The Cramer-Rao Bound and DMT Signal Optimisation for the Identification of a Wiener-Type Model

In linear system identification, optimal excitation signals can be determined using the Cramer-Rao bound. This problem has not been thoroughly studied for the nonlinear case. In this work, the Cramer-Rao bound for a factorisable Volterra model is derived. The analytical result is supported with simulation examples. The bound is then used to find the optimal excitation signal out of the class of discrete multitone signals. As the model is nonlinear in the parameters, the bound depends on the model parameters themselves. On this basis, a three-step identification procedure is proposed. To illustrate the procedure, signal optimisation is explicitly performed for a third-order nonlinear model. Methods of nonlinear optimisation are applied for the parameter estimation of the model. As a baseline, the problem of optimal discrete multitone signals for linear FIR filter estimation is reviewed

Primordial Black Holes: sirens of the early Universe

Primordial Black Holes (PBHs) are, typically light, black holes which can form in the early Universe. There are a number of formation mechanisms, including the collapse of large density perturbations, cosmic string loops and bubble collisions. The number of PBHs formed is tightly constrained by the consequences of their evaporation and their lensing and dynamical effects. Therefore PBHs are a powerful probe of the physics of the early Universe, in particular models of inflation. They are also a potential cold dark matter candidate.Comment: 21 pages. To be published in "Quantum Aspects of Black Holes", ed. X. Calmet (Springer, 2014

Two years after molecular diagnosis of familial hypercholesterolemia: Majority on cholesterol-lowering treatment but a minority reaches treatment goal

Background: The risk of premature cardiovascular disease in patients with familial hypercholesterolemia (FH) can be profoundly reduced by cholesterol-lowering therapy, and current guidelines for FH advocate ambitious low-density lipoprotein cholesterol (LDL-C) goals. In the present study, we determined whether these goals are reflected in current clinical practice once FH has been diagnosed. Methodology/Principal Findings: In 2008, we sent questionnaires to all subjects (aged 18-65 years) who were molecularly diagnosed with FH in the year 2006 through the screening program in the Netherlands. Of these 1062 subjects, 781 completed the questionnaire (46% males; mean age: 42±12 years; mean LDL-C at molecular diagnosis (baseline): 4.1±1.3 mmol/L). The number of persons that used cholesterol-lowering therapy increased from 397 (51%) at baseline to 636 (81%) after diagnosis. Mean treated LDL-C levels decreased significantly to 3.2±1.1 mmol/L two years after diagnosis. Only 22% achieved the LDL-C target level of ≤2.5 mmol/L. Conclusions/Significance: The proportion of patients using cholesterol-lowering medication was significantly increased after FH diagnosis through

The Cramer-Rao Bound and DMT Signal Optimisation for the Identification of a Wiener-Type Model

In linear system identification, optimal excitation signals can be determined using the Cramer-Rao bound. This problem has not been thoroughly studied for the nonlinear case. In this work, the Cramer-Rao bound for a factorisable Volterra model is derived. The analytical result is supported with simulation examples. The bound is then used to find the optimal excitation signal out of the class of discrete multitone signals. As the model is nonlinear in the parameters, the bound depends on the model parameters themselves. On this basis, a three-step identification procedure is proposed. To illustrate the procedure, signal optimisation is explicitly performed for a third-order nonlinear model. Methods of nonlinear optimisation are applied for the parameter estimation of the model. As a baseline, the problem of optimal discrete multitone signals for linear FIR filter estimation is reviewed.</p

A network meta-analysis of retreatment rates following bevacizumab, ranibizumab, aflibercept and laser for retinopathy of prematurity

Topic: To compare bevacizumab, ranibizumab, aflibercept and laser as primary therapies for retinopathy of prematurity (ROP) in terms of retreatment rate. Clinical relevance: Anti-VEGF agents are increasingly used as primary treatment for ROP and may provide superior outcomes compared with laser in posterior disease. Head-to-head comparisons between different anti-VEGFs are lacking. Methods: We searched CENTRAL, EMBASE, MEDLINE and CINAHL for randomised controlled trials and non-randomised comparative studies as of March 2022. We included studies that used bevacizumab, ranibizumab, aflibercept and laser for ROP with comparable cohorts and treatment criteria. Studies were evaluated by the GRADE framework and those with biased case selection, non-randomised case-control, or lack of control group were excluded. Frequentist meta-analyses of proportions were performed to determine the absolute primary retreatment rate of each modality followed by Bayesian network meta-analyses to compare pairs of treatments in Type 1 and Zone I ROP. Results: 30 studies (4686 eyes) were included in the network meta-analyses. For Type 1 ROP, single treatment success rates (i.e. likelihood of needing no further treatment) were 89.3% (95% CI: 83.8-93.8; n=1552) for laser, 87.0% (78.6-93.8; n=2081) for bevacizumab, 80.7% (62.0-94.4; n=326) for aflibercept, and 74.0% (62.7-84.1; n=727) for ranibizumab. Bayesian network meta-analysis indicates that laser is associated with a significant 62% (95% CrI: 16-83) reduction in retreatment risk compared with ranibizumab, while no significant differences were found between other pair-wise comparisons. The mean time to secondary treatment following primary aflibercept (12.96 weeks ±0.47 SEM) and bevacizumab (11.36±0.54) were significantly longer than primary ranibizumab (9.29±0.43) therapy (p=7E-07 and p=9E-03 respectively). For Zone I ROP, single treatment success rates were 91.2% (83.6-96.9; n=231) for bevacizumab, 78.3% (61.4-91.9; n=100) for ranibizumab, and 65.9% (41.4-87.2; n=158) for laser. In this case, Bayesian network meta-analysis suggests that primary bevacizumab is associated with a significant 67% (10-90) reduction in retreatment risk compared with laser. No moderating effects were found to arise from gestational age, birth weight, or post-menstrual age at treatment when considering each modality in isolation using a frequentist approach. Conclusions: Laser was associated with a lower rate of retreatment than ranibizumab in Type 1 ROP (Zones I and II combined), while bevacizumab was associated with lower rate of retreatment than laser in Zone I ROP. Aflibercept and bevacizumab demonstrate longer duration of action than ranibizumab for ROP.</p

