Classification of Human Retinal Microaneurysms Using Adaptive Optics Scanning Light Ophthalmoscope Fluorescein Angiography

Purpose. Microaneurysms (MAs) are considered a hallmark of retinal vascular disease, yet what little is known about them is mostly based upon histology, not clinical observation. Here, we use the recently developed adaptive optics scanning light ophthalmoscope (AOSLO) fluorescein angiography (FA) to image human MAs in vivo and to expand on previously described MA morphologic classification schemes. Methods. Patients with vascular retinopathies (diabetic, hypertensive, and branch and central retinal vein occlusion) were imaged with reflectance AOSLO and AOSLO FA. Ninety-three MAs, from 14 eyes, were imaged and classified according to appearance into six morphologic groups: focal bulge, saccular, fusiform, mixed, pedunculated, and irregular. The MA perimeter, area, and feret maximum and minimum were correlated to morphology and retinal pathology. Select MAs were imaged longitudinally in two eyes. Results. Adaptive optics scanning light ophthalmoscope fluorescein angiography imaging revealed microscopic features of MAs not appreciated on conventional images. Saccular MAs were most prevalent (47%). No association was found between the type of retinal pathology and MA morphology (P = 0.44). Pedunculated and irregular MAs were among the largest MAs with average areas of 4188 and 4116 μm2, respectively. Focal hypofluorescent regions were noted in 30% of MAs and were more likely to be associated with larger MAs (3086 vs. 1448 μm2, P = 0.0001). Conclusions. Retinal MAs can be classified in vivo into six different morphologic types, according to the geometry of their two-dimensional (2D) en face view. Adaptive optics scanning light ophthalmoscope fluorescein angiography imaging of MAs offers the possibility of studying microvascular change on a histologic scale, which may help our understanding of disease progression and treatment response

Quintessence, inflation and baryogenesis from a single pseudo-Nambu-Goldstone boson

We exhibit a model in which a single pseudo-Nambu-Goldstone boson explains dark energy, inflation and baryogenesis. The model predicts correlated signals in future collider experiments, WIMP searches, proton decay experiments, dark energy probes, and the PLANCK satellite CMB measurements.Comment: 16 pages, 3 color figure

Relationship Between Foveal Cone Specialization and Pit Morphology in Albinism

Purpose.Albinism is associated with disrupted foveal development, though intersubject variability is becoming appreciated. We sought to quantify this variability, and examine the relationship between foveal cone specialization and pit morphology in patients with a clinical diagnosis of albinism. Methods. We recruited 32 subjects with a clinical diagnosis of albinism. DNA was obtained from 25 subjects, and known albinism genes were analyzed for mutations. Relative inner and outer segment (IS and OS) lengthening (fovea-to-perifovea ratio) was determined from manually segmented spectral domain-optical coherence tomography (SD-OCT) B-scans. Foveal pit morphology was quantified for eight subjects from macular SD-OCT volumes. Ten subjects underwent imaging with adaptive optics scanning light ophthalmoscopy (AOSLO), and cone density was measured. Results. We found mutations in 22 of 25 subjects, including five novel mutations. All subjects lacked complete excavation of inner retinal layers at the fovea, though four subjects had foveal pits with normal diameter and/or volume. Peak cone density and OS lengthening were variable and overlapped with that observed in normal controls. A fifth hyper-reflective band was observed in the outer retina on SD-OCT in the majority of the subjects with albinism. Conclusions. Foveal cone specialization and pit morphology vary greatly in albinism. Normal cone packing was observed in the absence of a foveal pit, suggesting a pit is not required for packing to occur. The degree to which retinal anatomy correlates with genotype or visual function remains unclear, and future examination of larger patient groups will provide important insight on this issue

The Effect of Cone Opsin Mutations on Retinal Structure and the Integrity of the Photoreceptor Mosaic

