GALILEO-1: a Phase I/II safety and efficacy study of FLT201 gene therapy for Gaucher disease type 1

Gaucher disease type 1 (GD1), caused by mutations in the GBA1 gene, results in β-glucocerebrosidase (GCase) deficiency. Gene therapy is under investigation as a potential treatment option for patients with GD1. The investigational gene therapy FLT201 consists of an adeno-associated virus (AAVS3) encoding a novel GCase variant (GCase-85). Preclinical characterization of FLT201 showed promising results, with GCase-85 being more stable at physiological pH than wild-type GCase and delivered effectively to target tissues. Here, we describe the design of GALILEO-1, a first-in-human Phase I/II safety, tolerability and efficacy study of FLT201 gene therapy in adult patients with GD1. The study results will inform the decision to start a Phase III study of FLT201 in patients with GD1

Architecture of error: matter, measure and the misadventures of precision

This PhD submission comprises two parts, the above book published in 2014 and its critical review. The latter, rather than transplant the book into the present, looks back to it, across the extraordinary contextual changes of the interval, to its making and reception, from the positions of both the present and 2014. Given the book employs diverse theoretical frameworks relevant to the material it interrogates, the review itself is framework-agnostic and instead is structured via a series of questions and recursive conceits or mirrors. Both the review’s (re)contextualisation and framework-agnosticism are elaborated in a foreword that acts as a guide. The review also comprises a summary of the book in question, the abstract of which is below: Last century witnessed a quantum increase in both effective and surplus precision in all material processes. ‘precision’ mean when it is redundant? What is the price we pay for our use of generative or explanatory models that are made more reductive in order to be (apparently) more precise? What might we learn from an elaboration of error as a productive category? To address these questions the analysis sets out a latent subtext in the body of architecture’s twentieth century discourse: the accelerated unravelling of the relations between precision and error. This takes the form of a critique of the role of precision – itself a complexly imprecise term – in architectural culture, and a claim that behind the architect’s now acute fetishisation of redundant precision lies a special fear of physical error. It posits that each of the seminal turns that govern our historiographies of modernity can be understood to have been silently orchestrated by a fear of error. In each, error does not go away but necessarily reconfigures, and in so doing, also reconfigures the architect’s ever-precarious relations to material life. Focusing on the key moments of intensification in the material ecologies of architecture’s twentieth century, the book examines how the cultivation of surplus precision laid the ground-work for the removal of ornament, the rejection of organic materials, the arrival of ‘science’ onto the building site, the rhetorical obstacles that blighted early cybernetics, the subsequent ‘death’ of concept and the digitised operations in which an algorithm arbitrates new form. The arc of the argument is organized not by the subject’s chronology but by its notional topography: we enter and exit at the surface with the drawing’s interrogation of precision in chapter 1 and with the substitution of ornament by redundant precision in the closing chapter. Following a second chapter that briefly sets out Aristotle’s conflation of error with matter (and not form), the middle chapters take us through the interior of error and precision relations via two key internal systems and their historic ruptures. The first, on materiality (in chapters 3 and 4) is defined technologically; the second, on reproduction (in chapters 5, 6, and 7), culturally. Although segregated, the analysis, if nothing else, demonstrates the inseparability of the technological from the cultural when it comes to error. At the time of writing many of the questions raised had been neglected in architectural research, however they had been keenly addressed by key voices in adjacent fields: visual art, the histories and philosophies of science, STS, feminist and Gender Studies. Thus the critiques of techno-determinism emerging in STS, Nancy Cartwright’s critique of inference and Evelyn Fox Keller’s of metaphoric epistemologies are brought to bear on the effect of instrumentalism, inference and metaphoric trading on precision in architecture. Equally, close analysis of the material techniques of several visual artists that maintain alternative economies of error in their practice – Vija Celmins, Barbara Hepworth, Gordon Matta Clark, Rachel Whiteread – illustrates the potential of error as an active, critical category in architectural production. Gordon Matta-Clark understood that precision in architecture is a political question first; surplus precision does serve a purpose, it is just undeclared. At the same time, any endeavour to produce a comprehensive or even coherent theory of error would by definition be a fallacy: error will always evade containment and mutate to escape. What I proposed in this book is an active elaboration of error as a category that acts critically on our relations to redundant or false precision, short-circuits its material interference, undercuts its hold on our practice and imagination, interrogates the mechanisms that install and protect it, and understands it for what it is: an architecture of fear whose politics we must question

Physician Review of Workers\u27 Compensation Case Files: Can It Affect Decision Outcomes?

