Comparative study of probabilistic modeling approaches for chloride ingress in concrete structures with macro‐cracks

Probabilistic service life analyses for assessing the risk of chloride-induced corrosion in uncracked concrete are often realized using the well-known chloride ingress model of the fib Model Code for Service Life Design. In practice, however, concrete includes cracks, which alter the resistance of the concrete against the chloride ingress. In the past, different approaches to account for preexisting cracks, were developed. In this study, these modeling approaches are summarized and compared in context of the probabilistic service life prognosis. Furthermore, a new approach to account for cracks by theoretically adapting the convection zone is presented. This study demonstrates that the choice of model extension to account for cracks vastly influences the prediction results and shows the limits of application of the current extensions

Tumor Treating Fields Concomitant with Sorafenib in Advanced Hepatocellular Cancer: Results of the HEPANOVA Phase II Study

Liver cancer; Solid tumor; SorafenibCàncer de fetge; Tumor sòlid; SorafenibCáncer de hígado; Tumor sólido; SorafenibAdvanced hepatocellular carcinoma (HCC) is an aggressive disease associated with poor prognosis. Tumor Treating Fields (TTFields) therapy is a non-invasive, loco-regional treatment approved for glioblastoma and malignant pleural mesothelioma. HCC preclinical and abdominal simulation data, together with clinical results in other solid tumors, provide a rationale for investigating TTFields with sorafenib in this patient population. HEPANOVA was a phase II, single arm, historical control study in adults with advanced HCC (NCT03606590). Patients received TTFields (150 kHz) for ≥18 h/day concomitant with sorafenib (400 mg BID). Imaging assessments occurred every 12 weeks until disease progression. The primary endpoint was the overall response rate (ORR). Safety was also evaluated. Patients (n = 27 enrolled; n = 21 evaluable) had a poor prognosis; >50% were Child–Turcotte–Pugh class B and >20% had a baseline Eastern Clinical Oncology Group performance status (ECOG PS) of 2. The ORR was higher, but not statistically significant, for TTFields/sorafenib vs. historical controls: 9.5% vs. 4.5% (p = 0.24), respectively; all responses were partial. Among patients (n = 11) with ≥12 weeks of TTFields/sorafenib, ORR was 18%. Common adverse events (AEs) were diarrhea (n = 15/27, 56%) and asthenia (n = 11/27, 40%). Overall, 19/27 (70%) patients had TTFields-related skin AEs; none were serious. TTFields/sorafenib improved response rates vs. historical controls in patients with advanced HCC, with no new safety concerns or related systemic toxicity.This study was funded by Novocure Inc

Cabozantinib in Advanced Hepatocellular Carcinoma: Efficacy and Safety Data from an International Multicenter Real-Life Cohort

Background and Aims: The multikinase inhibitor cabozantinib has been approved for hepatocellular carcinoma (HCC) previously treated with sorafenib. We report safety and efficacy data of an international, multicenter, real-life cohort of patients with advanced HCC treated with cabozantinib. Methods: Patients with HCC who were treated with cabozantinib were retrospectively identified across 11 centers in Austria, Switzerland, and Germany. Patients’ characteristics, adverse events, duration of treatment and overall survival (OS) data were analyzed until April 1, 2020. Results: Eighty-eight patients from 11 centers were included. The predominant underlying liver diseases were NAFLD/NASH in 26 (30%) and hepatitis C infection in 21 (24%) patients. Seventy-eight patients (89%) were classified as Barcelona clinic liver cancer (BCLC) stage C. Sixty patients (68%) were Child-Pugh A, whereas 22 (25%) were Child-Pugh B, respectively. Cabozantinib was used as systemic second- and third-line or later treatment in 41 (47%) and 46 (52%) patients, respectively. The following best responses under cabozantinib were documented: partial response in 6 (7%), stable disease in 28 (32%), and progressive disease in 28 (32%) patients, respectively. Fifty-two patients (59%) died during follow-up. The median OS from start of cabozantinib treatment was 7.0 months in the entire cohort and 9.7 months in Child-Pugh A patients, while Child-Pugh B patients had a median OS of 3.4 months, respectively. Thirty-seven (42%) patients fulfilled the CELESTIAL inclusion and exclusion criteria, showing a median OS of 11.1 months. Most common adverse events were fatigue (15.6%) and diarrhea (15.6%). Conclusion: Cabozantinib treatment was effective, safe, and feasible in patients with advanced HCC in patients with compensated cirrhosis. Patients in the real-life setting had more advanced liver disease – in which 25% of patients were Child-Pugh B. However, OS in patients with Child-Pugh A cirrhosis was similar to that reported in the phase 3 trial (CELESTIAL)

