Survival analysis for AdVerse events with VarYing follow-up times (SAVVY)-estimation of adverse event risks.

BACKGROUND: The SAVVY project aims to improve the analyses of adverse events (AEs), whether prespecified or emerging, in clinical trials through the use of survival techniques appropriately dealing with varying follow-up times and competing events (CEs). Although statistical methodologies have advanced, in AE analyses, often the incidence proportion, the incidence density, or a non-parametric Kaplan-Meier estimator are used, which ignore either censoring or CEs. In an empirical study including randomized clinical trials from several sponsor organizations, these potential sources of bias are investigated. The main purpose is to compare the estimators that are typically used to quantify AE risk within trial arms to the non-parametric Aalen-Johansen estimator as the gold-standard for estimating cumulative AE probabilities. A follow-up paper will consider consequences when comparing safety between treatment groups. METHODS: Estimators are compared with descriptive statistics, graphical displays, and a more formal assessment using a random effects meta-analysis. The influence of different factors on the size of deviations from the gold-standard is investigated in a meta-regression. Comparisons are conducted at the maximum follow-up time and at earlier evaluation times. CEs definition does not only include death before AE but also end of follow-up for AEs due to events related to the disease course or safety of the treatment. RESULTS: Ten sponsor organizations provided 17 clinical trials including 186 types of investigated AEs. The one minus Kaplan-Meier estimator was on average about 1.2-fold larger than the Aalen-Johansen estimator and the probability transform of the incidence density ignoring CEs was even 2-fold larger. The average bias using the incidence proportion was less than 5%. Assuming constant hazards using incidence densities was hardly an issue provided that CEs were accounted for. The meta-regression showed that the bias depended mainly on the amount of censoring and on the amount of CEs. CONCLUSIONS: The choice of the estimator of the cumulative AE probability and the definition of CEs are crucial. We recommend using the Aalen-Johansen estimator with an appropriate definition of CEs whenever the risk for AEs is to be quantified and to change the guidelines accordingly.

3D Plotting of Silica/Collagen Xerogel Granules in an Alginate Matrix for Tissue-Engineered Bone Implants.

Today, materials designed for bone regeneration are requested to be degradable and resorbable, bioactive, porous, and osteoconductive, as well as to be an active player in the bone-remodeling process. Multiphasic silica/collagen Xerogels were shown, earlier, to meet these requirements. The aim of the present study was to use these excellent material properties of silica/collagen Xerogels and to process them by additive manufacturing, in this case 3D plotting, to generate implants matching patient specific shapes of fractures or lesions. The concept is to have Xerogel granules as active major components embedded, to a large proportion, in a matrix that binds the granules in the scaffold. By using viscoelastic alginate as matrix, pastes of Xerogel granules were processed via 3D plotting. Moreover, alginate concentration was shown to be the key to a high content of irregularly shaped Xerogel granules embedded in a minimum of matrix phase. Both the alginate matrix and Xerogel granules were also shown to influence viscoelastic behavior of the paste, as well as the dimensionally stability of the scaffolds. In conclusion, 3D plotting of Xerogel granules was successfully established by using viscoelastic properties of alginate as matrix phase.

Fabrication of microoptical freeform arrays on wafer level for imaging applications.

Miniaturized imaging systems combining an ultra-compact form factor in combination with the ability of refocusing and depth imaging have gained much interest in the field of mobile imaging. Therefore, artificial compound eye cameras are an extremely promising approach for the realization of compact monolithic camera modules on wafer level. Up to now, their imaging performance was limited to low resolution in the range of VGA format according to fabrication constrains given by the established microoptical fabrication methods, namely the reflow of photoresist. In order to overcome these classical limitations, the use of refractive freeform arrays (RFFA) instead of conventional microlens arrays is inevitable. To enable high volume and cost efficient mass production of artificial compound eye cameras for mass markets like the consumer electronics industry, their fabrication on wafer level is essential, but has not been published up to now. We present a wafer level based process chain enabling the fabrication of these elements for the first time.

Hardware architecture and cutting-edge assembly process of a tiny curved compound eye.

