Visual pigment concentration and photoreceptor outer segment length in the human retina.

PURPOSE: The Beer-Lambert law suggests that visual pigment optical density (OD) should be linearly related to the length of photoreceptor outer segments (POSs). Mammalian studies indicate that visual pigment concentration increases with POS length, but the nature of this relationship may vary due to factors such as visual pigment packing density or retinal eccentricity, and may not necessarily be linearly related. The purpose of this study was to establish the relationship between OD and POS length in humans. METHODS: Spectral domain optical coherence tomography (OCT) was used to image POS, and imaging retinal densitometry (IRD) was used to measure OD at corresponding locations in 19 healthy participants (age range 25-82 years). POS length and OD measurements were extracted from OCT and IRD images at 23 discrete locations spanning the central 9° of the retina. The averaged data from all participants were fitted with models based on the Beer-Lambert law to establish the relationship between OD and POS length. RESULTS: Visual pigment OD increased monotonically with POS length, but the relationship was non-linear, and a straight-line fit, based on a simple interpretation of the Beer-Lambert law, provided a poor description. A model allowing for different rod and cone visual pigment concentrations provided a superior fit. Specifically, the data were well described by a model where the molar concentration of visual pigment in cones and rods were 3.8 × 10-3 mol/L and 1.8 × 10-3mol/L, respectively. CONCLUSIONS: In accordance with the Beer-Lambert law, the results indicate that OD increases monotonically with POS length in humans, but the precise relationship is dependent on photoreceptor type. These results suggest that visual pigment concentration in rods is only about 48% of that found in cones. This may be due to the ubiquitous nature of artificial light that works to reduce the concentration of rhodopsin in rod photoreceptors.

Clinicopathologic Heterogeneity and Glial Activation Patterns in Alzheimer Disease.

Importance: Factors associated with clinical heterogeneity in Alzheimer disease (AD) lay along a continuum hypothesized to associate with tangle distribution and are relevant for understanding glial activation considerations in therapeutic advancement. Objectives: To examine clinicopathologic and neuroimaging characteristics of disease heterogeneity in AD along a quantitative continuum using the corticolimbic index (CLix) to account for individuality of spatially distributed tangles found at autopsy. Design, Setting, and Participants: This cross-sectional study was a retrospective medical record review performed on the Florida Autopsied Multiethnic (FLAME) cohort accessioned from 1991 to 2020. Data were analyzed from December 2022 to December 2023. Structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) were evaluated in an independent neuroimaging group. The FLAME cohort includes 2809 autopsied individuals; included in this study were neuropathologically diagnosed AD cases (FLAME-AD). A digital pathology subgroup of FLAME-AD cases was derived for glial activation analyses. Main Outcomes and Measures: Clinicopathologic factors of heterogeneity that inform patient history and neuropathologic evaluation of AD; CLix score (lower, relative cortical predominance/hippocampal sparing vs higher, relative cortical sparing/limbic predominant cases); neuroimaging measures (ie, structural MRI and tau-PET). Results: Of the 2809 autopsied individuals in the FLAME cohort, 1361 neuropathologically diagnosed AD cases were evaluated. A digital pathology subgroup included 60 FLAME-AD cases. The independent neuroimaging group included 93 cases. Among the 1361 FLAME-AD cases, 633 were male (47%; median [range] age at death, 81 [54-96] years) and 728 were female (53%; median [range] age at death, 81 [53-102] years). A younger symptomatic onset (Spearman ρ = 0.39, P < .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P < .001) correlated with a lower CLix score in FLAME-AD series. Cases with a nonamnestic syndrome had lower CLix scores (median [IQR], 13 [9-18]) vs not (median [IQR], 21 [15-27]; P < .001). Hippocampal MRI volume (Spearman ρ = -0.45; P < .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = -0.74; P < .001) inversely correlated with CLix score. Although AD cases with a CLix score less than 10 had higher cortical tangle count, we found lower percentage of CD68-activated microglia/macrophage burden (median [IQR], 0.46% [0.32%-0.75%]) compared with cases with a CLix score of 10 to 30 (median [IQR], 0.75% [0.51%-0.98%]) and on par with a CLix score of 30 or greater (median [IQR], 0.40% [0.32%-0.57%]; P = .02). Conclusions and Relevance: Findings show that AD heterogeneity exists along a continuum of corticolimbic tangle distribution. Reduced CD68 burden may signify an underappreciated association between tau accumulation and microglia/macrophages activation that should be considered in personalized therapy for immune dysregulation.

