The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.

https://cdr.lib.unc.edu/downloads/v692t8920

A global reference for human genetic variation.

Objective To determine the effects of antiplatelet therapy among patients at high risk of occlusive vascular events. Design Collaborative meta-analyses (systematic overviews). Inclusion criteria Randomised trials of an antiplatelet regimen versus control or of one antiplatelet regimen versus another in high risk patients (with acute or previous vascular disease or some other predisposing condition) from which results were available before September 1997. Trials had to use a method of randomisation that precluded prior knowledge of the next treatment to be allocated and comparisons had to be unconfounded-that is, have study groups that differed only in terms of antiplatelet regimen. Studies reviewed 287 studies involving 135 000 patients in comparisons of antiplatelet therapy versus control and 77 000 in comparisons of different antiplatelet regimens. Main outcome measure "Serious vascular event": non-fatal myocardial infarction, non-fatal stroke, or vascular death. Results Overall, among these High risk patients, allocation to antiplatelet therapy reduced the combined outcome of any serious vascular event by about one quarter; non-fatal myocardial infarction was reduced by one third, non-fatal stroke by one quarter, and vascular mortality by one sixth (with no apparent adverse effect on other deaths). Absolute reductions in the risk of having a serious vascular event were 36 (SE 5) per 1000 treated for two years among patients with previous myocardial infarction; 38 (5) per 1000 patients treated for one month among patients with acute myocardial infarction; 36 (6) per 1000 treated for two years among those with previous stroke or transient ischaemic attack; 9 (3) per 1000 treated for three weeks among those with acute stroke; and 22 (3) per 1000 treated for two years among other high risk patients (with separately significant results for those with stable angina (P=0.0005), peripheral arterial disease (P=0.004), and atrial fibrillation (P=0.01)). In each of these high risk categories, the absolute benefits substantially outweighed the absolute risks of major extracranial bleeding. Aspirin was the most widely studied antiplatelet drug, with doses of 75-150 mg daily at least as effective as higher daily doses. The effects of doses lower than 75 mg daily were less certain. Clopidogrel reduced serious vascular events by 10% (4%) compared with aspirin, which was similar to the 12% (7%) reduction observed with its analogue ticlopidine. Addition of dipyridamole to aspirin produced no significant further reduction in vascular events compared with aspirin alone. Among patients at high risk of immediate coronary occlusion, short term addition of an intravenous glycoprotein IIb/IIIa antagonist to aspirin prevented a further 20 (4) vascular events per 1000 (P <0.0001) but caused 23 major (but rarely fatal) extracranial bleeds per 1000. Conclusions Aspirin (or another oral antiplatelet drug) is protective in most types of patient at increased risk of occlusive vascular events, including those with an acute myocardial infarction or ischaemic stroke, unstable or stable angina, previous myocardial infarction, stroke or cerebral ischaemia, peripheral arterial disease, or atrial fibrillation, Low dose aspirin (75-150 mg daily) is an effective antiplatelet regimen for long term use, but in acute settings an initial loading dose of at least 150 mg aspirin may be required. Adding a second antiplatelet drug to aspirin may produce additional benefits in some clinical circumstances, but more research into this strategy is needed.

/pdf/collaborative-meta-analysis-of-randomised-trials-of-8dyu3duelv.pdf

Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients

Background Retinal ischemia induces intraocular neovascularization, which often leads to glaucoma, vitreous hemorrhage, and retinal detachment, presumably by stimulating the release of angiogenic molecules. Vascular endothelial growth factor (VEGF) is an endothelial-cell-specific angiogenic factor whose production is increased by hypoxia. Methods We measured the concentration of VEGF in 210 specimens of ocular fluid obtained from 164 patients undergoing intraocular surgery, using both radioimmunoassays and radioreceptor assays. Vitreous proliferative potential was measured with in vitro assays of the growth of retinal endothelial cells and with VEGF-neutralizing antibody. Results VEGF was detected in 69 of 136 ocular-fluid samples from patients with diabetic retinopathy, 29 of 38 samples from patients with neovascularization of the iris, and 3 of 4 samples from patients with ischemic occlusion of the central retinal vein, as compared with 2 of 31 samples from patients with no neovascular disorders (P<0.00...

https://www.nejm.org/doi/pdf/10.1056/NEJM199412013312203

Vascular Endothelial Growth Factor in Ocular Fluid of Patients with Diabetic Retinopathy and Other Retinal Disorders

A global reference for human genetic variation

Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.

