Highly Sensitive Detection of the Antibiotic Ciprofloxacin by Means of Fiber Enhanced Raman Spectroscopy

Sepsis and septic shock exhibit a rapid course and a high fatality rate. Antibiotic treatment is time-critical and precise knowledge of the antibiotic concentration during the patients’ treatment would allow individual dose adaption. Over- and underdosing will increase the antimicrobial efficacy and reduce toxicity. We demonstrated that fiber enhanced Raman spectroscopy (FERS) can be used to detect very low concentrations of ciprofloxacin in clinically relevant doses, down to 1.5 µM. Fiber enhancement was achieved in bandgap shifted photonic crystal fibers. The high linearity between the Raman signals and the drug concentrations allows a robust calibration for drug quantification. The needed sample volume was very low (0.58 µL) and an acquisition time of 30 s allowed the rapid monitoring of ciprofloxacin levels in a less invasive way than conventional techniques. These results demonstrate that FERS has a high potential for clinical in-situ monitoring of ciprofloxacin levels

Multi-scale X-ray Tomography of Solder Interconnects in Microelectronics

Advanced packaging, including 3D IC integration, is one of the main drivers in packaging and system integration to meet the requirements for miniaturized smart systems with high functionality and high performance. For 3D stacking of wafers or dies, interconnections like micro solder bumps and Cu pillars are used. Figure 1 (left) shows a stack with a TSV interposer structure [1]. 3D-stacked products and advanced packaging challenge materials and process characterization. The control of the micro-bump quality is a particular issue. Special tasks are the characterization of the geometry of the solder bumps to estimate the stress enhancement risks, the nondestructive imaging of micron-size pores and of intermetallic phases as well as the visualization of cracks. Several NDE techniques for metrology and failure analysis are currently under discussion. In this paper, the potential and the limits of micro XCT and nano XCT for NDE of solder interconnects are described. Strategies for nondestructive evaluation of geometry, materials and defects are discussed. It is shown that multi-scale imaging with several resolution ranges is one potential approach. Micro XCT (resolution about 1 m) and nano XCT (resolution about 50 nm) are very useful lab-based techniques with a promising prospect for the future. We demonstrate the capabilities for nondestructive imaging of multi-die stacks with TSVs and micro solder bumps. Figure 1 (middle and right) right demonstrates a micro XCT overview and a nano XCT ROI study of such a multi-die stack with solder interconnects. An analysis of individual solder bumps reveals mismatches in relative positioning, variability in the shape, micron-size pores, and the distribution of intermetallic phases. This information is important to evaluate the respective process steps (process control) and the product reliability (quality control). Since deviations from the targeted geometry and defects are difficult to locate precisely from a two-dimensional image, X-ray computed tomography has to be applied

The Effect of Donor Age and Recipient Characteristics on Renal Outcomes in Patients Receiving Prolonged-Release Tacrolimus After Liver Transplantation : Post-Hoc Analyses of the DIAMOND Study

Background: The DIAMOND study of de novo liver transplant patients showed that prolonged-release tacrolimus exposure in the acute post-transplant period maintained renal function over 24 weeks of treatment. To assess these findings further, we performed a post-hoc analysis in patients according to baseline kidney function, Model for End-stage Liver Disease [MELD] scores, and donor age. Material/Methods: Patients received prolonged-release tacrolimus (initial-dose, Arm 1: 0.2 mg/kg/day, Arm 2: 0.15-0.175 mg/kg/day, Arm 3: 0.2 mg/kg/day delayed until Day 5), mycophenolate mofetil and 1 steroid bolus. Arms 2 and 3 also received basiliximab. The recommended tacrolimus target trough levels to Day 42 post-transplantation were 5-15 ng/mL in all arms. In this post-hoc analysis, change in renal outcome, based on estimated glomerular filtration rate (eGFR), Modified Diet in Renal Disease-4 (MDRD4), values from baseline to Week 24 post-transplantation, were assessed according to baseline patient factors: eGFR (>= 60 and = 25) and donor age (= 50 years). Results: Baseline characteristics were comparable (Arms 1-3: n=283, n=287, n=274, respectively). Patients with baseline renal function, eGFR >= 60 mL/min/1.73 m(2), experienced a decrease in eGFR in all tacrolimus treatment arms. In patients with lower baseline renal function (eGFR Conclusions: Pre-transplantation factors, such as renal function and donor age, could guide the choice of prolonged-release tacrolimus regimen following liver transplantation.Peer reviewe

Correct Outcome Prognostication via Sonographic Volumetry in Supratentorial Intracerebral Hemorrhage