Pain related to intravitreal injections for age-related macular degeneration: a qualitative study of the perspectives of patients and practitioners.

OBJECTIVES: Ocular pain is a commonly reported finding in the intravitreal injection procedure, but post-injection experiences and patient adherence to treatment remain underexplored. We therefore aimed to identify key variations in the intravitreal injection procedure that may influence pain, and to gain insights into the post-injection experience and treatment adherence from the perspective of patients and practitioners. DESIGN: Qualitative semistructured interview study using reflexive thematic analysis of transcripts. SETTING: Hospital Eye Clinic in Wales, UK. Interviews were conducted between May and September 2019. PARTICIPANTS: Purposive sample of patients aged ≥50 years with neovascular age-related macular degeneration and no other retinal pathology who had received at least six intravitreal injections, and practitioners including ophthalmologists, registered nurses and optometrists who performed intravitreal injections at the research site. RESULTS: Data saturation was reached with 21 interviews: 14 patients and 7 practitioners. Three main themes were identified from the analysis: fear of losing eyesight and treatment anxiety influence patient adherence to treatment, variability in pain experience during treatment, and post-injection experience and impact on patient recovery. To reassure patients feeling apprehensive about the injections, practitioners promoted safety and trust, and used techniques to manage anxiety. Key variations that may influence pain identified were application of antiseptic or anaesthetic, injecting methods and communication. During injection, patients reported a dull-aching and sharp pain, contrary to practitioners' perspective of feeling a 'pressure'. Patients described prolonged soreness and irritation of up to 36 hours post-injection affecting their sleep and recovery. CONCLUSION: Establishing rapport supported patients to recognise the necessity of ongoing treatment to prevent sight loss; however, inadequate pain management led to undesirable outcomes. Practitioners should use pain assessment tools during and immediately after injection and provide ongoing consistent information to help patients manage pain at home.

Preparation of Nucleic Acid Aptamer Functionalized Silver/Gold Nanoparticle Conjugates Using Thiol-Substituted Oligonucleotides.

Silver and gold nanoparticle-aptamer conjugates have been extensively utilized as biosensors and microscopic vehicles that deliver a therapeutic cargo to cells. Here, we describe facile procedures to attach nucleic acid aptamers with a free thiol group to silver or gold nanoparticles. Methods to purify the nanoparticle-aptamer conjugates, verify aptamer attachment, and quantify aptamer-nanoparticle ratios are also discussed and compared. Additionally, a simple protocol that describes the aqueous synthesis of gold nanoparticles (~10 nm) is included.

Evaluation of Automated Multiclass Fluid Segmentation in Optical Coherence Tomography Images Using the Pegasus Fluid Segmentation Algorithms.

Purpose: To evaluate the performance of the Pegasus-OCT (Visulytix Ltd) multiclass automated fluid segmentation algorithms on independent spectral domain optical coherence tomography data sets. Methods: The Pegasus automated fluid segmentation algorithms were applied to three data sets with edematous pathology, comprising 750, 600, and 110 b-scans, respectively. Intraretinal fluid (IRF), sub-retinal fluid (SRF), and pigment epithelial detachment (PED) were automatically segmented by Pegasus-OCT for each b-scan where ground truth from data set owners was available. Detection performance was assessed by calculating sensitivities and specificities, while Dice coefficients were used to assess agreement between the segmentation methods. Results: For two data sets, IRF detection yielded promising sensitivities (0.98 and 0.94, respectively) and specificities (1.00 and 0.98) but less consistent agreement with the ground truth (dice coefficients 0.81 and 0.59); likewise, SRF detection showed high sensitivity (0.86 and 0.98) and specificity (0.83 and 0.89) but less consistent agreement (0.59 and 0.78). PED detection on the first data set showed moderate agreement (0.66) with high sensitivity (0.97) and specificity (0.98). IRF detection in a third data set yielded less favorable agreement (0.46-0.57) and sensitivity (0.59-0.68), attributed to image quality and ground truth grader discordance. Conclusions: The Pegasus automated fluid segmentation algorithms were able to detect IRF, SRF, and PED in SD-OCT b-scans acquired across multiple independent data sets. Dice coefficients and sensitivity and specificity values indicate the potential for application to automated detection and monitoring of retinal diseases such as age-related macular degeneration and diabetic macular edema. Translational Relevance: The potential of Pegasus-OCT for automated fluid quantification and differentiation of IRF, SRF, and PED in OCT images has application to both clinical practice and research.

