Genome-wide association identifies ATOH7 as a major gene determining human optic disc size

Optic nerve assessment is important for many blinding diseases, with cup-to-disc ratio (CDR) assessments commonly used in both diagnosis and progression monitoring of glaucoma patients. Optic disc, cup, rim area and CDR measurements all show substantial variation between human populations and high heritability estimates within populations. To identify loci underlying these quantitative traits, we performed a genome-wide association study in two Australian twin cohorts and identified rs3858145, P = 6.2 × 10−10, near the ATOH7 gene as associated with the mean disc area. ATOH7 is known from studies in model organisms to play a key role in retinal ganglion cell formation. The association with rs3858145 was replicated in a cohort of UK twins, with a meta-analysis of the combined data yielding P = 3.4 × 10−10. Imputation further increased the evidence for association for several SNPs in and around ATOH7 (P = 1.3 × 10−10 to 4.3 × 10−11, top SNP rs1900004). The meta-analysis also provided suggestive evidence for association for the cup area at rs690037, P = 1.5 × 10−7, in the gene RFTN1. Direct sequencing of ATOH7 in 12 patients with optic nerve hypoplasia, one of the leading causes of blindness in children, revealed two novel non-synonymous mutations (Arg65Gly, Ala47Thr) which were not found in 90 unrelated controls (combined Fisher's exact P = 0.0136). Furthermore, the Arg65Gly variant was found to have very low frequency (0.00066) in an additional set of 672 controls

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Screening for glaucomatous disc changes prior to diagnosis of glaucoma in myocilin pedigrees

OBJECTIVE: To investigate whether structural differences of the optic nerve head are evident in young people who do not have manifest glaucoma but are known to carry myocilin mutations. METHODS: A case-control design was adopted. Subjects from Australian pedigrees known to have either the Gln368STOP myocilin mutation (cutoff age, <40 years) or the Thr377Met myocilin mutation (cutoff age, <30 years) were examined for signs of glaucoma. Stereoscopic disc photographs were digitalized. Analysis of the optic disc area, optic cup area, and neuroretinal rim area was performed using digital stereoscopy with a Z-screen. Mutation analysis was conducted using direct sequencing. The t test, corrected for multiple comparison testing, was used in analysis. RESULTS: A total of 29 myocilin mutation-carrying (case) and 33 mutation-free (control) individuals were reviewed. The mean +/- SD ages were 19.9 +/- 9.0 and 22.1 +/- 9.5 years in the mutation and mutation-free groups, respectively (P = .35). There was no significant difference in intraocular pressure between mutation carriers and noncarriers (P = .44). There were no statistically significant differences in the mean disc, neuroretinal rim, and cup areas between the groups. The mean +/- SD neuroretinal rim area was 1.24 +/- 0.24 mm(2) in the noncarrier group and 1.25 +/- 0.23 mm(2) in the mutation group (P = .46). No notch, nerve fiber layer defect, or neuroretinal rim hemorrhage was noted in any eye examined. CONCLUSIONS: Although confounded by penetrance and expressivity, no quantified structural difference in the optic nerve head was observed in individuals who had a myocilin mutation prior to the diagnosis of glaucoma

The optic nerve head in myocilin glaucoma

PURPOSE. Approximately 1 in 30 unselected patients with open-angle glaucoma (OAG) have a mutation in the myocilin gene. The purpose of this study was to describe the morphologic features of the optic nerve head (ONH) in myocilin glaucoma. METHODS. A case-control design was adopted. Sixty-six patients heterozygous for a range of myocilin mutation (cases) were matched in disease severity to 105 patients with OAG known not to have a myocilin mutation (controls), using visual field findings. Quantifiable analysis of the ONH was undertaken of stereoscopic photographs, by using custom software with a z-screen. Subjective grading of the cup depth, lamina cribrosa pore shape and orientation, and the slope of the neuroretinal rim was performed by an examiner masked to the subject’s mutation status. Mutation screening was conducted using either direct sequencing or single-stranded conformation polymorphism analysis. RESULTS. Patients with a myocilin mutation had glaucoma diagnosed earlier (P 0.05) difference in global disc area, global neuroretinal rim area, -parapapillary atrophy, ß-parapapillary atrophy, slope of neuroretinal rim, or visible lamina cribrosa morphology between myocilin mutation carriers and patients with nonmyocilin glaucoma. Disc hemorrhages were identified more frequently in those without mutations (14/209 vs. 1/129), though this was not significant after correction for multiple hypothesis testing. CONCLUSIONS. No major structural or morphologic difference of the ONH was detected in pooled data from subjects who had myocilin mutations compared with data from individuals with nonmyocilin glaucoma

