Planning decision-making: Independence, subsidiarity, impartiality and the state

This paper explores recent changes that involve the Planning Inspectorate in England, considering as part of this the relevance and value of independence and impartiality in effective decision-making, together with a consideration of the significance of these changes in the context of localism and the subsidiarity narrative. To inform this debate, this paper focuses upon the value of having an independent body for planning decisions through a comparison with the Planning Appeals Commission (PAC) in Northern Ireland. The paper points towards the potential need for change in the structural approach and arrangements of the system in England, drawing particularly upon the PAC as a potential model for consideration

Foundational guiding principles for a flourishing Earth System

In this perspectives article, we maintain that the current local to global sustainable development predicaments we face are the result of humanity's impact on the Earth System (ES)—that is to say, on the very systemic fabric of the ES (i.e., its functioning and configuration), combined with an insufficiently coherent application of sustainable development policy to address and resolve this systemic problem. In response to what is an urgent crisis, we propose four foundational guiding principles, which we contend provide an overarching framing that, if implemented, would offer an approach to steer global sustainable development policy in a manner that would be to the benefit of the ES and the securing of a flourishing future for all. Our principles are applicable at the levels from a local business ecosystem, national-regional networks, to global policy

Rapid, cost-effective and scalable gmp-compliant simian adenovirus-vectored vaccine production for early-phase clinical trials using entirely disposable product-contact components

The Jenner Institute, University of Oxford, develops and produces a range of vaccines against emerging threats (such as Zika) and current global health challenges (including malaria, HIV and rabies). The Jenner Clinical Biomanufacturing Facility (CBF) manufactures multiple simian adenovirus-vectored vaccines for early phase clinical trials each year. Hitherto we have used shake flasks for upstream production and caesium chloride gradient ultracentrifugation for downstream purification. This process is robust and simple but also slow, human resource intensive and lacks scalability. Here we report the development of a novel process using a 2 x 3L single-use stirred tank bioreactor system (MilliporeSigma Mobius®), coupled to a tangential flow filtration (TFF) and anion exchange chromatography (AEX)-based downstream process. The process also includes particle lysis and nucleic acid digestion inside the bioreactor, as well as clarification of cells and debris using depth filters. As our test case, we used a novel simian adenovirus-vectored rabies vaccine (ChAdOx2 RabG), which we will manufacture to GMP standards in the coming year. Each process run yields \u3e5x1013 ChAdOx2 RabG virus particles (approximately 1000 human doses), with residual host cell DNA, host cell protein and nuclease levels suitable for clinical trial use. While similar processes have been previously reported for adenovirus manufacture, we will report a number of points of novelty. Firstly, we use single-use disposable product-contact components from beginning to end, greatly simplifying small-scale GMP manufacturing of multiple products. Secondly, we will report results of comparative testing with a range of modern ion exchange media (including resins, membrane adsorbers, monoliths and functionalized hydrogel formats). Thirdly, we will report the development and validation of novel quality control methods suitable for this process. The resulting process will allow the CBF to increase production yield and produce more vaccines that transfer more easily to larger facilities

Thermostabilization of adenovirus-vectored vaccines, removing the need for continual cold-chain storage