Introduction: The intracerebral hemorrhage (ICH)-score is used for estimation of patients' prognosis. The hemorrhage volume calculated from computed tomography (CT) contributes as one main factor. Several studies have proven that dimensions of an ICH may be displayed sufficiently by transcranial sonography (TCS). Yet, the adequacy of ICH-volumetry via TCS in calculating the ICH-score and its use as prognostic tool has not been studied.Methods: Forty consecutive patients with supratentorial ICH diagnosed via CT were included in this prospective observational pilot study. 45 examination-series via CT and TCS were done in order to perform an ICH-volumetry and calculate the ICH-score. Volume was calculated using the ABC/2 estimation. Results of both imaging techniques were compared regarding quantification of ICH- volume and correct prognostication. A modified Rankin Scale (mRS)-score of 0–3 points was valued as good outcome.Results: The imaging techniques did not show a difference in volumetry (p = 0.794) and TCS derived hemorrhage volume correlated significantly with ICH-volume measured on CT-scans. Calculated ICH-scores also did not differ (p = 0.323). Patients with an ICH-score larger than 2 points were predicted to experience a poor outcome at discharge with mRS 4–6 points, and the prognostication of the outcome was correct. Patients with a good outcome showed a smaller ICH-volume (11.2 ± 9.1ml) than patients with a poor outcome (38.2 ± 41.2 ml; p = 0.002).Conclusion: Volumetry in supratentorial ICH via TCS is feasible and the prognostication with the ICH-score based on its results is comparable to CT-imaging and sufficient

KnowTox: pipeline and case study for confident prediction of potential toxic effects of compounds in early phases of development

Risk assessment of newly synthesised chemicals is a prerequisite for regulatory approval. In this context, in silico methods have great potential to reduce time, cost, and ultimately animal testing as they make use of the ever-growing amount of available toxicity data. Here, KnowTox is presented, a novel pipeline that combines three different in silico toxicology approaches to allow for confident prediction of potentially toxic effects of query compounds, i.e. machine learning models for 88 endpoints, alerts for 919 toxic substructures, and computational support for read-across. It is mainly based on the ToxCast dataset, containing after preprocessing a sparse matrix of 7912 compounds tested against 985 endpoints. When applying machine learning models, applicability and reliability of predictions for new chemicals are of utmost importance. Therefore, first, the conformal prediction technique was deployed, comprising an additional calibration step and per definition creating internally valid predictors at a given significance level. Second, to further improve validity and information efficiency, two adaptations are suggested, exemplified at the androgen receptor antagonism endpoint. An absolute increase in validity of 23% on the in-house dataset of 534 compounds could be achieved by introducing KNNRegressor normalisation. This increase in validity comes at the cost of efficiency, which could again be improved by 20% for the initial ToxCast model by balancing the dataset during model training. Finally, the value of the developed pipeline for risk assessment is discussed using two in-house triazole molecules. Compared to a single toxicity prediction method, complementing the outputs of different approaches can have a higher impact on guiding toxicity testing and de-selecting most likely harmful development-candidate compounds early in the development process

A commonly used rumen-protected conjugated linoleic acid supplement marginally affects fatty acid distribution of body tissues and gene expression of mammary gland in heifers during early lactation

Background: Conjugated linoleic acids (CLA) in general, and in particular the trans-10, cis-12 (t10, c12-CLA) isomer are potent modulators of milk fat synthesis in dairy cows. Studies in rodents, such as mice, have revealed that t10, c12-CLA is responsible for hepatic lipodystrophy and decreased adipose tissue with subsequent changes in the fatty acid distribution. The present study aimed to investigate the fatty acid distribution of lipids in several body tissues compared to their distribution in milk fat in early lactating cows in response to CLA treatment. Effects in mammary gland are further analyzed at gene expression level. Methods: Twenty-five Holstein heifers were fed a diet supplemented with (CLA groups) or without (CON groups) a rumen-protected CLA supplement that provided 6 g/d of c9, t11-and t10, c12-CLA. Five groups of randomly assigned cows were analyzed according to experimental design based on feeding and time of slaughter. Cows in the first group received no CLA supplement and were slaughtered one day postpartum (CON0). Milk samples were taken from the remaining cows in CON and CLA groups until slaughter at 42 (period 1) and 105 (period 2) days in milk (DIM). Immediately after slaughter, tissue samples from liver, retroperitoneal fat, mammary gland and M. longissimus (13th rib) were obtained and analyzed for fatty acid distribution. Relevant genes involved in lipid metabolism of the mammary gland were analyzed using a custom-made microarray platform. Results: Both supplemented CLA isomers increased significantly in milk fat. Furthermore, preformed fatty acids increased at the expense of de novo-synthesized fatty acids. Total and single trans-octadecenoic acids (e. g., t10-18:1 and t11-18:1) also significantly increased. Fatty acid distribution of the mammary gland showed similar changes to those in milk fat, due mainly to residual milk but without affecting gene expression. Liver fatty acids were not altered except for trans-octadecenoic acids, which were increased. Adipose tissue and M. longissimus were only marginally affected by CLA supplementation. Conclusions: Daily supplementation with CLA led to typical alterations usually observed in milk fat depression (reduction of de novo-synthesized fatty acids) but only marginally affected tissue lipids. Gene expression of the mammary gland was not influenced by CLA supplementation