A consistent relaxation of optimal design problems for coupling shape and topological derivatives

In this article, we introduce and analyze a general procedure for approximating a ‘black and white’ shape and topology optimization problem with a density optimization problem, allowing for the presence of ‘grayscale’ regions. Our construction relies on a regularizing operator for smearing the characteristic functions involved in the exact optimization problem, and on an interpolation scheme, which endows the intermediate density regions with fictitious material properties. Under mild hypotheses on the smoothing operator and on the interpolation scheme, we prove that the features of the approximate density optimization problem (material properties, objective function, etc.) converge to their exact counterparts as the smoothing parameter vanishes. In particular, the gradient of the approximate objective functional with respect to the density function converges to either the shape or the topological derivative of the exact objective. These results shed new light on the connections between these two different notions of sensitivities for functions of the domain, and they give rise to different numerical algorithms which are illustrated by several experiment

Design of percutaneous transluminal coronary angioplasty balloon catheters.

BACKGROUND Eight commercially available percutaneous transluminal coronary angioplasty (PTCA), including semi-compliant and non-compliant balloons, have been assessed in detail on their tip, balloon, shaft, RX-Port, and hypotube design. Important performance characteristics such as tip deformation, balloon elongation, and deflation rate have been quantified. METHODS Five catheters of each model were evaluated during various tests. The robustness of the tips was evaluated through compression, measuring any occurrence of damage. The longitudinal growth of the balloons was recorded during inflation up to Rated Burst Pressure (RBP). The forces required to move the catheter forward and retract it into the guide catheter were measured in a simulated use test setup. The deflation behavior was studied by measuring extracted contrast media over time. Furthermore, balloon compliance and catheter dimensions were investigated. RESULTS The outer dimensions of the catheter were found to be smallest at the hypotube (0.59-0.69 mm) and highest at the balloon, respectively, the crossing profile (0.9-1.2 mm). The tip diameter increased after compression by 1.7-22%. Cross-sections of the folded balloons revealed a tri- and two-fold, respectively. The measured balloon elongation ranged from 0.6 to 2.0 mm. After the inflation of the balloon, an increase in friction between the guide wire and the catheter was observed on four catheters. A maximum increase of 0.12 N to 1.07 N was found. Cross-sections of the RX-Port revealed a semicircular-shaped inflation lumen and a circular guide wire lumen. The measured deflation rate ranged from 0.004 to 0.013 µL/s, resulting in an estimated balloon deflation time of 10.2-28.1 s. CONCLUSION This study provides valuable insights into the design characteristics of RX PTCA balloon catheters, which can contribute to facilitating the development of improved catheter designs and enhancing clinical outcomes. Distinctions between SC and NC catheters, such as balloon performance and dimensions, are evident. It is important to note that no single catheter excels in all aspects, as each possesses unique strengths. Therefore, it is essential to consider individual intervention requirements when selecting a catheter. The research also identifies specific catheter weaknesses, such as reduced wall thickness, fringes at the tip, and reduced performance characteristics

Influence of crack history on the stable tearing behavior of a thin-sheet material with multiple cracks

Fracture tests were conducted on 2.3mm thick, 305mm wide sheets of 2024-T3 aluminum alloy with from one to five collinear cracks. The cracks were introduced (crack history) into the specimens by three methods: saw cutting, fatigue precracking at a low stress range, and fatigue precracking at a high stress range. For the single crack tests, the initial crack history influenced the stress required for the onset of stable crack growth and the first 10mm of crack growth. The effect on failure stress was about 4 percent or less. For the multiple crack tests, the initial crack history was shown to cause differences of more than 20 percent in the link-up stress and 13 percent in failure stress. An elastic-plastic finite element analysis employing the CTOA fracture criterion was used to predict the fracture behavior of the single and multiple crack tests. The numerical predictions were within 7 percent of the observed link-up and failure stress in all the tests

Stable tearing behavior of a thin-sheet material with multiple cracks

Fracture tests were conducted on 2.3mm thick, 305mm wide sheets of 2024-T3 aluminum alloy with 1-5 collinear cracks. The cracks were introduced (crack history) into the specimens by three methods: (1) saw cutting; (2) fatigue precracking at a low stress range; and (3) fatigue precracking at a high stress range. For the single crack tests, the initial crack history influenced the stress required for the onset of stable crack growth and the first 10mm of crack growth. The effect on failure stress was about 4 percent or less. For the multiple crack tests, the initial crack history was shown to cause differences of more than 20 percent in the link-up stress and 13 percent in failure stress. An elastic-plastic finite element analysis employing the Crack Tip Opening Angle (CTOA) fracture criterion was used to predict the fracture behavior of the single and multiple crack tests. The numerical predictions were within 7 percent of the observed link-up and failure stress in all the tests

