Strong Stability Preserving Two-Step Runge-Kutta Methods

We investigate the strong stability preserving (SSP) property of two-step Runge– Kutta (TSRK) methods. We prove that all SSP TSRK methods belong to a particularly simple\ud subclass of TSRK methods, in which stages from the previous step are not used. We derive simple order conditions for this subclass. Whereas explicit SSP Runge–Kutta methods have order at most four, we prove that explicit SSP TSRK methods have order at most eight. We present TSRK methods of up to eighth order that were found by numerical search. These methods have larger SSP coefficients than any known methods of the same order of accuracy, and may be implemented in a form with relatively modest storage requirements. The usefulness of the TSRK methods is demonstrated through numerical examples, including integration of very high order WENO discretizations

Long time motion of NLS solitary waves in a confining potential

We study the motion of solitary-wave solutions of a family of focusing generalized nonlinear Schroedinger equations with a confining, slowly varying external potential, $V(x)$. A Lyapunov-Schmidt decomposition of the solution combined with energy estimates allows us to control the motion of the solitary wave over a long, but finite, time interval. We show that the center of mass of the solitary wave follows a trajectory close to that of a Newtonian point particle in the external potential $V(x)$ over a long time interval.Comment: 42 pages, 2 figure

Long Time Motion of NLS Solitary Waves in a Confining Potential

Abstract.: We study the motion of solitary-wave solutions of a family of focusing generalized nonlinear Schrödinger equations with a confining, slowly varying external potential, V(x). A Lyapunov-Schmidt decomposition of the solution combined with energy estimates allows us to control the motion of the solitary wave over a long, but finite, time interval. We show that the center of mass of the solitary wave follows a trajectory close to that of a Newtonian point particle in the external potential V(x) over a long time interval. Communicated by Rafael D. Benguri

Paving the road from transport models to “new mobilities” models

For half a century, tremendous efforts have been invested in developing transport models as a decision aid for policy makers in designing effective policy interventions and deciding among costly public projects for the benefit of the population. Transport and activity-based models are often criticized for neglecting the “new mobilities” turn (Urry 2007, Cresswell 2006), namely multiple mobility aspects and rationales, including social, cultural, material, aesthetic and affective, in analyzing travel behavior. This paper aims at taking a tentative first step in bridging the gap between the traditional transport modeling approach and “new mobilities” research by suggesting a model framework that considers non-instrumental transport rationales, personal latent traits and intra-household decision dynamics

Paving the road from transport models to “new mobilities” models

For half a century, tremendous efforts have been invested in developing transport models as a decision aid for policy makers in designing effective policy interventions and deciding among costly public projects for the benefit of the population. Transport and activity-based models are often criticized for neglecting the “new mobilities” turn (Urry 2007, Cresswell 2006), namely multiple mobility aspects and rationales, including social, cultural, material, aesthetic and affective, in analyzing travel behavior. This paper aims at taking a tentative first step in bridging the gap between the traditional transport modeling approach and “new mobilities” research by suggesting a model framework that considers non-instrumental transport rationales, personal latent traits and intra-household decision dynamics

Tuberculosis and COVID-19 in the elderly: factors driving a higher burden of disease

Mycobacterium tuberculosis (M.tb) and SARS-CoV-2 are both infections that can lead to severe disease in the lower lung. However, these two infections are caused by very different pathogens (Mycobacterium vs. virus), they have different mechanisms of pathogenesis and immune response, and differ in how long the infection lasts. Despite the differences, SARS-CoV-2 and M.tb share a common feature, which is also frequently observed in other respiratory infections: the burden of disease in the elderly is greater. Here, we discuss possible reasons for the higher burden in older adults, including the effect of co-morbidities, deterioration of the lung environment, auto-immunity, and a reduced antibody response. While the answer is likely to be multifactorial, understanding the main drivers across different infections may allow us to design broader interventions that increase the health-span of older people

Sensitive electrochemiluminescence (ECL) immunoassays for detecting lipoarabinomannan (LAM) and ESAT-6 in urine and serum from tuberculosis patients.