Safety and Outcomes of Combined Liver Transplantation and Cardiac Surgery in Cirrhosis.

BACKGROUND: Decompensation of liver function after cardiac surgery in patients with cirrhosis has resulted in high morbidity and mortality. A treatment strategy, for which there is a scarcity of data in the literature, encompasses combined liver transplantation and cardiac surgery. METHODS: We performed a retrospective analysis of prospectively collected data on 15 patients who underwent combined liver transplantation and cardiac surgery between 2005 to 2017 at our institution. RESULTS: Between 2005 and 2017, 15 patients with cirrhosis and coronary artery disease or valve disease were identified who underwent combined liver transplantation and cardiac surgery. The cardiac disease was considered severe enough to preclude liver transplantation alone. Likewise, the advanced cirrhosis precluded cardiac surgery alone. Eighty percent of the patients were male and average age was 60 years. Six patients had coronary artery disease, 2 patients had severe aortic stenosis and coronary artery disease, 1 patient had severe mitral regurgitation and coronary artery disease, 2 patients had severe aortic stenosis, 1 patient had mitral valve prolapse, and 3 patients had severe aortic insufficiency. The mean model for end-stage liver disease score was 24. Four subjects were Child-Pugh class B, and 11 were class C. One-year survival was 73.3%. CONCLUSIONS: Combined liver transplant and cardiac surgery is feasible in this selected, otherwise inoperable, patient population with an acceptable early and midterm survival when performed in high volume centers with a cohesive multidisciplinary team.

Graft-Versus-Host Disease After Liver Transplantation.

http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-2-reading-wood a video presentation of this article http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-2-interview-lindenmeyer an interview with the author.

Functional Imaging of the Outer Retinal Complex using High Fidelity Imaging Retinal Densitometry.

We describe a new technique, high fidelity Imaging Retinal Densitometry (IRD), which probes the functional integrity of the outer retinal complex. We demonstrate the ability of the technique to map visual pigment optical density and synthesis rates in eyes with and without macular disease. A multispectral retinal imaging device obtained precise measurements of retinal reflectance over space and time. Data obtained from healthy controls and 5 patients with intermediate AMD, before and after photopigment bleaching, were used to quantify visual pigment metrics. Heat maps were plotted to summarise the topography of rod and cone pigment kinetics and descriptive statistics conducted to highlight differences between those with and without AMD. Rod and cone visual pigment synthesis rates in those with AMD (v = 0.043 SD 0.019 min-1 and v = 0.119 SD 0.046 min-1, respectively) were approximately half those observed in healthy controls (v = 0.079 SD 0.024 min-1 for rods and v = 0.206 SD 0.069 min-1 for cones). By mapping visual pigment kinetics across the central retina, high fidelity IRD provides a unique insight into outer retinal complex function. This new technique will improve the phenotypic characterisation, diagnosis and treatment monitoring of various ocular pathologies, including AMD.

DISEASE CLASSIFICATION OF MACULAR OPTICAL COHERENCE TOMOGRAPHY SCANS USING DEEP LEARNING SOFTWARE: Validation on Independent, Multicenter Data.

PURPOSE: To evaluate Pegasus optical coherence tomography (OCT), a clinical decision support software for the identification of features of retinal disease from macula OCT scans, across heterogenous populations involving varying patient demographics, device manufacturers, acquisition sites, and operators. METHODS: Five thousand five hundred and eighty-eight normal and anomalous macular OCT volumes (162,721 B-scans), acquired at independent centers in five countries, were processed using the software. Results were evaluated against ground truth provided by the data set owners. RESULTS: Pegasus-OCT performed with areas under the curve of the receiver operating characteristic of at least 98% for all data sets in the detection of general macular anomalies. For scans of sufficient quality, the areas under the curve of the receiver operating characteristic for general age-related macular degeneration and diabetic macular edema detection were found to be at least 99% and 98%, respectively. CONCLUSION: The ability of a clinical decision support system to cater for different populations is key to its adoption. Pegasus-OCT was shown to be able to detect age-related macular degeneration, diabetic macular edema, and general anomalies in OCT volumes acquired across multiple independent sites with high performance. Its use thus offers substantial promise, with the potential to alleviate the burden of growing demand in eye care services caused by retinal disease.