Objective: To identify common attributes of Federal workers compensation cases referred to Navy physicians for medical opinions and to determine the impact of the review on the final case decision. Methods: Retrospective case study and descriptive analysis of 258 opinion letters written by physicians on referred cases from 2006 to 2010. Results: Navy physician opinions were considered in the outcome in some of the cases, and there was a statistically significant difference between the claim acceptance rate in the study population and the total population. Worker age was correlated with certain claim types. Conclusions: There is preliminary evidence that the opinion letters of Navy physicians influenced case decisions. Because of the selection bias in how the cases came to the study population, a prospective cohort study is warranted to establish whether this conclusion and the other results noted are valid

Mapping ground instability in areas of geotechnical infrastructure using satellite InSAR and Small UAV Surveying: a case study in Northern Ireland

Satellite Interferometric Synthetic Aperture Radar (InSAR), geological data and Small Unmanned Aerial Vehicle (SUAV) surveying was used to enhance our understanding of ground movement at five areas of interest in Northern Ireland. In total 68 ERS-1/2 images 1992–2000 were processed with the Small Baseline Subset (SBAS) InSAR technique to derive the baseline ground instability scenario of key areas of interest for five stakeholders: TransportNI, Northern Ireland Railways, Department for the Economy, Arup, and Belfast City Council. These stakeholders require monitoring of ground deformation across either their geotechnical infrastructure (i.e., embankments, cuttings, engineered fills and earth retaining structures) or assessment of subsidence risk as a result of abandoned mine workings, using the most efficient, cost-effective methods, with a view to minimising and managing risk to their businesses. The InSAR results provided an overview of the extent and magnitude of ground deformation for a 3000 km2 region, including the key sites of the disused salt mines in Carrickfergus, the Belfast–Bangor railway line, Throne Bend and Ligoniel Park in Belfast, Straidkilly and Garron Point along the Antrim Coast Road, plus other urbanised areas in and around Belfast. Tailored SUAV campaigns with a X8 airframe and generation of very high resolution ortho-photographs and a 3D surface model via the Structure from Motion (SfM) approach at Maiden Mount salt mine collapse in Carrickfergus in 2016 and 2017 also demonstrate the benefits of very high resolution surveying technologies to detect localised deformation and indicators of ground instabilit

Interferon gamma responses to proteome-determined specific recombinant proteins: Potential as diagnostic markers for ovine Johne’s disease

Johne’s disease (JD), or paratuberculosis is a fatal enteritis of animals caused by infection with Mycobacterium avium subspecies paratuberculosis (Map). There may be a long subclinical phase with no signs of clinical disease. Diagnosis of JD is problematic and no test can reliably detect sub-clinical disease. Th1 responses to Map are believed to be activated first with a later switch to Th2 responses and progression to clinical disease. Detection of a cell-mediated response, indicated by interferon gamma (IFN-) produced in response to mycobacterial antigens, may give an early indication of infection. Crude extracts of Map (PPDj) have been used to detect the cell-mediated response, but more specific, quantifiable antigens would improve the test. Thirty Map-specific proteins were screened for their ability to raise a cell-mediated response in subclinically infected sheep. Four proteins were selected and tested using blood from subclinical animals and controls from a JD-free flock. Three proteins elicited IFN- levels which were higher in the subclinical group than in the control group, two were statistically significant. Thus these proteins have the ability to discriminate groups of infected and uninfected animals and may have use in diagnosis of JD

