Goal-oriented sensitivity analysis for lattice kinetic Monte Carlo simulations

In this paper we propose a new class of coupling methods for the sensitivity analysis of high dimensional stochastic systems and in particular for lattice Kinetic Monte Carlo. Sensitivity analysis for stochastic systems is typically based on approximating continuous derivatives with respect to model parameters by the mean value of samples from a finite difference scheme. Instead of using independent samples the proposed algorithm reduces the variance of the estimator by developing a strongly correlated-"coupled"- stochastic process for both the perturbed and unperturbed stochastic processes, defined in a common state space. The novelty of our construction is that the new coupled process depends on the targeted observables, e.g. coverage, Hamiltonian, spatial correlations, surface roughness, etc., hence we refer to the proposed method as em goal-oriented sensitivity analysis. In particular, the rates of the coupled Continuous Time Markov Chain are obtained as solutions to a goal-oriented optimization problem, depending on the observable of interest, by considering the minimization functional of the corresponding variance. We show that this functional can be used as a diagnostic tool for the design and evaluation of different classes of couplings. Furthermore the resulting KMC sensitivity algorithm has an easy implementation that is based on the Bortz-Kalos-Lebowitz algorithm's philosophy, where here events are divided in classes depending on level sets of the observable of interest. Finally, we demonstrate in several examples including adsorption, desorption and diffusion Kinetic Monte Carlo that for the same confidence interval and observable, the proposed goal-oriented algorithm can be two orders of magnitude faster than existing coupling algorithms for spatial KMC such as the Common Random Number approach

Automated Method for Tracking Human Muscle Architecture on Ultrasound Scans during Dynamic Tasks

Existing approaches for automated tracking of fascicle length (FL) and pennation angle (PA) rely on the presence of a single, user-defined fascicle (feature tracking) or on the presence of a specific intensity pattern (feature detection) across all the recorded ultrasound images. These prerequisites are seldom met during large dynamic muscle movements or for deeper muscles that are difficult to image. Deep-learning approaches are not affected by these issues, but their applicability is restricted by their need for large, manually analyzed training data sets. To address these limitations, the present study proposes a novel approach that tracks changes in FL and PA based on the distortion pattern within the fascicle band. The results indicated a satisfactory level of agreement between manual and automated measurements made with the proposed method. When compared against feature tracking and feature detection methods, the proposed method achieved the lowest average root mean squared error for FL and the second lowest for PA. The strength of the proposed approach is that the quantification process does not require a training data set and it can take place even when it is not possible to track a single fascicle or observe a specific intensity pattern on the ultrasound recording

Long-term fluvastatin reduces the hazardous effect of renal impairment on four-year atherosclerotic outcomes (a LIPS substudy)

peer reviewedMild renal impairment is an important risk factor for late cardiovascular complications. This substudy of the Lescol Intervention Prevention Study (LIPS) assessed the effect of fluvastatin on outcome of patients who had renal dysfunction and those who did not. Complete data for creatinine clearance calculation. (Cockcroft=Gault formula) were available for 1,558 patients (92.9% of the LIPS population). Patients were randomized to fluvastatin or placebo after successful completion of a first percutaneous coronary intervention. Follow-up time was, 3 to 4 years. The effect of baseline creatinine clearance on coronary atherosclerotic events (cardiac death, non-fatal myocardial infarction, and coronary reinterventions not related to restenosis) was evaluated. Baseline creatinine clearance (logarithmic transformation) was inversely associated with an incidence of adverse events among patients who received, placebo. (hazard ratio 0.99, 95% confidence interval 0.982 to 0.998, p = 0.01). However, no association was noted between creatinine clearance and the incidence of adverse events among patients who received fluvastatin (hazard ratio 1.0, 95% confidence interval 0.99 to 1.0, p = 0.63). No further deterioration in creatinine clearance was observed during follow-up; regardless of baseline renal function or allocated treatment. Occurrence of adverse events was not related to changes in renal function during follow-up. Fluvastatin therapy markedly decreased the risk of coronary atherosclerotic events after percutaneous intervention in: patients who had lower values of creatinine clearance at baseline: The benefit of fluvastatin was unrelated to any effect on renal function. (C) 2005 by Excerpta Medica Inc

In Vivo Strain Patterns in the Achilles Tendon During Dynamic Activities: A Comprehensive Survey of the Literature

