Online Selection of CMA-ES Variants

In the field of evolutionary computation, one of the most challenging topics is algorithm selection. Knowing which heuristics to use for which optimization problem is key to obtaining high-quality solutions. We aim to extend this research topic by taking a first step towards a selection method for adaptive CMA-ES algorithms. We build upon the theoretical work done by van Rijn \textit{et al.} [PPSN'18], in which the potential of switching between different CMA-ES variants was quantified in the context of a modular CMA-ES framework. We demonstrate in this work that their proposed approach is not very reliable, in that implementing the suggested adaptive configurations does not yield the predicted performance gains. We propose a revised approach, which results in a more robust fit between predicted and actual performance. The adaptive CMA-ES approach obtains performance gains on 18 out of 24 tested functions of the BBOB benchmark, with stable advantages of up to 23\%. An analysis of module activation indicates which modules are most crucial for the different phases of optimizing each of the 24 benchmark problems. The module activation also suggests that additional gains are possible when including the (B)IPOP modules, which we have excluded for this present work.Comment: To appear at Genetic and Evolutionary Computation Conference (GECCO'19) Appendix will be added in due tim

Clinical pharmacology of ertapenem in the treatment of multidrug-resistant tuberculosis

Tuberculosis (TB) is caused by Mycobacterium tuberculosis and is the deadliest infectious disease worldwide. It is necessary to improve current treatment by developing more active - sterilizing - TB drugs. A particularly effective strategy is the rediscovery of old medicines as new agents for the treatment of multidrug-resistant tuberculosis (MDR-TB). Ertapenem, a beta-lactam antimicrobial drug, appears to be active against MDR-TB. To better understand the potential role of ertapenem in the treatment of M / XDR-TB, the aim of this thesis was to evaluate current literature, in vitro activity, pharmacokinetics and safety in TB patients. We investigated the potential of carbapenems for the treatment of M / XDR-TB tested. The aim of this literature review was to evaluate the currently available in vitro, in vivo and clinical data on carbapenems in the treatment of M. tuberculosis and the detection of knowledge gaps, to focus on future research. Subsequently, we developed an LC-MS / MS method, a retrospective study for all suspected MDR-TB patients who received ertapenem as part of their treatment regimen. We demonstrated the rapid decline of ertapenem during a drug susceptibility test (DST) and identified ertapenem exposure associated with optimal sterilization effect to subsequently design a once-daily dose for clinical use. Finally, we developed a Limited Sampling strategy using a population pharmacokinetic model to predict ertapenem exposure in MDR-TB patients. We conclude that 2 g ertapenem in combination with clavulanic acid can be a valuable asset in the treatment of multiresistant TB

Neuroelectromagnetic signatures of the reproduction of supra-second durations

AbstractWhen participants are asked to reproduce an earlier presented duration, EEG recordings typically show a slow potential that develops over the fronto-central regions of the brain and is assumed to be generated in the supplementary motor area (SMA). This contingent negative variation (CNV) has been linked to anticipation, preparation and formation of temporal judgment (Macar, Vidal, and Casini, 1999, Experimental Brain Research, 125(3), 271–80). Although the interpretation of the CNV amplitude is problematic (Kononowicz and Van Rijn, (2011), Frontiers in Integrative Neuroscience, 5(48); Ng, Tobin, and Penney, 2011, Frontiers in Integrative Neuroscience, 5(77)), the observation of this slow potential is extremely robust, and thus one could assume that magnetic recordings of brain activity should show similar activity patterns. However, interval timing studies using durations shorter than one second did not provide unequivocal evidence as to whether CNV has a magnetic counterpart (CMV). As interval timing has been typically associated with durations longer than one second, participants in this study were presented intervals of 2, 3 or 4s that had to be reproduced in setup similar to the seminal work of Elbert et al. (1991, Psychophysiology, 28(6), 648–55) while co-recording EEG and MEG.The EEG data showed a clear CNV during the standard and the reproduction interval. In the reproduction interval the CNV steadily builds up from the onset of interval for both stimulus and response locked data. The MEG data did not show a CNV-resembling ramping of activity, but only showed a pre-movement magnetic field (preMMF) that originated from the SMA, occurring approximately 0.6s before the termination of the timed interval. These findings support the notion that signatures of timing are more straightforwardly measured using EEG, and show that the measured MEG signal from the SMA is constrained to the end of reproduction interval, before the voluntary movement.Moreover, we investigated a link between timing behavior and the early iCNV and late CNV amplitudes to evaluate the hypothesis that these amplitudes reflect the accumulation of temporal pulses. Larger iCNV amplitudes predicted shorter reproduced durations. This effect was more pronounced for the 2s interval reproduction, suggesting that preparatory strategies depend on the length of reproduced interval. Similarly to Elbert et al. (1991, Psychophysiology, 28(6), 648–55), longer reproductions were associated with smaller CNV amplitudes, both between conditions and across participants within the same condition. As the temporal accumulation hypothesis predicts the inverse, these results support the proposal by Van Rijn et al. (2011, Frontiers in Integrative Neuroscience, 5) that the CNV reflects other temporally driven processes such as temporal expectation and preparation rather than temporal accumulation itself