Luminescence Lifetime-Based Sensing Platform Based on Cyclometalated Iridium(III) Complexes for the Detection of Perfluorooctanoic Acid in Aqueous Samples

Luminescence lifetimes are an attractive analytical method for detection due to its high sensitivity and stability. Iridium probes exhibit luminescence with long excited-state lifetimes, which are sensitive to the local environment. Perfluorooctanoic acid (PFOA) is listed as a chemical of high concern regarding its toxicity and is classified as a "forever chemical". In addition to strict limits on the presence of PFOA in drinking water, environmental contamination from industrial effluent or chemical spills requires rapid, simple, accurate, and cost-effective analysis in order to aid containment. Herein, we report the fabrication and function of a novel and facile luminescence sensor for PFOA based on iridium modified on gold surfaces. These surfaces were modified with lipophilic iridium complexes bearing alkyl chains, namely, IrC6 and IrC12, and Zonyl-FSA surfactant. Upon addition of PFOA, the modified surfaces IrC6-FSA@Au and IrC12-FSA @Au show the largest change in the red luminescence signal with changes in the luminescence lifetime that allow monitoring of PFOA concentrations in aqueous solutions. The platform was tested for the measurement of PFOA in aqueous samples spiked with known concentrations of PFOA and demonstrated the capacity to determine PFOA at concentrations &gt;100 μg/L (240 nM).</p

CLEC-2 and Syk in the megakaryocytic/platelet lineage are essential for development

The C-type lectin receptor CLEC-2 signals through a pathway that is critically dependent on the tyrosine kinase Syk. We show that homozygous loss of either protein results in defects in brain vascular and lymphatic development, lung inflation and perinatal lethality. Furthermore, we find that conditional deletion of Syk in the haematopoietic lineage, or conditional deletion of CLEC-2 or Syk in the megakaryocyte/platelet lineage, also causes defects in brain vascular and lymphatic development, although the mice are viable. In contrast, conditional deletion of Syk in other haematopoietic lineages had no effect on viability or brain vasculature and lymphatic development. We show that platelets, but not platelet releasate, modulate the migration and intercellular adhesion of lymphatic endothelial cells through a pathway that is dependent on CLEC-2 and Syk. These studies demonstrate that megakaryocyte/platelet expression of CLEC-2 and Syk is required for normal brain vasculature and lymphatic development and that platelet CLEC-2 and Syk directly modulate lymphatic endothelial cell behaviour in vitro

The European Large Area ISO Survey IX: the 90 micron luminosity function from the Final Analysis sample

We present the 90 micron luminosity function of the Final Analysis of the European Large Area ISO Survey (ELAIS), extending the sample size of our previous analysis (paper IV) by about a factor of 4. Our sample extends to z=1.1, around 50 times the comoving volume of paper IV, and 10^{7.7} < h^{-2}L/Lsun < 10^{12.5}. From our optical spectroscopy campaigns of the northern ELAIS 90 mircon survey (7.4 deg^2 in total, to S(90um)>70mJy), we obtained redshifts for 61% of the sample (151 redshifts) to B<21 identified at 7 microns, 15 microns, 20cm or with bright (B<18.5) optical identifications. The selection function is well-defined, permitting the construction of the 90 micron luminosity function of the Final Analysis catalogue in the ELAIS northern fields, which is in excellent agreement with our Preliminary Analysis luminosity function in the ELAIS S1 field from paper IV. The luminosity function is also in good agreement with the IRAS-based prediction of Serjeant & Harrison (2004), which if correct requires luminosity evolution of (1+z)^{3.4 +/- 1.0} for consistency with the source counts. This implies an evolution in comoving volume averaged star formation rate at z<~1 consistent with that derived from rest-frame optical and ultraviolet surveys.Comment: MNRAS accepted. 7 pages, 5 figures. Uses BoxedEPS (included

Temporal binding window and sense of agency are related processes modifiable via occipital tACS