Refractive Error Has Minimal Influence on the Risk of Age-Related Macular Degeneration: A Mendelian Randomization Study.

PURPOSE: To test the hypothesis that refractive errors such as myopia and hyperopia cause an increased risk of age-related macular degeneration (AMD) and to quantify the degree of risk. DESIGN: Two-sample Mendelian randomization analysis of data from a genome-wide association study. PARTICIPANTS: As instrumental variables for refractive error, 126 genome-wide significant genetic variants identified by the Consortium for Refractive Error and Myopia and 23andMe Inc. were chosen. The association with refractive error for the 126 variants was obtained from a published study for a sample of 95,505 European ancestry participants from UK Biobank. Association with AMD for the 126 genetic variants was determined from a genome-wide association study (GWAS) published by the International Age-related Macular Degeneration Genomics consortium of 33,526 (16,144 cases and 17,832 controls) European ancestry participants. METHODS: Two-sample Mendelian randomization (MR) analysis was used to assess the causal role of refractive error on AMD risk, using the 126 genetic variants associated with refractive error as instrumental variables, under the assumption that the relationship between refractive error and AMD risk is linear. MAIN OUTCOME MEASUREMENT: the risk AMD was caused by a 1-diopter (D) change in refractive error. RESULTS: MR analysis suggested that refractive error had very limited influence on the risk of AMD. Specifically, 1 D more hyperopic refractive error was associated with an odds ratio (OR) of 1.080 (95% confidence interval [CI], 1.021-1.142; P = 0.007) increased risk of AMD. MR-Egger, MR pleiotropy residual sum and outlier, weighted median, and Phenoscanner-based sensitivity analyses detected minimal evidence to suggest that this result was biased by horizontal pleiotropy. CONCLUSIONS: Under the assumption of a linear relationship between refractive error and the risk of AMD, myopia and hyperopia only minimally influence the causal risk for AMD. Thus, inconsistently reported strong associations between refractive error and AMD are likely to be the result of noncausal factors such as stochastic variation, confounding, or selection bias.

Provider Reimbursement Following the Affordable Care Act.

Decreasing health care expenditures has been one of the main objectives of the Affordable Care Act. To achieve this goal, the Centers for Medicare and Medicaid Services (CMS) has been tasked with experimenting with provider reimbursement methods in an attempt to increase quality, while decreasing costs. The purpose of this research was to study the effects of the Affordable Care Act on physician reimbursement rates from CMS to determine the most cost-effective method of delivering health care services. The CMS has experimented with payment methods in an attempt to increase cost-effectiveness. Medicare has offered shared cost-savings incentives to reward quality care to both primary care providers and preventative services. The CMS has determined fee-for-service payments obsolete, opting instead for a value-based purchasing method of payment. Although a universal payment method has yet to be adopted, it has been evident that a value-based purchasing model and preventative care can be used to decrease health care expenditure.

The Scope of Extraprofessional Caregiving Challenges Among Early Career Faculty: Findings From a University Medical Center.

PURPOSE: Academic scientists work in competitive environments, and many institutions invest in career development supports. These investments may be imperiled when extraprofessional demands challenge a faculty member's reserve capacity. This research assessed prevalence of caregiving challenges and estimated incidence of stressful life events. METHOD: In 2015-2016, the authors surveyed recipients of career development awards supporting ≥ 75% effort and individuals within the funding period of their first National Institutes of Health R01 or equivalent at Vanderbilt University Medical Center. Domains included family structure, hospitalizations of family members, responsibility for coordination of caregiving, and an inventory of stressful life events. RESULTS: Seventy-two percent (152 of 210) of early career researchers responded. Over half endorsed experiencing one or more substantial caregiving challenges in the prior year. This included 35 (23%) having a child or adult in the household hospitalized in the prior year and 36 (24%) being responsible for health care needs for a child or adult in the household, or for coordinating elder care, assisted living, or hospice care. The majority experienced one or more caregiving challenges. Stressful life events increased relative risk of "thinking about leaving academics" by 70% (risk ratio: 1.7; 95% confidence interval: 1.2, 2.4). Prevalence and incidence of caregiving demands did not differ by gender. CONCLUSIONS: Leaders, administrators, mentors, and faculty should anticipate that most women and men early career researchers will experience substantial caregiving challenges and life events in any given year. Sufficient need exists to warrant investigation of institutional programs to address caregiving challenges.