Finding Efficient Trade-offs in Multi-Fidelity Response Surface Modeling

In the context of optimization approaches to engineering applications, time-consuming simulations are often utilized which can be configured to deliver solutions for various levels of accuracy, commonly referred to as different fidelity levels. It is common practice to train hierarchical surrogate models on the objective functions in order to speed-up the optimization process. These operate under the assumption that there is a correlation between the high- and low-fidelity versions of the problem that can be exploited to cheaply gain information. In the practical scenario where the computational budget has to be allocated between multiple fidelities, limited guidelines are available to help make that division. In this paper we evaluate a range of different choices for a two-fidelity setup that provide helpful intuitions about the trade-off between evaluating in high- or low-fidelity. We present a heuristic method based on subsampling from an initial Design of Experiments (DoE) to find a suitable division of the computational budget between the fidelity levels. This enables the setup of multi-fidelity optimizations which utilize the available computational budget efficiently, independent of the multi-fidelity model used.Comment: 12 pages, 9 figures, submitted to Numerical Methods in Engineering Journa

Unsuccessful Stent Graft Repair of a Hepatic Artery Aneurysm Presenting with Haemobilia:Case Report and Comprehensive Literature Review

AIMS: To discuss treatment strategies for non-traumatic, non-iatrogenic hepatic artery aneurysms (HAAs) in the presence of an arteriobiliary fistula, illustrated by a case and followed by a comprehensive review of the literature. METHODS: Following the PRISMA guidelines, 24 eligible HAA cases presenting with haemobilia were identified. Characteristics of patients, aneurysms, treatment strategies and their outcomes were collected. RESULTS: A 69 year old patient with no previous hepatobiliary intervention or trauma, presented with jaundice and haemobilia caused by a HAA. Initial treatment by endovascular stenting was chosen to prevent ischaemic liver complications. Unfortunately, this strategy failed because of stent migration due to ongoing infection leading to a type 1A endoleak. The patient had to be converted to open surgery with ligation of the HAA. The patient recovered uneventfully and no complications occurred during the following 12 months. COMPREHENSIVE LITERATURE REVIEW: Of the 24 cases, nine had a true HAA and 15 were pseudo/mycotic aneurysms, mainly caused by endocarditis or cholecystitis. The majority were located in the right hepatic artery. In 20 cases, an endovascular first approach was chosen with embolisation, none with covered stents. Three of these cases had to be converted to open surgery because of rebleeding. In all open (primary or secondary) cases, ligation of the HAA was performed. One patient in these series died. No liver ischaemia or abscesses were reported, although one patient developed an ischaemic gallbladder. CONCLUSIONS: Patients who present with a HAA and haemobilia may be treated safely by embolisation or open ligation. Using a covered stent graft in these patients can cause problems due to ongoing infection and should be monitored closely by imaging. Publication bias and lack of long term follow up imply cautious interpretation of these findings

Epidemiology and (Patho)physiology of folic acid supplement use in obese women before and during pregnancy