BackgroundTuberculosis (TB) infection was responsible for an estimated 1.3 million deaths in 2017. Better diagnostic tools are urgently needed. We sought to determine whether accurate TB antigen detection in blood or urine has the potential to meet the WHO target product profiles for detection of active TB.Materials and methodsWe developed Electrochemiluminescence (ECL) immunoassays for Lipoarabinomannan (LAM) and ESAT-6 detection with detection limits in the pg/ml range and used them to compare the concentrations of the two antigens in the urine and serum of 81 HIV-negative and -positive individuals with presumptive TB enrolled across diverse geographic sites.ResultsLAM and ESAT-6 overall sensitivities in urine were 93% and 65% respectively. LAM and ESAT-6 overall sensitivities in serum were 55% and 46% respectively. Overall specificity was ≥97% in all assays. Sensitivities were higher in HIV-positive compared to HIV-negative patients for both antigens and both sample types, with signals roughly 10-fold higher on average in urine than in serum. The two antigens showed similar concentration ranges within the same sample type and correlated.ConclusionsLAM and ESAT-6 can be detected in the urine and serum of TB patients, regardless of the HIV status and further gains in clinical sensitivity may be achievable through assay and reagent optimization. Accuracy in urine was higher with current methods and has the potential to meet the WHO accuracy target if the findings can be transferred to a point-of-care TB test

A Novel Sensitive Immunoassay Targeting the 5-Methylthio-d-Xylofuranose-Lipoarabinomannan Epitope Meets the WHO's Performance Target for Tuberculosis Diagnosis.

The only currently commercialized point-of-care assay for tuberculosis (TB) that measures lipoarabinomannan (LAM) in urine (Alere LF-LAM) has insufficient sensitivity. We evaluated the potential of 100 novel monoclonal antibody pairs targeting a variety of LAM epitopes on a sensitive electrochemiluminescence platform to improve the diagnostic accuracy. In the screening, many antibody pairs showed high reactivity to purified LAM but performed poorly at detecting urinary LAM in clinical samples, suggesting differences in antigen structure and immunoreactivity of the different LAM sources. The 12 best antibody pairs from the screening were tested in a retrospective case-control study with urine samples from 75 adults with presumptive TB. The best antibody pair reached femtomolar analytical sensitivity for LAM detection and an overall clinical sensitivity of 93% (confidence interval [CI], 80% to 97%) and specificity of 97% (CI, 85% to 100%). Importantly, in HIV-negative subjects positive for TB by sputum smear microscopy, the test achieved a sensitivity of 80% (CI, 55% to 93%). This compares to an overall sensitivity of 33% (CI, 20% to 48%) of the Alere LF-LAM and a sensitivity of 13% (CI, 4% to 38%) in HIV-negative subjects in the same sample set. The capture antibody targets a unique 5-methylthio-d-xylofuranose (MTX)-dependent epitope in LAM that is specific to the Mycobacterium tuberculosis complex and shows no cross-reactivity with fast-growing mycobacteria or other bacteria. The present study provides evidence that improved assay methods and reagents lead to increased diagnostic accuracy. The results of this work have informed the development of a sensitive and specific novel LAM point-of-care assay with the aim to meet the WHO's performance target for TB diagnosis

Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy

Latency and ongoing replication have both been proposed to explain the drug-insensitive human immunodeficiency virus (HIV) reservoir maintained during antiretroviral therapy. Here we explore a novel mechanism for ongoing HIV replication in the face of antiretroviral drugs. We propose a model whereby multiple infections per cell lead to reduced sensitivity to drugs without requiring drug-resistant mutations, and experimentally validate the model using multiple infections per cell by cell-free HIV in the presence of the drug tenofovir. We then examine the drug sensitivity of cell-to-cell spread of HIV, a mode of HIV transmission that can lead to multiple infection events per target cell. Infections originating from cell-free virus decrease strongly in the presence of antiretrovirals tenofovir and efavirenz whereas infections involving cell-to-cell spread are markedly less sensitive to the drugs. The reduction in sensitivity is sufficient to keep multiple rounds of infection from terminating in the presence of drugs. We examine replication from cell-to-cell spread in the presence of clinical drug concentrations using a stochastic infection model and find that replication is intermittent, without substantial accumulation of mutations. If cell-to-cell spread has the same properties in vivo, it may have adverse consequences for the immune system, lead to therapy failure in individuals with risk factors, and potentially contribute to viral persistence and hence be a barrier to curing HIV infection