Purpose. To evaluate retinal structure and photoreceptor mosaic integrity in subjects with OPN1LW and OPN1MW mutations. Methods. Eleven subjects were recruited, eight of whom have been previously described. Cone and rod density was measured using images of the photoreceptor mosaic obtained from an adaptive optics scanning light ophthalmoscope (AOSLO). Total retinal thickness, inner retinal thickness, and outer nuclear layer plus Henle fiber layer (ONL+HFL) thickness were measured using cross-sectional spectral-domain optical coherence tomography (SD-OCT) images. Molecular genetic analyses were performed to characterize the OPN1LW/OPN1MW gene array. Results. While disruptions in retinal lamination and cone mosaic structure were observed in all subjects, genotype-specific differences were also observed. For example, subjects with “L/M interchange” mutations resulting from intermixing of ancestral OPN1LW and OPN1MW genes had significant residual cone structure in the parafovea (∼25% of normal), despite widespread retinal disruption that included a large foveal lesion and thinning of the parafoveal inner retina. These subjects also reported a later-onset, progressive loss of visual function. In contrast, subjects with the C203R missense mutation presented with congenital blue cone monochromacy, with retinal lamination defects being restricted to the ONL+HFL and the degree of residual cone structure (8% of normal) being consistent with that expected for the S-cone submosaic. Conclusions. The photoreceptor phenotype associated with OPN1LW and OPN1MW mutations is highly variable. These findings have implications for the potential restoration of visual function in subjects with opsin mutations. Our study highlights the importance of high-resolution phenotyping to characterize cellular structure in inherited retinal disease; such information will be critical for selecting patients most likely to respond to therapeutic intervention and for establishing a baseline for evaluating treatment efficacy

Minimal Noncanonical Cosmologies

We demonstrate how much it is possible to deviate from the standard cosmological paradigm of inflation-assisted LambdaCDM, keeping within current observational constraints, and without adding to or modifying any theoretical assumptions. We show that within a minimal framework there are many new possibilities, some of them wildly different from the standard picture. We present three illustrative examples of new models, described phenomenologically by a noncanonical scalar field coupled to radiation and matter. These models have interesting implications for inflation, quintessence, reheating, electroweak baryogenesis, and the relic densities of WIMPs and other exotics.Comment: 20 pages, 5 figures, 3 table

Disruption of the Cr2 Locus Results in a Reduction in B-1a Cells and in an Impaired B Cell Response to T-Dependent Antigen

AbstractCovalent attachment of activated products of the third component of complement to antigen enhances its immunogenicity, but the mechanism is not clear. This effect is mediated by specific receptors, mCR1 (CD35) and mCR2 (CD21), expressed primarily on B cells and follicular dendritic cells in mice. To dissect the role of mCR1 and mCR2 in the humoral response, we have disrupted the Cr2 locus to generate mice deficient in both receptors. The deficient mice (Cr2−/−) were found to have a reduction in the CD5+ population of peritoneal B-1 cells, although their serum IgM levels were within the range of normal mice. Moreover, Cr2−/− mice had a severe defect in their humoral response to T-dependent antigens that was characterized by a reduction in serum antibody titers and in the number and size of germinal centers within splenic follicles. Reconstitution of the deficient mice with bone marrow from MHC-matched Cr2+/+ donors corrected the defect, demonstrating that the defect was due to B cells themselves. These results indicate an obligatory role of B cell complement receptors in responses of the B cells to protein antigens

Detection of a Pair Density Wave State in UTe2_2

Although UTe$_2$ is a very promising candidate material to embody bulk topological superconductivity, its superconductive order-parameter $\Delta(\mathbf{k})$ remains unknown. Many diverse forms for $\Delta(\mathbf{k})$ are physically possible because, in uranium-based heavy fermion materials, strongly hybridized flat bands of composite fermions generate highly complex interactions. Moreover, in such materials intertwined density waves of spin (SDW), charge (CDW) and pairs (PDW) may interpose, with the latter state exhibiting spatially modulating superconductive order-parameter $\Delta(\mathbf{r})$, electron pair density and pairing energy-gap. Hence, the newly discovered CDW state in UTe$_2$ motivates the exciting prospect that a PDW state may exist in this material. To search for a PDW in UTe$_2$, we visualize the pairing energy-gap with $\mu$$V$-scale energy-resolution made possible by superconductive STM tips at subkelvin temperatures. We detect three PDWs, each with peak-peak gap modulations circa 10 $\mu$$eV$ and at incommensurate wavevectors $\mathbf{P}_{i=1,2,3}$ that are indistinguishable from the wavevectors $\mathbf{Q}_{i=1,2,3}$ of the prevenient CDW. Concurrent visualization of the UTe$_2$ superconductive PDWs and the non-superconductive CDWs reveals that every $\mathbf{P}_i$ : $\mathbf{Q}_i$ pair is registered to each other spatially, but with a relative phase $\delta\phi \approx \pi$. From these observations, and given UTe$_2$ as a spin-triplet superconductor, the PDW state detected here should be a spin-triplet pair density wave. While such states do exist in superfluid $^{3}$He, for superconductors they are unprecedented.Comment: 37 pages, 13 figure

