Age-related macular degeneration (AMD) is the leading cause of severe irreversible central vision loss in individuals over 65 years old. Genome-wide association studies (GWASs) have shown that the ...region at chromosome 10q26, where the age-related maculopathy susceptibility (ARMS2/LOC387715) and HtrA serine peptidase 1 (HTRA1) genes are located, represents one of the strongest associated loci for AMD. However, the underlying biological mechanism of this genetic association has remained elusive. In this article, we extensively review the literature by us and others regarding the ARMS2/HTRA1 risk alleles and their functional significance. We also review the literature regarding the presumed function of the ARMS2 protein and the molecular processes of the HTRA1 protein in AMD pathogenesis in vitro and in vivo, including those of transgenic mice overexpressing HtrA1/HTRA1 which developed Bruch's membrane (BM) damage, choroidal neovascularization (CNV), and polypoidal choroidal vasculopathy (PCV), similar to human AMD patients. The elucidation of the molecular mechanisms of the ARMS2 and HTRA1 susceptibility loci has begun to untangle the complex biological pathways underlying AMD pathophysiology, pointing to new testable paradigms for treatment.
HMG Co-A reductase inhibitors are ubiquitous in our community yet their potential role in age-related macular degeneration (AMD) remains to be determined.
To evaluate the effect of simvastatin on AMD ...progression and the effect modification by polymorphism in apolipoprotein E (ApoE) and complement factor H (CFH) genes.
A proof of concept double-masked randomized controlled study.
114 participants aged 53 to 91 years, with either bilateral intermediate AMD or unilateral non-advanced AMD (with advanced AMD in fellow eye), BCVA ≥ 20/60 in at least one eye, and a normal lipid profile.
Simvastatin 40 mg/day or placebo, allocated 1:1.
Progression of AMD either to advanced AMD or in severity of non-advanced AMD. Results. The cumulative AMD progression rates were 70% in the placebo and 54% in the simvastatin group. Intent to treat multivariable logistic regression analysis, adjusted for age, sex, smoking and baseline AMD severity, showed a significant 2-fold decrease in the risk of progression in the simvastatin group: OR 0.43 (0.18-0.99), p = 0.047. Post-hoc analysis stratified by baseline AMD severity showed no benefit from treatment in those who had advanced AMD in the fellow eye before enrolment: OR 0.97 (0.27-3.52), p = 0.96, after adjusting for age, sex and smoking. However, there was a significant reduction in the risk of progression in the bilateral intermediate AMD group compared to placebo adjusted OR 0.23 (0.07-0.75), p = 0.015. The most prominent effect was observed amongst those who had the CC (Y402H) at risk genotype of the CFH gene OR 0.08 (0.02-0.45), p = 0.004. No evidence of harm from simvastatin intervention was detected.
Simvastatin may slow progression of non-advanced AMD, especially for those with the at risk CFH genotype CC (Y402H). Further exploration of the potential use of statins for AMD, with emphasis on genetic subgroups, is warranted.
Australian New Zealand Clinical Trial Registry (ANZCTR) ACTRN1260500032065.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
International export and import of corneas is dependent on the stakeholders involved in the process and how those organizations engage to move corneas from one point to another. Our article presents ...the pathway of corneal donation from the export nation until its use in the import nation. It presents opinion on how aspects, such as competition and promotional behaviors, the use of online systems, and third-party engagement may influence allocation.
We interviewed n = 92 international eye tissue and eye bank (EB) professionals to garner their opinion. We used saturation and sentiment methods to extract and consolidate group opinion.
Interviewees indicated that competition and promotional behaviors existed in some EB nations-although it was not universal. They indicated that the behavioral approach used by the individual EB, rather than the act of information sharing, influenced allocation. They also indicated that organizational models and allocation systems (eg, online ordering) and engagement with nonstate actors were important in allocation practice and decision making.
We mapped the pathways for corneas involved in export and import from the point of recovery to their point of transplantation. Although generalist in nature and limited by the paucity of the existing literature, our article outlines that different business models, partnerships, and applied methods influence corneal export and import.
PURPOSE:There is a global demand for corneal tissue (CT) for transplantation, with some nations potentially able to export donations to those nations without. Unfortunately, there remains a global ...paucity of information that explains the process of exportation and importation (transnational activity), supports or defines practice, or informs those seeking to engage. Without knowledge, inclusive of the pros and cons, participating nations and decision makers are unable to make effective and informed decisions.