The demand for bendable sensors increases constantly in the challenging field of soft and micro-scale robotics. We present here, in more detail, the flexible, functional, insect-inspired curved artificial compound eye (CurvACE) that was previously introduced in the Proceedings of the National Academy of Sciences (PNAS, 2013). This cylindrically-bent sensor with a large panoramic field-of-view of 180° × 60° composed of 630 artificial ommatidia weighs only 1.75 g, is extremely compact and power-lean (0.9 W), while it achieves unique visual motion sensing performance (1950 frames per second) in a five-decade range of illuminance. In particular, this paper details the innovative Very Large Scale Integration (VLSI) sensing layout, the accurate assembly fabrication process, the innovative, new fast read-out interface, as well as the auto-adaptive dynamic response of the CurvACE sensor. Starting from photodetectors and microoptics on wafer substrates and flexible printed circuit board, the complete assembly of CurvACE was performed in a planar configuration, ensuring high alignment accuracy and compatibility with state-of-the art assembling processes. The characteristics of the photodetector of one artificial ommatidium have been assessed in terms of their dynamic response to light steps. We also characterized the local auto-adaptability of CurvACE photodetectors in response to large illuminance changes: this feature will certainly be of great interest for future applications in real indoor and outdoor environments.

Miniature curved artificial compound eyes.

In most animal species, vision is mediated by compound eyes, which offer lower resolution than vertebrate single-lens eyes, but significantly larger fields of view with negligible distortion and spherical aberration, as well as high temporal resolution in a tiny package. Compound eyes are ideally suited for fast panoramic motion perception. Engineering a miniature artificial compound eye is challenging because it requires accurate alignment of photoreceptive and optical components on a curved surface. Here, we describe a unique design method for biomimetic compound eyes featuring a panoramic, undistorted field of view in a very thin package. The design consists of three planar layers of separately produced arrays, namely, a microlens array, a neuromorphic photodetector array, and a flexible printed circuit board that are stacked, cut, and curved to produce a mechanically flexible imager. Following this method, we have prototyped and characterized an artificial compound eye bearing a hemispherical field of view with embedded and programmable low-power signal processing, high temporal resolution, and local adaptation to illumination. The prototyped artificial compound eye possesses several characteristics similar to the eye of the fruit fly Drosophila and other arthropod species. This design method opens up additional vistas for a broad range of applications in which wide field motion detection is at a premium, such as collision-free navigation of terrestrial and aerospace vehicles, and for the experimental testing of insect vision theories.

Gastrointestinal adverse effects of short-term aspirin use: a meta-analysis of published randomized controlled trials.

BACKGROUND AND OBJECTIVES: Aspirin is widely used for short-term treatment of pain, fever or colds, but there are only limited data regarding the safety of this use. To summarize the available data on this topic, we conducted a meta-analysis of the published clinical trial literature regarding the gastrointestinal adverse effects of short-term use of aspirin in comparison with placebo and other medications commonly used for the same purpose. DATA SOURCES AND METHODS: An extensive literature search identified 119,310 articles regarding possible adverse effects of aspirin, among which 23,131 appeared to possibly include relevant data. An automated text-mining procedure was used to score the references for potential relevance for the meta-analysis. The 3,983 highest-scoring articles were reviewed individually to identify those with data that could be included in this analysis. Ultimately, 78 relevant articles were identified that contained gastrointestinal adverse event data from clinical trials of aspirin versus placebo or an active comparator. Odds ratios (ORs) computed using a Mantel-Haenszel estimator were used to summarize the comparative effects on dyspepsia, nausea/vomiting, and abdominal pain, considered separately and also aggregated as 'minor gastrointestinal events'. Gastrointestinal bleeds, ulcers, and perforations were also investigated. RESULTS: Data were obtained regarding 19,829 subjects (34 % treated with aspirin, 17 % placebo, and 49 % an active comparator). About half of the aspirin subjects took a single dose. Aspirin was associated with a higher risk of minor gastrointestinal events than placebo or active comparators: the summary ORs were 1.46 (95 % confidence interval [CI] 1.15-1.86) and 1.81 (95 % CI 1.61-2.04), respectively. Ulcers, perforation, and serious bleeding were not seen after use of aspirin or any of the other interventions. CONCLUSIONS: During short-term use, aspirin is associated with a higher frequency of gastrointestinal complaints than other medications commonly used for treatment of pain, colds, and fever. Serious adverse events were not observed with aspirin or any of the comparators.

