The FLASSH study: protocol for a randomised controlled trial evaluating falls prevention after stroke and two sub-studies

This randomised controlled trial aims to evaluate the effectiveness of a multi-factorial falls prevention program for stroke survivors who are at high risk of falling when they return home after rehabilitation. Intervention will consist of a home exercise program as well as individualised falls prevention and injury minimisation strategies based on identified risk factors for falls. Additionally, two sub-studies will be implemented in order to explore other key areas related to falls in this population. The first of these is a longitudinal study evaluating the relationship between fear of falling, falls and function over twelve months, and the second evaluates residual impairment in gait stability and obstacle crossing twelve months after discharge from rehabilitation

EPHA2 Is Associated with Age-Related Cortical Cataract in Mice and Humans

Age-related cataract is a major cause of blindness worldwide, and cortical cataract is the second most prevalent type of age-related cataract. Although a significant fraction of age-related cataract is heritable, the genetic basis remains to be elucidated. We report that homozygous deletion of Epha2 in two independent strains of mice developed progressive cortical cataract. Retroillumination revealed development of cortical vacuoles at one month of age; visible cataract appeared around three months, which progressed to mature cataract by six months. EPHA2 protein expression in the lens is spatially and temporally regulated. It is low in anterior epithelial cells, upregulated as the cells enter differentiation at the equator, strongly expressed in the cortical fiber cells, but absent in the nuclei. Deletion of Epha2 caused a significant increase in the expression of HSP25 (murine homologue of human HSP27) before the onset of cataract. The overexpressed HSP25 was in an underphosphorylated form, indicating excessive cellular stress and protein misfolding. The orthologous human EPHA2 gene on chromosome 1p36 was tested in three independent worldwide Caucasian populations for allelic association with cortical cataract. Common variants in EPHA2 were found that showed significant association with cortical cataract, and rs6678616 was the most significant in meta-analyses. In addition, we sequenced exons of EPHA2 in linked families and identified a new missense mutation, Arg721Gln, in the protein kinase domain that significantly alters EPHA2 functions in cellular and biochemical assays. Thus, converging evidence from humans and mice suggests that EPHA2 is important in maintaining lens clarity with age

Shear behavior of DFDP-1 borehole samples from the Alpine Fault, New Zealand, under a wide range of experimental conditions

The Alpine Fault is a major plate-boundary fault zone that poses a major seismic hazard in southern New Zealand. The initial stage of the Deep Fault Drilling Project has provided sample material from the major lithological constituents of the Alpine Fault from two pilot boreholes. We use laboratory shearing experiments to show that the friction coefficient µ of fault-related rocks and their precursors varies between 0.38 and 0.80 depending on the lithology, presence of pore fluid, effective normal stress, and temperature. Under conditions appropriate for several kilometers depth on the Alpine Fault (100 MPa, 160 °C, fluid-saturated), a gouge sample located very near to the principal slip zone exhibits µ = 0.67, which is high compared with other major fault zones targeted by scientific drilling, and suggests the capacity for large shear stresses at depth. A consistent observation is that every major lithological unit tested exhibits positive and negative values of friction velocity dependence. Critical nucleation patch lengths estimated using representative values of the friction velocity-dependent parameter a−b and the critical slip distance D c , combined with previously documented elastic properties of the wall rock, may be as low as ~3 m. This small value, consistent with a seismic moment M o = ~4 × 1010 for an M w = ~1 earthquake, suggests that events of this size or larger are expected to occur as ordinary earthquakes and that slow or transient slip events are unlikely in the approximate depth range of 3–7 km

A randomised, double-blind, placebo-controlled trial of repeated nebulisation of non-viral cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy in patients with cystic fibrosis