Preconception folic acid supplement use is a well-known method of primary prevention of neural tube defects (NTDs). Obese women are at a higher risk for having a child with a NTD. As different international recommendations on folic acid supplement use for obese women before and during pregnancy exist, this narrative review provides an overview of epidemiology of folate deficiency in obese (pre)pregnant women, elaborates on potential mechanisms underlying folate deficiency, and discusses considerations for the usage of higher doses of folic acid supplements. Women with obesity more often suffer from an absolute folate deficiency, as they are less compliant to periconceptional folic acid supplement use recommendations. In addition, their dietary folate intake is limited due to an unbalanced diet (relative malnutrition). The association of obesity and NTDs also seems to be independent of folate intake, with studies suggesting an increased need of folate (relative deficiency) due to derangements involved in other pathways. The relative folate deficiency, as a result of an increased metabolic need for folate in obese women, can be due to: (1) low-grade chronic inflammation (2) insulin resistance, (3) inositol, and (4) dysbiotic gut microbiome, which plays a role in folate production and uptake. In all these pathways, the folate-dependent one-carbon metabolism is involved. In conclusion, scientific evidence of the involvement of several folate-related pathways implies to increase the recommended folic acid supplementation in obese women. However, the physiological uptake of synthetic folic acid is limited and side-effects of unmetabolized folic acid in mothers and offspring, in particular variations in epigenetic (re)programming with long-term health effects, cannot be excluded. Therefore, we emphasize on the urgent need for further research and preconception personalized counseling on folate status

Aneurysm Sac Dynamics and its Prognostic Significance Following Fenestrated and Branched Endovascular Aortic Aneurysm Repair

Objective: This study aimed to assess aneurysm sac dynamics and its prognostic significance following fenestrated and branched endovascular aneurysm repair (F/BEVAR). Methods: Patients undergoing F/BEVAR for degenerative complex aortic aneurysm from 2008 to 2020 at two large vascular centres with two imaging examinations (30 day and one year) were included. Patients were categorised as regression and non-regression, determined by the proportional volume change (&gt; 5%) at one year compared with 30 days. All cause mortality and freedom from graft related events were assessed using Kaplan–Meier methods. Factors associated with non-regression at one year and aneurysm sac volume over time were examined for FEVAR and BEVAR independently using multivariable logistic regression and linear mixed effects modelling. Results: One hundred and sixty-five patients were included: 122 FEVAR, of whom 34% did not regress at one year imaging (20% stable, 14% expansion); and 43 BEVAR, of whom 53% failed to regress (26% stable, 28% expansion). Following F/BEVAR, after risk adjusted analysis, non-regression was associated with higher risk of all cause mortality within five years (hazard ratio [HR] 2.56, 95% confidence interval [CI] 1.09 – 5.37; p = .032) and higher risk of graft related events within five years (HR 2.44, 95% CI 1.10 – 5.26; p = .029). Following multivariable logistic regression, previous aortic repair (odds ratio [OR] 2.56, 95% CI 1.11 – 5.96; p = .029) and larger baseline aneurysm diameter (OR/mm 1.04, 95% CI 1.00 – 1.09; p = .037) were associated with non-regression at one year, whereas smoking history was inversely associated with non-regression (OR 0.21, 95% CI 0.04 – 0.96; p = .045). Overall following FEVAR, aneurysm sac volume decreased significantly up to two years (baseline vs. two year, 267 [95% CI 250 – 285] cm 3 vs. 223 [95% CI 197 – 248] cm 3), remaining unchanged thereafter. Overall following BEVAR, aneurysm sac volume remained stable over time. Conclusion: Like infrarenal EVAR, non-regression at one year imaging is associated with higher five year all cause mortality and graft related events risks after F/BEVAR. Following FEVAR for juxtarenal aortic aneurysm, aneurysm sacs generally displayed regression (66% at one year), whereas after BEVAR for thoraco-abdominal aortic aneurysm, aneurysm sacs displayed a concerning proportion of growth at one year (28%), potentially suggesting a persistent risk of rupture and consequently requiring intensified surveillance following BEVAR. Future studies will have to elucidate how to improve sac regression following complex EVAR, and whether the high expansion risk after BEVAR is due to advanced disease extent.</p