Abstract Achilles’ tendon (AT) injuries such as ruptures and tendinopathies have experienced a dramatic rise in the mid- to older-aged population. Given that the AT plays a key role at all stages of locomotion, unsuccessful rehabilitation after injury often leads to long-term, deleterious health consequences. Understanding healthy in vivo strains as well as the complex muscle–tendon unit interactions will improve access to the underlying aetiology of injuries and how their functionality can be effectively restored post-injury. The goals of this survey of the literature with a systematic search were to provide a benchmark of healthy AT strains measured in vivo during functional activities and identify the sources of variability observed in the results. Two databases were searched, and all articles that provided measured in vivo peak strains or the change in strain with respect to time were included. In total, 107 articles that reported subjects over the age of 18 years with no prior AT injury and measured while performing functional activities such as voluntary contractions, walking, running, jumping, or jump landing were included in this review. In general, unclear anatomical definitions of the sub-tendon and aponeurosis structures have led to considerable confusion in the literature. MRI, ultrasound, and motion capture were the predominant approaches, sometimes coupled with modelling. The measured peak strains increased from 4% to over 10% from contractions, to walking, running, and jumping, in that order. Importantly, measured AT strains were heavily dependent on measurement location, measurement method, measurement protocol, individual AT geometry, and mechanical properties, as well as instantaneous kinematics and kinetics of the studied activity. Through a comprehensive review of approaches and results, this survey of the literature therefore converges to a united terminology of the structures and their common underlying characteristics and presents the state-of-knowledge on their functional strain patterns

Actionable cancer vulnerability due to translational arrest, p53 aggregation and ribosome biogenesis stress evoked by the disulfiram metabolite CuET.

We would like to thank M.Oren (Weizmann Institute of Science) for kindly providing the MDM2 antibodies, the core facility for Bioinformatics and Expression Analysis (BEA, Karolinska, Huddinge) for assisting in massive parallel sequencing and computational infrastructure, as well as E Dratkiewicz, AS Nilsson, and JF Martinez for excellent technical assistance.Drug repurposing is a versatile strategy to improve current therapies. Disulfiram has long been used in the treatment of alcohol dependency and multiple clinical trials to evaluate its clinical value in oncology are ongoing. We have recently reported that the disulfiram metabolite diethyldithiocarbamate, when combined with copper (CuET), targets the NPL4 adapter of the p97VCP segregase to suppress the growth of a spectrum of cancer cell lines and xenograft models in vivo. CuET induces proteotoxic stress and genotoxic effects, however important issues concerning the full range of the CuET-evoked tumor cell phenotypes, their temporal order, and mechanistic basis have remained largely unexplored. Here, we have addressed these outstanding questions and show that in diverse human cancer cell models, CuET causes a very early translational arrest through the integrated stress response (ISR), later followed by features of nucleolar stress. Furthermore, we report that CuET entraps p53 in NPL4-rich aggregates leading to elevated p53 protein and its functional inhibition, consistent with the possibility of CuET-triggered cell death being p53-independent. Our transcriptomics profiling revealed activation of pro-survival adaptive pathways of ribosomal biogenesis (RiBi) and autophagy upon prolonged exposure to CuET, indicating potential feedback responses to CuET treatment. The latter concept was validated here by simultaneous pharmacological inhibition of RiBi and/or autophagy that further enhanced CuET's tumor cytotoxicity, using both cell culture and zebrafish in vivo preclinical models. Overall, these findings expand the mechanistic repertoire of CuET's anti-cancer activity, inform about the temporal order of responses and identify an unorthodox new mechanism of targeting p53. Our results are discussed in light of cancer-associated endogenous stresses as exploitable tumor vulnerabilities and may inspire future clinical applications of CuET in oncology, including combinatorial treatments and focus on potential advantages of using certain validated drug metabolites, rather than old, approved drugs with their, often complex, metabolic profiles.This work was funded by the following grants: the Swedish Cancer Society (grant number: 170176), the Swedish Research Council (VR-MH 2014-46602-117891-30), Novo Nordisk Foundation (NNF20OC0060590), Danish National Research Foundation (project CARD, DNRF 125), the Danish Cancer Society (R204-A12617-B153), DFF 1026-00241B (all granted to JB), and the Grant agency of the Czech Republic: GACR 20-28685S (granted to ZS and MM). Open access funding provided by Karolinska Institute.S

Short- and long-term clinical benefit of sirolimus-eluting stents compared to conventional bare stents for patients with acute myocardial infarction

