The ‘two global flash' mfERG in high and normal tension primary open-angle glaucoma

Purpose: To analyse the sensitivity of the ‘2 global flash' multifocal electroretinogram (mfERG) to detect glaucomatous dysfunction in normal tension (NTG) and high tension primary open angle glaucoma (POAG) patients. Methods: MfERGs were recorded from 20 NTG and 20 POAG patients and compared to those of 20 controls. The mfERG array consisted of 103 hexagons. Each m-sequence step started with a focal flash that could be either dark or light (m-sequence: 2^13, L max: 200cd/m2, L min: 1cd/m2), followed by two global flashes (L max: 200cd/m2) at an interval of ∼26ms. Focal scalar products (SP) were calculated using focal templates derived from the control recordings (VERIS 4.8). We analyzed 5 response averages (central 7.5 degrees and 4 adjoining quadrants) of the response to the focal flash, the direct component at 10-40 ms (DC) and the following two components induced by the effects of the preceding focal flash on the response to the global flashes at 40-70ms (IC-1) and at 70-100 ms (IC-2). Results: Both NTG and POAG patients differed from controls in the IC-1 response to the superior quadrants, and POAG patients also differed from controls in the centre. The most sensitive parameter was the IC-1 of the superior temporal quadrant with an area under the ROC curve of 0.82 for POAG and 0.79 for NTG. The DC and the IC-2 did not differ significantly between the groups. When all five response averages of the IC-1 were taken into consideration 90% of the NTG patients and 85% of the POAG patients were correctly classified as abnormal while 80% of the control subjects were correctly classified as normal. Conclusions: This stimulus sequence holds promise for the diagnosis of early functional changes in POAG. A new finding is that both NTG, as well as POAG can be differentiated from control subject

Genome editing of HBG1 and HBG2 to induce fetal hemoglobin

Induction of fetal hemoglobin (HbF) via clustered regularly interspaced short palindromic repeats/Cas9-mediated disruption of DNA regulatory elements that repress gamma-globin gene (HBG1 and HBG2) expression is a promising therapeutic strategy for sickle cell disease (SCD) and beta-thalassemia, although the optimal technical approaches and limiting toxicities are not yet fully defined. We disrupted an HBG1/HBG2 gene promoter motif that is bound by the transcriptional repressor BCL11A. Electroporation of Cas9 single guide RNA ribonucleoprotein complex into normal and SCD donor CD34+ hematopoietic stem and progenitor cells resulted in high frequencies of on-target mutations and the induction of HbF to potentially therapeutic levels in erythroid progeny generated in vitro and in vivo after transplantation of hematopoietic stem and progenitor cells into nonobese diabetic/severe combined immunodeficiency/Il2rgamma-/-/KitW41/W41 immunodeficient mice. On-target editing did not impair CD34+ cell regeneration or differentiation into erythroid, T, B, or myeloid cell lineages at 16 to 17 weeks after xenotransplantation. No off-target mutations were detected by targeted sequencing of candidate sites identified by circularization for in vitro reporting of cleavage effects by sequencing (CIRCLE-seq), an in vitro genome-scale method for detecting Cas9 activity. Engineered Cas9 containing 3 nuclear localization sequences edited human hematopoietic stem and progenitor cells more efficiently and consistently than conventional Cas9 with 2 nuclear localization sequences. Our studies provide novel and essential preclinical evidence supporting the safety, feasibility, and efficacy of a mechanism-based approach to induce HbF for treating hemoglobinopathies

Conflict, coexistence, or both? Cougar habitat selection, prey composition, and mortality in a multiple-use landscape