Challenges around affordable and reliable supply of vaccines that need to be transported and maintained in the cold-chain to remain effective are a hindrance to realizing their full potential. We will describe preparation for GMP manufacture and Phase I clinical trial of a new technology for vaccine thermostabilisation. We will also describe application of the same technology to a novel veterinary vaccine which is entering advanced development. The sugar-matrix thermostabilisation (SMT) technology involves application of vaccine in a simple disaccharide-based buffer to a non-woven matrix, similar to a pad of filter paper. This is followed by drying at ambient temperature and pressure (i.e. without a freezing step, enhancing suitability for freeze-sensitive products). The materials and process are simple and cheap. We have previously shown that SMT allows for the storage of viral vectored vaccines such as modified vaccinia virus Ankara (MVA) and adenovirus vectors at up to 45oC for several months with minimal losses1,2. More recently we have shown the technique can improve stability of various other vaccine types, ranging from virus-like particles through to enveloped RNA viruses. In many cases, the level of thermostability achieved would allow for “last mile” vaccine distribution via the ‘extended controlled temperature chain’ (ECTC), or even allow prolonged storage at uncontrolled ambient temperature. This would decrease distribution-associated costs/ losses and increase vaccination feasibility in hard-to-reach areas. We have now received funding for GMP manufacture and Phase I clinical trial of an SMT-formulated adenovirus-vectored rabies vaccine, ChAdOx2 RabG. We will describe the production of custom wet-laid non-woven matrices with optimized SMT performance, using processes and materials suitable for use as an input to a GMP process. We will further describe the development of simple apparatus suitable for executing the process for pilot GMP batches, the optimization of the drying process and excipient composition, and the application of frequency modulation spectroscopy for non-destructive analysis of residual moisture content. Finally, we will describe the application of the technology to a formulation of ChAdOx1 RVF, an adenovirus-vectored vaccine against Rift Valley Fever Virus which is being developed for both human and veterinary use. In this case, SMT is applied to an ultra-low-cost drug substance designed for veterinary use (cell lysate which has been clarified and ultrafiltered but not chromatographically purified), emphasizing the suitability of the approach for low-cost and One Health applications. 1. Alcock, R., et al., Long-Term Thermostabilization of Live Poxviral and Adenoviral Vaccine Vectors at Supraphysiological Temperatures in Carbohydrate Glass. Science Translational Medicine, 2010. 2(19):19ra12. 2. Dulal, P., et al., Potency of a thermostabilised chimpanzee adenovirus Rift Valley Fever vaccine in cattle. Vaccine, 2016. 34(20): p. 2296-8

Structural neuroimaging in preclinical dementia: From microstructural deficits and grey matter atrophy to macroscale connectomic changes.

The last decade has witnessed a proliferation of neuroimaging studies characterising brain changes associated with Alzheimer's disease (AD), where both widespread atrophy and 'signature' brain regions have been implicated. In parallel, a prolonged latency period has been established in AD, with abnormal cerebral changes beginning many years before symptom onset. This raises the possibility of early therapeutic intervention, even before symptoms, when treatments could have the greatest effect on disease-course modification. Two important prerequisites of this endeavour are (1) accurate characterisation or risk stratification and (2) monitoring of progression using neuroimaging outcomes as a surrogate biomarker in those without symptoms but who will develop AD, here referred to as preclinical AD. Structural neuroimaging modalities have been used to identify brain changes related to risk factors for AD, such as familial genetic mutations, risk genes (for example apolipoprotein epsilon-4 allele), and/or family history. In this review, we summarise structural imaging findings in preclinical AD. Overall, the literature suggests early vulnerability in characteristic regions, such as the medial temporal lobe structures and the precuneus, as well as white matter tracts in the fornix, cingulum and corpus callosum. We conclude that while structural markers are promising, more research and validation studies are needed before future secondary prevention trials can adopt structural imaging biomarkers as either stratification or surrogate biomarkers.This study was supported by the National Institute for Health Research (NIHR, RG64473), Cambridge Biomedical Research Centre and Biomedical Research Unit in Dementia, and the Alzheimer's Society. Elijah Mak was in the receipt of the Gates Cambridge studentship

Context, ethics and pharmacogenetics

Most of the literature on pharmacogenetics assumes that the main problems in implementing the technology will be institutional ones (due to funding or regulation) and that although it involves genetic testing, the ethical issues involved in pharmacogenetics are different from, even less than, 'traditional' genetic testing. Very little attention has been paid to how clinicians will accept this technology, their attitudes towards it and how it will affect clinical practice. This paper presents results from interviews with clinicians who are beginning to use pharmacogenetics and explores how they view the ethics of pharmacogenetic testing, its use to exclude some patients from treatment, and how this kind of testing fits into broader debates around genetics. In particular this paper examines the attitudes of breast cancer and Alzheimer's disease specialists. The results of these interviews will be compared with the picture of pharmacogenetics painted in the published literature, as a way of rooting this somewhat speculative writing in clinical practice