Response to ranibizumab therapy in neovascular AMD - an evaluation of good and bad responders

Background: Treatment of neovascular age-related macular degeneration (AMD) with Lucentis® shows a broad spectrum regarding the course of visual acuity (VA). While some patients show a good response (increase in VA), others disclose much less promising results. Patients and Methods: A retrospective data analysis of all eyes treated for neovascular AMD at the University Hospital of Zurich, Switzerland for at least 12 months was carried out. The courses of VA between the 90th (good responders, GR) and the 10th (bad responders, BR) percentiles were compared at 3, 12 and 24 months from baseline. An analysis regarding demographic data, lesion type and size as well as injection frequency and visits was done and predictive factors for GR and BR were evaluated. Results: Marked differences in the course of VA between GR (n = 30) and BR (n = 30) are already observed 3 months from baseline. In GR the gains in VA after 3, 12 and 24 were 15.7 ± 9 letters ETDRS, 25.3 ± 7 and 14.0 ± 14. BR showed a deterioration of 8.3 ± 11 letters ETDRS after 3, 22.1 ± 8 after 12 and 23.6 ± 13 after 24 months. The gender distribution was equal with a higher percentage of female patients (64 % in BR and 66 % in GR). The baseline VA was statistically significantly lower in GR (45.7 ± 10 vs. 55.4 ± 11, p < 0.05) than in BR. No other significant differences in baseline data were found, and no predictor for group membership could be identified. Conclusions: Only the course of VA in the first three months seems to be of value for an estimation of the response to treatment. In the future the response to treatment in the early phase may influence the treatment algorithm and the injection frequency

Macropinocytotic uptake and infection of human epithelial cells with species B2 adenovirus type 35

The human adenovirus serotype 35 (HAdV-35, short Ad35) causes kidney and urinary tract infections, and infects respiratory organs of immunocompromised individuals. Unlike other adenoviruses, Ad35 has a low seroprevalence which makes Ad35-based vectors promising candidates for gene therapy. Ad35 utilizes CD46 and integrins as receptors for infection of epithelial and hematopoietic cells. Here, we show that infectious entry of Ad35 into HeLa, human kidney HK-2 cells and normal human lung fibroblasts strongly depended on CD46 and integrins but not heparan sulfate, and variably required the large GTPase dynamin. Ad35 infections were independent of expression of the carboxy-terminal domain of AP180 which effectively blocks clathrin-mediated uptake. Ad35 infections were inhibited by small chemicals against the serine/threonine kinase Pak1 (p21-activated kinase), protein kinase C (PKC), sodium-proton exchangers, actin and acidic organelles. Remarkably, the F-actin inhibitor jasplakinolide, the Pak1 inhibitor IPA-3 or the sodium-proton exchange inhibitor EIPA blocked the endocytic uptake of Ad35. Dominant-negative proteins or small interfering RNAs against factors driving macropinocytosis, including the small GTPase Rac1, Pak1 or the Pak1 effector C-terminal binding protein 1 (CtBP1) potently inhibited Ad35 infection. Confocal laser scanning microscopy, electron microscopy and live cell imaging showed that Ad35 colocalized with fluid phase markers in large endocytic structures that were positive for CD46, alpha v integrins and also CtBP1. Our results extend earlier observations with HAdV-3 (Ad3), and establish macropinocytosis as an infectious pathway for species B human adenoviruses in epithelial and hematopoietic cells

Formation of Structure in Snowfields: Penitentes, Suncups, and Dirt Cones

Penitentes and suncups are structures formed as snow melts, typically high in the mountains. When the snow is dirty, dirt cones and other structures can form instead. Building on previous field observations and experiments, this work presents a theory of ablation morphologies, and the role of surface dirt in determining the structures formed. The glaciological literature indicates that sunlight, heating from air, and dirt all play a role in the formation of structure on an ablating snow surface. The present work formulates a mathematical model for the formation of ablation morphologies as a function of measurable parameters. The dependence of ablation morphologies on weather conditions and initial dirt thickness are studied, focusing on the initial growth of perturbations away from a flat surface. We derive a single-parameter expression for the melting rate as a function of dirt thickness, which agrees well with a set of measurements by Driedger. An interesting result is the prediction of a dirt-induced travelling instability for a range of parameters.Comment: 28 pages, 13 figure

