Electrophysiological investigation of age-related macular degeneration

Age-related macular degeneration (AMD) affects 12.7 million people in Europe and North America (Klein et al., 1995 Klein et al. 1999). As a combination of decreasing birth rate and increasing longevity alter the demographic of the population, the impact of this disease can only increase. This places an immense burden, not only on the individuals afflicted by the condition, but on the financial resources of society as a whole. Unfortunately, treatment for AMD is still very restricted, and even our understanding of the pathogenesis of the disease is far from complete One concern in tackling the growing problem of AMD is that methods used in the assessment of the condition are limited, usually based on fundus appearance and visual acuity. The aim of this study was to develop a battery of electrophysiological tests which would be sensitive to the most subtle changes in retinal function in AMD. Such tests may aid diagnosis, provide a more sensitive measure of disease progression, and allow an early identification of phenotypic subtypes. Protocols were included for the recording of the focal rod ERG, the focal cone ERG, the S-cone ERG and the dynamic focal cone ERG, along with psychophysical tests of colour vision and dark adaptation. These tests were then applied to 31 subjects with ARM (12 with bilateral ARM, 11 with unilateral wet AMD and 8 with unilateral dry AMD), and 28 controls. In the analysis of ERG amplitudes a ratio of focal to full-field amplitude was introduced as a novel means of reducing intersubject variability in response. This was found to increase the accuracy of all tests in distinguishing between subject groups. The greatest separation between ARM and control groups was provided by the dynamic tests of visual function i.e. rod-cone break time of the dark adaptation function, and time constant of recovery of the dynamic focal cone ERG. The time to rod-cone break also showed potential in identifying subjects at increased risk of exudative retinal changes. Subjects were assigned to groups in this study on the basis of fundus appearance. However, individuals within each subject group showed a range of retinal function which belied the homogeneity of retinal signs. This raises the question of whether 'form' or 'function' should form the basis of classification and assessment of individuals with ARM and AMD.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Electrophysiological investigation of age-related macular degeneration

Age-related macular degeneration (AMD) affects 12.7 million people in Europe and North America (Klein et al., 1995 Klein et al. 1999). As a combination of decreasing birth rate and increasing longevity alter the demographic of the population, the impact of this disease can only increase. This places an immense burden, not only on the individuals afflicted by the condition, but on the financial resources of society as a whole. Unfortunately, treatment for AMD is still very restricted, and even our understanding of the pathogenesis of the disease is far from complete One concern in tackling the growing problem of AMD is that methods used in the assessment of the condition are limited, usually based on fundus appearance and visual acuity. The aim of this study was to develop a battery of electrophysiological tests which would be sensitive to the most subtle changes in retinal function in AMD. Such tests may aid diagnosis, provide a more sensitive measure of disease progression, and allow an early identification of phenotypic subtypes. Protocols were included for the recording of the focal rod ERG, the focal cone ERG, the S-cone ERG and the dynamic focal cone ERG, along with psychophysical tests of colour vision and dark adaptation. These tests were then applied to 31 subjects with ARM (12 with bilateral ARM, 11 with unilateral wet AMD and 8 with unilateral dry AMD), and 28 controls. In the analysis of ERG amplitudes a ratio of focal to full-field amplitude was introduced as a novel means of reducing intersubject variability in response. This was found to increase the accuracy of all tests in distinguishing between subject groups. The greatest separation between ARM and control groups was provided by the dynamic tests of visual function i.e. rod-cone break time of the dark adaptation function, and time constant of recovery of the dynamic focal cone ERG. The time to rod-cone break also showed potential in identifying subjects at increased risk of exudative retinal changes. Subjects were assigned to groups in this study on the basis of fundus appearance. However, individuals within each subject group showed a range of retinal function which belied the homogeneity of retinal signs. This raises the question of whether 'form' or 'function' should form the basis of classification and assessment of individuals with ARM and AMD

MACUSTAR: Development and Clinical Validation of Functional, Structural, and Patient-Reported Endpoints in Intermediate Age-Related Macular Degeneration

Purpose: Currently, no outcome measures are clinically validated and accepted as clinical endpoints by regulatory agencies for drug development in intermediate age-related macular degeneration (iAMD). The MACUSTAR Consortium, a public-private research group funded by the European Innovative Medicines Initiative intends to close this gap. Procedures: Development of study protocol and statistical analysis plan including predictive modelling of multimodal endpoints based on a review of the literature and expert consensus. Results: This observational study consists of a cross-sectional and a longitudinal part. Functional outcome measures assessed under low contrast and low luminance have the potential to detect progression of visual deficit within iAMD and to late AMD. Structural outcome measures will be multimodal and investigate topographical relationships with function. Current patient-reported outcome measures (PROMs) are not acceptable to regulators and may not capture the functional deficit specific to iAMD with needed precision, justifying development of novel PROMs for iAMD. The total sample size will be n = 750, consisting mainly of subjects with iAMD (n = 600). Conclusions: As clinical endpoints currently accepted by regulators cannot detect functional loss or patient-relevant impact in iAMD, we will clinically validate novel candidate endpoints for iAMD

