Microfabricated liquid density sensors using polyimide-guided surface acoustic waves

The simultaneous measurements of liquid density and refractive index on the same liquid sample are desirable. This thesis investigates the development of a micro- fabricated liquid density sensor that can be integrated into existing refractometers. A discussion of density sensing techniques and review of suitable sensors is given, leading to the choice of a Love mode surface acoustic wave (SAW) device. Love modes are formed by focussing the acoustic energy in a thin waveguide layer on a surface acoustic wave device. The horizontal-shear wave motion reduces attenuation in liquid environments, and the high surface energy density theoretically gives the highest sensitivity of all SAW devices. This study follows the development of a Love mode liquid density sensor using a polyimide waveguide layer. The novel use of polyimide offers simple and cheap fabrication, and theoretically gives a very high sensitivity to surface loading due to its low acoustic velocity. Love mode devices were fabricated with different polyimide waveguide thicknesses. The optimum thickness for a compromise between low loss and high sensitivity was 0.90 - 1.0 μm. These devices exhibited a linear shift in frequency with the liquid density-viscosity product for low viscosities. The response was smaller for high viscosities due to non-Newtonian liquid behaviour. Dual delay-line structures with a smooth 'reference' and corrugated 'sense' delay- lines were used to trap the liquid and separate the density from the density-viscosity product. A sensitivity up to 0.13 μgcm(^-3)Hz(^-1) was obtained. This is the highest density sensitivity obtained from an acoustic mode sensor. Experimental results show a zero temperature coefficient of frequency is possible using polyimide waveguides. These are the first Love mode devices that demonstrate temperature independence, highlighting the importance of polyimide as a new waveguide material

On the need to consider wood formation processes in global vegetation models and a suggested approach

Dynamic global vegetation models are key tools for interpreting and forecasting the responses of terrestrial ecosystems to climatic variation and other drivers. They estimate plant growth as the outcome of the supply of carbon through photosynthesis. However, growth is itself under direct control, and not simply controlled by the amount of available carbon. Therefore predictions by current photosynthesis driven models of large increases in future vegetation biomass due to increasing concentrations of atmospheric CO2 may be significant over-estimations. We describe how current understanding of wood formation can be used to reformulate global vegetation models, with potentially major implications for their behaviour

The spatial distribution and temporal variability of föhn winds over the Larsen C Ice Shelf, Antarctica

The eastern side of the Antarctic Peninsula (AP) mountain range and the adjacent ice shelves are frequently affected by föhn winds originating from upwind of the mountains. Six automatic weather stations (AWS) and archived model output from 5km resolution Antarctic Mesoscale Prediction System (AMPS) forecasts have been combined to identify the occurrence of föhn conditions, and their spatial distribution over the Larsen C Ice Shelf (LCIS) from 2009 to 2012. Algorithms for semi‐automatic detection of föhn conditions have been developed for both AWS and AMPS data. The frequency of föhn varies by location, being most frequent at the foot of the AP and in the north of the ice shelf. They are most common in spring, when they can prevail for 50% of the time. The results of this study have important implications for further research, investigating the impact of föhn on surface melting, and the surface energy budget of the ice shelf. This is of particular interest due to the collapse of Larsen A and B ice shelves in 1995 and 2002 respectively, and the potential instability issues following a large calving event on Larsen C in 2017

Monocytes and γδ T cells control the acute phase response to intravenous zoledronate: insights from a phase IV safety trial

Aminobisphosphonates (NBPs) are used widely against excessive bone resorption in osteoporosis and Paget’s disease as well as in metastatic bone disease and multiple myeloma. Intravenous NBP administration often causes mild to severe acute phase responses (APRs) that may require intervention with analgesics and antipyretics and lead to treatment noncompliance and non-adherence. We here undertook a phase IV safety trial in patients with osteoporosis to investigate the APR of otherwise healthy individuals to first-time intravenous treatment with the NBP zoledronate. This study provides unique insight into sterile acute inflammatory responses in vivo, in the absence of confounding factors such as infection or cancer. Our data show that both periphera

Task-specific training versus usual care to improve upper limb function after stroke: The “Task-AT Home” randomised controlled trial protocol

