A closer look at adaptive regret

For the prediction with expert advice setting, we consider methods to construct algorithms that have low adaptive regret. The adaptive regret of an algorithm on a time interval [t1,t2] is the loss of the algorithm minus the loss of the best expert over that interval. Adaptive regret measures how well the algorithm approximates the best expert locally, and so is different from, although closely related to, both the classical regret, measured over an initial time interval [1,t], and the tracking regret, where the algorithm is compared to a good sequence of experts over [1,t]. We investigate two existing intuitive methods for deriving algorithms with low adaptive regret, one based on specialist experts and the other based on restarts. Quite surprisingly, we show that both methods lead to the same algorithm, namely Fixed Share, which is known for its tracking regret. We provide a thorough analysis of the adaptive regret of Fixed Share. We obtain the exact worst-case adaptive regret for Fixed Share, from which the classical tracking bounds follow. We prove that Fixed Share is optimal for adaptive regret: the worst-case adaptive regret of any algorithm is at least that of an instance of Fixed Share

Ontwerpen aan klimaatadaptatie : plannen voor het ondenkbare

In Nederland zal het natter worden ten gevolge van de klimaatverandering. Meer regens, meer smeltwater in rivieren en een stijging van de zeespiegel zorgen voor een groter risico op overstromingen. Daarmee wordt klimaatverandering een niet weg te denken element in waterbeheer, kustverdediging, stedelijke ontwikkeling en natuurbeheer. Ieder ontwerp voor stedelijke of gebiedsontwikkeling zal rekening moeten houden met de mogelijke gevolgen van de opwarming van de aarde, of met een mooi woord ‘klimaatbestendig’ moeten zijn. De vraag hoe je klimaatbestendige landschappen kunt ontwerpen, speelt een grote rol binnen Europese projecten waar de groene hogeschool aan heeft deelgenomen en deelneemt

The Erd\H{o}s-Ko-Rado theorem for twisted Grassmann graphs

We present a "modern" approach to the Erd\H{o}s-Ko-Rado theorem for Q-polynomial distance-regular graphs and apply it to the twisted Grassmann graphs discovered in 2005 by van Dam and Koolen.Comment: 5 page

Clinical implications of food-drug interactions with small-molecule kinase inhibitors

During the past two decades, small-molecule kinase inhibitors have proven to be valuable in the treatment of solid and haematological tumours. However, because of their oral administration, the intrapatient and interpatient exposure to small-molecule kinase inhibitors (SMKIs) is highly variable and is affected by many factors, such as concomitant use of food and herbs. Food-drug interactions are capable of altering the systemic bioavailability and pharmacokinetics of these drugs. The most important mechanisms underlying food-drug interactions are gastrointestinal drug absorption and hepatic metabolism through cytochrome P450 isoenzymes. As food-drug interactions can lead to therapy failure or severe toxicity, knowledge of these interactions is essential. This Review provides a comprehensive overview of published studies involving food-drug interactions and herb-drug interactions for all registered SMKIs up to Oct 1, 2019. We critically discuss US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines concerning food-drug interactions and offer clear recommendations for their management in clinical practice

Leishmanicidal activity of fractions rich in aporphine alkaloids from amazonian unonopsis species

In vitro evaluation of alkaloidal fractions of twigs, barks and leaves from two Unonopsis species, Unonopsis guatterioides R.E. Fr. and Unonopsis duckei R.E. Fr., Annonaceae, against promastigote forms of Leishmania amazonensis revealed these species as sources of substances with promising leishmanicidal potential. All alkaloidal fractions from twigs, barks and leaves of U. guatterioides were classified as highly active, with IC50 1.07, 1.90, and 2.79 mg/mL, respectively. Only the alkaloidal fraction from the twigs of U. duckei was classified as inactive2261368137

Leishmanicidal activity of fractions rich in aporphine alkaloids from Amazonian Unonopsis species

In vitro evaluation of alkaloidal fractions of twigs, barks and leaves from two Unonopsis species, Unonopsis guatterioides R.E. Fr. and Unonopsis duckei R.E. Fr., Annonaceae, against promastigote forms of Leishmania amazonensis revealed these species as sources of substances with promising leishmanicidal potential. All alkaloidal fractions from twigs, barks and leaves of U. guatterioides were classified as highly active, with IC50 1.07, 1.90, and 2.79 mg/mL, respectively. Only the alkaloidal fraction from the twigs of U. duckei was classified as inactive.2261368137

Darolutamide does not interfere with OATP-mediated uptake of docetaxel

The addition of darolutamide, an androgen receptor signalling inhibitor, to therapy with docetaxel has recently been approved as a strategy to treat metastatic prostate cancer. OATP1B3 is an SLC transporter that is highly expressed in prostate cancer and is responsible for the accumulation of substrates, including docetaxel, into tumours. Given that darolutamide inhibits OATP1B3 in vitro, we sought to characterise the impact of darolutamide on docetaxel pharmacokinetics. We investigated the influence of darolutamide on OATP1B3 transport using in vitro and in vivo models. We assessed the impact of darolutamide on the tumour accumulation of docetaxel in a patient-derived xenograft (PDX) model and on an OATP1B biomarker in patients. Darolutamide inhibited OATP1B3 in vitro at concentrations higher than the reported Cmax. Consistent with these findings, in vivo studies revealed that darolutamide does not influence the pharmacokinetics of Oatp1b substrates, including docetaxel. Docetaxel accumulation in PDX tumours was not decreased in the presence of darolutamide. Metastatic prostate cancer patients had similar levels of OATP1B biomarkers, regardless of treatment with darolutamide. Consistent with a low potential to inhibit OATP1B3-mediated transport in vitro, darolutamide does not significantly impede the transport of Oatp1b substrates in vivo or in patients. Our findings support combined treatment with docetaxel and darolutamide, as no OATP1B3 transporter based drug–drug interaction was identified

Obesity Alters Endoxifen Plasma Levels in Young Breast Cancer Patients: A Pharmacometric Simulation Approach

Endoxifen is the most important metabolite of the prodrug tamoxifen. High interindividual variability in endoxifen steady-state concentrations (CSS,min ENDX) is observed under tamoxifen standard dosing breast cancer patients that do not reach endoxifen concentrations above a proposed therapeutic threshold of 5.97 ng/mL may be at higher recurrence risk. In this investigation, 10 clinical tamoxifen studies were pooled (nPatients=1388) to investigate influential factors on CSS,min ENDX using nonlinear mixed-effects modelling. Age and body weight were found to significantly impact CSS,min ENDX in addition to CYP2D6 phenotype. Compared to post-menopausal patients, pre-menopausal patients had a 30% higher risk for subtarget CSS,min ENDX at tamoxifen 20 mg per day. In treatment simulations for distinct patient subpopulations, young overweight patients had a 3.1-13.8-fold higher risk for subtarget CSS,min ENDX compared to elderly low-weight patients. Considering ever-rising obesity rates and the clinical importance of tamoxifen for pre-menopausal patients, this subpopulation may benefit most from individualised tamoxifen dosing