This study attempts to determine whether midwall myocardial fibrosis burden is associated with adverse clinical outcomes in asymptomatic patients and whether those with more fibrosis derive greater benefit from early intervention. QuestionIn asymptomatic patients with severe aortic stenosis, is myocardial fibrosis burden associated with adverse events and potential benefits of early valve intervention?FindingsIn this post hoc analysis of a randomized clinical trial, higher midwall fibrosis burden was associated with increasing incidence of the primary composite end point of all-cause death or unplanned aortic stenosis-related hospitalization. However, the potential beneficial effects of early valve intervention demonstrated no significant heterogeneity by the degree of midwall fibrosis.MeaningIn this study, in asymptomatic patients with severe aortic stenosis, higher fibrosis burden was associated with adverse outcomes; benefits of early intervention were similar between patients with high and low fibrosis burden. ImportanceMyocardial fibrosis burden has been associated with adverse clinical outcomes in symptomatic patients with aortic stenosis.ObjectiveTo determine whether midwall myocardial fibrosis burden is associated with adverse clinical outcomes in asymptomatic patients and whether those with more fibrosis derive greater benefit from early intervention.Design, Setting, and ParticipantsThis post hoc analysis of a randomized clinical trial was conducted between August 2017 and October 2022. The trial took place at 24 cardiac centers across the United Kingdom and Australia. Participants included asymptomatic patients with severe aortic stenosis and midwall fibrosis on cardiac magnetic resonance. These data were analyzed from October 2024 through June 2025.InterventionEarly intervention with transcatheter or surgical aortic valve replacement.Main Outcomes and MeasuresPrimary outcome was all-cause death or unplanned aortic stenosis-related hospitalization. Secondary outcomes included the individual components of the primary outcome.ResultsIn 224 trial participants (mean [SD] age, 73 [9] years; 63 women and 161 men, and mean [SD] aortic valve peak velocity 4.3 [0.5] m per second) with a median follow-up of 42 months, fibrosis burden (per 1% increase) was associated with an increase in the primary end point (hazard ratio [HR], 1.23; 95% CI, 1.08-1.37) and its component of unplanned aortic stenosis-related hospitalizations (HR, 1.22; 95% CI, 1.03-1.40) but not all-cause death (HR, 1.17; 95% CI, 0.98-1.35). There were no interactions between randomization arm and the midwall fibrosis burden for the primary (P for interaction = .39) or secondary end points. In patients with high fibrosis burden above the median, the primary end point occurred in 12 of 59 (20%) of those randomized to early intervention and 17 of 53 (32%) of those randomized to guideline-directed conservative management (HR, 0.62; 95% CI, 0.29-1.28). For the individual components, all-cause death occurred in 9 (15%) and 10 (19%) patients, respectively (HR, 0.84; 95% CI, 0.33-2.07), and unplanned aortic stenosis-related hospitalization in 4 (7%) and 13 (25%) patients respectively (HR, 0.27; 95% CI, 0.08-0.77). In patients with low fibrosis burden below the median, there were no differences in the primary outcome (HR, 1.05; 95% CI, 0.39-2.86) or its components between intervention groups.Conclusions and RelevanceIn this study, in asymptomatic patients with severe aortic stenosis, higher midwall fibrosis burden was associated with adverse outcomes. There was no demonstrable heterogeneity by the degree of midwall fibrosis for the treatment effects of early surgical or transcatheter aortic valve replacement compared to clinical surveillance.Trial RegistrationClinicalTrials.gov Identifier: NCT03094143

Microvascular dysfunction is increasingly recognized as an important contributor to ocular and systemic diseases, including diabetic retinopathy, cardiovascular disease, and Alzheimer's disease and related dementias. Elucidating how early microvascular injury contributes to disease pathobiology, and development of sensitive, quantifiable features of microvascular dysfunction, represents a critical frontier for improving risk stratification, enabling earlier diagnosis and guiding targeted interventions. In this context, retinal imaging has emerged as a powerful modality, enabling non-invasive, high-resolution visualization of the microvasculature with color and (ultra)widefield fundus imaging. Rapid technological advances have led to an array of, open-source tools for quantitative extraction of retinal microvascular features. However, progress in this field is hampered by poor comparability between tools, limiting reproducibility and cross-study integration. Differences between tools originate from variations in image processing steps, including vessel segmentation, arteriole-venule classification, optic disc detection, region-of-interest definition, image quality assessment, and the algorithms for metric calculation. In this review we comprehensively compare existing analytical analysis tools for static vessel analyses and delineate how these methodological differences influence the vascular measure quantification. To advance robust, scalable biomarker development, we propose a methodological framework to standardize and harmonize retinal microvascular quantification. This framework can guide future studies in addressing key gaps in literature and in developing imaging biomarkers for clinical use. Critical open questions include whether and when retinal imaging features change during ocular and systemic disease, whether microvascular dysfunction is reversible, how microvascular dysfunction contributes to neurodegeneration, and how central and peripheral retinal microvascular dysfunction differ.

