Gamma-rays from ultracompact minihalos: potential constraints on the primordial curvature perturbation

Ultracompact minihalos (UCMHs) are dense dark matter structures which can form from large density perturbations shortly after matter-radiation equality. If dark matter is in the form of Weakly Interacting Massive Particles (WIMPs), then UCMHs may be detected via their gamma-ray emission. We investigate how the {\em{Fermi}} satellite could constrain the abundance of UCMHs and place limits on the power spectrum of the primordial curvature perturbation. Detection by {\em Fermi} would put a lower limit on the UCMH halo fraction. The smallest detectable halo fraction, $f_{\rm UCMH} \gtrsim 10^{-7}$, is for $M_{\rm UCMH} \sim 10^{3} M_{\odot}$. If gamma-ray emission from UCMHs is not detected, an upper limit can be placed on the halo fraction. The bound is tightest, $f_{\rm UCMH} \lesssim 10^{-5}$, for $M_{\rm UCMH} \sim 10^{5} M_{\odot}$. The resulting upper limit on the power spectrum of the primordial curvature perturbation in the event of non-detection is in the range $\mathcal{P_R} \lesssim 10^{-6.5}- 10^{-6}$ on scales $k \sim 10^{1}-10^{6} \, {\rm Mpc}^{-1}$. This is substantially tighter than the existing constraints from primordial black hole formation on these scales, however it assumes that dark matter is in the form of WIMPs and UCMHs are not disrupted during the formation of the Milky Way halo.Comment: 5 pages, 2 figures, version to appear in Phys. Rev. D, minor change

Microperimetry as an outcome measure in RPGR-associated retinitis pigmentosa clinical trials

Purpose: To explore which microperimetry sensitivity index (pointwise sensitivity, mean sensitivity, and volume sensitivity) is suitable as a microperimetry outcome measure in patients with X-linked RPGR-associated retinitis pigmentosa (RP). Methods: Microperimetry data from patients with RPGR-associated RP were collected and analyzed retrospectively. Fourteen participants completed triplicate microperimetry testing, across 2 consecutive days for the repeatability analyses. Longitudinal data was obtained from 13 participants who completed microperimetry testing at two separate visits. Results: The test–retest coefficients of repeatability (CoR) for pointwise sensitivity were ±9.5 dB and ±9.3 dB, in the right and left eyes, respectively. The mean sensitivity CoR for the right and left eyes was ±0.7 dB and ±1.3 dB. Volume sensitivity CoR was ±144.5 dB*deg2 and ±324.2 dB*deg2 for the right and left eyes, respectively. The mean sensitivities were positively skewed toward zero in those with a high number of nonseeing points (arbitrarily assigned to −1.0 dB) and just seen points (0.0 dB). Volume sensitivities were unaffected by the averaging effects of skewed data. Conclusions: Clinical trials should report population-specific test–retest variability to determine a clinically significant change. Pointwise sensitivity indices should be used with caution as outcome measures in clinical trials owing to high levels of test–retest variability. Global indices seem to be less prone to variability. Volume sensitivity indices seem to be superior for use in RPGR-associated RP clinical trials compared with mean sensitivity because they are unaffected by the averaging effects of highly skewed data. Translational Relevance: Careful selection of sensitivity indices (VA) is required when using microperimetry as a clinical trial outcome measure

Investigating the impact of asymmetric macular sensitivity on visual acuity chart reading in choroideraemia

