Formulation of Cannabidiol in Colloidal Lipid Carriers.

In this study, the general processability of cannabidiol (CBD) in colloidal lipid carriers was investigated. Due to its many pharmacological effects, the pharmaceutical use of this poorly water-soluble drug is currently under intensive research and colloidal lipid emulsions are a well-established formulation option for such lipophilic substances. To obtain a better understanding of the formulability of CBD in lipid emulsions, different aspects of CBD loading and its interaction with the emulsion droplets were investigated. Very high drug loads (>40% related to lipid content) could be achieved in emulsions of medium chain triglycerides, rapeseed oil, soybean oil and trimyristin. The maximum CBD load depended on the type of lipid matrix. CBD loading increased the particle size and the density of the lipid matrix. The loading capacity of a trimyristin emulsion for CBD was superior to that of a suspension of solid lipid nanoparticles based on trimyristin (69% vs. 30% related to the lipid matrix). In addition to its localization within the lipid core of the emulsion droplets, cannabidiol was associated with the droplet interface to a remarkable extent. According to a stress test, CBD destabilized the emulsions, with phospholipid-stabilized emulsions being more stable than poloxamer-stabilized ones. Furthermore, it was possible to produce emulsions with pure CBD as the dispersed phase, since CBD demonstrated such a pronounced supercooling tendency that it did not recrystallize, even if cooled to -60 °C.

Photolytic radical persistence due to anoxia in viscous aerosol particles.

In viscous, organic-rich aerosol particles containing iron, sunlight may induce anoxic conditions that stabilize reactive oxygen species (ROS) and carbon-centered radicals (CCRs). In laboratory experiments, we show mass loss, iron oxidation and radical formation and release from photoactive organic particles containing iron. Our results reveal a range of temperature and relative humidity, including ambient conditions, that control ROS build up and CCR persistence in photochemically active, viscous organic particles. We find that radicals can attain high concentrations, altering aerosol chemistry and exacerbating health hazards of aerosol exposure. Our physicochemical kinetic model confirmed these results, implying that oxygen does not penetrate such particles due to the combined effects of fast reaction and slow diffusion near the particle surface, allowing photochemically-produced radicals to be effectively trapped in an anoxic organic matrix.

Using interpretability approaches to update "black-box" clinical prediction models: an external validation study in nephrology.

Despite advances in machine learning-based clinical prediction models, only few of such models are actually deployed in clinical contexts. Among other reasons, this is due to a lack of validation studies. In this paper, we present and discuss the validation results of a machine learning model for the prediction of acute kidney injury in cardiac surgery patients initially developed on the MIMIC-III dataset when applied to an external cohort of an American research hospital. To help account for the performance differences observed, we utilized interpretability methods based on feature importance, which allowed experts to scrutinize model behavior both at the global and local level, making it possible to gain further insights into why it did not behave as expected on the validation cohort. The knowledge gleaned upon derivation can be potentially useful to assist model update during validation for more generalizable and simpler models. We argue that interpretability methods should be considered by practitioners as a further tool to help explain performance differences and inform model update in validation studies.

Novel strategies for the formulation and processing of poorly water-soluble drugs.

Low aqueous solubility of active pharmaceutical ingredients presents a serious challenge in the development process of new drug products. This article provides an overview on some of the current approaches for the formulation of poorly water-soluble drugs with a special focus on strategies pursued at the Center of Pharmaceutical Engineering of the TU Braunschweig. These comprise formulation in lipid-based colloidal drug delivery systems and experimental as well as computational approaches towards the efficient identification of the most suitable carrier systems. For less lipophilic substances the preparation of drug nanoparticles by milling and precipitation is investigated for instance by means of microsystem-based manufacturing techniques and with special regard to the preparation of individualized dosage forms. Another option to overcome issues with poor drug solubility is the incorporation into nanospun fibers.

Eyes are on us, but nobody cares: are eye cues relevant for strong reciprocity?

Strong reciprocity is characterized by the willingness to altruistically reward cooperative acts and to altruistically punish norm-violating, defecting behaviours. Recent evidence suggests that subtle reputation cues, such as eyes staring at subjects during their choices, may enhance prosocial behaviour. Thus, in principle, strong reciprocity could also be affected by eye cues. We investigate the impact of eye cues on trustees' altruistic behaviour in a trust game and find zero effect. Neither the subjects who are classified as prosocial nor the subjects who are classified as selfish respond to these cues. In sharp contrast to the irrelevance of subtle reputation cues for strong reciprocity, we find a large effect of explicit, pecuniary reputation incentives on the trustees' prosociality. Trustees who can acquire a good reputation that benefits them in future interactions honour trust much more than trustees who cannot build a good reputation. These results cast doubt on hypotheses suggesting that strong reciprocity is easily malleable by implicit reputation cues not backed by explicit reputation incentives.

Disrupting the prefrontal cortex diminishes the human ability to build a good reputation.

