Rate-of-Kill (RoK) assays to triage large compound sets for Chagas disease drug discovery: Application to GSK Chagas Box

Chagas disease (CD) is a human disease caused by Trypanosoma cruzi. Whilst endemic in Latin America, the disease is spread around the world due to migration flows, being estimated that 8 million people are infected worldwide and over 10,000 people die yearly of complications linked to CD. Current chemotherapeutics is restricted to only two drugs, i.e. benznidazole (BNZ) and nifurtimox (NIF), both being nitroaromatic compounds sharing mechanism of action and exerting suboptimal efficacy and serious adverse effects. Recent clinical trials conducted to reposition antifungal azoles have turned out disappointing due to poor efficacy outcomes despite their promising preclinical profile. This apparent lack of translation from bench models to the clinic raises the question of whether we are using the right in vitro tools for compound selection. We propose that speed of action and cidality, rather than potency, are properties that can differentiate those compounds with better prospect of success to show efficacy in animal models of CD. Here we investigate the use of in vitro assays looking at the kinetics of parasite kill as a valuable surrogate to tell apart slow- (i.e. azoles targeting CYP51) and fast-acting (i.e. nitroaromatic) compounds. Data analysis and experimental design have been optimised to make it amenable for high-throughput compound profiling. Automated data reduction of experimental kinetic points to tabulated curve descriptors in conjunction with PCA, k-means and hierarchical clustering provide drug discoverers with a roadmap to guide navigation from hit qualification of a screening campaign to compound optimisation programs and assessment of combo therapy potential. As an example, we have studied compounds belonging to the GSK Chagas Box stemmed from the HTS campaign run against the full GSK 1.8 million compounds collection [1].

24. Summary Judgment

Summary judgment is used where a purported defence can be shown to have no real prospect of success and there is no other compelling reason why the case should be disposed of at trial. The procedure for entering summary judgment is not limited to use by claimants against defendants. Defendants may apply for summary judgment to attack weak claims brought by claimants. This chapter discusses time for applying for summary judgment; defendant’s application for summary judgment; excluded proceedings; orders available; amendment at hearing; other compelling reasons for a trial; directions on summary judgment hearing; and specific performance, rescission, and forfeiture in property cases.

How Some Lawyers Prioritise Earnings and Not Necessarily the Best Interests of Their Clients

This case deals with an employee seeking justice in a labour dispute and who ends up paying a small fortune in legal fees and still fails to find satisfaction. The case provides food for thought for human resource practitioners and particularly lawyers regarding under the circumstances when they should be ethically bound to advise disgruntled employees to cease pursuing a grievance that has little prospect of success. How and when should the human resource practitioner provide professional and independent advice, and when should the ethical (sic) lawyer refuse to approach the courts with a case containing insufficient merit?

Wir müssen abwägen – aber wie sollen wir abwägen?

The global Covid-19 crisis raises at least three moral questions, which my contribution answers as follows: (1) Which patient should get treatment according to triage criteria? The patient whose treatment has the best prospect of success. (2) How should we resolve the conflict between public health measures and economic needs? Public health should have priority, but reaches its limits where the individual right to stay afloat through one’s own work is violated. (3) How should we resolve the conflict between public health measures and civil liberties? Public health should have priority, but reaches its limits where the restriction of freedom violates the integrity of individual health and personal freedom. The answers and the arguments behind these are developed through the discussion of a wide range of current public health policies, concrete measures, and competing approaches to moral questions in the Covid-19 pandemic.

Migration trends and challenges in the Visegrad countries

The Visegrad region experienced the aging and the decline of its population in the past 30 years, as happened in other Eastern European countries. That development was aggravated by net emigration, the scale of which was overestimated at the time of the political regime changes and underestimated after the EU Eastern expansion. This article presents and analyses the main trends in migration to and from the Visegrad countries, and tries to prove that political considerations and public attitudes often prevented the formulation of appropriate government responses. Research on the motivations for emigration found that economic opportunities prevail as the most decisive factor in individual decisions on migration. Therefore, at the governmental level, the prospect of success to slow down or reverse the flow of net emigration depends on economic convergence between the Visegrad countries and the West.

Decisions on the allocation of intensive care resources in the context of the COVID-19 pandemic

In view of the globally evolving coronavirus disease (COVID-19) pandemic, German hospitals rapidly expanded their intensive care capacities. However, it is possible that even with an optimal use of the increased resources, these will not suffice for all patients in need. Therefore, recommendations for the allocation of intensive care resources in the context of the COVID-19 pandemic have been developed by a multidisciplinary group of authors with the support of eight scientific medical societies. The recommendations for procedures and criteria for prioritisations in case of resource scarcity are based on scientific evidence, ethicolegal considerations and practical experience. Medical decisions must always be based on the need and the treatment preferences of the individual patient. In addition to this patient-centred approach, prioritisations in case of resource scarcity require a supraindividual perspective. In such situations, prioritisations should be based on the criterion of clinical prospect of success in order to minimize the number of preventable deaths due to resource scarcity and to avoid discrimination based on age, disabilities or social factors. The assessment of the clinical prospect of success should take into account the severity of the current illness, severe comorbidities and the patient’s general health status prior to the current illness.

24. Summary Judgment

Summary judgment is used where a purported defence can be shown to have no real prospect of success and there is no other compelling reason why the case should be disposed of at trial. The procedure for entering summary judgment is not limited to use by claimants against defendants. Defendants may apply for summary judgment to attack weak claims brought by claimants. This chapter discusses time for applying for summary judgment; defendant’s application for summary judgment; excluded proceedings; orders available; amendment at hearing; other compelling reasons for a trial; directions on summary judgment hearing; and specific performance, rescission, and forfeiture in property cases.