Benefits, Barriers and Enablers of Breastfeeding: Factor Analysis of Population Perceptions in Western Australia

Objective: The objective of this study was to investigate knowledge and community perceptions of breastfeeding in Western Australia using a factor analysis approach. Methods: Data were pooled from five Nutrition Monitoring Survey Series which included information on breastfeeding from 4,802 Western Australian adults aged 18–64 years. Tetrachoric factor analysis was conducted for data reduction and significant associations identified using logistic, ordinal and poisson regression analyses. Results: Four factors were derived for benefits (it’s natural, good nutrition, good for the baby, and convenience), barriers (breastfeeding problems, poor community acceptability, having to go back to work, and inconvenience) and for enablers (breastfeeding education, community support, family support and not having to work).As assessed by standardized odds ratios the most important covariates across benefit factors were: importance of breastfeeding (ORs range from 1.22–1.44),female gender (ORs range from 0.80 to 1.46), being able to give a time for how long a baby should be breastfed (ORs range from 0.96 to 1.27) and education (less than high school to university completion) (ORs range from 0.95 to 1.23); the most important covariate across barrier factors was being able to give a time for how long a baby should be breastfed (ORs range from 0.89 to 1.93); and the most important covariates across all enabling factors were education (ORs range from 1.14 to1.32) and being able to give a time for how long a baby should be breastfed (ORs range from 1.17 to 1.42).Conclusions: Being female, rating breastfeeding as important, believing that babies should be breastfed for a period of time and education accounted for most of the statistically significant associations. The differences between male and female perceptions require investigation particularly in relation to returning to work

Detection of early age-related macular degeneration using novel functional parameters of the focal cone electroretinogram

The focal cone electroretinogram is a sensitive marker for macular disease, but have we unlocked its full potential? Typically assessment of waveform parameters is subjective and focuses on a small number of locations (e.g. the a-wave). This study evaluated the discriminatory and diagnostic potential of 4 conventional and 15 novel, objectively determined, parameters in patients with early Age-related Macular Degeneration. Focal cone electroretinograms were recorded in 54 participants with early Age-related Macular Degeneration (72.9±8.2 years) and 54 healthy controls (69±7.7 years). Conventional a and b wave amplitudes and implicit times were measured and compared to novel parameters derived from both the 1st and 2nd derivatives and the frequency-domain power spectrum of the electroretinogram.Statistically significant differences between groups were shown for all conventional parameters, the majority of 1st and 2nd derivative parameters and the power spectrum at 25 and 30 Hz. Receiver operating characteristics showed that both conventional and 1st and 2nd derivative implicit times had provided the best diagnostic potential. A regression model showed a small improvement over any individual parameter investigated. The non-conventional parameters enhanced the objective evaluation of the focal electroretinogram, especially when the amplitude was low. Furthermore, the novel parameters described here allow the implicit time of the electroretinogram to be probed at points other than the peaks of the a and b waves. Consequently these novel analysis techniques could prove valuable in future electrophysiological investigation, detection and monitoring of Age-related Macular Degeneration

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

Focal cone ERG waveforms & derivatives.

<p>Representative raw, fourier smoothed, 1^st derivative and 2^nd derivative waveforms of the focal cone ERG are shown for 10 study participants. The waveforms shown were recorded from five healthy participants (TOP) and five early AMD participants (BOTTOM).</p

Example focal cone ERG waveform and frequency-domain power spectrum.

<p>(A) A focal cone ERG waveform before (shown in grey) and after fourier smoothing (overlaid in black). Arrows exemplify measurement of ‘a’ and ‘b’ wave amplitudes. (B) The focal cone ERG shown in the frequency-domain (power spectrum) at the fundamental frequency (f₀ = 5 Hz) and its harmonics up to 45 Hz.</p

Focal cone ERG parameters for Control and AMD groups showing discriminatory and diagnostic ability.

<p>μ - mean</p><p>σ - standard deviation</p><p>* - statistically significant (p<0.05)</p><p>AUC - Area under the curve for Receiver operating characteristics</p

Labelled focal cone ERG waveform and derivatives.

<p>(A) A fourier smoothed focal cone ERG waveform with 20 ms pre-flash baseline and the conventional waveform components, the negative a-wave, the positive b wave and the Photopic Negative Response (PhNR) labelled. (B) 1^st derivative showing gradient or the “rate of change” against time. (C) 2^nd derivative showing zero crossings which correspond to inflection points in the original waveform. Dashed vertical lines correspond to the location of 3 inflection points in the Fourier smoothed waveform (A) and time of flash (labelled) across the 3 waveforms (A, B & C) shown.</p