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Understanding the relation between cortical neuronal network structure and neuronal activity is a fundamental unresolved question in neuroscience, with implications to our understanding of the mechanism by which neuronal networks evolve over time, spontaneously or under stimulation. It requires a method for inferring the structure and composition of a network from neuronal activities. Tracking the evolution of networks and their changing functionality will provide invaluable insight into the occurrence of plasticity and the underlying learning process. We devise a probabilistic method for inferring the effective network structure by integrating techniques from Bayesian statistics, statistical physics and principled machine learning. The method and resulting algorithm allow one to infer the effective network structure, identify the excitatory and inhibitory nature of its constituents, and predict neuronal spiking activities by employing the inferred structure. We validate the method and algorithm's performance using synthetic data, spontaneous activity of an in silico emulator and realistic in vitro neuronal networks of modular and homogeneous connectivity, demonstrating excellent structure inference and activity prediction. We also show that our method outperforms commonly used existing methods for inferring neuronal network structure. Inferring the evolving effective structure of neuronal networks will provide new insight into the learning process due to stimulation in general and will facilitate the development of neuron-based circuits with computing capabilities.

Novel beam-intercepting materials and targetry concepts are essential to improve the performance, reliability and operation lifetimes of next generation multi-megawatt (multi-MW) accelerator target facilities. The beam-intercepting materials and components must sustain an order-of-magnitude increase in particle beam intensities and are beyond the current state-of-the-art. With conventional materials already limiting the scope of experiments, it is crucial to investigate novel target materials, technologies and concepts that will satisfy the requirements and maximize the physics benefits of future energy and intensity frontier experiments. This paper provides an overview of the related targetry R&D required over the next 10 years to support and enable future high-power accelerator target facilities.

Objective: We aim to utilise real world data in evidence synthesis to optimise an evidence base for the effectiveness of biologic therapies in rheumatoid arthritis in order to allow for evidence on first-line therapies to inform second-line effectiveness estimates. Study design and setting: We use data from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA) to supplement RCT evidence obtained from the literature, by emulating target trials of treatment sequences to estimate treatment effects in each line of therapy. Treatment effects estimates from the target trials inform a bivariate network meta-analysis (NMA) of first and second-line treatments. Results: Summary data were obtained from 21 trials of biologic therapies including 2 for second-line treatment and results from six emulated target trials of both treatment lines. Bivariate NMA resulted in a decrease in uncertainty around the effectiveness estimates of the second-line therapies, when compared to the results of univariate NMA, and allowed for predictions of treatment effects not evaluated in second-line RCTs. Conclusion: Bivariate NMA provides effectiveness estimates for all treatments in first- and second-line, including predicted effects in second-line where these estimates did not exist in the data. This novel methodology may have further applications, for example for bridging networks of trials in children and adults.

Background and Aims: The methods with which prediction models are usually developed mean that neither the parameters nor the predictions should be interpreted causally. However, when prediction models are used to support decision making, there is often a need for predicting outcomes under hypothetical interventions. We aimed to identify published methods for developing and validating prediction models that enable risk estimation of outcomes under hypothetical interventions, utilizing causal inference: their main methodological approaches, underlying assumptions, targeted estimands, and potential pitfalls and challenges with using the method, and unresolved methodological challenges. Methods: We systematically reviewed literature published by December 2019, considering papers in the health domain that used causal considerations to enable prediction models to be used for predictions under hypothetical interventions. Results: We identified 4919 papers through database searches and a further 115 papers through manual searches, of which 13 were selected for inclusion, from both the statistical and the machine learning literature. Most of the identified methods for causal inference from observational data were based on marginal structural models and g-estimation. Conclusions: There exist two broad methodological approaches for allowing prediction under hypothetical intervention into clinical prediction models: 1) enriching prediction models derived from observational studies with estimated causal effects from clinical trials and meta-analyses; and 2) estimating prediction models and causal effects directly from observational data. These methods require extending to dynamic treatment regimes, and consideration of multiple interventions to operationalise a clinical decision support system. Techniques for validating 'causal prediction models' are still in their infancy.

Background: In view of the growth of published papers, there is an increasing need for studies that summarise scientific research. An increasingly common review is a 'Methodology scoping review', which provides a summary of existing analytical methods, techniques and software, proposed or applied in research articles, which address an analytical problem or further an analytical approach. However, guidelines for their design, implementation and reporting are limited. Methods: Drawing on the experiences of the authors, which were consolidated through a series of face-to-face workshops, we summarise the challenges inherent in conducting a methodology scoping review and offer suggestions of best practice to promote future guideline development. Results: We identified three challenges of conducting a methodology scoping review. First, identification of search terms; one cannot usually define the search terms a priori and the language used for a particular method can vary across the literature. Second, the scope of the review requires careful consideration since new methodology is often not described (in full) within abstracts. Third, many new methods are motivated by a specific clinical question, where the methodology may only be documented in supplementary materials. We formulated several recommendations that build upon existing review guidelines. These recommendations ranged from an iterative approach to defining search terms through to screening and data extraction processes. Conclusion: Although methodology scoping reviews are an important aspect of research, there is currently a lack of guidelines to standardise their design, implementation and reporting. We recommend a wider discussion on this topic., Comment: 22 pages, 2 tables

