Efficient Algorithms for Fully Multimodal Journey Planning

We study the journey planning problem for fully multimodal networks consisting of public transit and an arbitrary number of non-schedule-based transfer modes (e.g., walking, e-scooter, bicycle). Obtaining reasonable results in this setting requires multicriteria optimization, making the problem highly complex. Previous approaches were either limited to a single transfer mode or suffered from prohibitively slow running times. We establish a fully multimodal journey planning model that excludes undesirable solutions and can be solved efficiently. We extend existing efficient bimodal algorithms to our model and propose a new algorithm, HydRA, which enables even faster queries. On metropolitan and mid-sized country networks with walking and e-scooter as transfer modes, HydRA achieves query times of around 30 ms, which is fast enough for interactive applications

Efficient Algorithms for Fully Multimodal Journey Planning

We study the journey planning problem for fully multimodal networks consisting of public transit and an arbitrary number of non-schedule-based transfer modes (e.g., walking, e-scooter, bicycle). Obtaining reasonable results in this setting requires multicriteria optimization, making the problem highly complex. Previous approaches were either limited to a single transfer mode or suffered from prohibitively slow running times. We establish a fully multimodal journey planning model that excludes undesirable solutions and can be solved efficiently. We extend existing efficient bimodal algorithms to our model and propose a new algorithm, HydRA, which enables even faster queries. On metropolitan and mid-sized country networks with walking and e-scooter as transfer modes, HydRA achieves query times of around 30 ms, which is fast enough for interactive applications

Dynamical Mean-Field Theory

The dynamical mean-field theory (DMFT) is a widely applicable approximation scheme for the investigation of correlated quantum many-particle systems on a lattice, e.g., electrons in solids and cold atoms in optical lattices. In particular, the combination of the DMFT with conventional methods for the calculation of electronic band structures has led to a powerful numerical approach which allows one to explore the properties of correlated materials. In this introductory article we discuss the foundations of the DMFT, derive the underlying self-consistency equations, and present several applications which have provided important insights into the properties of correlated matter.Comment: Chapter in "Theoretical Methods for Strongly Correlated Systems", edited by A. Avella and F. Mancini, Springer (2011), 31 pages, 5 figure

Functional Energetics of CD4+-Cellular Immunity in Monoclonal Antibody-Associated Progressive Multifocal Leukoencephalopathy in Autoimmune Disorders

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is an opportunistic central nervous system- (CNS-) infection that typically occurs in a subset of immunocompromised individuals. An increasing incidence of PML has recently been reported in patients receiving monoclonal antibody (mAb) therapy for the treatment of autoimmune diseases, particularly those treated with natalizumab, efalizumab and rituximab. Intracellular CD4(+)-ATP-concentration (iATP) functionally reflects cellular immunocompetence and inversely correlates with risk of infections during immunosuppressive therapy. We investigated whether iATP may assist in individualized risk stratification for opportunistic infections during mAb-treatment. METHODOLOGY/PRINCIPAL FINDINGS: iATP in PHA-stimulated, immunoselected CD4(+)-cells was analyzed using an FDA-approved assay. iATP of mAb-associated PML (natalizumab (n = 8), rituximab (n = 2), efalizumab (n = 1)), or other cases of opportunistic CNS-infections (HIV-associated PML (n = 2), spontaneous PML, PML in a psoriasis patient under fumaric acids, natalizumab-associated herpes simplex encephalitis (n = 1 each)) was reduced by 59% (194.5±29 ng/ml, mean±SEM) in comparison to healthy controls (HC, 479.9±19.8 ng/ml, p<0.0001). iATP in 14 of these 16 patients was at or below 3(rd) percentile of healthy controls, similar to HIV-patients (n = 18). In contrast, CD4(+)-cell numbers were reduced in only 7 of 15 patients, for whom cell counts were available. iATP correlated with mitochondrial transmembrane potential (ΔΨ(m)) (iATP/ΔΨ(m)-correlation:tau = 0.49, p = 0.03). Whereas mean iATP of cross-sectionally analysed natalizumab-treated patients was unaltered (448.7±12 ng/ml, n = 150), iATP was moderately decreased (316.2±26.1 ng/ml, p = 0.04) in patients (n = 7) who had been treated already during the pivotal phase III trials and had received natalizumab for more than 6 years. 2/92 (2%) patients with less than 24 months natalizumab treatment revealed very low iATP at or below the 3(rd) percentile of HC, whereas 10/58 (17%) of the patients treated for more than 24 months had such low iATP-concentrations. CONCLUSION: Our results suggest that bioenergetic parameters such as iATP may assist in risk stratification under mAb-immunotherapy of autoimmune disorders

Intracellular CD4⁺-ATP-concentrations in mAb-associated opportunistic CNS-infections.

<p>Patients with progressive multifocal leukoencephalopathy (PML) without or with preceeding mAb-therapy. iATP levels of HIV patients were significantly lower than the HC cohort (p<0.0001). For patients with PML occurring under efalizumab or rituximab therapy and HSV-encephalitis under natalizumab, samples were only available after PLEX, as indicated. All other patients had not received PLEX. Total number of CD4⁺-cells per microliter (µl) and clinical course are shown above respective data points. HIV: HIV-patients at risk for opportunistic infections (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0018506#pone-0018506-t001" target="_blank">table 1</a> for details). Black bar indicates mean iATP values and red bar 3^rd percentile of healthy controls.</p

Clinical data of subjects analyzed for iATP – PML and HSVE with various underlying diseases and/or monocloncal antibodies.

<p>Clinical characteristics and disease course of patients with or withour preceeding immunodeficient conditions and/or mAb-immunotherapy who developed PML or Herpes simplex virus encephalitis (HSVE) tested for iATP.</p

Clinical data of subjects analyzed for iATP – Natalizumab associated PML.

<p>MS Patients tested for iATP who developed PML under natalizumab immunotherapy. IRIS = immune reconstitution inflammatory syndrome, NA = not applicable, NK = not known.</p

Relationship between total number of CD4⁺-cells and intracellular CD4⁺-ATP-concentrations.

<p>The X-axis depicts CD4⁺ -cell number per µl, y-axis intracellular CD4⁺-concentrations (iATP; ng/ml) of patients with PML and HIV-patients (black dots) at risk for opportunistic infections. Red dots indicate natalizumab-associated PML, green dots other PML cases (HIV-/rituximab-/efalizumab-associated or without previous immunotherapy). Red lines: 3^rd percentile of healthy controls.</p