Background: Sixty percent of people have non-functional arms 6 months after stroke. More effective treatments are needed. Cochrane Reviews show low-quality evidence that task-specific training improves upper limb function. Our feasibility trial showed 56 h of task-specific training over 6 weeks resulted in an increase of a median 6 points on the Action Research Arm test (ARAT), demonstrating the need for more definitive evidence from a larger randomised controlled trial. Task-AT Home is a two-arm, assessor-blinded, multicentre randomised, controlled study, conducted in the home setting. Aim: The objective is to determine whether task-specific training is a more effective treatment than usual care, for improving upper limb function, amount of upper limb use, and health related quality of life at 6 weeks and 6 months after intervention commencement. Our primary hypothesis is that upper limb function will achieve a ≥ 5 point improvement on the ARAT in the task-specific training group compared to the usual care group, after 6 weeks of intervention. Methods: Participants living at home, with remaining upper limb deficit, are recruited at 3 months after stroke from sites in NSW and Victoria, Australia. Following baseline assessment, participants are randomised to 6 weeks of either task-specific or usual care intervention, stratified for upper limb function based on the ARAT score. The task-specific group receive 14 h of therapist-led task-specific training plus 42 h of guided self-practice. The primary outcome measure is the ARAT at 6 weeks. Secondary measures include the Motor Activity Log (MAL) at 6 weeks and the ARAT, MAL and EQ5D-5 L at 6 months. Assessments occur at baseline, after 6 weeks of intervention, and at 6 months after intervention commencement. Analysis will be intention to treat using a generalised linear mixed model to report estimated mean differences in scores between the two groups at each timepoint with 95% confidence interval and value of p. Discussion: If the task-specific home-based training programme is more effective than usual care in improving arm function, implementation of the programme into clinical practice would potentially lead to improvements in upper limb function and quality of life for people with stroke. Clinical Trial Registration: ANZCTR.org.au/ACTRN12617001631392p.asp

Atlantic Ocean Observing Networks: Cost and feasibility study

Results of a cost and feasibility study of the present and planned integrated Atlantic Ocean Observing System, including assessing the readiness and feasibility of implementation of different observing technologie

Mendelian adult-onset leukodystrophy genes in Alzheimer´s disease. Critical influence of CSF1R and NOTCH3

Mendelian adult-onset leukodystrophies are a spectrum of rare inherited progressive neurodegenerative disorders affecting the white matter of the central nervous system. Among these, Cerebral Autosomal Dominant and Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL and CARASIL), Cerebroretinal vasculopathy (CRV), Metachromatic leukodystrophy (MLD), Hereditary diffuse Leukoencephalopathy with spheroids (HDLS), Vanishing white matter disease (VWM) present with rapidly progressive dementia as dominant feature and are caused by mutations in NOTCH3, HTRA1, TREX1, ARSA, CSF1R, EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5, respectively. Given the rare incidence of these disorders and the lack of unequivocally diagnostic features, leukodystrophies are frequently misdiagnosed with common sporadic dementing diseases such as Alzheimer’s disease (AD), raising the question of whether these overlapping phenotypes may be explained by shared genetic risk factors. To investigate this intriguing hypothesis, we have combined gene expression analysis 1) in 6 different AD mouse strains (APPPS1, HOTASTPM, HETASTPM, TPM, TAS10 and TAU), at 5 different developmental stages (Embryo [E15], 2 months, 4 months, 8 months and 18 months), 2) in APPPS1 primary cortical neurons under stress conditions (oxygen-glucose deprivation) and single-variant and single-gene (c-alpha and SKAT tests) based genetic screening in a cohort composed of 332 Caucasian late-onset AD patients and 676 Caucasian elderly controls. Csf1r was significantly overexpressed (Log2FC>1, adj. p-val<0.05) in the cortex and hippocampus of aged HOTASTPM mice with extensive Aβ core dense plaque pathology. We identified 3 likely pathogenic mutations in CSF1R TK domain (p.L868R, p.Q691H and p.H703Y) in our discovery and validation cohort, composed of 465 AD and MCI Caucasian patients from the UK. Moreover, NOTCH3 was a significant hit in the c-alpha test (adj p-val = 0.01). Adult onset Mendelian leukodystrophy genes are not common factors implicated in AD. Nevertheless, our study suggests a potential pathogenic link between NOTCH3, CSF1R and sporadic LOAD, that warrants further investigation