Ageing, physical function, and the diurnal rhythms of cortisol and dehydroepiandrosterone

The present study examined the relationship between ageing, physical function and the diurnal rhythms of cortisol and dehydroepiandrosterone (DHEA). Participants were 36 community dwelling older adults aged between 65-86 years old. Salivary cortisol and DHEA were measured over the course of one day: immediately upon awakening, 30 min later, and then 3 h, 6 h, 9 h and 12 h post-awakening. Participants completed the Nottingham extended activities of daily living index, the Berg Balance Scale and their handgrip strength was assessed. Older participants had a significantly higher cortisol area under the curve (AUC), lower overall DHEA levels, lower DHEA AUC, a decreased diurnal slope of decline and increased cortisol:DHEA ratio. Lower diurnal cortisol levels were associated with poorer performance on the Berg Balance Scale and lower handgrip strength, and those with a flattened DHEA diurnal profile reported less independence in carrying out daily tasks. These associations withstood adjustment for age. In conclusion, this study suggests an association between cortisol, DHEA, ageing and physical function

Change in Cone Structure Over 24 Months in USH2A-Related Retinal Degeneration

PurposeTo describe cone structure changes using adaptive optics scanning laser ophthalmoscopy (AOSLO) in the Rate of Progression of USH2A-related Retinal Degeneration (RUSH2A) study.DesignMulticenter, longitudinal natural history study.MethodsAOSLO images were acquired at 4 centers, twice at baseline and annually for 24 months in this natural history study. For each eye, at least 10 regions of interest (ROIs) with ≥50 contiguous cones were analyzed by masked, independent graders. Cone spacing Z-scores, standard deviations from the normal mean at the measured location, were compared between graders and tests at baseline. The association of cone spacing with clinical characteristics was assessed using linear mixed effects regression models weighted by image quality score. Annual rates of change were calculated based on differences between visits.ResultsFourteen eyes of 14 participants were imaged, with 192 ROIs selected at baseline. There was variability among graders, which was greater in images with lower image quality score (P < .001). Cone spacing was significantly correlated with eccentricity, quality score, and disease duration (P < .02). On average, the cone spacing Z-score increased 0.14 annually (about 9%, P < .001). We observed no significant differences in rate of change between disease type (Usher syndrome or retinitis pigmentosa), imaging site, or grader.ConclusionsUsing current methods, the analysis of quantitative measures of cone structure showed some challenges, yet showed promise that AOSLO images can be used to characterize progressive change over 24 months. Additional multicenter studies using AOSLO are needed to advance cone mosaic metrics as sensitive outcome measures for clinical trials. NOTE: Publication of this article is sponsored by the American Ophthalmological Society

Racial and Ethnic Differences in Total Knee Arthroplasty in the Veterans Affairs Health Care System, 2001-2013

OBJECTIVE: To examine black-white and Hispanic-white differences in total knee arthroplasty from 2001 to 2013 in a large cohort of patients diagnosed with osteoarthritis (OA) in the Veterans Affairs (VA) health care system. METHODS: Data were from the VA Musculoskeletal Disorders cohort, which includes data from electronic health records of more than 5.4 million veterans with musculoskeletal disorders diagnoses. We included white (non-Hispanic), black (non-Hispanic), and Hispanic (any race) veterans, age ≥50 years, with an OA diagnosis from 2001-2011 (n = 539,841). Veterans were followed from their first OA diagnosis until September 30, 2013. As a proxy for increased clinical severity, analyses were also conducted for a subsample restricted to those who saw an orthopedic or rheumatology specialist (n = 148,844). We used Cox proportional hazards regression to examine racial and ethnic differences in total knee arthroplasty by year of OA diagnosis, adjusting for age, sex, body mass index, physical and mental diagnoses, and pain intensity scores. RESULTS: We identified 12,087 total knee arthroplasty procedures in a sample of 473,170 white, 50,172 black, and 16,499 Hispanic veterans. In adjusted models examining black-white and Hispanic-white differences by year of OA diagnosis, total knee arthroplasty rates were lower for black than for white veterans diagnosed in all but 2 years. There were no Hispanic-white differences regardless of when diagnosis occurred. These patterns held in the specialty clinic subsample. CONCLUSION: Black-white differences in total knee arthroplasty appear to be persistent in the VA, even after controlling for potential clinical confounders