METHODS:Through the example of our own nation, Australia, which may be entering a surplus-to-domestic demand phase and able to export, we conducted qualitative grounded-theory semistructured interviews with sector experts. Our approach ascertained whether Australia should export and under what arrangements. Through saturation and sentiment methods, we capture for the first time, global opinion on CT transnational activity (although primarily exportation), key themes, and finally determine whether Australia should engage.
RESULTS:Eighty-four (91%) of 92 participants directly commented on our question “should Australia export corneal tissue?” Of 84, n = 67 (80%) stated yes, n = 17 (20%) indicated mixed opinions. No participant categorically stated that there should be no export.
CONCLUSIONS:Eye tissue and eye care experts whom we interviewed, supported the concept of Australia exporting CT; however, they advise several safeguards to protect both import and export nations. Principally, they recommended practice be transparent with donors, nationally coordinated, part of a wider humanitarian program, nonprofit, short term for the importing nations as they move toward self-sufficiency and that Australia must define and confirm domestic need and ensure that demand is met before routine exportation.
We conducted grounded theory semistructured interviews, purposively inviting participants until themed saturation was met. Sentiment analysis was used to determine opinion.
We interviewed n = 92 ...global eye tissue and eye bank professionals. We determined that corneal tissue, which is exported, costs between US $100 and US $6000 or is provided as gratis. Collectively, interviewees indicated that, globally, there were no fixed fee structures in place, and the fee was influenced by multiple factors on both export and import sides. They indicated that ultimately corneas were allocated based on the importers' ability to pay the price determined by the exporting eye bank.
Allocation of corneal tissue, which is exported, is influenced by the fees charged by the exporters to meet their bottom line and the funds available to importers. Therefore, export allocation is not equitable, with those who can pay a higher fee, prioritized. Steps to guide and support exporters with the development of fee structures that promote equitable allocation are essential. This will assist both export and import eye bank development, corneal tissue access development, and those awaiting a corneal transplant.
PURPOSE:Globally, an estimated 12.7 million people await a corneal transplant. Of these, 53% are without routine access to a domestic supply and are reliant on transnational activity (TNA) ...(importation) of corneal tissue (CT) for transplantation. Although CT TNA commenced in 1961, there has been no evaluation of its impact on import and export nations.
METHODS:We wished to examine the impact of clinical and nonclinical CT TNA on export and import nations, with nonclinical aspects our primary focus, to help guide future practice. We conducted a review of the academic literature through various search engines. We prefix and place our review in the relevant historical practice and global context.
RESULTS:Despite commencement in 1961, we only located 14 studies (11 clinical and 3 nonclinical) pertaining to CT TNA. These were published between 1991 and 2018. Clinical papers reported death-to-preservation time, preservation-to-transplantation time, logistics, donor and recipient selection, and quality as relevant. Nonclinical studies identified emerging themes pertaining to financial, ethical, and sustainability aspects of TNA.
CONCLUSIONS:All aspects of CT TNA are grossly under-reported, resulting in our inability to effectively analyze the overall impact to export and import nations. The few clinical studies in our review concluded that despite endothelial cell loss and other risk factors, imported CT appears comparable with domestic CT and remains an option in the absence of domestic supply. Nonclinical aspects (eg, ethical, equitable, and economic) have also not been adequately addressed.
PURPOSE:Corneal tissue international activity is only possible because of the willingness of export populations to donate their corneas on their death. Current predonation public education campaigns ...and at-the-point-of-donation consent practice generally includes consent for transplantation, research, and/or training. It is unclear whether a consent-for-export step is universally included in the consent process or, indeed, whether it should. We interviewed eye tissue and eye care professionals from around the world, who exported, imported, or did neither to understand current consent-for-export awareness and determine opinion on future practice.
METHOD:During wider qualitative grounded-theory semistructured interviews with sector experts, to determine whether Australia should export, we captured sector opinion on consent-for-export. We used saturation and sentiment methods to determine opinion and χ correlation coefficients to examine association, using an α of P = 0.05.
RESULTS:We interviewed 92 individuals, 83 of whom discussed consent-for-export. Of those, 51% (42/83) demonstrated some awareness of the practice; however, there were contradictions between interviewees from the same location. Regardless of current awareness, 57% (41/72) believed donors should be informed or consented for export. Their approval did not extend to donor-directed decisions, which would allow donors to decide which nation their donation should be sent, with 62.5% (45/72) opposing that notion.
