An Overview of Real-World Data Infrastructure for Cancer Research.

AIMS: There is increasing interest in the opportunities offered by Real World Data (RWD) to provide evidence where clinical trial data does not exist, but access to appropriate data sources is frequently cited as a barrier to RWD research. This paper discusses current RWD resources and how they can be accessed for cancer research. MATERIALS AND METHODS: There has been significant progress on facilitating RWD access in the last few years across a range of scales, from local hospital research databases, through regional care records and national repositories, to the impact of federated learning approaches on internationally collaborative studies. We use a series of case studies, principally from the UK, to illustrate how RWD can be accessed for research and healthcare improvement at each of these scales. RESULTS: For each example we discuss infrastructure and governance requirements with the aim of encouraging further work in this space that will help to fill evidence gaps in oncology. CONCLUSION: There are challenges, but real-world data research across a range of scales is already a reality. Taking advantage of the current generation of data sources requires researchers to carefully define their research question and the scale at which it would be best addressed.

Radiomics biopsy signature for predicting survival in patients with spinal bone metastases (SBMs).

STUDY DESIGN: Retrospective analysis of a registered cohort of patients treated and irradiated for metastases in the spinal column in a single institute. OBJECTIVE: This is the first study to develop and internally validate radiomics features for predicting six-month survival probability for patients with spinal bone metastases (SBM). BACKGROUND DATA: Extracted radiomics features from routine clinical CT images can be used to identify textural and intensity-based features unperceivable to human observers and associate them with a patient survival probability or disease progression. METHODS: A study was conducted on 250 patients treated for metastases in the spinal column irradiated for the first time between 2014 and 2016, at the MAASTRO clinic in Maastricht, the Netherlands. The first 150 available patients were used to develop the model and the subsequent 100 patient were considered as a test set for the model. A bootstrap (B = 400) stepwise model selection, which combines both the forward and backward variable elimination procedure, was used to select the most useful predictive features from the training data based on the Akaike information criterion (AIC). The stepwise selection procedure was applied to the 400 bootstrap samples, and the results were plotted as a histogram to visualize how often each variable was selected. Only variables selected more than 90 % of the time over the bootstrap runs were used to build the final model.A prognostic index (PI) called radiomics score (radscore) and clinical score (clinscore) was calculated for each patient. The prognostic index was not scaled, the original values were used which can be extracted from the model directly or calculated as a linear combination of the variables in the model multiplied by the respective beta value for each patient. RESULTS: The clinical model had a good discrimination power. The radiomics model, on the other hand, had an inferior performance with no added predictive power to the clinical model. The internal imaging characteristics do not seem to have a value in the prediction of survival. However, the Shape features were excluded from further analyses in our study since all biopsies had a standard shape hence no variability.

Results Multi-Laboratory Trial ISO/CD 22184-IDF/WD 244: Milk and Milk Products-Determination of the Sugar Contents-High-Performance Anion Exchange Chromatography Method with Pulsed Amperometric Detection.

BACKGROUND: In this international Multi-Laboratory Trial (MLT) the precision data and the accuracy of the ISO/CD 22184 IDF/WD 244 analytical method for the quantification of 6 different mono- and disaccharides (galactose, glucose, fructose, sucrose, lactose, and maltose) in milk and milk products with high-performance anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD) are established. OBJECTIVE: Thirteen different laboratories participated (located in New Zealand, the United States, and Europe). The study was divided into two parts. First, the learning/familiarization part in which the participants got experienced with the method. After successfully completing this part, the participants were allowed to continue with the second part of this trial: the analyses of the seven blind MLT duplicate samples. METHOD: The selected seven MLT samples comprise five MUVA reference dairy samples, one NIST-certified infant formula and one industrial sample. In the Tables S-1 to S-6 the results of this MLT study have been summarized per sugar. There is a very good agreement between the MUVA and NIST-certified sugar contents in the MLT samples and in the MLT established sugar contents in those MUVA and NIST samples. RESULTS: This demonstrates that the accuracy of the newly developed HPAEC-PAD method is very good. CONCLUSIONS: Certificates of analysis were available for both the MUVA samples and the NIST sample. There is a very good agreement between the by MUVA- and NIS-certified sugar contents in the MLT samples and the corresponding in the MLT established sugar contents. This demonstrates that the accuracy of the HPAEC-PAD method is very good. In the IDF/ISO Analytical Week in June 2019 in Prague the report on the MLT study were discussed and adopted.

Results Multi-Laboratory Trial ISO/CD 22184 - IDF/WD 244: Milk and milk products - Determination of the sugar contents - High performance anion exchange chromatography method with pulsed amperometric detection (HPAEC-PAD).