AbstractObjectivesThis study investigated the clinical outcomes of patients with ST-segment elevation myocardial infarction (MI) treated with sirolimus-eluting stents (SESs) or with conventional bare stents.BackgroundThe clinical impact of SES implantation for patients with ST-segment elevation MI is currently unknown.MethodsPrimary angioplasty was performed with SESs in 186 consecutive patients with acute MI who were compared with 183 patients treated with bare stents. The incidence of death, reinfarction, and repeat revascularization was assessed at 30 and 300 days.ResultsPostprocedure vessel patency, enzymatic release, and the incidence of short-term adverse events were similar in both the sirolimus and the bare stents (30-day rate of death, reinfarction, or repeat revascularization: 7.5% vs. 10.4%, respectively; p = 0.4). Stent thrombosis was not diagnosed in any patient in the sirolimus group and occurred in 1.6% of patients treated with bare stents (p = 0.1). At 300 days, treatment with SESs significantly reduced the incidence of combined adverse events (9.4% vs. 17%; hazard ratio [HR] 0.52 [95% confidence interval (CI) 0.30 to 0.92]; p = 0.02), mainly due to a marked reduction in the risk of repeat intervention (1.1% vs. 8.2%; HR 0.21 [95% CI 0.06 to 0.74]; p = 0.01).ConclusionsCompared to conventional bare stents, the SESs were not associated with an increased risk of stent thrombosis and were effective in reducing the incidence of adverse events at 300 days in unselected patients with ST-segment elevation acute MI referred for primary angioplasty

Significant reduction in restenosis after the use of sirolimus-eluting stents in the treatment of chronic total occlusions

AbstractObjectivesThe aim of this study was to assess sirolimus-eluting stent (SES) implantation for the treatment of chronic total coronary occlusions (CTO).BackgroundLong-term results after percutaneous coronary intervention (PCI) in the treatment of CTOs is hindered by a significant rate of restenosis and reocclusion. In the treatment of relatively simple nonocclusive lesions, SESs have shown dramatically reduced restenosis rates compared with bare metal stents (BMS), but whether these results are more widely applicable is unknown.MethodsFrom April 2002, all patients at our institution were treated with SES as the device of choice during PCI. During the first six months, 563 patients were treated solely with SES, with treatment of a de novo CTO in 56 (9.9%). This CTO cohort was compared with a similar group of patients (n = 28) treated in the preceding six-month period with BMS.ResultsAt one year, the cumulative survival-free of major adverse cardiac events was 96.4% in the SES group versus 82.8% in the BMS group, p < 0.05. At six-month follow-up, 33 (59%) patients in the SES group underwent angiography with a binary restenosis rate (>50% diameter stenosis) of 9.1% and in-stent late loss of 0.13 ± 0.46 mm. One patient (3.0%) at follow-up was found to have reoccluded the target vessel.ConclusionsThe use of SESs in the treatment of chronic total coronary occlusions is associated with a reduction in the rate of major adverse cardiac events and restenosis compared with BMS

Prediction of balance perturbations and falls on stairs in older people using a biomechanical profiling approach: A 12-month longitudinal study.

BACKGROUND: Stair falls are a major health problem for older people, but presently there are no specific screening tools for stair fall prediction. The purpose of the present study was to investigate whether stair fallers could be differentiated from non-fallers by biomechanical risk factors or physical/psychological parameters and to establish the biomechanical stepping profile posing the greatest risk for a stair fall. METHODS: Eighty-seven older adults (age: 72.1±5.2 y) negotiated an instrumented seven-step staircase and performed a range of physical/psychological tasks. K-means clustering was used to profile the overall stair negotiation behaviour with biomechanical parameters indicative of fall risk as input. Falls and events of balance perturbation (combined "hazardous events") were then monitored during a 12-month follow-up. Cox-regression analysis was performed to examine if physical/psychological parameters or biomechanical outcome measures could predict future hazardous events. Kaplan-Meier survival curves were obtained to identify the stepping strategy posing a risk for a hazardous event. RESULTS: Physical/psychological parameters did not predict hazardous events and the commonly used Fall Risk Assessment Tool (FRAT) classified only 1/17 stair fallers at risk for a fall. Single biomechanical risk factors could not predict hazardous events on stairs either. On the contrary, two particular clusters identified by the stepping profiling method in stair ascent were linked with hazardous events. CONCLUSION: This highlights the potential of the stepping profiling method to predict stair fall risk in older adults against the limited predictability of single parameter approaches currently used as screening tools