Background: Cystic fibrosis (CF) is a chronic, life-limiting disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene leading to abnormal airway surface ion transport, chronic lung infections, inflammation and eventual respiratory failure. With the exception of the small-molecule potentiator, ivacaftor (Kalydeco®, Vertex Pharmaceuticals, Boston, MA, USA), which is suitable for a small proportion of patients, there are no licensed therapies targeting the basic defect. The UK Cystic Fibrosis Gene Therapy Consortium has taken a cationic lipid-mediated CFTR gene therapy formulation through preclinical and clinical development. Objective: To determine clinical efficacy of the formulation delivered to the airways over a period of 1 year in patients with CF. Design: This was a randomised, double-blind, placebo-controlled Phase IIb trial of the CFTR gene–liposome complex pGM169/GL67A. Randomisation was performed via InForm™ version 4.6 (Phase Forward Incorporated, Oracle, CA, USA) and was 1 : 1, except for patients in the mechanistic subgroups (2 : 1). Allocation was blinded by masking nebuliser chambers. Settings: Data were collected in the clinical and scientific sites and entered onto a trial-specific InForm, version 4.6 database. Participants: Patients with CF aged ≥ 12 years with forced expiratory volume in the first second (FEV1) between 50% and 90% predicted and any combination of CFTR mutations. The per-protocol group (≥ 9 doses) consisted of 54 patients receiving placebo (62 randomised) and 62 patients receiving gene therapy (78 randomised). Interventions: Subjects received 5 ml of nebulised pGM169/G67A (active) or 0.9% saline (placebo) at 28 (±5)-day intervals over 1 year. Main outcome measures: The primary end point was the relative change in percentage predicted FEV1 over the 12-month period. A number of secondary clinical outcomes were assessed alongside safety measures: other spirometric values; lung clearance index (LCI) assessed by multibreath washout; structural disease on computed tomography (CT) scan; the Cystic Fibrosis Questionnaire – Revised (CFQ-R), a validated quality-of-life questionnaire; exercise capacity and monitoring; systemic and sputum inflammatory markers; and adverse events (AEs). A mechanistic study was performed in a subgroup in whom transgene deoxyribonucleic acid (DNA) and messenger ribonucleic acid (mRNA) was measured alongside nasal and lower airway potential difference. Results: There was a significant (p = 0.046) treatment effect (TE) of 3.7% [95% confidence interval (CI) 0.1% to 7.3%] in the primary end point at 12 months and in secondary end points, including forced vital capacity (FVC) (p = 0.031) and CT gas trapping (p = 0.048). Other outcomes, although not reaching statistical significance, favoured active treatment. Effects were noted by 1 month and were irrespective of sex, age or CFTR mutation class. Subjects with a more severe baseline FEV1 had a FEV1 TE of 6.4% (95% CI 0.8% to 12.1%) and greater changes in many other secondary outcomes. However, the more mildly affected group also demonstrated benefits, particularly in small airway disease markers such as LCI. The active group showed a significantly (p = 0.032) greater bronchial chloride secretory response. No difference in treatment-attributable AEs was seen between the placebo and active groups. Conclusions: Monthly application of the pGM169/GL67A gene therapy formulation was associated with an improvement in lung function, other clinically relevant parameters and bronchial CFTR function, compared with placebo. Limitations: Although encouraging, the improvement in FEV1 was modest and was not accompanied by detectable improvement in patients’ quality of life. Future work: Future work will focus on attempts to increase efficacy by increasing dose or frequency, the coadministration of a CFTR potentiator, or the use of modified viral vectors capable of repeated administration. Trial registration: ClinicalTrials.gov NCT01621867. Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research partnership

Neoarchean orogenic, magmatic and hydrothermal events in the Kalgoorlie-Kambalda area, Western Australia: constraints on gold mineralization in the Boulder Lefroy-Golden Mile fault system

The Boulder Lefroy-Golden Mile (BLF-GMF) fault system is the most intensely mineralized structure (>2150 t Au to 2015) in the Archean Yilgarn Craton, Western Australia. The fault system links the Kalgoorlie and Kambalda mining districts in the Eastern Goldfields Province, a continental-margin orogen subdivided into the western Kalgoorlie ensialic rift and the eastern Kurnalpi volcanic arc. After rifting, the 2.73–2.66 Ga greenstone-greywacke succession in the Kalgoorlie-Kambalda area underwent five phases of orogenic deformation, predominantly during ENE-WSW shortening: D1 upright folding at ca. 2680 Ma, D2 sinistral strike-slip faulting at 2678–2663 Ma, D3 folding of late conglomerate-turbidite successions at 2665–2655 Ma, D4 dextral strike-slip faulting at 2655–2640 Ma and D5 east-northeast-striking normal faulting. Regional prehnite-pumpellyite to greenschist facies burial metamorphism took place during D1 and D3 crustal thickening, and amphibolite facies aureoles formed around granite batholiths during and after D3 at 400 ± 100 MPa pressure. The D2 BLF offsets D1 folds by 12 km SW-side south and contains a porphyry dyke (2676 ± 7 Ma) boudinaged by transtensional oblique-slip along a line pitching 21° southeast. The BLF is linked by transverse D2 thrusts to other sinistral faults recording strike-slip until 2663 ± 7 Ma. Late D2 strike-slip movement alternated with early D3 shortening. D3 thrusts accommodated strain in fault blocks of rigid mafic-ultramafic volcanic rocks consolidated during D1, while the sedimentary rocks in D3 synclines were foliated at high strain.Biotite-sericite alteration and gold-pyrite mineralization in the BLF-GMF system took place at 11 ± 4 km burial depth in faults active during D2 and D3. The Golden Mile (1708 t Au) and other deposits are associated with stocks and dykes of high-Mg monzodiorite-tonalite porphyry, part of a late-orogenic (2665–2645 Ma) mantle-derived suite of adakitic affinity. Hornblende and apatite compositions indicate that these intrusions are characterized by high water contents (5–6 wt% H2O in melt), by high oxidation states (dNNO +1.0 to +2.4 log units) and by igneous anhydrite. Some stocks contain pervasive anhydrite-pyrite mineralization of low gold grade (0.4 g/t). Biotite-sericite-pyrite ore bodies such as those at Kanowna Belle (140 t Au) also replace faulted metamorphic rocks above batholith domes cored by plutons of the monzodiorite suite. The D4 strike-slip faults are barren at Kambalda but control gold quartz-vein ore at Kalgoorlie (2651 ± 9 Ma), and Au-Ag breccia ore at Black Flag (<2648 ± 6 Ma)