Planning and reporting of quality-of-life outcomes in cancer trials

BACKGROUND Information about the impact of cancer treatments on patients' quality of life (QoL) is of paramount importance to patients and treating oncologists. Cancer trials that do not specify QoL as an outcome or fail to report collected QoL data, omit crucial information for decision making. To estimate the magnitude of these problems, we investigated how frequently QoL outcomes were specified in protocols of cancer trials and subsequently reported. DESIGN Retrospective cohort study of RCT protocols approved by six research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. We compared protocols to corresponding publications, which were identified through literature searches and investigator surveys. RESULTS Of the 173 cancer trials, 90 (52%) specified QoL outcomes in their protocol, 2 (1%) as primary and 88 (51%) as secondary outcome. Of the 173 trials, 35 (20%) reported QoL outcomes in a corresponding publication (4 modified from the protocol), 18 (10%) were published but failed to report QoL outcomes in the primary or a secondary publication, and 37 (21%) were not published at all. Of the 83 (48%) trials that did not specify QoL outcomes in their protocol, none subsequently reported QoL outcomes. Failure to report pre-specified QoL outcomes was not associated with industry sponsorship (versus non-industry), sample size, and multicentre (versus single centre) status but possibly with trial discontinuation. CONCLUSIONS About half of cancer trials specified QoL outcomes in their protocols. However, only 20% reported any QoL data in associated publications. Highly relevant information for decision making is often unavailable to patients, oncologists, and health policymaker

Discontinuation and non-publication of randomised clinical trials supported by the main public funding body in Switzerland: a retrospective cohort study.

The Swiss National Science Foundation (SNSF) promotes academic excellence through competitive selection of study proposals and rigorous evaluation of feasibility, but completion status and publication history of SNSF-supported randomised clinical trials (RCTs) remain unclear. The main objectives were to review all healthcare RCTs supported by the SNSF for trial discontinuation and non-publication, to investigate potential risk factors for trial discontinuation due to poor recruitment and non-publication, and to compare findings to other Swiss RCTs not supported by the SNSF. We established a retrospective cohort of all SNSF-supported RCTs for which recruitment and funding had ended in 2015 or earlier. For each RCT, two investigators independently searched corresponding publications in electronic databases. In addition, we approached all principal investigators to ask for additional publications and information about trial discontinuation. Teams of two investigators independently extracted details about study design, recruitment of participants, outcomes, analysis and sample size from the original proposal and, if available, from trial registries and publications. We used multivariable regression analysis to explore potential risk factors associated with discontinuation due to poor recruitment and with non-publication, and to compare our results with data from a previous cohort of Swiss RCTs not supported by the SNSF. We included 101 RCTs supported by the SNSF between 1986 and 2015. Eighty-seven (86%) principal investigators responded to our survey. Overall, 69 (68%) RCTs were completed, 26 (26%) RCTs were prematurely discontinued (all due to slow recruitment) and the completion status remained unclear for 6 (6%) RCTs. For analysing publication status, we excluded 4 RCTs for which follow-up was still ongoing and 9 for which manuscripts were still in preparation. Of the remaining 88 RCTs, 53 (60%) were published as full articles in peer-reviewed journals. Multivariable regression models suggested that discontinued trials were at higher risk for non-publication than completed trials (adjusted OR 7.61; 95% CI 2.44 to 27.09). Compared with other Swiss RCTs, the risk of discontinuation for SNSF-supported RCTs was higher than in industry-initiated RCTs (adjusted OR 3.84; 95% CI 1.68 to 8.74), but not significantly different from investigator-initiated RCTs not supported by the SNSF (adjusted OR 1.05; 95% CI 0.51 to 2.11). We found no evidence that the proportion of discontinued or unpublished RCTs decreased over the last 20 years. One out of four SNSF-supported RCTs were prematurely discontinued due to slow recruitment, 40% of all included RCTs and 70% of all discontinued RCTs were not published in peer-reviewed journals. There is a case to reconsider how public funding bodies such as the SNSF could improve their feasibility assessment and promote publication of RCTs irrespective of completion status