Towards population coding principles in the primate premotor and parietal grasping network

As humans, the only way for us to interact with the world around us is by utilizing our highly trained motor system. Therefore, understanding how the brain generates movement is essential to understanding all aspects of human behavior. Despite the importance the motor system, the manner in which the brain prepares and executes movements, especially grasping movements, is still unclear. In this thesis I undertake a number of electrophysiological and computational experiments on macaque monkeys, primates showing similar grasping behavior to humans, to shed light on how grasping movements are planned and executed across distributed brain regions in both parietal and premotor cortices. Through these experiments, I reveal how the use of large-scale electrophysiological recording of hundreds of neurons simultaneously in primates allows the investigation of network computational principles essential for grasping, and I develop a series of analytical techniques for dissecting the large data sets collected from these experiments. In chapter 2.1 I show how large-scale parallel recordings can be leveraged to make behavioral predictions on single trials. The methods used to extract single-trial predictions varied in their performance, but population-based methods provided the most consistent and meaningful interpretation of the data. In addition, the success of these behavioral predictions could be used to make inferences about how areas differ in their contribution to preparation of grasping movements. It was found that while reaction time could be predicted from the population activity of either area, performance was significantly higher using the data from premotor cortex, suggesting that population activity in premotor cortex may have a more direct effect on behavior. In chapter 2.2 I show how preparation and movement intermingle and interact with one another on the continuum between immediate and withheld movement. Our population-based and dimensionality reduction techniques enable interpretation of the data, even when single neuron tuning properties are highly temporally and functionally complex. Activity in parietal cortex stabilizes during the memory period, while it continues to evolve in premotor cortex, revealing a decodable signature of time. Furthermore, activity during movement initiation clusters into two groups, movements initiated as fast as possible and movements from memory, showing how a state shift likely occurs on the border between these two types of actions. In chapter 2.3 I show that the question of how motor cortex controls movement is an ongoing issue in the field. I address crucial details about recent methodology used to extract rotational dynamics in motor cortex. I show how a simple neural network simulation and novel statistical test reveal properties of motor cortex not examined before, showing how models of movement generation can be essential tools in adding perspective to empirical results. Finally, in chapter 2.4 I show how the specificity of hand use can be used as a tool to dissociate levels of abstraction in the visual to motor transformation in parietal and premotor cortex. While preparatory activity is mostly hand-invariant in parietal cortex, activity in premotor cortex dissociates the intended hand use well before movement. Importantly, we show how appropriate dimensionality reduction techniques can disentangle the effects of multiple task parameters and find latent dimensions consistent between areas and animals. Together, the results of my experiments reinforce the importance of seeing the motor system not as a collection of individually tuned neurons, but as a dynamic network of neurons continuously acting together to produce the complex and flexible behavior we observe in all primates

Safety and efficacy of BAY 94–9027, an extended-half-life factor VIII, during minor surgical procedures in patients with severe haemophilia A

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Analysis of clinical benefit, harms, and cost-effectiveness of screening women for abdominal aortic aneurysm.

BACKGROUND: A third of deaths in the UK from ruptured abdominal aortic aneurysm (AAA) are in women. In men, national screening programmes reduce deaths from AAA and are cost-effective. The benefits, harms, and cost-effectiveness in offering a similar programme to women have not been formally assessed, and this was the aim of this study. METHODS: We developed a decision model to assess predefined outcomes of death caused by AAA, life years, quality-adjusted life years, costs, and the incremental cost-effectiveness ratio for a population of women invited to AAA screening versus a population who were not invited to screening. A discrete event simulation model was set up for AAA screening, surveillance, and intervention. Relevant women-specific parameters were obtained from sources including systematic literature reviews, national registry or administrative databases, major AAA surgery trials, and UK National Health Service reference costs. FINDINGS: AAA screening for women, as currently offered to UK men (at age 65 years, with an AAA diagnosis at an aortic diameter of ≥3·0 cm, and elective repair considered at ≥5·5cm) gave, over 30 years, an estimated incremental cost-effectiveness ratio of £30 000 (95% CI 12 000-87 000) per quality-adjusted life year gained, with 3900 invitations to screening required to prevent one AAA-related death and an overdiagnosis rate of 33%. A modified option for women (screening at age 70 years, diagnosis at 2·5 cm and repair at 5·0 cm) was estimated to have an incremental cost-effectiveness ratio of £23 000 (9500-71 000) per quality-adjusted life year and 1800 invitations to screening required to prevent one AAA-death, but an overdiagnosis rate of 55%. There was considerable uncertainty in the cost-effectiveness ratio, largely driven by uncertainty about AAA prevalence, the distribution of aortic sizes for women at different ages, and the effect of screening on quality of life. INTERPRETATION: By UK standards, an AAA screening programme for women, designed to be similar to that used to screen men, is unlikely to be cost-effective. Further research on the aortic diameter distribution in women and potential quality of life decrements associated with screening are needed to assess the full benefits and harms of modified options. FUNDING: UK National Institute for Health Research Health Technology Assessment programme