Western North America is experiencing remarkable human population growth and land-use change. Irrigation and associated cultivation have led to colonization of urban-wildland interface (UWI) environments by mule deer (Odocoileus hemionus), and consequently, cougars (Puma concolor). In the wake of these changes, human-wildlife conflicts have increased in tandem with questions about long-term species conservation. To address these concerns, we fit 79 cougars with radio-telemetry collars in the Oquirrh Mountains near Salt Lake City, Utah (2002–2010). Our goal was to evaluate variation in cougar habitat selection, diet, and cause-specific mortality in a landscape dominated by urban, military, and industrial activities. We used radio-telemetry data in concert with Re-source Selection Functions to address three hypotheses: (1) that cougars would select wildland over UWI land-uses; (2) prey composition would reflect differences in land-use; and (3) mortality would be predominantly human-caused. Cougars largely selected wildland habitats associated with seasonal mule deer presence, but contrary to expectation, they also selected habitats closer to urban and mined areas. Prey composition in the UWI did not differ from wildland habitats. Domestic ungulates represented only 2% of 540 recovered prey items and were found primarily in wildlands. Native ungulates comprised \u3e 90% of the total kill, irrespective of season or land-use, suggesting that use of UWI habitats was linked to mule deer presence. Cougar mortality was disproportionately due to natural causes in wildlands, but individuals that died of human causes in UWI habitats were more likely to be inexperienced hunters, supporting young kittens, or compromised by physical handicaps. In general, presence of mule deer was the key predictor of cougar habitat use, even in this highly disturbed, anthropogenically altered landscape. As such, management designed to reduce conflict and ensure conservation will need to focus on urban deer, land-use planning, and targeted education campaigns to reduce food subsidies

Thermal Conductivity and Erosion Durability of Composite Two-Phase Air Plasma Sprayed Thermal Barrier Coatings

To enhance efficiency of gas turbines, new thermal barrier coatings (TBCs) must be designed which improve upon the thermal stability limit of 7 wt% yttria stabilized zirconia (7YSZ), approximately 1200 C. This tenant has led to the development of new TBC materials and microstructures capable of improved high temperature performance. This study focused on increasing the erosion durability of cubic zirconia based TBCs, traditionally less durable than the metastable t' zirconia based TBCs. Composite TBC microstructures composed of a low thermal conductivity/high temperature stable cubic Low-k matrix phase and a durable t' Low-k secondary phase were deposited via APS. Monolithic coatings composed of cubic Low-k and t' Low-k were also deposited, in addition to a 7YSZ benchmark. The thermal conductivity and erosion durability were then measured and it was found that both of the Low-k materials have significantly reduced thermal conductivities, with monolithic t' Low-k and cubic Low-k improving upon 7YSZ by approximately 13 and approximately 25%, respectively. The 40 wt% t' Low-k composite (40 wt% t' Low-k - 60 wt% cubic Low-k) showed a approximately 22% reduction in thermal conductivity over 7YSZ, indicating even at high levels, the t' Low-k secondary phase had a minimal impact on thermal in the composite coating. It was observed that a mere 20 wt% t' Low-k phase addition can reduce the erosion of a cubic Low-k matrix phase composite coating by over 37%. Various mixing rules were then investigated to assess this non-linear composite behavior and suggestions were made to further improve erosion durability

A Changing Landscape for Lifelong Learning in Health Globally.

On 25 July 2022, the Continuing Professional Development (CPD) Special Interest Group of the Association for Medical Education in Europe came together to open up discussions during a live webinar on 'Exploring the Evolution of CPD'. The objective was to bring together global medical educators to consider perspectives of CPD from the role of global lifelong learners, the role of educators and the role of education providers and health regulators. The landscape of CPD is evolving, and the roles of each key player must include specific actions for facilitated change. Delivering competency outcomes-based learning, fit for purpose, to lifelong learners in health will require (1) learner agency, (2) leadership from educators and (3) providers of lifelong learning to come together to improve delivery of CPD that leads to meaningful change in practice care delivery

RELIABILITY OF KNEE JOINT MEASURES IN A CUTTING MOVEMENT

Eight female soccer athletes performed six horizontal jump and cut maneuvers onto two AMTI force platforms. 3D kinematic analysis of 22 marked body landmarks coupled with ground reaction forces (GRF) were analyzed for peak knee flexion and valgus angles, GRF, and knee abduction moments with repeated measures ANOVA. Analysis indicated no significant difference between trials (p > 0.05). Average measures Intraclass Correlation Coefficients resulted in values of r = 0.71 to 0.99. Results indicate good reliability for flexion angles and excellent reliability for valgus angles, GRF, and knee abduction moments