CONCLUSIONS:Our research indicates that the consent-for-export practice is not universally applied by exporting nations and that eye tissue and eye care professionals have limited awareness of the practice. Universally implementing a consent-for-export step within general consent practice would improve awareness, reduce confusion, and support donor wishes.
12.7 million people await a corneal transplant, but 53% are without access to corneal tissue. Sharing corneal tissue across nations can provide some access, however the willingness of export ...populations, like Australians, to export their donation on death, has never been evaluated. Our research samples the Australian population, determining their willingness to export.
We conducted e-surveys. N = 1044 Australians participated. The sample represented the Australian population, based on population demographics. Chi-Square and bivariate correlation coefficients examined associations between categorical variables, with a sample size of N = 1044, power of 0.80, and alpha of p = 0.05. Outcome measures were based on population sampling, by exploring willingness export, through the e-survey method.
38% (n = 397) of respondents said yes to exportation, 23.8% (n = 248) said no, and 38.2% (n = 399) were undecided. We found no relationship between willingness to export and general demographics, though those registered on the Donatelife Register (p = < .001), and those already willing to donate their eyes (p = < .001) were significantly more willing to export.
More Australians are willing to export their corneas than not, though a significant portion remain undecided. The Donatelife Register, and donation awareness, are key components of respondent decision making. Therefore, the provision of information about exportation prior to, and at the point-of-donation, is essential for assisting Australian's to decide to export or not. Further examination and development of consent-for-export systems are necessary before routine exportation is undertaken.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Currently available evidence on predictors of anti-vascular endothelial growth factor (VEGF) treatment response in neovascular age-related macular degeneration was reviewed. No meta-analysis ...of results is possible because of a lack of controlled and randomized trials, varying treatment regimes and outcome measures used, as well as suboptimal reporting. For genetic factors, most evidence to date has been generated for single nucleotide polymorphisms (SNPs) in the complement factor H (CFH), and VEGF-A genes. Just under half of the SNPs assessed in the CFH gene and 15% of the SNPs assessed in the VEGF gene were found to be associated with visual outcomes or the number of injections required during follow-up. Some evidence suggests association of worse treatment outcomes as well as a younger age at treatment onset with an increasing number of risk alleles in known risk genes (CFH and ARMS2/HTRA1) and polymorphisms in the VEGF-A gene. Clinical factors such as higher age, a better visual acuity (VA), a larger choroidal neovascularization (CNV) lesion at baseline, and a delay between symptom onset and initiation of treatment of more than 3 weeks also impact outcomes. Conversely, a worse acuity at baseline predicted more gain in vision. Overall, patients presenting with good acuity at baseline were more likely to have good VA at follow up, but the gain afforded by treatment was impacted by a ceiling effect. Most available evidence suggests a strong association of clinical factors such as age, baseline VA, and CNV lesion size with anti-VEGF treatment outcomes. No behavioral factors such as smoking influence treatment outcomes. Based on the studies conducted so far, the evidence suggests that underlying genotype of known AMD risk associated genes or of the VEGF-A gene have a limited effect, whereas presenting clinical factors appear to be more important in determining treatment outcomes.
DNA barcoding of aquatic macroinvertebrates holds much promise as a tool for taxonomic research and for providing the reliable identifications needed for water quality assessment programs. A ...prerequisite for identification using barcodes is a reliable reference library. We gathered 4165 sequences from the barcode region of the mitochondrial cytochrome c oxidase subunit I gene representing 264 nominal and 90 provisional species of mayflies (Insecta: Ephemeroptera) from Canada, Mexico, and the United States. No species shared barcode sequences and all can be identified with barcodes with the possible exception of some Caenis. Minimum interspecific distances ranged from 0.3-24.7% (mean: 12.5%), while the average intraspecific divergence was 1.97%. The latter value was inflated by the presence of very high divergences in some taxa. In fact, nearly 20% of the species included two or three haplotype clusters showing greater than 5.0% sequence divergence and some values are as high as 26.7%. Many of the species with high divergences are polyphyletic and likely represent species complexes. Indeed, many of these polyphyletic species have numerous synonyms and individuals in some barcode clusters show morphological attributes characteristic of the synonymized species. In light of our findings, it is imperative that type or topotype specimens be sequenced to correctly associate barcode clusters with morphological species concepts and to determine the status of currently synonymized species.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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