic stability potentially contributing to 17p13.3 duplication syndrome

A novel microduplication syndrome involving various-sized contiguous duplications in 17p13.3 has recently been described, suggesting that increased copy number of genes in 17p13.3, particularly PAFAH1B1, is associated with clinical features including facial dysmorphism, developmental delay, and autism spectrum disorder. We have previously shown that patient-derived cell lines from individuals with haploinsufficiency of RPA1, a gene within 17p13.3, exhibit an impaired ATR-dependent DNA damage response (DDR). Here, we show that cell lines from patients with duplications specifically incorporating RPA1 exhibit a different although characteristic spectrum of DDR defects including abnormal S phase distribution, attenuated DNA double strand break (DSB)-induced RAD51 chromatin retention, elevated genomic instability, and increased sensitivity to DNA damaging agents. Using controlled conditional over-expression of RPA1 in a human model cell system, we also see attenuated DSB-induced RAD51 chromatin retention. Furthermore, we find that transient over-expression of RPA1 can impact on homologous recombination (HR) pathways following DSB formation, favouring engagement in aberrant forms of recombination and repair. Our data identifies unanticipated defects in the DDR associated with duplications in 17p13.3 in humans involving modest RPA1 over-expression

Multiple structure alignment and consensus identification for proteins

<p>Abstract</p> <p>Background</p> <p>An algorithm is presented to compute a multiple structure alignment for a set of proteins and to generate a consensus (pseudo) protein which captures common substructures present in the given proteins. The algorithm represents each protein as a sequence of triples of coordinates of the alpha-carbon atoms along the backbone. It then computes iteratively a sequence of transformation matrices (i.e., translations and rotations) to align the proteins in space and generate the consensus. The algorithm is a heuristic in that it computes an approximation to the optimal alignment that minimizes the sum of the pairwise distances between the consensus and the transformed proteins.</p> <p>Results</p> <p>Experimental results show that the algorithm converges quite rapidly and generates consensus structures that are visually similar to the input proteins. A comparison with other coordinate-based alignment algorithms (MAMMOTH and MATT) shows that the proposed algorithm is competitive in terms of speed and the sizes of the conserved regions discovered in an extensive benchmark dataset derived from the HOMSTRAD and SABmark databases.</p> <p>The algorithm has been implemented in C++ and can be downloaded from the project's web page. Alternatively, the algorithm can be used via a web server which makes it possible to align protein structures by uploading files from local disk or by downloading protein data from the RCSB Protein Data Bank.</p> <p>Conclusions</p> <p>An algorithm is presented to compute a multiple structure alignment for a set of proteins, together with their consensus structure. Experimental results show its effectiveness in terms of the quality of the alignment and computational cost.</p

Delineation of prognostic biomarkers in prostate cancer

Prostate cancer is the most frequently diagnosed cancer in American men(1,2). Screening for prostate-specific antigen (PSA) has led to earlier detection of prostate cancer(3), but elevated serum PSA levels may be present in non-malignant conditions such as benign prostatic hyperlasia (BPH). Characterization of gene-expression profiles that molecularly distinguish prostatic neoplasms may identify genes involved in prostate carcinogenesis, elucidate clinical biomarkers, and lead to an improved classification of prostate cancer(4-6). Using microarrays of complementary DNA, we examined gene-expression profiles of more than 50 normal and neoplastic prostate specimens and three common prostate-cancer cell lines. Signature expression profiles of normal adjacent prostate (NAP), BPH, localized prostate cancer, and metastatic, hormone-refractory prostate cancer were determined. Here we establish many associations between genes and prostate cancer. We assessed two of these genes-hepsin, a transmembrane serine protease, and pim-1, a serine/threonine kinase-at the protein level using tissue microarrays consisting of over 700 clinically stratified prostate-cancer specimens. Expression of hepsin and pim-1 proteins was significantly correlated with measures of clinical outcome. Thus, the integration of cDNA microarray, high-density tissue microarray, and linked clinical and pathology data is a powerful approach to molecular profiling of human cancer.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62849/1/412822a0.pd

A Comparison of Initial Antiretroviral Therapy in the Swiss HIV Cohort Study and the Recommendations of the International AIDS Society-USA

BACKGROUND: In order to facilitate and improve the use of antiretroviral therapy (ART), international recommendations are released and updated regularly. We aimed to study if adherence to the recommendations is associated with better treatment outcomes in the Swiss HIV Cohort Study (SHCS). METHODS: Initial ART regimens prescribed to participants between 1998 and 2007 were classified according to IAS-USA recommendations. Baseline characteristics of patients who received regimens in violation with these recommendations (violation ART) were compared to other patients. Multivariable logistic and linear regression analyses were performed to identify associations between violation ART and (i) virological suppression and (ii) CD4 cell count increase, after one year. RESULTS: Between 1998 and 2007, 4189 SHCS participants started 241 different ART regimens. A violation ART was started in 5% of patients. Female patients (adjusted odds ratio aOR 1.83, 95%CI 1.28-2.62), those with a high education level (aOR 1.49, 95%CI 1.07-2.06) or a high CD4 count (aOR 1.53, 95%CI 1.02-2.30) were more likely to receive violation ART. The proportion of patients with an undetectable viral load (<400 copies/mL) after one year was significantly lower with violation ART than with recommended regimens (aOR 0.54, 95% CI 0.37-0.80) whereas CD4 count increase after one year of treatment was similar in both groups. CONCLUSIONS: Although more than 240 different initial regimens were prescribed, violations of the IAS-USA recommendations were uncommon. Patients receiving these regimens were less likely to have an undetectable viral load after one year, which strengthens the validity of these recommendations