Outcomes of aortic aneurysm surgery in England : a nationwide cohort study using hospital admissions data from 2002 to 2015

Background The United Kingdom aortic aneurysms (AA) services have undergone reconfiguration to improve outcomes. The National Health Service collects data on all hospital admissions in England. The complex administrative datasets generated have the potential to be used to monitor activity and outcomes, however, there are challenges in using these data as they are primarily collected for administrative purposes. The aim of this study was to develop standardised algorithms with the support of a clinical consensus group to identify all AA activity, classify the AA management into clinically meaningful case mix groups and define outcome measures that could be used to compare outcomes among AA service providers. \ud Methods In-patient data about aortic aneurysm (AA) admissions from the 2002/03 to 2014/15 were acquired. A stepwise approach, with input from a clinical consensus group, was used to identify relevant cases. The data is primarily coded into episodes, these were amalgamated to identify admissions; admissions were linked to understand patient pathways and index admissions. Cases were then divided into case-mix groups based upon examination of individually sampled and aggregate data. Consistent measures of outcome were developed, including length of stay, complications within the index admission, post-operative mortality and re-admission. Results Several issues were identified in the dataset including potential conflict in identifying emergency and elective cases and potential confusion if an inappropriate admission definition is used. Ninety six thousand seven hundred thirty-five patients were identified using the algorithms developed in this study to extract AA cases from Hospital episode statistics. From 2002 to 2015, 83,968 patients (87% of all cases identified) underwent repair for AA and 12,767 patients (13% of all cases identified) died in hospital without any AA repair. Six thousand three hundred twenty-nine patients (7.5%) had repair for complex AA and 77,639 (92.5%) had repair for infra-renal AA. Conclusion The proposed methods define homogeneous clinical groups and outcomes by combining administrative codes in the data. These methodologically robust methods can help examine outcomes associated with previous and current service provisions and aid future reconfiguration of aortic aneurysm surgery services

Screening women aged 65 years or over for abdominal aortic aneurysm: a modelling study and health economic evaluation.