Applying Precision Medicine to Ovarian Cancer: Proof-of-Principle for a "Molecular Second Look".

OBJECTIVES: The objectives of this study were to assess if targeted investigation for tumor-specific mutations by ultradeep DNA sequencing of peritoneal washes of ovarian cancer patients after primary surgical debulking and chemotherapy, and clinically diagnosed as disease free, provides a more sensitive and specific method to assess actual treatment response and tailor future therapy and to compare this "molecular second look" with conventional cytology and histopathology-based findings. METHODS/MATERIALS: We identified 10 patients with advanced-stage, high-grade serous ovarian cancer who had undergone second-look laparoscopy and for whom DNA could be isolated from biobanked paired blood, primary and recurrent tumor, and second-look peritoneal washes. A targeted 56 gene cancer-relevant panel was used for next-generation sequencing (average coverage, >6500×). Mutations were validated using either digital droplet polymerase chain reaction (ddPCR) or Sanger sequencing. RESULTS: A total of 25 tumor-specific mutations were identified (median, 2/patient; range, 1-8). TP53 mutations were identified in at least 1 sample from all patients. All 5 pathology-based second-look positive patients were confirmed positive by molecular second look. Genetic analysis revealed that 3 of the 5 pathology-based negative second looks were actually positive. In the 2 patients, the second-look mutations were present in either the original primary or recurrent tumors. In the third, 2 high-frequency, novel frameshift mutations in MSH6 and HNF1A were identified. CONCLUSIONS: The molecular second look detects tumor-specific evidence of residual disease and provides genetic insight into tumor evolution and future recurrences beyond standard pathology. In the precision medicine era, detecting and genetically characterizing residual disease after standard treatment will be invaluable for improving patient outcomes.

Automated Retinal Layer Segmentation Using Spectral Domain Optical Coherence Tomography: Evaluation of Inter-Session Repeatability and Agreement between Devices.

Retinal and intra-retinal layer thicknesses are routinely generated from optical coherence tomography (OCT) images, but on-board software capabilities and image scaling assumptions are not consistent across devices. This study evaluates the device-independent Iowa Reference Algorithms (Iowa Institute for Biomedical Imaging) for automated intra-retinal layer segmentation and image scaling for three OCT systems. Healthy participants (n = 25) underwent macular volume scans using a Cirrus HD-OCT (Zeiss), 3D-OCT 1000 (Topcon), and a non-commercial long-wavelength (1040nm) OCT on two occasions. Mean thickness of 10 intra-retinal layers was measured in three ETDRS subfields (fovea, inner ring and outer ring) using the Iowa Reference Algorithms. Where available, total retinal thicknesses were measured using on-board software. Measured axial eye length (AEL)-dependent scaling was used throughout, with a comparison made to the system-specific fixed-AEL scaling. Inter-session repeatability and agreement between OCT systems and segmentation methods was assessed. Inter-session coefficient of repeatability (CoR) for the foveal subfield total retinal thickness was 3.43µm, 4.76µm, and 5.98µm for the Zeiss, Topcon, and long-wavelength images respectively. For the commercial software, CoR was 4.63µm (Zeiss) and 7.63µm (Topcon). The Iowa Reference Algorithms demonstrated higher repeatability than the on-board software and, in addition, reliably segmented all 10 intra-retinal layers. With fixed-AEL scaling, the algorithm produced significantly different thickness values for the three OCT devices (P<0.05), with these discrepancies generally characterized by an overall offset (bias) and correlations with axial eye length for the foveal subfield and outer ring (P<0.05). This correlation was reduced to an insignificant level in all cases when AEL-dependent scaling was used. Overall, the Iowa Reference Algorithms are viable for clinical and research use in healthy eyes imaged with these devices, however ocular biometry is required for accurate quantification of OCT images.

A beginning of the end: new insights into the functional organization of telomeres.