Laser lithographic approach to micro-optical freeform elements with extremely large sag heights.

Artificial compound eye cameras are an attractive approach to generate imaging systems of maximum miniaturization. Their thickness can be reduced by a factor of two in comparison to miniaturized single aperture cameras with the same pixel size and resolution. The imaging performance of these systems can be improved significantly by the use of micro-optical refractive freeform arrays (RFFA). Due to the complexity of these non-symmetric surface profiles with sag heights larger than 50 µm in combination with extreme profile accuracies better than λ/14 (rms), there is no dedicated fabrication technology currently available. In the presented research, significant improvements in the fabrication of these elements with laser lithography were reached. Therefore, a laser lithographic process based on several coating steps in combination with a multiple exposure strategy was developed that is suitable for the fabrication of arbitrary freeform structures with sag heights up to 60 µm. In order to minimize surface deviations caused by unavoidable process nonlinearities, a compensation strategy based on an empirical process model is used. The achievable accuracy of the proposed method and its limitations were investigated by fabricating a spherical micro lens array for demonstration. The fabricated elements possess a shape deviation of less than 1.3 µm (rms) and can be used as master structures for a subsequent replication process in order to realize a cost efficient mass production of artificial compound eye optics on wafer level.

Optical Cluster Eye fabricated on wafer-level.

Wafer-level optics is considered as a cost-effective approach to miniaturized cameras, because fabrication and assembly are carried out for thousands of lenses in parallel. However, in most cases the micro-optical fabrication process is not mature enough to reach the required accuracy of the optical elements, which may have complex profiles and sags in the mm-scale. Contrary, the creation of microlens arrays is well controllable so that we propose a multi aperture system called "Optical Cluster Eye" which is based on conventional micro-optical fabrication techniques. The proposed multi aperture camera consists of many optical channels each transmitting a segment of the whole field of view. The design of the system provides the stitching of the partial images, so that a seamless image is formed and a commercially available image sensor can be used. The system can be fabricated on wafer-level with high yield due to small aperture diameters and low sags. The realized optics has a lateral size of 2.2 × 2.9 mm2, a total track length of 1.86 mm, and captures images at VGA video resolution.

Thin wafer-level camera lenses inspired by insect compound eyes.

We propose a microoptical approach to ultra-compact optics for real-time vision systems that are inspired by the compound eyes of insects. The demonstrated module achieves approx. VGA resolution with a total track length of 1.4 mm which is about two times shorter than comparable single-aperture optics on images sensors of the same pixel pitch. The partial images that are separately recorded in different optical channels are stitched together to form a final image of the whole field of view by means of image processing. A software correction is applied to each partial image so that the final image is made free of distortion. The microlens arrays are realized by state of the art microoptical fabrication techniques on wafer-level which are suitable for a potential application in high volume e.g. for consumer electronic products.

Development and validation of a risk-score model for subjects with impaired glucose tolerance for the assessment of the risk of type 2 diabetes mellitus-The STOP-NIDDM risk-score.

AIMS: To develop a risk-score model, based on available clinical data to assess absolute risk of type 2 diabetes among people with impaired glucose tolerance (IGT). METHODS: Data from the study to prevent non-insulin dependent diabetes mellitus (STOP-NIDDM) investigating acarbose treatment in individuals with IGT were used to develop multivariable Cox proportional hazards model for the time to onset of diabetes. The final model equation was externally validated using data from the Finnish Cardiovascular Risk Factor (FINRISK) population. RESULTS: The risk-score model included the variables acarbose treatment, gender, serum triglyceride level, waist circumference, fasting plasma glucose, height, history of cardiovascular disease (CVD) and hypertension. The final model yielded an area under the receiver-operating-characteristic curve (AUC(ROC)) of 0.64 when applied to people with IGT in the STOP-NIDDM, and 0.84 and 0.90 when applied to FINRISK population with IGT alone and IGT and normal glucose tolerance combined, respectively; AUC(ROC) is a measure of the discriminatory power of the model (1, perfect discrimination). CONCLUSIONS: The STOP-NIDDM risk-score is a simple and validated tool that can identify high-risk individuals with IGT who would benefit most from type 2 diabetes or CVD prevention strategies, such as lifestyle management or early acarbose treatment.

The Gabor superlens as an alternative wafer-level camera approach inspired by superposition compound eyes of nocturnal insects.