BACKGROUND: In this international Multi Laboratory Trial (MLT) the precision data and the accuracy of the ISO/CD 22184 IDF/WD 244 analytical method for the quantification of 6 different mono- and disaccharides (galactose, glucose, fructose, sucrose, lactose and maltose) in milk and milk products with high performance anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD) are established. OBJECTIVE: Thirteen different laboratories participated (located in New Zealand, United States, Europe). The study was divided into two parts. Firstly, the learning/familiarization part in which the participants got experienced with the method. After successfully completing this part, the participants were allowed to continue with the second part of this trial: the analyses of the seven blind MLT duplicate samples. METHOD: The selected seven MLT samples comprise five MUVA reference dairy samples, one NIST certified infant formula and one industrial sample. In the Tables S-1 to S-6 the results of this MLT study have been summarized per sugar. There is a very good agreement between the MUVA and NIST certified sugar contents in the MLT samples and the in the MLT established sugar contents in those MUVA and NIST samples. RESULTS: This demonstrates that the accuracy of the newly developed HPAEC-PAD method is very good. CONCLUSIONS: Certificates of analysis were available for both the MUVA samples and the NIST sample. There is a very good agreement between the by MUVA and NIS certified sugar contents in the MLT samples and the corresponding in the MLT established sugar contents. This demonstrates that the accuracy of the HPAEC-PAD method is very good.In the IDF/ISO Analytical Week in June 2019 in Prague the report on the MLT study were discussed and adopted.

Clinical efficacy of intravenous administration of marbofloxacin in a Staphylococcus aureus infection in tissue cages in ponies.

Tissue cages (TC), implanted subcutaneously in the neck in eight ponies, were inoculated with Staphylococcus aureus (S. aureus) to determine the clinical efficacy of marbofloxacin in the treatment of this infection. From 21 h after inoculation, marbofloxacin (6 mg/kg) was administered intravenously (i.v.) once daily for 7 days. Samples of the tissue cage fluid (TCF) were taken to determine marbofloxacin concentrations (days 1, 3 and 7), using high-pressure liquid chromatography, and numbers of viable bacteria [colony forming units (CFU)] (days 1, 3, 7, 14 and 21). Statistical analysis was used to compare CFU before and after treatment. Clinical signs and CFU were used to evaluate the efficacy of treatment. Although, there was a slight decrease in CFU in all TC initially, the infection was not eliminated by marbofloxacin treatment in any of the ponies and abscesses formed. As the MIC (0.25 microg/mL) did not change during treatment and the concentration of marbofloxacin during treatment (mean concentration in TCF was 0.89 microg/mL on day 1, 0.80 microg/mL on day 3 and 2.77 microg/mL on day 7) was above MIC, we consider that the treatment failure might be attributable to the formation of a biofilm by S. aureus. Based on the present results, i.v. administration of marbofloxacin alone is not suitable for the elimination of S. aureus infections from secluded sites.

The influence of plasticiser on molecular organisation in dry amylopectin measured by differential scanning calorimetry and solid state nuclear magnetic resonance spectroscopy.

The interaction of crystalline and amorphous amylopectin with the plasticisers glycerol and ethylene glycol in the absence of water was studied with differential scanning calorimetry (DSC) and solid state NMR. At room temperature glycerol interacts mainly with the amorphous regions, while for ethylene glycol the amylopectin crystallinity does not effect the interaction. After heating the mixtures, an additional immobilisation of the plasticiser occurs.

The influence of plasticiser on molecular organisation in dry amylopectin measured by differential scanning calorimetry and solid state nuclear magnetic resonance spectroscopy.

The interaction of crystalline and amorphous amylopectin with the plasticisers glycerol and ethylene glycol in the absence of water was studied with differential scanning calorimetry (DSC) and solid state NMR. At room temperature glycerol interacts mainly with the amorphous regions, while for ethylene glycol the amylopectin crystallinity does not effect the interaction. After heating the mixtures, an additional immobilisation of the plasticiser occurs.

Role of ATP-dependent K(+) channels in the electrical excitability of early embryonic stem cell-derived cardiomyocytes.