Ever since the first demonstration of their repetitive sequence and unique replication pathway, telomeres have beguiled researchers with how they function in protecting chromosome ends. Of course much has been learned over the years, and we now appreciate that telomeres are comprised of the multimeric protein/DNA shelterin complex and that the formation of t-loops provides protection from DNA damage machinery. Deriving their name from D-loops, t-loops are generated by the insertion of the 3' overhang into telomeric repeats facilitated by the binding of TRF2. Recent studies have uncovered novel forms of chromosome end-structure that may implicate telomere organization in cellular processes beyond its essential role in telomere protection and homeostasis. In particular, we have recently described that t-loops form in a TRF2-dependent manner at interstitial telomere repeat sequences, which we termed interstitial telomere loops (ITLs). These structures are also dependent on association of lamin A/C, a canonical component of the nucleoskeleton that is mutated in myriad human diseases, including human segmental progeroid syndromes. Since ITLs are associated with telomere stability and require functional lamin A/C, our study suggests a mechanistic link between cellular aging (replicative senescence induced by telomere shortening) and organismal aging (modeled by Hutchinson Gilford Progeria Syndrome). Here we speculate on other potential ramifications of ITL formation, from gene expression to genome stability to chromosome structure.

Eating disorders and sense of self: a learning theory conceptualization.

The learning theory view of sense of self is that problems in one's knowledge about the self arise when: (1) caregivers fail to recognize indicators of a child's private emotional and visceral experiences and (2) subsequently fail to offer appropriate labels that discriminate among those experiences. The purpose of this study was to evaluate the relationship of the process believed to build a sense of self to level of interoceptive awareness (IA) and to risk for eating disorders. One hundred twenty seven undergraduate and graduate students (112 women) completed the Eating Disorders Inventory-3 (EDI-3). Authors assigned (EDI-3) subscales to one of two groups based on their relevance to IA (i.e., IA-relevant and Not IA-relevant.) The classification was supported by factor analysis. Subscales from the EDI-3 were thus used as a measure of a respondent's IAlevel. Students also completed the Experience of Self Scale (EOSS). The EOSS was used as a measure of a respondent's likely exposure to the experiential process believed to build sense of self. Product-moment correlations and multiple regression modeling were used to test the relationships between EOSS and EDI-3 IA-relevant, Not IA-relevant, and Eating Disorder risk scores. With few exceptions, results suggested that IAlevel and sense of selfprocess are related. These findings warrant further exploration of the relationship between IAlevel and sense of selfprocess. A link between the two would inform our understanding of how problems in IA develop and how best to prevent and treat them.

TRF2 and lamin A/C interact to facilitate the functional organization of chromosome ends.

Telomeres protect the ends of linear genomes, and the gradual loss of telomeres is associated with cellular ageing. Telomere protection involves the insertion of the 3' overhang facilitated by telomere repeat-binding factor 2 (TRF2) into telomeric DNA, forming t-loops. We present evidence suggesting that t-loops can also form at interstitial telomeric sequences in a TRF2-dependent manner, forming an interstitial t-loop (ITL). We demonstrate that TRF2 association with interstitial telomeric sequences is stabilized by co-localization with A-type lamins (lamin A/C). We also find that lamin A/C interacts with TRF2 and that reduction in levels of lamin A/C or mutations in LMNA that cause an autosomal dominant premature ageing disorder--Hutchinson Gilford Progeria Syndrome (HGPS)-lead to reduced ITL formation and telomere loss. We propose that cellular and organismal ageing are intertwined through the effects of the interaction between TRF2 and lamin A/C on chromosome structure.

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.

A Crowdsourced nucleus: understanding nuclear organization in terms of dynamically networked protein function.

The spatial organization of the nucleus results in a compartmentalized structure that affects all aspects of nuclear function. This compartmentalization involves genome organization as well as the formation of nuclear bodies and plays a role in many functions, including gene regulation, genome stability, replication, and RNA processing. Here we review the recent findings associated with the spatial organization of the nucleus and reveal that a common theme for nuclear proteins is their ability to participate in a variety of functions and pathways. We consider this multiplicity of function in terms of Crowdsourcing, a recent phenomenon in the world of information technology, and suggest that this model provides a novel way to synthesize the many intersections between nuclear organization and function. This article is part of a Special Issue entitled: Chromatin and epigenetic regulation of animal development.