High-altitude chronic hypoxia can induce excessive erythrocytosis (EE, defined as a haemoglobin concentration of ≥21 g/dL in men), leading to hyperviscosity and promoting endothelial dysfunction. We aimed to assess whether EE affects the retinal vascular phenotype and the ophthalmological vascular response to CO2. We conducted an ophthalmological cross-sectional study among highlanders permanently living at 5100 m (La Rinconada, Peru). The central retinal artery equivalent (CRAE), central retinal vein equivalent (CRVE) and retinal vessel tortuosity were measured using semi-automatic imaging software (VAMPIRE) from the diameters of the six largest arteries and veins on fundus images. Choroidal blood flow was assessed using laser Doppler flowmetry. Measurements were performed at rest and during a hypercapnic challenge (+10.1 ± 1.4 mmHg end-tidal CO2). Among the 62 included highlanders, 38 (61%) had EE. Compared with non-EE, highlanders with EE exhibited higher CRVE (278 ± 25 vs. 249 ± 24 µm, P < 0.001), with no other significant ophthalmological differences. Resting CRVE was significantly correlated (all P-values < 0.001) with haematocrit (r = 0.56), haemoglobin concentration (r = 0.65), blood volume (r = 0.55) and the arterial partial pressure of carbon dioxide (r = 0.46). Hypercapnia led to a moderate overall decrease in CRVE (-8.6 ± 22.0 µm, P = 0.02), without a specific effect of EE, and induced no other retinal vascular or choroidal blood flow changes in either group. We observed larger retinal vein diameters in EE highlanders compared with non-EE. Although hypercapnia is known to increase retinal vessel diameter in healthy lowlanders, it selectively decreased CRVE in highlanders, irrespective of EE status. These findings suggest a retinal vascular dysfunction in highlanders, probably induced by chronic exposure to severe hypoxia.

BACKGROUND:There is an unmet need for biomarkers that can dynamically track maternal vascular health and guide interventions in disordered pregnancies. The retina and choroid provide a window into the systemic vasculature. We aimed to characterize longitudinal trajectories of retinal and choroidal features during healthy pregnancy and explore differences associated with preeclampsia. METHODS:Overall, 251 pregnant women underwent multimodal retinal imaging with color fundus photography, scanning laser ophthalmoscopy, and optical coherence tomography at multiple antenatal (12±3 or 20±3 weeks' gestation and 36±3 weeks' gestation, n=183) or a single third-trimester (36±3 weeks' gestation, n=68) time point. Retinal and choroidal vascular features were extracted using an automated pipeline. We examined gestational trajectories of these features and their associations with blood pressure change and serum angiogenic factors. Trajectories were compared for women with preeclampsia and those without placental dysfunction. RESULTS:Significant reductions in measurements of retinal vessel caliber and density and of choroidal thickness, and increases in retinal thickness measurements, were seen over healthy pregnancy. These changes were not correlated with maternal blood pressure change. Third-trimester retinal arteriolar caliber and density were weakly correlated with placental growth factor (r=0.32, P<0.001 and r=0.31, P<0.001) and soluble fms-like tyrosine kinase 1 (r=-0.21, P=0.006 and r=-0.33, P<0.001) levels. Preeclampsia was associated with significantly greater reductions in retinal arteriolar caliber (P=0.022 for right eye, P=0.019 for left) and density (P<0.001 for each eye) across gestation. CONCLUSIONS:Retinal and choroidal features change throughout pregnancy, and these trajectories are altered in preeclampsia. REGISTRATION:URL: https://doi.org/10.1186/ISRCTN40843826; Unique identifier: ISRCTN40843826.