The temporal binding window refers to the time frame within which temporal grouping of sensory information takes place. Sense of agency is the feeling of being in control of one’s actions, and their associated outcomes. While previous research has shown that temporal cues and multisensory integration play a role in sense of agency, no studies have directly assessed whether individual differences in the temporal binding window and sense of agency are associated. In all three experiments, to assess sense of agency, participants pressed a button triggering, after a varying delay, the appearance of the circle, and reported their sense of agency over the effect. To assess the temporal binding window a simultaneity judgment task (Experiment 1) and a double-flash illusion task (Experiment 2 and 3) was also performed. As expected, the temporal binding window correlated with the sense of agency window. In Experiment 3, these processes were modulated by applying occipital tACS at either 14Hz or 8Hz. We found 14Hz tACS stimulation was associated with narrower temporal biding window and sense of agency window. Our results suggest the temporal binding window and the time window of sense of agency are related. They also point towards a possible underlying neural mechanism (alpha peak frequency) for this association

Continuous subcutaneous insulin infusion versus multiple daily injection regimens in children and young people at diagnosis of type 1 diabetes: pragmatic randomised controlled trial and economic evaluation

ObjectiveTo compare the efficacy, safety, and cost utility of continuous subcutaneous insulin infusion (CSII) with multiple daily injection (MDI) regimens during the first year following diagnosis of type 1 diabetes in children and young people.DesignPragmatic, multicentre, open label, parallel group, randomised controlled trial and economic evaluation.Setting15 paediatric National Health Service (NHS) diabetes services in England and Wales. The study opened to recruitment in May 2011 and closed in January 2017.ParticipantsPatients aged between 7 months and 15 years, with a new diagnosis of type 1 diabetes were eligible to participate. Patients who had a sibling with the disease, and those who took drug treatments or had additional diagnoses that could have affected glycaemic control were ineligible.InterventionsParticipants were randomised, stratified by age and treating centre, to start treatment with CSII or MDI within 14 days of diagnosis. Starting doses of aspart (CSII and MDI) and glargine or detemir (MDI) were calculated according to weight and age, and titrated according to blood glucose measurements and according to local clinical practice.Main outcome measuresPrimary outcome was glycaemic control (as measured by glycated haemoglobin; HbA1c) at 12 months. Secondary outcomes were percentage of patients in each treatment arm with HbA1c within the national target range, incidence of severe hypoglycaemia and diabetic ketoacidosis, change in height and body mass index (as measured by standard deviation scores), insulin requirements (units/kg/day), partial remission rate (insulin dose adjusted HbA1c Results294 participants were randomised and 293 included in intention to treat analyses (CSI, n=144; MDI, n=149). At 12 months, mean HbA1c was comparable with clinically unimportant differences between CSII and MDI participants (60.9 mmol/mol v 58.5 mmol/mol, mean difference 2.4 mmol/mol (95% confidence interval -0.4 to 5.3), P=0.09). Achievement of HbA1c lower than 58 mmol/mol was low among the two groups (66/143 (46%) CSII participants v 78/142 (55%) MDI participants; relative risk 0.84 (95% confidence interval 0.67 to 1.06)). Incidence of severe hypoglycaemia and diabetic ketoacidosis were low in both groups. Fifty four non-serious and 14 serious adverse events were reported during CSII treatment, and 17 non-serious and eight serious adverse events during MDI treatment. Parents (but not children) reported superior PedsQL scores for those patients treated with CSII compared to those treated with MDI. CSII was more expensive than MDI by £1863 (€2179; $2474; 95% confidence interval £1620 to £2137) per patient, with no additional QALY gains (difference -0.006 (95% confidence interval -0.031 to 0.018)).ConclusionDuring the first year following type 1 diabetes diagnosis, no clinical benefit of CSII over MDI was identified in children and young people in the UK setting, and treatment with either regimen was suboptimal in achieving HbA1c thresholds. CSII was not cost effective.Trial registrationCurrent Controlled Trials ISRCTN29255275; European Clinical Trials Database 2010-023792-25