Low luminance visual acuity as a clinical measure and clinical trial outcome measure: a scoping review

Purpose: The measurement of standard visual acuity (VA) is the most well‐known part of any ophthalmic examination to indicate visual function. Despite this, it is insensitive in detecting early disease changes. Therefore, other visual function tests have been developed including low luminance VA (LLVA) and low luminance deficit (LLD). This scoping literature review aims to summarise the current published applications of LLVA and LLD assessments to evaluate their utility as clinical markers and research outcome measures in a variety of ophthalmic conditions. Recent findings: Sixty‐five peer‐reviewed publications were included. LLVA was pioneered for use in geographic atrophy, a subtype of age‐related macular degeneration, which remains the mainstay of its clinical application. However, other studies have reported additional useful applications in inherited retinal diseases including rare maculopathies and rod‐cone dystrophies. Although there are some variations in testing methodology, use of the standard Early Treatment Diabetic Retinopathy Study (ETDRS) chart with a 2.0 log unit neutral density filter is the most popular approach. The optimal testing luminance is still to be defined. Summary: Overall, LLVA is an earlier clinical marker of change in central retinal function than standard VA. It has been shown to be a risk factor for disease progression and a better indicator of a patient’s level of everyday visual function. It is inexpensive and simple to implement using readily available standard ophthalmic equipment.</p

Low luminance visual acuity and low luminance deficit in choroideremia and RPGR-associated retinitis pigmentosa

Introduction: Choroideremia and RPGR-associated retinitis pigmentosa (RP) are two distinct inherited rod-cone degenerations, where good visual acuity (VA) is maintained until late disease stages, limiting its usefulness as a disease marker. Low luminance VA and low luminance deficit (standard VA minus low luminance VA) may be more sensitive visual function measures. Methods: Standard VA was obtained using Early Treatment Diabetic Retinopathy Study letter charts (Precision Vision, Bloomington, IL, USA). Low luminance VA was assessed using a 2.0-log unit neutral density filter, with the same chart setup, without formal dark adaptation. Mean central retinal sensitivity was assessed using MAIA microperimetry (Centervue SpA, Padova, Italy). Optical coherence tomography imaging was attained with Heidelberg Eye Explorer software (Heidelberg Engineering, Heidelberg, Germany). Results: Twenty-four male participants with confirmed pathogenic RPGR mutations, 44 male participants with confirmed pathogenic CHM mutations, and 62 age-matched controls underwent clinical assessment prior to clinical trial recruitment. Low luminance VA was significantly reduced in both disease groups compared to controls. The low luminance deficit correlated with microperimetry retinal sensitivity and ellipsoid zone width. Eleven participants with moderate VA had poor low luminance VA (subsequently a large low luminance deficit), no detectable microperimetry sensitivity, and severely constricted ellipsoid zone widths. Conclusions:Low luminance VA and subsequently low luminance deficit are useful markers of central macular visual function in both choroideremia and RPGR-associated RP, when standard VA is preserved. Translational Relevance: Low luminance visual acuity and low luminance deficit are useful vision measures in two distinct rod-cone degenerations and may be useful in other retinal degenerations

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

Emerging lipoprotein-related therapeutics for patients with diabetes

Dyslipidemia is a major risk factor for atherosclerosis in both diabetic and nondiabetic subjects, which is a common cause of morbidity and premature mortality. Based on and supported by favorable outcomes of clinical trials, drugs targeting lipoprotein metabolism are widely used, particularly in developed countries. Drugs to improve lipid levels, in particular to lower low-density lipoprotein (LDL) cholesterol (LDL-C), are commonly used for the primary and secondary prevention of cardiovascular disease. Of the LDL-C-lowering drugs, HMG-CoA reductase inhibitors (“statins”) are particularly effective at reducing cardiovascular disease, both in people with and without diabetes mellitus [1, 2], with more intensive LDL-C lowering being more effective than less intensive LDL-C lowering [3–12]. Statins are effective cardioprotective agents in both type 1 and type 2 diabetes patients [2]