Reputation formation pervades human social life. In fact, many people go to great lengths to acquire a good reputation, even though building a good reputation is costly in many cases. Little is known about the neural underpinnings of this important social mechanism, however. In the present study, we show that disruption of the right, but not the left, lateral prefrontal cortex (PFC) with low-frequency repetitive transcranial magnetic stimulation (rTMS) diminishes subjects' ability to build a favorable reputation. This effect occurs even though subjects' ability to behave altruistically in the absence of reputation incentives remains intact, and even though they are still able to recognize both the fairness standards necessary for acquiring and the future benefits of a good reputation. Thus, subjects with a disrupted right lateral PFC no longer seem to be able to resist the temptation to defect, even though they know that this has detrimental effects on their future reputation. This suggests an important dissociation between the knowledge about one's own best interests and the ability to act accordingly in social contexts. These results link findings on the neural underpinnings of self-control and temptation with the study of human social behavior, and they may help explain why reputation formation remains less prominent in most other species with less developed prefrontal cortices.

Portal vein embolization with N-butyl cyanoacrylate before partial hepatectomy in patients with hepatocellular carcinoma and underlying cirrhosis or advanced fibrosis.

PURPOSE: To describe the safety, complications, and liver regeneration associated with the left liver after embolization of the right portal vein (PV) in patients with hepatocellular carcinoma (HCC) developed in the setting of advanced liver fibrosis and cirrhosis. MATERIALS AND METHODS: Forty patients (31 men, nine women; mean age, 62 years) with HCC underwent PV embolization over a 4-year period. Embolization was performed from a left PV percutaneous access with use of n-butyl cyanoacrylate (NBCA) mixed with iodized oil. Computed tomography (CT) volumetry was performed before and 1 month after PV embolization to measure the left lobe volume as well as the functional liver ratio defined by the ratio between the left lobe and the total liver volume minus tumoral volume. PV pressure and liver enzyme levels were compared before and 1 month after the procedure and complications were registered. Factors potentially affecting regeneration (age, sex, diabetes, chemoembolization, functional liver ratio before PV embolization, and Knodell histologic score) were evaluated by one-way and stepwise regression analysis. RESULTS: PV embolization could be achieved successfully in all cases. Two patients had partial PV thrombosis on the 1-month follow-up CT and two patients developed transient ascites after PV embolization. The left lobe volume increase was 41% +/- 32% after PV embolization and the functional liver ratio increased from 28% +/- 10% to 36% +/- 10% (P < .0001). Hypertrophy of the left lobe was greater in patients with a low functional liver ratio before PV embolization and those with an F3 fibrosis score. Other factors had no influence on left lobe regeneration. CONCLUSION: PV embolization with use of NBCA is feasible in patients with advanced fibrosis and cirrhosis. Hypertrophy of the left lobe of the liver after PV embolization has a statistically significant correlation with lower functional liver ratio and lower degrees of fibrosis.

Detection of liver metastases under 2 cm: comparison of different acquisition protocols in four row multidetector-CT (MDCT).

This study compared different acquisition protocols performance to detect small liver metastases (<2 cm). Thirty consecutive patients with histologically proven hepatic metastases were explored by MDCT at the liver equilibrium phase by four successive acquisitions. We compared the following protocols (1-4): 5/30/1.5 (section thickness/table speed/pitch); 5/15/0.75; 5/11.25/0.75; and 2.5/15/1.5 with the same X-ray dose. The gold standard was based on patient radiological follow-up. Evolutive lesions were considered as true positive (TP). The described lesions, not found on the follow-up exams despite tumoral progression, were considered as false positive (FP). Stable lesions could not be considered as metastasis and were eliminated. One hundred and seventy-six lesions were detected: 61 TP and 91 FP. Twenty-four lesions were eliminated. The mean kappa values for protocols 1, 2, 3 and 4 were, respectively, 0.43, 0.68, 0.73 and 0.51 (0.61-0.80: substantial agreement) and the mean areas under the ROC curve were, respectively, 0.76, 0.87, 0.86 and 0.80. The results of protocols 2 and 3 were significantly superior to those of protocols 1 and 4. MDCT protocols using thin sections or an increased table speed are less efficient in detecting small metastases.

Break-dance: an unusual cause of hammer syndrome.

We report the case of a young break-dancer presenting with hammer syndrome. This syndrome has been correlated with many professional and recreational activities but this is, to our knowledge, the first description of hammer syndrome caused by break-dancing. The etiology, diagnosis and treatment modalities of this rare syndrome are considered.

Indications for and limitations of portal vein embolization before major hepatic resection for hepatobiliary malignancy.

Portal vein embolization is a promising adjunctive tool in liver surgery; however, the understanding of liver regeneration and PVE is still in its infancy. Refinement in patient selection criteria and methods to evaluate hepatic hypertrophy and function should increase the potential indications for PVE and expand the field of major liver surgery.