Dipeptidyl peptidase-1 inhibition in patients hospitalised with COVID-19:a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial

This study was funded by an investigator-initiated research grant from Insmed (Bridgewater, NJ, USA). The authors acknowledge the funding and logistical support from the UK National Institute for Health and Care Research.Background: Neutrophil serine proteases are involved in the pathogenesis of COVID-19 and increased serine protease activity has been reported in severe and fatal infection. We investigated whether brensocatib, an inhibitor of dipeptidyl peptidase-1 (DPP-1; an enzyme responsible for the activation of neutrophil serine proteases), would improve outcomes in patients hospitalised with COVID-19. Methods: In a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial, across 14 hospitals in the UK, patients aged 16 years and older who were hospitalised with COVID-19 and had at least one risk factor for severe disease were randomly assigned 1:1, within 96 h of hospital admission, to once-daily brensocatib 25 mg or placebo orally for 28 days. Patients were randomly assigned via a central web-based randomisation system (TruST). Randomisation was stratified by site and age (65 years or ≥65 years), and within each stratum, blocks were of random sizes of two, four, or six patients. Participants in both groups continued to receive other therapies required to manage their condition. Participants, study staff, and investigators were masked to the study assignment. The primary outcome was the 7-point WHO ordinal scale for clinical status at day 29 after random assignment. The intention-to-treat population included all patients who were randomly assigned and met the enrolment criteria. The safety population included all participants who received at least one dose of study medication. This study was registered with the ISRCTN registry, ISRCTN30564012. Findings: Between June 5, 2020, and Jan 25, 2021, 406 patients were randomly assigned to brensocatib or placebo; 192 (47·3%) to the brensocatib group and 214 (52·7%) to the placebo group. Two participants were excluded after being randomly assigned in the brensocatib group (214 patients included in the placebo group and 190 included in the brensocatib group in the intention-to-treat population). Primary outcome data was unavailable for six patients (three in the brensocatib group and three in the placebo group). Patients in the brensocatib group had worse clinical status at day 29 after being randomly assigned than those in the placebo group (adjusted odds ratio 0·72 [95% CI 0·57-0·92]). Prespecified subgroup analyses of the primary outcome supported the primary results. 185 participants reported at least one adverse event; 99 (46%) in the placebo group and 86 (45%) in the brensocatib group. The most common adverse events were gastrointestinal disorders and infections. One death in the placebo group was judged as possibly related to study drug. Interpretation: Brensocatib treatment did not improve clinical status at day 29 in patients hospitalised with COVID-19.Publisher PDFPeer reviewe

ABCA7 p.G215S as potential protective factor for Alzheimer’s disease

Genome-wide association studies (GWASs) have been effective approaches to dissect common genetic variability underlying complex diseases in a systematic and unbiased way. Recently, GWASs have led to the discovery of over 20 susceptibility loci for Alzheimer’s disease (AD). Despite the evidence showing the contribution of these loci to AD pathogenesis, their genetic architecture has not been extensively investigated, leaving the possibility that low frequency and rare coding variants may also occur and contribute to the risk of disease. We have used exome and genome sequencing data to analyse the single independent and joint effect of rare and low frequency protein coding variants in 9 AD GWAS loci with the strongest effect sizes after APOE (BIN1, CLU, CR1, PICALM, MS4A6A, ABCA7, EPHA1, CD33, CD2AP) in a cohort of 332 sporadic AD cases and 676 elderly controls of British and North American ancestry. We identified coding variability in ABCA7 as contributing to AD risk. This locus harbors a low frequency coding variant (p.G215S, rs72973581, MAF=4.3%) conferring a modest but statistically significant protection against AD (p-value= 6x10-4, OR=0.57, 95% CI 0.41-0.80). Notably, our results are not driven by an enrichment of loss of function variants in ABCA7, recently reported as main pathogenic factor underlying AD risk at this locus. In summary, our study confirms the role of ABCA7 in AD and provide new insights that should address functional studies