Introduction: Degeneration in choroideraemia, unlike typical centripetal photoreceptor degenerations, is centred temporal to the fovea. Once the fovea is affected, the nasal visual field (temporal retina) is relatively spared, and the preferred retinal locus shifts temporally. Therefore, when reading left to right, only the right eye reads into a scotoma. We investigate how this unique property affects the ability to read an eye chart. Methods: Standard‐ and low‐luminance visual acuity (VA) for right and left eyes were measured with the Early Treatment of Diabetic Retinopathy Study (ETDRS) chart. Letters in each line were labelled by column position. The numbers of letter errors for each position across the whole chart were summed to produce total column error scores for each participant. Macular sensitivity was assessed using microperimetry. Central sensitivity asymmetry was determined by the temporal‐versus‐nasal central macular difference and subsequently correlated to a weighted ETDRS column error score. Healthy volunteers and participants with X‐linked retinitis pigmentosa GTPase regulator associated retinitis pigmentosa (RPGR‐RP) were used as controls. Results: Thirty‐nine choroideraemia participants (median age 44.9 years [IQR 35.7–53.5]), 23 RPGR‐RP participants (median age 30.8 years [IQR 26.5–40.5]) and 35 healthy controls (median age 23.8 years [IQR 20.3–29.0]) were examined. In choroideraemia, standard VA in the right eye showed significantly greater ETDRS column errors on the temporal side compared with the nasal side (p = 0.002). This significantly correlated with greater asymmetry in temporal‐versus‐nasal central macular sensitivity (p = 0.04). No significant patterns in ETDRS column errors or central macular sensitivity were seen in the choroideraemia left eyes, nor in RPGR‐RP and control eyes. Conclusion: Difficulty in tracking across lines during ETDRS VA testing may cause excess errors independent of true VA. VA assessment with single‐letter optotype systems may be more suitable, particularly for patients with choroideraemia, and potentially other retinal diseases with asymmetric central macular sensitivity or large central scotomas including geographic atrophy

Generalised constraints on the curvature perturbation from primordial black holes

Primordial black holes (PBHs) can form in the early Universe via the collapse of large density perturbations. There are tight constraints on the abundance of PBHs formed due to their gravitational effects and the consequences of their evaporation. These abundance constraints can be used to constrain the primordial power spectrum, and hence models of inflation, on scales far smaller than those probed by cosmological observations. We compile, and where relevant update, the constraints on the abundance of PBHs before calculating the constraints on the curvature perturbation, taking into account the growth of density perturbations prior to horizon entry. We consider two simple parameterizations of the curvature perturbation spectrum on the scale of interest: constant and power-law. The constraints from PBHs on the amplitude of the power spectrum are typically in the range 10^{-2}-10^{-1} with some scale dependence.Comment: 10 pages, 2 figures, version to appear in Phys. Rev. D with minor change to calculation of constraints for spectral index not equal to on

Structural and Functional Characteristics of Color Vision Changes in Choroideremia

Color vision is considered a marker of cone function and its assessment in patients with retinal pathology is complementary to the assessments of spatial vision [best-corrected visual acuity (BCVA)] and contrast detection (perimetry). Rod-cone and chorioretinal dystrophies—such as choroideremia—typically cause alterations to color vision, making its assessment a potential outcome measure in clinical trials. However, clinical evaluation of color vision may be compromised by pathological changes to spatial vision and the visual field. The low vision Cambridge Color Test (lvCCT) was developed specifically to address these latter issues. We used the trivector version of the lvCCT to quantify color discrimination in a cohort of 53 patients with choroideremia. This test enables rapid and precise characterization of color discrimination along protan, deutan, and tritan axes more reliably than the historically preferred test for clinical trials, namely the Farnsworth Munsell 100 Hue test. The lvCCT demonstrates that color vision defects—particularly along the tritan axis—are seen early in choroideremia, and that this occurs independent of changes in visual acuity, pattern electroretinography and ellipsoid zone area on optical coherence tomography (OCT). We argue that the selective loss of tritan color discrimination can be explained by our current understanding of the machinery of color vision and the pathophysiology of choroideremia

A cross-sectional study to assess the clinical utility of modern visual function assessments in patients with inherited retinal disease: a mixed methods observational study protocol

