Patterns of retinal thickness prior to and following treatment with fluocinolone acetonide 190 µg intravitreal implant for diabetic macular edema

Objectives: To compare retinal thickness before and after treatment with the fluocinolone acetonide (FAc) 190 µg intravitreal implant in people with diabetic macular edema (DME) using data from the Iluvien Clinical Evidence study in the UK (ICE-UK). Methods: For this retrospective cohort study, data on people attending any one of 13 participating ophthalmology departments and treated with FAc intravitreal implant between April 1, 2013 and April 15, 2015 were collected for 12 months prior to and at least 12 months after implantation. Cross-sectional and longitudinal patterns of central foveal thickness (CFT) were compared before and after FAc implant. Results: There were 208 people who contributed data from 233 individual eyes treated with the FAc implant. Mean age was 68.1 years and 62% were male. Median (interquartile range) CFT decreased from 462 µm (354–603 µm) at time of implant to 309 µm (222–433 µm) at 12 months post-implant (p < .001). Over the same period, a reduction of ≥10%, ≥25%, and ≥50% in CFT was observed in 113 (65%), 87 (50%), and 37 (21%) treated eyes, respectively. Eyes with a CFT of ≥400 µm at the time of implant were significantly more likely to achieve a reduction in CFT of ≥10%, ≥25%, and ≥50% at 12 months (all p < .001) compared with eyes with a CFT of <400 µm at implant. Both retinal thickness and changes in retinal thickness were loosely correlated with visual acuity. Conclusion: A marked reduction in retinal thickness was observed in people following FAc intravitreal implant for DME. The response was related to the degree of retinal thickness prior to treatment

Photo-antagonism of the GABAA receptor

Neurotransmitter receptor trafficking is fundamentally important for synaptic transmission and neural network activity. GABAA receptors and inhibitory synapses are vital components of brain function, yet much of our knowledge regarding receptor mobility and function at inhibitory synapses is derived indirectly from using recombinant receptors, antibody-tagged native receptors and pharmacological treatments. Here we describe the use of a set of research tools that can irreversibly bind to and affect the function of recombinant and neuronal GABAA receptors following ultraviolet photoactivation. These compounds are based on the competitive antagonist gabazine and incorporate a variety of photoactive groups. By using site-directed mutagenesis and ligand-docking studies, they reveal new areas of the GABA binding site at the interface between receptor β and α subunits. These compounds enable the selected inactivation of native GABAA receptor populations providing new insight into the function of inhibitory synapses and extrasynaptic receptors in controlling neuronal excitation

Genomes as geography: using GIS technology to build interactive genome feature maps

BACKGROUND: Many commonly used genome browsers display sequence annotations and related attributes as horizontal data tracks that can be toggled on and off according to user preferences. Most genome browsers use only simple keyword searches and limit the display of detailed annotations to one chromosomal region of the genome at a time. We have employed concepts, methodologies, and tools that were developed for the display of geographic data to develop a Genome Spatial Information System (GenoSIS) for displaying genomes spatially, and interacting with genome annotations and related attribute data. In contrast to the paradigm of horizontally stacked data tracks used by most genome browsers, GenoSIS uses the concept of registered spatial layers composed of spatial objects for integrated display of diverse data. In addition to basic keyword searches, GenoSIS supports complex queries, including spatial queries, and dynamically generates genome maps. Our adaptation of the geographic information system (GIS) model in a genome context supports spatial representation of genome features at multiple scales with a versatile and expressive query capability beyond that supported by existing genome browsers. RESULTS: We implemented an interactive genome sequence feature map for the mouse genome in GenoSIS, an application that uses ArcGIS, a commercially available GIS software system. The genome features and their attributes are represented as spatial objects and data layers that can be toggled on and off according to user preferences or displayed selectively in response to user queries. GenoSIS supports the generation of custom genome maps in response to complex queries about genome features based on both their attributes and locations. Our example application of GenoSIS to the mouse genome demonstrates the powerful visualization and query capability of mature GIS technology applied in a novel domain. CONCLUSION: Mapping tools developed specifically for geographic data can be exploited to display, explore and interact with genome data. The approach we describe here is organism independent and is equally useful for linear and circular chromosomes. One of the unique capabilities of GenoSIS compared to existing genome browsers is the capacity to generate genome feature maps dynamically in response to complex attribute and spatial queries

Effectiveness of a telehealth physiotherapist-delivered intensive dietary weight loss program combined with exercise in people with knee osteoarthritis and overweight or obesity: study protocol for the POWER randomized controlled trial.