We present the microoptical adaption of the natural superposition compound eye, which is termed "Gabor superlens". Enabled by state-of-the-art microoptics technology, this well known principle has been adapted for ultra-compact imaging systems for the first time. By numerical ray tracing optimization, and by adding diaphragm layers and a field lens array, the optical performance of the Gabor superlens is potentially comparable to miniaturized conventional lens modules, such as currently integrated in mobile phones. However, in contrast to those, the Gabor superlens is fabricated using a standard microlens array technology with low sag heights and small diameter microlenses. Hence, there is no need for complex diamond turning for the generation of the master structures. This results in a simple and well controllable lens manufacturing process with the potential to high yield.

Analytic modeling of the angular sensitivity function and modulation transfer function of ultrathin multichannel imaging systems.

We propose what we believe to be a novel, refined model of the angular sensitivity function of artificial apposition compound eyes. Compared with the formerly used Gaussian approximation that was derived for natural compound eyes, our model is better suited to describe the resolution capacity of artificial compound eyes accounting for the cylindrical sensitivity function of technical receptors. It is shown that this analytic model is valid over a broad range of parameters of the optical system, which was not fulfilled by one of the previous models. Finally, an analytic approach is used to derive the modulation transfer function of these multichannel imaging systems.

Artificial neural superposition eye.

We propose an ultra-thin imaging system which is based on the neural superposition compound eye of insects. Multiple light sensitive pixels in the footprint of each lenslet of this multi-channel configuration enable the parallel imaging of the individual object points. Together with the digital superposition of related signals this multiple sampling enables advanced functionalities for artificial compound eyes. Using this technique, color imaging and a circumvention for the trade-off between resolution and sensitivity of ultra-compact camera devices have been demonstrated in this article. The optical design and layout of such a system is discussed in detail. Experimental results are shown which indicate the attractiveness of microoptical artificial compound eyes for applications in the field of machine vision, surveillance or automotive imaging.

Artificial compound eye applying hyperacuity.

Inspired by the natural phenomenon of hyperacuity, redundant sampling in combination with the knowledge about the impulse response of the imaging system is used to extract highly accurate information using a low resolving artificial apposition compound eye. Thus the implementation of a precise position detection for simple objects like point sources and edges is described.

Safety and tolerability of acarbose in the treatment of type 1 and type 2 diabetes mellitus.

OBJECTIVE: To assess the safety profile of acarbose treatment over a 1-year period at a dose range of 50-300mg three times daily in patients with type 1 or type 2 diabetes mellitus. STUDY DESIGN AND PATIENTS: In this 56-week, double-blind, parallel-group, multicentre comparison, patients were randomised to acarbose or placebo in a 2 : 1 ratio. An 8-week forced titration phase (from 50-300mg three times daily) was followed by a 48-week maintenance phase during which patients received the highest dose tolerated during titration. Patients were assessed at 13 visits with respect to adverse events/intercurrent illnesses, abnormal laboratory values (serum chemistry, urinalysis, complete blood and reticulocyte count, serum iron and total iron binding capacity, and serum vitamin B(6), B(12), D and folate levels), discontinuation rates, ECG findings, vital signs and evaluation of the patients' diaries with regard to gastrointestinal events. A total of 359 patients (acarbose 240, placebo 119) were valid for analysis; 21% had type 1 diabetes. Most patients received concomitant insulin or sulfonylurea treatment. RESULTS: Study withdrawal was reported for 35% of acarbose and 24% of placebo recipients (p = 0.053); adverse events were the main reason for withdrawal in acarbose recipients (20%; placebo group 5%; p < 0.01). The most common adverse events for acarbose recipients were gastrointestinal (abdominal pain, flatulence and diarrhoea), which were more frequent than in placebo patients (p < 0.01). These events occurred more often early in the study and attenuated over time. CONCLUSION: Acarbose was safe and well tolerated by the majority of diabetic patients over a 1-year treatment period.

Long-term efficacy and tolerability of acarbose treatment in patients with type 2 diabetes mellitus.