BACKGROUND: Abdominal aortic aneurysm (AAA) screening programmes have been established for men in the UK to reduce deaths from AAA rupture. Whether or not screening should be extended to women is uncertain. OBJECTIVE: To evaluate the cost-effectiveness of population screening for AAAs in women and compare a range of screening options. DESIGN: A discrete event simulation (DES) model was developed to provide a clinically realistic model of screening, surveillance, and elective and emergency AAA repair operations. Input parameters specifically for women were employed. The model was run for 10 million women, with parameter uncertainty addressed by probabilistic and deterministic sensitivity analyses. SETTING: Population screening in the UK. PARTICIPANTS: Women aged ≥ 65 years, followed up to the age of 95 years. INTERVENTIONS: Invitation to ultrasound screening, followed by surveillance for small AAAs and elective surgical repair for large AAAs. MAIN OUTCOME MEASURES: Number of operations undertaken, AAA-related mortality, quality-adjusted life-years (QALYs), NHS costs and cost-effectiveness with annual discounting. DATA SOURCES: AAA surveillance data, National Vascular Registry, Hospital Episode Statistics, trials of elective and emergency AAA surgery, and the NHS Abdominal Aortic Aneurysm Screening Programme (NAAASP). REVIEW METHODS: Systematic reviews of AAA prevalence and, for elective operations, suitability for endovascular aneurysm repair, non-intervention rates, operative mortality and literature reviews for other parameters. RESULTS: The prevalence of AAAs (aortic diameter of ≥ 3.0 cm) was estimated as 0.43% in women aged 65 years and 1.15% at age 75 years. The corresponding attendance rates following invitation to screening were estimated as 73% and 62%, respectively. The base-case model adopted the same age at screening (65 years), definition of an AAA (diameter of ≥ 3.0 cm), surveillance intervals (1 year for AAAs with diameter of 3.0-4.4 cm, 3 months for AAAs with diameter of 4.5-5.4 cm) and AAA diameter for consideration of surgery (5.5 cm) as in NAAASP for men. Per woman invited to screening, the estimated gain in QALYs was 0.00110, and the incremental cost was £33.99. This gave an incremental cost-effectiveness ratio (ICER) of £31,000 per QALY gained. The corresponding incremental net monetary benefit at a threshold of £20,000 per QALY gained was -£12.03 (95% uncertainty interval -£27.88 to £22.12). Almost no sensitivity analyses brought the ICER below £20,000 per QALY gained; an exception was doubling the AAA prevalence to 0.86%, which resulted in an ICER of £13,000. Alternative screening options (increasing the screening age to 70 years, lowering the threshold for considering surgery to diameters of 5.0 cm or 4.5 cm, lowering the diameter defining an AAA in women to 2.5 cm and lengthening the surveillance intervals for the smallest AAAs) did not bring the ICER below £20,000 per QALY gained when considered either singly or in combination. LIMITATIONS: The model for women was not directly validated against empirical data. Some parameters were poorly estimated, potentially lacking relevance or unavailable for women. CONCLUSION: The accepted criteria for a population-based AAA screening programme in women are not currently met. FUTURE WORK: A large-scale study is needed of the exact aortic size distribution for women screened at relevant ages. The DES model can be adapted to evaluate screening options in men. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015020444 and CRD42016043227. FUNDING: The National Institute for Health Research Health Technology Assessment programme

Supervised exercise training as an adjunctive therapy for venous leg ulcers: study protocol for a randomised controlled trial

Background: Venous leg ulcers are common, chronic wounds that are painful and reduce quality of life. Compression therapy is known to assist in the healing of venous leg ulceration. Supervised exercise training that targets an improvement in calf muscle pump function might be a useful adjunctive therapy for enhancing ulcer healing and other aspects of physical and mental health. However, the evidence of exercise for individuals with venous ulcers is sparse. Here, we describe the protocol for a study that aims to assess the feasibility of undertaking a randomised controlled trial of a supervised exercise programme in people who are receiving compression for venous ulceration. Methods/Design: This is a randomised, controlled, assessor-blinded, two-centre, feasibility trial with two parallel groups. Eighty adults who are receiving lower-limb compression for a venous leg ulcer will be randomly assigned to receive usual care (compression only) or usual care plus a 12-week supervised exercise programme. Participants in the exercise group will be invited to undertake three, 60-minute sessions of supervised exercise each week, and each session will involve a combination of treadmill walking, upright cycling and strength and flexibility exercises for the lower limbs. Participants will be assessed before randomisation and 3, 6 and 12 months after randomisation. Primary outcomes include rates of recruitment, retention and adherence. Secondary outcomes include time to ulcer healing, proportion of participants healed, percentage and absolute change in ulcer size, health-related quality of life (EQ-5D-5L and VEINES-QOL/Sym), lower-limb cutaneous microvascular function (laser Doppler flowmetry coupled with iontophoresis) and physical fitness (30-second sit-to-stand test, chair sit and reach test, 6-minute walk test and ankle range of motion). The costs associated with the exercise programme and health-care utilisation will be calculated. We will also complete interviews with a sub-sample of participants to explore their experiences of having a venous ulcer and the acceptability of the exercise intervention and study procedures. Discussion: Data from this study will be used to refine the supervised exercise programme, investigate the acceptability of the intervention and study design and determine the most appropriate outcome measures, thereby providing estimates of the factors needed to design an adequately powered trial across several centres