Background: Pre-marketing authorisation estimates of survival are generally restricted to those observed directly in randomised controlled trials (RCTs). However, for regulatory and Health Technology Assessment (HTA) decision-making a longer time horizon is often required than is studied in RCTs. Therefore, extrapolation is required to estimate long-term treatment effect. Registry data can provide evidence to support extrapolation of treatment effects from RCTs, which are considered the main sources of evidence of effect for new drug applications. A number of methods are available to extrapolate survival data, such as Exponential, Weibull, Gompertz, log-logistic or log-normal parametric models. The different methods have varying functional forms and can result in different survival estimates. Methods: The aim of this paper was to use registry data to supplement the relatively short term RCT data to obtain long term estimates of effect. No formal hypotheses were tested. We explore the above parametric regression models as well as a nonparametric regression model based on local linear (parametric) regression. We also explore a Bayesian model constrained to the long term estimate of survival reported in literature, a Bayesian power prior approach on the variability observed from published literature, and a Bayesian Model Averaging (BMA) approach. The methods were applied to extrapolate overall survival of a RCT in metastatic melanoma. Results: The results showed that the BMA approach was able to fit the RCT data well, with the lowest variability of the area under the curve up to 72 months with or without the SEER Medicare registry. Conclusion: the BMA approach is a viable approach to extrapolate overall survival in the absence of long term data., Comment: 21 Pages, 7 named figures, 3 tables

Closed-loop adaptive optics systems which use minimum mean square error wavefront reconstruction require the computation of pseudo open loop wavefront slopes. These techniques incorporate a knowledge of atmospheric statistics which must therefore be represented within the wavefront slope measurements. These pseudo open loop slopes are computed from the sum of the measured residual slopes and the reconstructed slopes that would be given if the deformable mirror was flat, generally involving the multiplication of an interaction matrix with actuator demands from the previous time-step. When using dense algebra, this multiplication is computationally expensive for Extremely Large Telescopes, requiring a large memory bandwidth. Here we show that this requirement can be significantly reduced, maintaining mathematical correctness and significantly reducing system complexity. This therefore reduces the cost of these systems and increases robustness and reliability., Comment: Accepted for publication in MNRAS

We propose a many-core CPU architecture for Extremely Large Telescope (ELT) scale adaptive optics (AO) real-time control (RTC) for the multi-conjugate AO (MCAO) and laser-tomographic AO (LTAO) modes. MCAO and LTAO differ from the more conventional single-conjugate (SCAO) mode by requiring more wavefront sensor (WFS) measurements and more deformable mirrors to achieve a wider field of correction, further increasing the computational requirements of ELT-scale AO. We demonstrate results of our CPU based AO RTC operating firstly in SCAO mode, using either Shack-Hartmann or Pyramid style WFS processing, and then in MCAO mode and in LTAO mode using the specifications of the proposed ELT instruments, MAORY and HARMONI. All results are gathered using a CPU based camera simulator utilising UDP packets to better demonstrate the pixel streaming and pipe-lining of the RTC software. We demonstrate the effects of switching parameters, streaming telemetry and implicit pseudo open-loop control (POLC) computation on the MCAO and LTAO modes. We achieve results of < 600$\mu$s latency with an ELT scale SCAO setup using Shack-Hartman processing and < 800$\mu$s latency with SCAO Pyramid WFS processing. We show that our MCAO and LTAO many core CPU architecture can achieve full system latencies of < 1000$\mu$s with jitters < 40$\mu$s RMS. We find that a CPU based AO RTC architecture has a good combination of performance, flexibility and maintainability for ELT-scale AO systems., Comment: Accepted 2019 March 01 MNRAS. Received 2019 February 28 ; in original form 2018 December 14. 12 pages, 17 figures, 2 tables

We propose a solution to the increased computational demands of Extremely Large Telescope (ELT) scale adaptive optics (AO) real-time control with the Intel Xeon Phi Knights Landing (KNL) Many Integrated Core (MIC) Architecture. The computational demands of an AO real-time controller (RTC) scale with the fourth power of telescope diameter and so the next generation ELTs require orders of magnitude more processing power for the RTC pipeline than existing systems. The Xeon Phi contains a large number (> 64) of low power x86 CPU cores and high bandwidth memory integrated into a single socketed server CPU package. The increased parallelism and memory bandwidth are crucial to providing the performance for reconstructing wavefronts with the required precision for ELT scale AO. Here, we demonstrate that the Xeon Phi KNL is capable of performing ELT scale single conjugate AO real-time control computation at over 1.0 kHz with less than 20 {\mu}s RMS jitter. We have also shown that with a wavefront sensor camera attached the KNL can process the real-time control loop at up to 966 Hz, the maximum frame-rate of the camera, with jitter remaining below 20 {\mu}s RMS. Future studies will involve exploring the use of a cluster of Xeon Phis for the real-time control of the MCAO and MOAO regimes of AO. We find that the Xeon Phi is highly suitable for ELT AO real time control., Comment: 10 pages, 12 figures, accepted MNRAS