The impact of therapeutic drug monitoring on antiretroviral therapy in critically ill infants - a pharmacokinetik investigation in South Africa

The role of therapeutic drug monitoring in pediatric antiretroviral therapy is unclear. A little pharmacokinetic datum from clinical practice exists beyond controlled approval studies including clinically stable children. The aim of this study is to quantify LPV exposure of critically ill infants in an ICU and-by identifying risk factors for inadequate exposure-to define sensible indications for TDM in pediatric HIV care; in addition, assume total drug adherence in ICU to compare LPV exposure with a setting of unknown adherence. In this prospective investigation, 15 blood samples from critically ill infants in the pediatric ICU at Tygerberg Hospital were analyzed for LPV-serum concentrations. They were then compared to those of 22 blood samples from out-patient children. Serum-level measurements were performed with an established high-performance liquid chromatography method. All LPV-serum levels of ICU patients were higher than a recommended Ctrough (= 1.000 ng/ml), 60% of levels were higher than Cmax (8.200 ng/ml). Partly, serum levels reached were extremely high (Maximum: 28.778 ng/ml). Low bodyweight and age correlated significantly with high LPV concentrations and were risk factors for serum levels higher than Cmax. Significantly fewer serum levels from infants in ICU care (mean: 11.552 ng/ml ± SD 7760 ng/ml) than from out-patient children (mean: 6.756 ng/ml ± SD 6.003 ng/ml) were subtherapeutic (0 vs. 28%, p = 0.008). Under total adherence in the ICU group, there were no subtherapeutic serum levels, while, in out-patient, children with unknown adherence 28% of serum levels were found subtherapeutic. Low bodyweight and age are risk factors for reaching potentially toxic LPV levels in this extremely fragile population. TDM can be a reasonable tool to secure sufficient and safe drug exposure in pediatric cART.Die Rolle des Therapeutischen Drug Monitorings (TDM) in der antiretroviralen Therapie bei Kindern ist unklar. Es existieren nur wenige pharmakokinetische Daten - insbesondere von kleinen Kindern – abseits der kontrollierter Zulassungsstudien an klinisch stabilen Patienten. Es ist das Ziel dieser Untersuchung, die Lopinavir-Exposition kritisch kranker Säuglinge auf einer pädiatrischen Intensivstation zu quantifizieren und durch die Identifikation von Risikofaktoren für inadäquate Exposition sinnvolle Indikation für einen Einsatz von TDM in der pädiatrischen HIV-Versorgung zu definieren. Des Weiteren verglichen wir unter Annahme totaler Adhärenz auf die Lopinavir-Exposition auf einer Intensivstation mit der einer ambulanten Versorgungsstruktur. In dieser prospektiven Studie untersuchten wir 15 Serum Proben kritisch kranker Säuglinge auf der pädiatrischen Intensivstation des Tygerberg Hospitals im Hinblick auf LPV-Serumkonzentrationen. Sie wurden verglichen mit 22 Konzentrationen von ambulant betreuten Kindern. Die Messungen wurden mit einer etablierten HPLC-Methode durchgeführt. Alle LPV-Konzentrationen der Intensiv-Patienten waren höher als die empfohlene Talspiegel (Ctrough = 1.000 ng/ml), 60% waren höher als Cmax (8.200 ng/ml). Es wurden zum Teil extrem hohe Konzentrationen erreicht (Max. 28.778 ng/ml). Ein geringes Körpergewicht und Alter korrelierten signifikant mit hohen LPV-Konzentrationen und waren Risikofaktoren für Spiegel, die über Cmax lagen. Signifikant weniger Konzentrationen von Intensivpatienten (MW: 11.552 ng/ml ± SD 7760 ng/ml) waren subtherapeutisch als von ambulant betreuten Kindern (mean: 6.756 ng/ml ± SD 6.003 ng/ml) (0 vs. 28%, p = 0.008). Unter totaler Adhärenz in der Intensiv-Gruppe waren keine subtherapeutischen Konzentrationen festzustellen, während 28% der ambulant betreuten Kinder subtherapeutischen Spiegel aufwiesen. Ein geringes Körpergewicht und Alter sind Risikofaktoren für das Erreichen potenziell toxischer Konzentrationen von Lopinavir in dieser extrem fragilen Population. TDM kann helfen LPV-Toxizität von anderen klinischen Erscheinungen zu differenzieren. TDM kann ein sinnvolles Hilfsmittel sein, um eine sichere und effektive antiretrovirale Therapie bei Kindern zu garantieren