Zoonotic Viruses Associated with Illegally Imported Wildlife Products

The global trade in wildlife has historically contributed to the emergence and spread of infectious diseases. The United States is the world's largest importer of wildlife and wildlife products, yet minimal pathogen surveillance has precluded assessment of the health risks posed by this practice. This report details the findings of a pilot project to establish surveillance methodology for zoonotic agents in confiscated wildlife products. Initial findings from samples collected at several international airports identified parts originating from nonhuman primate (NHP) and rodent species, including baboon, chimpanzee, mangabey, guenon, green monkey, cane rat and rat. Pathogen screening identified retroviruses (simian foamy virus) and/or herpesviruses (cytomegalovirus and lymphocryptovirus) in the NHP samples. These results are the first demonstration that illegal bushmeat importation into the United States could act as a conduit for pathogen spread, and suggest that implementation of disease surveillance of the wildlife trade will help facilitate prevention of disease emergence

Nitrogen fixation and transfer in open ocean diatom–cyanobacterial symbioses

Many diatoms that inhabit low-nutrient waters of the open ocean live in close association with cyanobacteria. Some of these associations are believed to be mutualistic, where N2-fixing cyanobacterial symbionts provide N for the diatoms. Rates of N2 fixation by symbiotic cyanobacteria and the N transfer to their diatom partners were measured using a high-resolution nanometer scale secondary ion mass spectrometry approach in natural populations. Cell-specific rates of N2 fixation (1.15–71.5 fmol N per cell h−1) were similar amongst the symbioses and rapid transfer (within 30 min) of fixed N was also measured. Similar growth rates for the diatoms and their symbionts were determined and the symbiotic growth rates were higher than those estimated for free-living cells. The N2 fixation rates estimated for Richelia and Calothrix symbionts were 171–420 times higher when the cells were symbiotic compared with the rates estimated for the cells living freely. When combined, the latter two results suggest that the diatom partners influence the growth and metabolism of their cyanobacterial symbionts. We estimated that Richelia fix 81–744% more N than needed for their own growth and up to 97.3% of the fixed N is transferred to the diatom partners. This study provides new information on the mechanisms controlling N input into the open ocean by symbiotic microorganisms, which are widespread and important for oceanic primary production. Further, this is the first demonstration of N transfer from an N2 fixer to a unicellular partner. These symbioses are important models for molecular regulation and nutrient exchange in symbiotic systems

Impact of Carotid Artery Stenosis on Quality of Life: A Systematic Review

© 2018, Springer Nature Switzerland AG. Objectives: The aim of this study was to identify themes that determine health-related quality of life (HRQoL) in patients with carotid artery stenosis and identify the patient-reported outcome measures (PROMs) that best cover the identified themes. Methods: A systematic review of the main six databases from inception to September 2018 was undertaken to identify primary qualitative studies reporting on the HRQoL of patients with carotid artery stenosis. The quality of studies was assessed using the Critical Appraisal Skills Programme (CASP) criteria. Findings from the included studies were analysed using framework analysis methodology. The identified themes were mapped against the items/domains from the PROMs used previously in patients with carotid artery stenosis. Results: The systematic review identified four papers that fulfilled the inclusion criteria. The included papers reported the views of 62 patients with symptomatic carotid artery stenosis; 24 of the patients were awaiting assessment for intervention, 26 had carotid endarterectomy, and 12 were turned down for intervention and received best medical therapy. The overall quality of the included studies was good based on CASP criteria. Framework analysis identified 16 themes that were divided into five main domains: anxiety, impact on personal roles and activities, effect on independence, psychological impact, and symptoms. The best-fit generic and disease-specific PROMs were the Medical Outcomes Study 36-Item Short Form (SF-36®) and the Carotid Stenosis Specific Outcome Measure (CSSOM), respectively. None of the PROMs covered all the themes identified in the qualitative systematic review. Conclusion: The findings from the review identified the important themes that affect patients with carotid stenosis disease. The current generic and disease-specific PROMs do not cover all themes that impact the HRQoL of patients suffering with this disease. The proposed themes can be used to develop a new disease-specific PROM to measure HRQoL