Recombination-mediated escape from primary CD8+ T cells in acute HIV-1 infection

Abstract Background A major immune evasion mechanism of HIV-1 is the accumulation of non-synonymous mutations in and around T cell epitopes, resulting in loss of T cell recognition and virus escape. Results Here we analyze primary CD8+ T cell responses and virus escape in a HLA B*81 expressing subject who was infected with two T/F viruses from a single donor. In addition to classic escape through non-synonymous mutation/s, we also observed rapid selection of multiple recombinant viruses that conferred escape from T cells specific for two epitopes in Nef. Conclusions Our study shows that recombination between multiple T/F viruses provide greater options for acute escape from CD8+ T cell responses than seen in cases of single T/F virus infection. This process may contribute to the rapid disease progression in patients infected by multiple T/F viruses

Functional neuroimaging findings in healthy middle-aged adults at risk of Alzheimer's disease.

It is well established that the neurodegenerative process of Alzheimer's disease (AD) begins many years before symptom onset. This preclinical phase provides a crucial time-window for therapeutic intervention, though this requires biomarkers that could evaluate the efficacy of future disease-modification treatments in asymptomatic individuals. The last decade has witnessed a proliferation of studies characterizing the temporal sequence of the earliest functional and structural brain imaging changes in AD. These efforts have focused on studying individuals who are highly vulnerable to develop AD, such as those with familial genetic mutations, susceptibility genes (i.e. apolipoprotein epsilon-4 allele), and/or a positive family history of AD. In this paper, we review the rapidly growing literature of functional imaging changes in cognitively intact individuals who are middle-aged: positron emission tomography (PET) studies of amyloid deposition, glucose metabolism, as well as arterial spin labeling (ASL), task-dependent, resting-state functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS) studies. The prevailing evidence points to early brain functional changes in the relative absence of cognitive impairment and structural atrophy, although there is marked variability in the directionality of the changes, which could, in turn, be related to antagonistic pleiotropy early in life. A common theme across studies relates to the spatial extent of these changes, most of which overlap with brain regions that are implicated in established AD. Notwithstanding several methodological caveats, functional imaging techniques could be preferentially sensitive to the earliest events of AD pathology prior to macroscopic grey matter loss and clinical manifestations of AD. We conclude that while these techniques have great potential to serve as biomarkers to identify at-risk individuals, more longitudinal studies with greater sample size and robust correction for multiple comparisons are still warranted to establish their utility.This study was supported by the National Institute for Health Research (NIHR, RG64473), Cambridge Biomedical Research Centre and Biomedical Research Unit in Dementia. Elijah Mak was in the receipt of the Gates Cambridge studentship

Structural neuroimaging in preclinical dementia: From microstructural deficits and grey matter atrophy to macroscale connectomic changes.

The last decade has witnessed a proliferation of neuroimaging studies characterising brain changes associated with Alzheimer's disease (AD), where both widespread atrophy and 'signature' brain regions have been implicated. In parallel, a prolonged latency period has been established in AD, with abnormal cerebral changes beginning many years before symptom onset. This raises the possibility of early therapeutic intervention, even before symptoms, when treatments could have the greatest effect on disease-course modification. Two important prerequisites of this endeavour are (1) accurate characterisation or risk stratification and (2) monitoring of progression using neuroimaging outcomes as a surrogate biomarker in those without symptoms but who will develop AD, here referred to as preclinical AD. Structural neuroimaging modalities have been used to identify brain changes related to risk factors for AD, such as familial genetic mutations, risk genes (for example apolipoprotein epsilon-4 allele), and/or family history. In this review, we summarise structural imaging findings in preclinical AD. Overall, the literature suggests early vulnerability in characteristic regions, such as the medial temporal lobe structures and the precuneus, as well as white matter tracts in the fornix, cingulum and corpus callosum. We conclude that while structural markers are promising, more research and validation studies are needed before future secondary prevention trials can adopt structural imaging biomarkers as either stratification or surrogate biomarkers.This study was supported by the National Institute for Health Research (NIHR, RG64473), Cambridge Biomedical Research Centre and Biomedical Research Unit in Dementia, and the Alzheimer's Society. Elijah Mak was in the receipt of the Gates Cambridge studentship