OBJECTIVE: The aim of the study was to investigate the efficacy and tolerability of long-term acarbose therapy in type 2 diabetic patients. STUDY DESIGN: In this double-blind, single-centre group comparison, patients were randomised to receive either acarbose or matching placebo, in addition to their regular antidiabetic therapy, over a period of 78 weeks. Eligibility for inclusion in the efficacy evaluation included a study duration of >/=510 days. METHODS: The primary efficacy parameter was the change in glycosylated haemoglobin (HbA(1)) from baseline to end of study. Secondary variables included changes in blood glucose and lipid parameters, as well as signs of retinopathy and nephropathy. PATIENTS: A total of 139 patients were assessed for safety and 88 patients (44 in each treatment group) were included in the efficacy analysis. Patients were generally overweight and the majority had previously been treated with sulphonylureas. RESULTS: Acarbose significantly improved fasting and 1-hour postprandial blood glucose levels compared with placebo (p = 0.039 and 0.009), and improvements in HbA(1) with acarbose versus placebo fell just short of significance (p = 0.057). There were no differences between treatments in changes in microvascular complications, but blood pressure improved with acarbose treatment. Two patients in the acarbose group experienced elevated liver enzyme levels. Generally, acarbose had a good safety profile and was well tolerated. CONCLUSION: Long-term treatment with acarbose was safe and efficacious in patients with type 2 diabetes mellitus that was insufficiently controlled by other oral antidiabetics.

Primary stability of a robodoc implanted anatomical stem versus manual implantation.

OBJECTIVE: To assess the initial stability of anatomical stems implanted in manually broached femoral cavities compared with that assessed in cavities milled with the robodoc system. DESIGN: The bone-prosthesis interface motion was measured in matched pairs of cadaveric femora to assess the initial stability of anatomical stems implanted with two different implantation techniques. BACKGROUND: The high costs of surgical robots and the increased perioperative efforts associated with their use can only be justified if measurable benefits for patients can be achieved. Increased initial stability of the stem as an early indicator for better bone ongrowth would be such a benefit. METHODS: Seven pairs of fresh frozen human cadaveric femora were used. One femur of each pair was randomly assigned to receive the robotic milling method; the other femur underwent manual broaching by an experienced surgeon. Initial micromotions of the anatomical stems were measured during simulated gait cycles with loads of < or =1500 N, and both groups underwent matched-pair analysis. Results. High motion of the prostheses was found for both implantation techniques. CONCLUSIONS: The robodoc system did not enhance the primary stability of the anatomical prosthesis compared with the manual broaching method.

Metallothionein and dendritic cells in skin of end-stage renal disease patients not on dialysis, or on hemodialysis or peritoneal dialysis.

OBJECTIVE: Renal failure leads to a variety of defects in immune function. The skin, as a major player in the immune system network, also exhibits multiple derangements. The pathogenesis of these defects and derangements are poorly understood; therefore, we studied immune competent cells, dermal dendrocytes (DC), and a special proinflammatory protein, metallothionein (MT), in the skin of these patients. DESIGN: 22 patients with end-stage renal disease (ESRD) but not on dialysis, 18 patients on hemodialysis (HD), 14 patients on peritoneal dialysis (PD), and 35 healthy controls were included in the study. Immunohistochemical staining of skin biopsies for DC and MT was performed with the following antibodies: for DC, antibody against factor XIIIa; and for MT, Dako-MT, E9 (Dako, Carpinteria, California, USA). Measurements were made by counting stained DC per square millimeter, and by optical density (OD) for MT (mean SEM). RESULTS: Metallothionein was increased in the skin of HD (OD 0.42 +/- 0.05, p < 0.01) and PD patients (OD 0.33 +/- 0.04, p < 0.05) compared to controls (OD 0.23 +/- 0.02) and ESRD patients not on dialysis (OD 0.22 +/- 0.05). In contrast, numbers of DC were reduced in patients on PD compared to controls (59 +/- 13 vs 96 +/- 59 DC/mm2, p < 0.01) and increased in patients with ESRD prior to dialysis (141 +/- 13 DC/mm2, p < 0.05). Patients on HD were in-between (105 +/- 20 DC/mm2), with a significant difference versus patients on PD (p < 0.05). CONCLUSIONS: Our data show that the mode of dialysis influences the number of antigen-presenting cells in the dermis. However, in both dialysis modes, a proinflammatory immune status of the skin (MT) was present and, therefore, other regulatory elements for dermal dendrocytes apart from proinflammation exist.