BACKGROUND: Obesity is associated with knee osteoarthritis (OA). Weight loss, alongside exercise, is a recommended treatment for individuals with knee OA and overweight/obesity. However, many patients cannot access weight loss specialists such as dietitians. Innovative care models expanding roles of other clinicians may increase access to weight loss support for people with knee OA. Physiotherapists may be well placed to deliver such support. This two-group parallel, superiority randomized controlled trial aims to compare a physiotherapist-delivered diet and exercise program to an exercise program alone, over 6 months. The primary hypothesis is that the physiotherapist-delivered diet plus exercise program will lead to greater weight loss than the exercise program. METHODS: 88 participants with painful knee OA and body mass index (BMI) > 27 kg/m2 will be recruited from the community. Following baseline assessment, participants will be randomised to either exercise alone or diet plus exercise groups. Participants in the exercise group will have 6 consultations (20-30 min) via videoconference with a physiotherapist over 6 months for a strengthening exercise program, physical activity plan and educational/exercise resources. Participants in the diet plus exercise group will have 6 consultations (50-75 min) via videoconference with a physiotherapist prescribing a ketogenic very low-calorie diet with meal replacements and educational resources to support weight loss and healthy eating, plus the intervention of the exercise only group. Outcomes are measured at baseline and 6 months. The primary outcome is percentage change in body weight measured by a blinded assessor. Secondary outcomes include self-reported knee pain, physical function, global change in knee problems, quality of life, physical activity levels, and internalised weight stigma, as well as BMI, waist circumference, waist-to-hip ratio, physical performance measures and quadriceps strength, measured by a blinded assessor. Additional measures include adherence, adverse events, fidelity and process measures. DISCUSSION: This trial will determine whether a physiotherapist-delivered diet plus exercise program is more effective for weight loss than an exercise only program. Findings will inform the development and implementation of innovative health service models addressing weight management and exercise for patients with knee OA and overweight/obesity. TRIAL REGISTRATION: NIH US National Library of Medicine, Clinicaltrials.gov NCT04733053 (Feb 1 2021)

ZD6474 reverses multidrug resistance by directly inhibiting the function of P-glycoprotein

P-glycoprotein (P-gp) pumps multiple types of drugs out of the cell, using energy generated from ATP, and confers multidrug resistance (MDR) on cancer cells. ZD6474 is an orally active, selective inhibitor of the vascular endothelial growth factor receptor, epidermal growth factor receptor, and rearranged during transfection tyrosine kinases. This study was designed to examine whether ZD6474 reverses P-gp-mediated MDR in cancer cells. Here, we show that clinically achievable levels of ZD6474 reverse P-gp-mediated MDR of the P-gp-overexpressing cell lines derived from breast cancer, MCF-7/adriamycin (ADR), and human oral epidermoid carcinoma, KBV200 to ADR, docetaxel, and vinorelbine. This ability to reverse the P-gp-mediated resistance is comparable to that of another frequently used reversal agent known as verapamil. ZD6474 itself moderately inhibits the proliferation of both MCF-7 and MCF-7/ADR cells with almost equal activity, but its inhibitory effect is not altered by co-incubation with verapamil, suggesting that ZD6474 may not be a substrate of P-gp. In addition, ZD6474 increases the intracellular accumulation of the P-gp substrate, rhodamine-123, and ADR, by enhancing the uptake and/or decreasing the efflux of these compounds in resistant cells. Further studies show that ZD6474 stimulates ATPase activity in a dose-dependent manner, which is required for the proper function of P-gp. In contrast, ZD6474 does not inhibit the expression level of P-gp. Our results suggest that ZD6474 is capable of reversing MDR in cancer cells by directly inhibiting the function of P-gp, a finding that may have clinical implications for ZD6474

Horizontal DNA transfer mechanisms of bacteria as weapons of intragenomic conflict

Horizontal DNA transfer (HDT) is a pervasive mechanism of diversification in many microbial species, but its primary evolutionary role remains controversial. Much recent research has emphasised the adaptive benefit of acquiring novel DNA, but here we argue instead that intragenomic conflict provides a coherent framework for understanding the evolutionary origins of HDT. To test this hypothesis, we developed a mathematical model of a clonally descended bacterial population undergoing HDT through transmission of mobile genetic elements (MGEs) and genetic transformation. Including the known bias of transformation toward the acquisition of shorter alleles into the model suggested it could be an effective means of counteracting the spread of MGEs. Both constitutive and transient competence for transformation were found to provide an effective defence against parasitic MGEs; transient competence could also be effective at permitting the selective spread of MGEs conferring a benefit on their host bacterium. The coordination of transient competence with cell-cell killing, observed in multiple species, was found to result in synergistic blocking of MGE transmission through releasing genomic DNA for homologous recombination while simultaneously reducing horizontal MGE spread by lowering the local cell density. To evaluate the feasibility of the functions suggested by the modelling analysis, we analysed genomic data from longitudinal sampling of individuals carrying Streptococcus pneumoniae. This revealed the frequent within-host coexistence of clonally descended cells that differed in their MGE infection status, a necessary condition for the proposed mechanism to operate. Additionally, we found multiple examples of MGEs inhibiting transformation through integrative disruption of genes encoding the competence machinery across many species, providing evidence of an ongoing "arms race." Reduced rates of transformation have also been observed in cells infected by MGEs that reduce the concentration of extracellular DNA through secretion of DNases. Simulations predicted that either mechanism of limiting transformation would benefit individual MGEs, but also that this tactic's effectiveness was limited by competition with other MGEs coinfecting the same cell. A further observed behaviour we hypothesised to reduce elimination by transformation was MGE activation when cells become competent. Our model predicted that this response was effective at counteracting transformation independently of competing MGEs. Therefore, this framework is able to explain both common properties of MGEs, and the seemingly paradoxical bacterial behaviours of transformation and cell-cell killing within clonally related populations, as the consequences of intragenomic conflict between self-replicating chromosomes and parasitic MGEs. The antagonistic nature of the different mechanisms of HDT over short timescales means their contribution to bacterial evolution is likely to be substantially greater than previously appreciated

