Search

Summary: System-level patient health signals, as captured by treatment-emergent adverse events (TEAEs), might contain correlates of immune checkpoint inhibitor (ICI) therapy response. Using all TEAEs and a novel machine learning modeling approach, we derived a composite signature predictive of, and potentially specific to, the response to the anti-PD-L1 ICI durvalumab in patients with non–small-cell lung cancer (NSCLC). We trained on data from the durvalumab arm and chemotherapy arm in the MYSTIC clinical trial and tested on data from four independent durvalumab-containing NSCLC trials using only the first 60 days’ TEAEs. We directly compared our signature performance against that of three different definitions of immune-related adverse events. Only our signature was predictive and identified longer survivors in patients treated with durvalumab but not in patients treated with chemotherapy or placebo. It also identified durvalumab-treated long survivors with stable disease at their first RECIST evaluation and a set of PD-L1-negative long survivors.

Monitoring and classification of dairy cattle behaviours is essential for optimising milk yields. Early detection of illness, days before the critical conditions occur, together with automatic detection of the onset of oestrus cycles is crucial for obviating prolonged cattle treatments and improving the pregnancy rates. Accelerometer-based sensor systems are becoming increasingly popular, as they are automatically providing information about key cattle behaviours such as the level of restlessness and the time spent ruminating and eating, proxy measurements that indicate the onset of heat events and overall welfare, at an individual animal level. This paper reports on an approach to the development of algorithms that classify key cattle states based on a systematic dimensionality reduction process through two feature selection techniques. These are based on Mutual Information and Backward Feature Elimination and applied on knowledge-specific and generic time-series extracted from raw accelerometer data. The extracted features are then used to train classification models based on a Hidden Markov Model, Linear Discriminant Analysis and Partial Least Squares Discriminant Analysis. The proposed feature engineering methodology permits model deployment within the computing and memory restrictions imposed by operational settings. The models were based on measurement data from 18 steers, each animal equipped with an accelerometer-based neck-mounted collar and muzzle-mounted halter, the latter providing the truthing data. A total of 42 time-series features were initially extracted and the trade-off between model performance, computational complexity and memory footprint was explored. Results show that the classification model that best balances performance and computation complexity is based on Linear Discriminant Analysis using features selected through Backward Feature Elimination. The final model requires 1.83 ± 1.00 ms to perform feature extraction with 0.05 ± 0.01 ms for inference with an overall balanced accuracy of 0.83.

Monitoring cattle behaviour is core to the early detection of health and welfare issues and to optimise the fertility of large herds. Accelerometer-based sensor systems that provide activity profiles are now used extensively on commercial farms and have evolved to identify behaviours such as the time spent ruminating and eating at an individual animal level. Acquiring this information at scale is central to informing on-farm management decisions. The paper presents the development of a Convolutional Neural Network (CNN) that classifies cattle behavioural states (‘rumination’, ‘eating’ and ‘other’) using data generated from neck-mounted accelerometer collars. During three farm trials in the United Kingdom (Easter Howgate Farm, Edinburgh, UK), 18 steers were monitored to provide raw acceleration measurements, with ground truth data provided by muzzle-mounted pressure sensor halters. A range of neural network architectures are explored and rigorous hyper-parameter searches are performed to optimise the network. The computational complexity and memory footprint of CNN models are not readily compatible with deployment on low-power processors which are both memory and energy constrained. Thus, progressive reductions of the CNN were executed with minimal loss of performance in order to address the practical implementation challenges, defining the trade-off between model performance versus computation complexity and memory footprint to permit deployment on micro-controller architectures. The proposed methodology achieves a compression of 14.30 compared to the unpruned architecture but is nevertheless able to accurately classify cattle behaviours with an overall F1 score of 0.82 for both FP32 and FP16 precision while achieving a reasonable battery lifetime in excess of 5.7 years.

Progressive multifocal leukoencephalopathy (PML) is a rare but debilitating and frequently fatal viral disease of the central nervous system, primarily affecting individuals with chronically and severely suppressed immune systems. The disease was relatively obscure until the outbreak of HIV/AIDS, when it presented as one of the more frequent opportunistic infections in this immune deficiency syndrome. It attracted additional attention from the medical and scientific community following the discovery of significant PML risk associated with natalizumab, a monoclonal antibody used for treatment of relapsing–remitting multiple sclerosis. This was followed by association of PML with other immunosuppressive or immunomodulating drugs. PML is currently untreatable disease with poor outcomes, so it is a significant concern when developing new immunotherapies. Current prophylaxis and treatment of PML are focused on immune reconstitution, restoration of immune responses to JC virus infection, and eventual suppression of immune reconstitution inflammatory syndrome. This approach was successful in reducing the incidence of PML and improved survival of PML patients with HIV infection. However, the outcome for the majority of PML patients, regardless of their medical history, is still relatively poor. There is a high unmet need for both prophylaxis and treatment of PML. The aim of this review is to discuss potential drug candidates for prophylaxis and treatment of PML with a critical review of previously conducted and completed PML treatment studies as well as to provide perspectives for future therapies.