Perinatal immunoprophylaxis in babies born to hepatitis B virus-positive mothers in Queensland Australia: a data linkage study

Vertical transmission from mother-to-child is an important mode of hepatitis B virus (HBV) infection, accounting for up to half of all incident cases globally. We evaluated the uptake of HBV neonatal vaccination and immunoglobulin delivery in Queensland, Australia, between 2001 and 2013. We identified HBV-positive mothers using linked notifiable conditions, hospitalisation, and perinatal administrative data. Perinatal receipt of monovalent HBV vaccine and hepatitis B immunoglobulin were examined. Of 710,859 live births, with 5753 infants (0.81%) born to identified HBV-positive mothers; 91.7% received HBV neonatal vaccine. Immunoglobulin uptake was 20.0% in 2012 and 36.6% in 2013. Uptake was higher when the mother's HBV-positive status was recorded in perinatal records (69.6% if maternal HBV status recorded on perinatal data collection vs 9.5% otherwise). Delivery of neonatal HBV vaccination in Queensland was high. Improved identification and documentation of HBV-positive mothers' status during the antenatal period was associated with increased immunoglobulin administration

Arboviral diseases and malaria in Australia, 2013-14: Annual report of the National Arbovirus and Malaria Advisory Committee.

This report describes the epidemiology of mosquito-borne diseases of public health importance in Australia during the 2013-14 season (1 July 2013 to 30 June 2014) and includes data from human notifications, sentinel chicken, vector and virus surveillance programs. The National Notifiable Diseases Surveillance System received notifications for 8,898 cases of disease transmitted by mosquitoes during the 2013-14 season. The Australasian alphaviruses Barmah Forest virus and Ross River virus accounted for 6,372 (72%) total notifications. However, over-diagnosis and possible false positive diagnostic test results for these 2 infections mean that the true burden of infection is likely overestimated, and as a consequence, the case definitions have been amended. There were 94 notifications of imported chikungunya virus infection and 13 cases of imported Zika virus infection. There were 212 notifications of dengue virus infection acquired in Australia and 1,795 cases acquired overseas, with an additional 14 cases for which the place of acquisition was unknown. Imported cases of dengue were most frequently acquired in Indonesia (51%). No cases of locally-acquired malaria were notified during the 2013-14 season, though there were 373 notifications of overseas-acquired malaria. In 2013-14, arbovirus and mosquito surveillance programs were conducted in most jurisdictions. Surveillance for exotic mosquitoes at international ports of entry continues to be a vital part of preventing the spread of vectors of mosquito-borne diseases such as dengue to new areas of Australia, with 13 detections of exotic mosquitoes at the ports of entry in 2013-14

Arboviral diseases and malaria in Australia, 2012-13: Annual report of the National Arbovirus and Malaria Advisory Committee.

This report describes the epidemiology of mosquito-borne diseases of public health importance in Australia during the 2012-13 season (1 July 2012 to 30 June 2013) and includes data from human notifications, sentinel chicken, vector and virus surveillance programs. The National Notifiable Diseases Surveillance System received notifications for 9,726 cases of disease transmitted by mosquitoes during the 2012-13 season. The Australasian alphaviruses Barmah Forest virus and Ross River virus accounted for 7,776 (80%) of total notifications. However, over-diagnosis and possible false positive diagnostic test results for these 2 infections mean that the true burden of infection is likely overestimated, and as a consequence, the case definitions were revised, effective from 1 January 2016. There were 96 notifications of imported chikungunya virus infection. There were 212 notifications of dengue virus infection acquired in Australia and 1,202 cases acquired overseas, with an additional 16 cases for which the place of acquisition was unknown. Imported cases of dengue were most frequently acquired in Indonesia. No locally-acquired malaria was notified during the 2012-13 season, though there were 415 notifications of overseas-acquired malaria. There were no cases of Murray Valley encephalitis virus infection in 2012-13. In 2012-13, arbovirus and mosquito surveillance programs were conducted in most jurisdictions with a risk of vectorborne disease transmission. Surveillance for exotic mosquitoes at the border continues to be a vital part of preventing the spread of mosquito-borne diseases such as dengue to new areas of Australia, and in 2012-13, there were 7 detections of exotic mosquitoes at the border