Prediction of the release process of the nitrogen-extinguishant binary mixture considering surface tension

© 2020 Springer-Verlag. The final publication is available at Springer via https://doi.org/10.1007/s10973-020-10040-2.Nitrogen used for pressurization in the extinguisher can be partially dissolved in the fire extinguishing agent. Consequently, the evolution of the dissolved nitrogen has a significant effect on the release behavior of the fire extinguishing agent in a rapid process. In this article, a new model was developed to predict the critical pressure of the nitrogen evolution and the release process of the fire extinguishing agent was described in detail. According to the Peng-Robinson (PR) equation of state and van der Waals mixing rule, the effect of the dissolved nitrogen on the surface tension of the fire extinguishant was analyzed by considering surface phase and fugacity coefficient. A method to calculate the surface tension of the liquid agent dissolved with nitrogen was proposed. The results showed that the proposed model can determine the accurate critical pressure of the evolution of the dissolved nitrogen and further evaluated whether nitrogen escapes. At different initial filling pressure, in addition, the release process of the nitrogen-extinguishant such as CF3I, FC218 (C3F8), HFC125 (C2HF5), and Halon1301 (CF3Br) was well predicted by the fluid release model when taking the surface tension and adiabatic index of the mixture into account. Compared with the previously obtained experimental data, the predictions obtained indicated that the present model can adequately describe the liquid and the gas mixture release stage in the release process of the nitrogen-extinguishant.Peer reviewe

Optically pure, water-stable metallo-helical ‘flexicate’ assemblies with antibiotic activity

The helicates—chiral assemblies of two or more metal atoms linked by short or relatively rigid multidentate organic ligands—may be regarded as non-peptide mimetics of α-helices because they are of comparable size and have shown some relevant biological activity. Unfortunately, these beautiful helical compounds have remained difficult to use in the medicinal arena because they contain mixtures of isomers, cannot be optimized for specific purposes, are insoluble, or are too difficult to synthesize. Instead, we have now prepared thermodynamically stable single enantiomers of monometallic units connected by organic linkers. Our highly adaptable self-assembly approach enables the rapid preparation of ranges of water-stable, helicate-like compounds with high stereochemical purity. One such iron(II) ‘flexicate’ system exhibits specific interactions with DNA, promising antimicrobial activity against a Gram-positive bacterium (methicillin-resistant Staphylococcus aureus, MRSA252), but also, unusually, a Gram-negative bacterium (Escherichia coli, MC4100), as well as low toxicity towards a non-mammalian model organism (Caenorhabditis elegans)

Boreal forest floor greenhouse gas emissions across a Pleurozium schreberi-dominated, wildfire-disturbed chronosequence

The boreal forest is a globally critical biome for carbon cycling. Its forests are shaped by wildfire events that affect ecosystem properties and climate feedbacks including greenhouse gas (GHG) emissions. Improved understanding of boreal forest floor processes is needed to predict the impacts of anticipated increases in fire frequency, severity, and extent. In this study, we examined relationships between time since last wildfire (TSF), forest floor soil properties, and GHG emissions (CO2, CH4, N2O) along a Pleurozium schreberi-dominated chronosequence in mid- to late succession located in northern Sweden. Over three growing seasons in 2012–2014, GHG flux measurements were made in situ and samples were collected for laboratory analyses. We predicted that P. schreberi-covered forest floor GHG fluxes would be related to distinct trends in the soil properties and microbial community along the wildfire chronosequence. Although we found no overall effect of TSF on GHG emissions, there was evidence that soil C/N, one of the few properties to show a trend with time, was inversely linked to ecosystem respiration. We also found that local microclimatic conditions and site-dependent properties were better predictors of GHG fluxes than TSF. This shows that site-dependent co-variables (that is, forest floor climate and plant-soil properties) need to be considered as well as TSF to predict GHG emissions as wildfires become more frequent, extensive and severe

Trends in type 2 diabetes incidence and mortality in Scotland between 2004 and 2013

No abstract available