Medical Therapy Cost Considerations for Glaucoma

The case of a 21-year-old woman with an optic nerve head coloboma and optic pit in one eye, a hypoplastic optic nerve head in the second eye, and a small retinochoroidal coloboma in each eye is presented. The probable etiology is some unknown insult involving several ocular embryonic structures and occurring during the 11-mm to 20-mm stage of development. The occurrence of these multiple anomalies in the same patient lends further support to the theory that optic disc colobomas and optic nerve hypoplasia represent a spectrum of developmental anomalies of the optic nerve.

Optic Nerve Hypoplasia and Colobomatous Defects

Value based ophthalmology

In their article in this issue of the BJO (p 57) Saunders and colleagues describe a methodology by which they evaluate the visual health state of patients with severe corneal disease requiring transplantation surgery. Rather than dealing with visual acuity as the only preoperative and outcome parameters, they evaluate patients according to three criteria: (1) visual acuity, (2) ocular pain, and (3) visual function. Concerning the latter criterion, visual function, they utilise a tool called the VFA (visual function assessment),1 which they have previously described; it is essentially a modification of the VF-142 and predominantly measures ocular function characterised by the ability to perform tasks such as driving, reading, cooking, etc. They found that patients who had a high preoperative priority score, as measured by the three above criteria, were more likely to have a good outcome. One measure in the study that is somewhat unclear, though, is how the results incorporate vision in the eye that did not receive a transplant. All too often our clinical trials and other studies fail to address the status of the second eye, perhaps a factor more important to the patient that the ocular intervention itself. The authors noted that 72.4% of patients demonstrated an improved VFA after transplant, but it is uncertain whether this was measured using only the operated eye or in a real world situation in which both eyes were used during the assessment.

The authors should be congratulated upon bringing more than visual acuity alone into the decision making process. Most ophthalmologists believe …

https://bjo.bmj.com/content/bjophthalmol/86/1/2.full.pdf

Outcome of corneal transplantation.

Reported herein are the cases of two patients who developed subretinal neovascularization at the margin of a retinochoroidal coloboma. Possible explanations for the occurrence of this previously unemphasized association are addressed.

Retinochoroidal coloboma associated with subretinal neovascularization.

BACKGROUND AND OBJECTIVE To assess the safety and efficacy of ranibizumab in patients who had inadequate response to pegaptanib or bevacizumab. PATIENTS AND METHODS In this single-center study, 19 patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration (AMD) previously treated with pegaptanib (n = 1), bevacizumab (n = 13), or both (n = 5) received 12 monthly ranibizumab injections (0.5 mg). Outcomes were measured from start of previous therapy (baseline) to start of ranibizumab treatment (day 0) through 12 months. RESULTS No drug- or injection-related adverse events and no serious adverse events were reported. At 6 and 12 months, 4 and 5 patients gained 3 or more lines of VA, respectively; 3 patients lost less than 3 lines of VA at 6 months, and 6 patients lost less than 3 lines at 12 months. At 6 and 12 months, VA increased by a mean (± standard error of the mean) of 2.06 ± 1.23 and 1.17 ± 0.62 lines, respectively. Central retinal thickness decreased by a mean of 62.65 ± 22.46 and 62.16 ± 29.20 μm at months 6 and 12, respectively. When stratified by pigment epithelial detachment (PED) status, patients without PED had better visual and anatomical outcomes than patients with PED. CONCLUSION Ranibizumab has favorable safety and efficacy profiles for patients with AMD without previous response to pegaptanib or bevacizumab.

Gary C. Brown

Papers

Medical Therapy Cost Considerations for Glaucoma

Optic Nerve Hypoplasia and Colobomatous Defects

Outcome of corneal transplantation.

Retinochoroidal coloboma associated with subretinal neovascularization.

Ranibizumab for eyes previously treated with pegaptanib or bevacizumab without clinical response.