Abstract Background Treatment options for patients with inherited retinal disease are limited, although research into novel therapies is underway. To ensure the success of future clinical trials, appropriate visual function outcome measures that can assess changes resulting from therapeutic interventions are urgently required. Rod-cone degenerations are the most common type of inherited retinal disease. Visual acuity is a standard measure but is typically preserved until late disease stages, frequently making it an unsuitable visual function marker. Alternative measures are required. This study investigates the clinical utility of a range of carefully selected visual function tests and patient reported outcome measures. The aim is to identify suitable outcome measures for future clinical trials that could be considered for regulatory approval. Methods This cross-sectional study involves two participant groups, patients with inherited retinal disease (n = 40) and healthy controls (n = 40). The study has been designed to be flexible and run alongside NHS clinics. The study is split into two parts. Part one includes examining standard visual acuity, low luminance visual acuity, the Moorfields acuity chart visual acuity, mesopic microperimetry and three separate patient reported outcome measures. Part two involves 20 min of dark adaptation followed by two-colour scotopic microperimetry. Repeat testing will be undertaken where possible to enable repeatability analyses. A subset of patients with inherited retinal disease will be invited to participate in a semi-structured interview to gain awareness of participants’ thoughts and feelings around the study and different study tests. Discussion The study highlights a need for reliable and sensitive validated visual function measures that can be used in future clinical trials. This work will build on work from other studies and be used to inform an outcome measure framework for rod-cone degenerations. The study is in keeping with the United Kingdom Department of Health and Social Care research initiatives and strategies for increasing research opportunities for NHS patients as part of their NHS care. Trial registration ISRCTN registry, ISRCTN24016133, Visual Function in Retinal Degeneration, registered on 18th August 2022

Scotopic microperimetry: evolution, applications and future directions

For many inherited and acquired retinal diseases, reduced night vision is a primary symptom. Despite this, the clinical testing options for spatially-resolved scotopic vision have until recently been limited. Scotopic microperimetry is a relatively new visual function test that combines two-colour perimetry with fundus-controlled perimetry performed in scotopic luminance conditions. The technique enables spatially-resolved mapping of central retinal sensitivity alongside the ability to distinguish between rod and cone photoreceptor sensitivities. Two companies produce commercially available scotopic microperimeters – Nidek (Nidek Technologies Srl, Padova, Italy) and CenterVue (CenterVue S.p.A., Padova, Italy). Scotopic microperimetry is a promising technology capable of detecting changes in retinal sensitivity before changes in other measures of visual function. Scotopic microperimetry is a promising functional biomarker that has potential as a useful clinical trial outcome measure. In this review, we summarise the evolution and applications of scotopic microperimetry, discuss testing options, including testing grid selection and dark-adaptation time and threshold sensitivity analyses

Microperimetry as an Outcome Measure in RPGR-associated Retinitis Pigmentosa Clinical Trials

Purpose: To explore which microperimetry sensitivity index (pointwise sensitivity, mean sensitivity, and volume sensitivity) is suitable as a microperimetry outcome measure in patients with X-linked RPGR-associated retinitis pigmentosa (RP). Methods: Microperimetry data from patients with RPGR-associated RP were collected and analyzed retrospectively. Fourteen participants completed triplicate microperimetry testing, across 2 consecutive days for the repeatability analyses. Longitudinal data was obtained from 13 participants who completed microperimetry testing at two separate visits. Results: The test–retest coefficients of repeatability (CoR) for pointwise sensitivity were ±9.5 dB and ±9.3 dB, in the right and left eyes, respectively. The mean sensitivity CoR for the right and left eyes was ±0.7 dB and ±1.3 dB. Volume sensitivity CoR was ±144.5 dB*deg2 and ±324.2 dB*deg2 for the right and left eyes, respectively. The mean sensitivities were positively skewed toward zero in those with a high number of nonseeing points (arbitrarily assigned to −1.0 dB) and just seen points (0.0 dB). Volume sensitivities were unaffected by the averaging effects of skewed data. Conclusions: Clinical trials should report population-specific test–retest variability to determine a clinically significant change. Pointwise sensitivity indices should be used with caution as outcome measures in clinical trials owing to high levels of test–retest variability. Global indices seem to be less prone to variability. Volume sensitivity indices seem to be superior for use in RPGR-associated RP clinical trials compared with mean sensitivity because they are unaffected by the averaging effects of highly skewed data. Translational Relevance: Careful selection of sensitivity indices (VA) is required when using microperimetry as a clinical trial outcome measure