Osteochondral defects in the ankle: why painful?

Osteochondral defects of the ankle can either heal and remain asymptomatic or progress to deep ankle pain on weight bearing and formation of subchondral bone cysts. The development of a symptomatic OD depends on various factors, including the damage and insufficient repair of the subchondral bone plate. The ankle joint has a high congruency. During loading, compressed cartilage forces its water into the microfractured subchondral bone, leading to a localized high increased flow and pressure of fluid in the subchondral bone. This will result in local osteolysis and can explain the slow development of a subchondral cyst. The pain does not arise from the cartilage lesion, but is most probably caused by repetitive high fluid pressure during walking, which results in stimulation of the highly innervated subchondral bone underneath the cartilage defect. Understanding the natural history of osteochondral defects could lead to the development of strategies for preventing progressive joint damage

Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen

The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.Peer reviewe

Assessing fish welfare in aquaculture

A framework for assessing the welfare of fish in aquaculture must have a suite of different welfare indicators that describe how well their welfare needs are met and thus their quality of life. The framework should utilise both input- and outcome-based welfare indicators. Input-based welfare indicators are parameters that describe the conditions the fish are subjected to, e.g. their environment. In many cases, input-based welfare indicators can give the farmer or assessor an early warning of deteriorating conditions, which can then be mitigated before they become too severe. However, it can be very challenging to have a complete overview of all the possible input parameters the fish are subjected to, at all times, and at all possible positions in the rearing facility that the fish may occupy. Further, their effects on welfare can also be subtle, delayed and also be dependent upon an array of complex interactions with other parameters and factors. It is, therefore, necessary to also include outcome-based indicators. These are parameters that are normally directly related to the animals, e.g. describing the animals themselves or their behaviour. A simple rule of thumb can be that as long as the fish look good, are doing well, are in good health, show normal behaviour and are thriving, it is not unreasonable to assume that the rearing system or operation is fulfilling, or has not markedly impacted upon, their welfare needs. If not, there is something wrong and this should be investigated further

Ethics and the Welfare of Fish

To what extent fish can experience suffering and enjoyment is not just an empirical question, but one that also calls for ethical reflection. This is firstly, because animal welfare research is value laden and secondly, because the empirical evidence requires a normative framework in order to become action guiding in practices involving fish, such as aquaculture. In this chapter, we describe the role of ethics and different ethical theories that have been applied in animal ethics and that are relevant for discussions on fish welfare. We particularly focus on utilitarian, rights based, relational, and virtue ethical animal ethics theories. We furthermore argue that fish welfare is a term that combines moral norms and biological concepts. After all, when we implement fish welfare measures we have already made certain normative choices. We illustrate the integration between ethics and science in seven steps, from implementing fish welfare at the farm level, to weighing welfare against other values, defining and measuring welfare, to the questions of why welfare is morally relevant and what this means for the moral status of fish. We then consider the question of whether fish should be attributed to moral status and hence whether their welfare should be taken into account in our moral deliberations. However, not all moral concerns regarding our treatment of fish can be addressed by focussing on welfare. We discuss a number of concerns beyond welfare that need to be taken into consideration in a moral discussion on how to relate to fish: does the killing of fish constitute a moral harm? and how should we morally evaluate the process of domesticating fish in aquaculture? The chapter concludes by pointing out a number of moral issues in four practices involving fish: aquaculture, wild fisheries, experimentation, and recreation