Progressive refinement rendering of implicit surfaces

The visualisation of implicit surfaces can be an inefficient task when such surfaces are complex and highly detailed. Visualising a surface by first converting it to a polygon mesh may lead to an excessive polygon count. Visualising a surface by direct ray casting is often a slow procedure. In this paper we present a progressive refinement renderer for implicit surfaces that are Lipschitz continuous. The renderer first displays a low resolution estimate of what the final image is going to be and, as the computation progresses, increases the quality of this estimate at an interactive frame rate. This renderer provides a quick previewing facility that significantly reduces the design cycle of a new and complex implicit surface. The renderer is also capable of completing an image faster than a conventional implicit surface rendering algorithm based on ray casting

In-Depth Characterization of Endo-Lysosomal Aβ in Intact Neurons

Amyloid-beta (Aβ) peptides are produced within neurons. Some peptides are released into the brain parenchyma, while others are retained inside the neurons. However, the detection of intracellular Aβ remains a challenge since antibodies against Aβ capture Aβ and its precursor proteins (i.e., APP and C99). To overcome this drawback, we recently developed 1) the C99 720-670 biosensor for recording γ-secretase activity and 2) a unique multiplexed immunostaining platform that enables the selective detection of intracellular Aβ with subcellular resolution. Using these new assays, we showed that C99 is predominantly processed by γ-secretase in late endosomes and lysosomes, and intracellular Aβ is enriched in the same subcellular loci in intact neurons. However, the detailed properties of Aβ in the acidic compartments remain unclear. Here, we report using fluorescent lifetime imaging microscopy (FLIM) that intracellular Aβ includes both long Aβ intermediates bound to γ-secretase and short peptides dissociated from the protease complex. Surprisingly, our results also suggest that the dissociated Aβ is bound to the glycoproteins on the inner membrane of lysosomes. Furthermore, we show striking cell-to-cell heterogeneity in intracellular Aβ levels in primary neurons and APP transgenic mouse brains. These findings provide a basis for the further investigation of the role(s) of intracellular Aβ and its relevance to Alzheimer’s disease (AD)

EFFECT OF ACUTE FEEDBACK ON KNEE ANGLE AND MOMENTS DURING A HORIZONTAL LAND AND CUT MANEUVER

The purpose of this study was to assess the effect of acute feedback and preferred plant leg on peak knee flexion and valgus angle, ground reaction force (GRF), and abduction moment of the knee during a horizontal land and cut maneuver. Eight division II women soccer players randomly performed horizontal landing and cutting maneuvers: 3 left and 3 right cuts pre- and post-feedback. Feedback was provided according to previous research. ANOVA revealed lower knee valgus angles for the feedback and preferred plant leg conditions (p0.05). There were no differences in GRF or knee abduction moment. Acute feedback may decrease knee valgus angle during cutting tasks, but does not appear to acutely alter other measures that are thought to decrease ACL injury risk

Herd-level risk factors of bovine tuberculosis in England and Wales after the 2001 foot-and-mouth disease epidemic

We present the results of a 2005 case–control study of bovine tuberculosis (bTB) breakdowns in English and Welsh herds. The herd management, farming practices, and environmental factors of 401matched pairs of case and control herds were investigated to provide a picture of herd-level risk factors in areas of varying bTB incidence. A global conditional logistic regression model, with region-specific variants, was used to compare case herds that had experienced a confirmed bTB breakdown to contemporaneous control herds matched on region, herd type, herd size, and parish testing interval. Contacts with cattle from contiguous herds and sourcing cattle from herds with a recent history of bTB were associated with an increased risk in both the global and regional analyses. Operating a farm over several premises, providing cattle feed inside the housing, and the presence of badgers were also identified as significantly associated with an increased bTB risk. Steps taken to minimize cattle contacts with neighboring herds and altering trading practices could have the potential to reduce the size of the bTB epidemic. In principle, limiting the interactions between cattle and wildlife may also be useful; however this study did not highlight any specific measures to implement