Radiological and Clinical Outcome after Multilevel Anterior Cervical Discectomy and/or Corpectomy and Fixation

Background: Multilevel anterior cervical decompression and fixation of four and more levels is a common surgical procedure used for several diseases. Methods: We reviewed the radiological and clinical outcomes after anterior cervical discectomy or corpectomy and fixation of four and more levels in 85 patients (55 men and 30 women) with an average age of 59.6 years. Surgical indication was multilevel cervical degenerative myelopathy and radiculopathy in 72 (85%) patients, multilevel cervical spondylodiscitis in four (5%), complex traumatic cervical fractures in four (5%), metastatic cervical spine tumor in two (2%), and ossification of the posterior longitudinal ligament in three (3%) patients. Results: There were no severe intraoperative complications such as spinal cord or vertebral artery injury or dissection. Seventy-three patients had four, 10 patients had five, and two patients had six anterior cervical level fixations. The visual analog scale (VAS) and Japanese Orthopedic Association (mJOA) scale scores improved (6.9 to 1.3 (p < 0.001) and 13.9 to 16.5 (p < 0.001), respectively). The Cobb angle increased from 5.7° to 17.6° postoperatively (p < 0.001). Secondary posterior fixation was necessary in three cases due to pseudarthrosis. Conclusion: The anterior approach appears to be optimal for ventral compressive pathology and lordosis restoration to the cervical spine. Limitations of multiple level decompression and fixation included increasing pseudoarthrosis rates, especially after corpectomy, and increasing fused level numbers

Revealing the sequence of switching mechanisms in polycrystalline ferroelectric/ferroelastic materials

Ferroelectric materials find application in numerous electronic devices and are continuously enabling the development of new technologies. Their versatility is intimately related to the unique property to switch the polarization with electric fields. However, the switching mechanisms in polycrystalline ferroelectric materials remain insufficiently understood. Here we reveal that switching in ferroelectric/ferroelastic materials consists of a sequence of individual events, separated into three regimes: rapid movement of non-180° domain walls, main switching phase with 180° and non-180° switching events, and creep-like non-180° domain wall movement. The determination of the mechanisms was enabled by a novel measurement approach, simultaneously tracking the time dynamics of switched polarization, macroscopic strain, and structural changes. Time-resolved in situ synchrotron diffraction allowed direct insight into the non-180° domain wall dynamics and lattice strains and gave evidence for strong time correlation of non-180° switching events in different grains of the polycrystalline material. The obtained results open new opportunities for targeted manipulation of individual switching events and tuning of material's functional properties