Single, murine embryonic stem cell-derived early stage cardiomyocytes dissociated from embryoid bodies expressed two inward rectifier K(+) channels, I(K1) and the ATP dependent K(+) current. I(K1) exhibited low density in early stage cardiomyocytes, but increased significantly in late stage cells. In contrast, the ATP dependent K(+) current was expressed at similar densities in early and late stage cardiomyocytes. This current was found to be involved in the determination of the membrane potential, since glibenclamide depolarized early cardiomyocytes and exerted a positive chronotropic effect. Some cardiomyocytes displayed a bursting behavior of action potentials, characterized by alternating periods with and without action potentials. During the phases without action potentials, the membrane potential was hyperpolarized, indicating the involvement of K(+) channels in the generation of this bursting behavior. Extracellular recording techniques were applied to spontaneously contracting areas of whole embryoid bodies. In 20% of these bursting behavior similar to that seen in the single cells was observed. In regularly beating embryoid bodies, bursting could be induced by reduction of substrates from the extracellular medium as well as by superfusion with the positive chronotropic agents Bay K 8644 or isoproterenol. Perfusion with substrate-reduced medium induced bursting behavior after a short latency, isoproterenol and Bay K 8644 resulted in a positive chronotropic response followed by bursting behavior with longer latencies. The spontaneous bursting was blocked by glibenclamide. These experimental results suggest that intermittent activation of ATP dependent K(+) channels underlies the bursting behavior observed in single cardiomyocytes and in the whole embryoid body. Conditions of metabolic stress lead to the rhythmic suppression of action potential generation. Our data indicate that ATP dependent K(+) channels play a prominent role in the cellular excitability of early cardiomyocytes.

Action potential propagation failures in long-term recordings from embryonic stem cell-derived cardiomyocytes in tissue culture.

Three-dimensional cell aggregates (embryoid bodies, EBs) containing clusters of spontaneously beating cardiomyocytes were derived from permanent mouse embryonic stem (ES) cells. Extracellular recordings of the population action potentials of cardiomyocyte clusters were made using permanently mounted silver wire electrodes and microelectrode arrays integrated into the bottom of the culture dish. These techniques allowed long-term recordings (for up to several weeks) from individual EBs under cell culture conditions. The normal electrical activity consisted of regular spiking with a frequency of 0.5-5 Hz. However, most EBs (87%) spontaneously developed temporary or persistent complex activity patterns because of intermittent block of action potential propagation at narrow pathways connecting larger beating areas. Similar propagation blocks could also be reversibly induced in regularly spiking EBs by nimodipine (NDP). In addition to a slowing of pacemaker activity, NDP (20-200 nM) induced a stepwise decrease of the action potential frequency at the recording site. Perforated patch-clamp recordings from enzymatically isolated ES-cell-derived cardiomyocytes showed that similar activity patterns do not occur at the single-cell level. We suggest that this novel approach may provide a useful tool for in vitro studies of chronotropy and phenomena of propagation failure similar to AV block.

Crystallinity in starch plastics: consequences for material properties.

The processing of starches with biodegradable additives has made biodegradable plastics suitable for a number of applications. Starch plastics are partially crystalline as a result of residual crystallinity and the recrystallization of amylose and amylopectin. Such crystallinity is a key determinant of the product's properties. This article describes the influence of processing and storage conditions on starch crystallinity and offers possible explanations for the various properties of starch plastics, in particular for the problems associated with ageing, in terms of the different crystalline structures.

Diffuse sclerosing osteomyelitis (chronic tendoperiostitis) of the mandible. An 11-year follow-up report.

Diffuse sclerosing osteomyelitis of the mandible is a disease that is characterized by a protracted course of recurrent pain, swelling of the cheek, and trismus. The cause of the lesion has been obscure for a long period of time. Recent research, however, pointed out that this disease is likely to be caused by overuse of the jaw musculature (chronic tendoperiostitis) and can be treated accordingly. The protracted course of the disease and the difficulty of treatment with an eventual positive outcome are illustrated by a case report of a 65-year-old man with an 11-year history of diffuse sclerosing osteomyelitis (chronic tendoperiostitis) of the mandible.

NMR studies of bipyrimidine cyclobutane photodimers.

Cyclobutane-type photodimers of dinucleoside monophosphates dCpdT, dTpdC and dTpdT were prepared by ultraviolet irradiation in the presence of acetophenone as photosensitizer. The cytosine-containing derivatives were found to deaminate forming uracil products. Using one- and two-dimensional NMR, the photoproducts were characterized as cis-syn and trans-syn cyclobutane photodimers. On the basis of NOE data the structures of the cis-syn and trans-syn products of dUpdT were determined using distance-geometry and restrained-energy-minimization methods. The cis-syn structures showed (high-ANTI/SYN)/high-ANTI glycosidic linkages while the trans-syn structures were in the SYN-ANTI region. The backbone conformations of both structures were in fair agreement with the coupling-constant-data. The trans-syn structures were found to be very rigid and similar in all three products. For the three cis-syn structures more conformational freedom and more variation among the three structures was observed.