Purpose:To evaluate retinal and choroidal vascular alterations in multiple sclerosis (MS) using multimodal imaging and determine their association with disability and disease progression. Design:Prospective, observational, single center, cross-sectional, case-control study. Participants:Sixteen MS and 25 control participants. Methods:Multimodal retinal imaging, including color fundus photography, ultra-widefield imaging, OCT, and OCT angiography, were performed. Retinal vascular parameters (RVPs) and choroidal vascular parameters (CVPs) were compared between control eyes and eyes with (eyes with a history of optic neuritis [MSON]) and without optic neuritis (ON) (eyes without a history of ON [MSnON]) using regression models. Associations of RVPs and CVPs with Expanded Disability Status Scale (EDSS) scores and annual EDSS progression rate were assessed. Subanalysis compared RVPs and CVPs between MSnON and MSON eyes using Wilcoxon rank-sum tests. Main Outcome Measures:Differences in RVPs and CVPs between groups and associations with EDSS and annual rate of EDSS progression. Results:Compared with controls, MSnON eyes showed narrower central retinal venules (P = 0.014), increased arteriole-to-venule ratio (AVR) (P = 0.031), and reduced venular fractal dimension (FD) (P = 0.013). Disability correlated with increased venular caliber (P < 0.001), vessel density (P = 0.026), superficial vascular complex (SVC) capillary density (P < 0.001), and choroidal thickness (P = 0.006), and decreased AVR (P = 0.006) and choroidal vascularity index (P = 0.030). Annual EDSS progression was associated with increased arteriolar caliber (P = 0.001), AVR (P= 0.025), SVC capillary density (P < 0.001), foveal avascular zone (FAZ) volume (P < 0.001), and deep FAZ area (P < 0.001) and a decreased venular width gradient (P = 0.011) and FD (P < 0.001). Eyes with a history of ON eyes showed narrower venular caliber (P = 0.008), density (P = 0.012), and FD (P = 0.006). When MSON and MSnON are compared, ON affected only central arteriolar caliber (P = 0.010) and global SVC density (P = 0.010). Conclusions:Structural retinal and choroidal vascular alterations in MS were associated with disability and disease progression. These findings highlight the importance of retinal vascular assessments in the diagnosis, monitoring, and prognostication of MS, warranting confirmation in longitudinal studies. Financial Disclosures:Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Bisphenol-A-ethoxylate dimethacrylate (BEMA) is an emerging non-cytotoxic, photo-responsive hydrogel that can be used to fabricate microchannel flow systems for use in ultrasound mediated drug delivery research. This study aims to assess the acoustic properties at ultrasound frequencies up to 50 MHz, in addition to the elastic properties of BEMA prior to its use in the fabrication of preclinical flow phantoms. As a comparison, acoustic and mechanical properties of both ex-vivo rat aorta and a series of conventional vessel-mimicking materials were also studied, including polyvinyl alcohol cryogel (1 to 7 freeze-thaw cycles), agar (prepared under IEC standard), and C-Flex®. In this study, BEMA hydrogel exhibited a mean speed-of-sound of 1608.6 ± 8.74 m/s, mean attenuation of 0.64 ± 0.12 dB·cm⁻1·MHz⁻1 and a median indentation elastic modulus of 425 kPa. In contrast, ex-vivo rat aorta was measured to have mean speed-of-sound of 1533.5 ± 46.9 to 1534.6 ± 38.5 m·s⁻1, attenuation at 0.61 ± 0.17 to 0.73 ± 0.20 dB·cm⁻1·MHz⁻1, for thoracic and abdominal aorta, respectively, and overall median indentation elastic modulus of 7.07 kPa (interquartile range: 4.92-10.14 kPa). Given the above results, BEMA hydrogel samples demonstrated high repeatability, however, to realistically mimic vessels, further optimization of the photopolymerization process is required to align the elastic modulus with that measured from vessels.

Morphological measurements of retinal vessel parameters are commonly obtained from fundus images using semi-automatic software packages. Since image quality, and image processing methods are potential sources of variation of such measurements, the aim of this study was to determine quantitatively the effect of using different fundus cameras and image resolutions on measurements of retinal vascular parameters. Fifty-four digital fundus images of 27 healthy subjects were acquired using two non-mydriatic cameras, Topcon TRC NW6S and Canon CR-2. Central retinal artery and vein equivalent (CRAE, CRVE), arteriolar and venular tortuosity (TortA and TortV) and fractal dimension (FD) were calculated using VAMPIRE software. First, VAMPIRE measurements were compared between Topcon images (3008 × 2000 pixels) and Canon images after resizing manually (CR2r, 3008 × 2000 px). The effect of different resolutions was studied using Canon images at full resolution (4147 × 2764 px, 100%) and then scaled at 83.8%, 75% and 50% in JPEG format using the dedicated Canon software. When comparing images acquired by CR2r and Topcon at the same resolution, all parameters were significantly affected. When using images with different resolutions from the same camera, significant increases of CRAE and CRVE and significant decreases of FD were found for decreasing resolutions. In conclusion, vascular measurements from images from different fundus cameras or at different resolutions are not, in general, directly comparable.

Excess adiposity has been associated with Hodgkin lymphoma (HL) development, but its implications remain unclear. Bone marrow (BM), a frequent extranodal involvement site, contains both red and fatty yellow marrow. We investigated whether obesity influences HL outcomes and characterized the BM and cytokine profiles. In this retrospective study, HL patients were analyzed to assess the association between obesity with relapse and mortality. Yellow and red marrow composition were evaluated using CT imaging and correlated with HL outcomes. A nested study analyzed cytokines in the interstitial marrow fluid (IMF) and in circulation of HL patients, in comparison to a control group of healthy blood donors. Further, in vitro functional analyses were performed. Overweight/obesity in HL patients was associated with lower rates of BM involvement, disease relapse, and mortality. Moreover, dense yellow marrow was related to increased risk of death. HL subjects had elevated levels of adiponectin in IMF compared to marrow donors, whereas higher insulin, interleukin 8, and osteoprotegerin levels in IMF were associated with shorter time to relapse. At the molecular level in BM, HL patients had overexpression of LEPR and IGFBP3 in adipocytes, while stromal cells overexpressed IGF-axis receptors. In in vitro studies, human recombinant IGF-1 significantly induced the L428 HL cell line proliferation, which when combined with IGFBP-3 modified apoptosis. The current findings suggest that obesity is associated with a lower incidence of BM involvement and mortality in patients with HL. The obesity together with HL mechanistically influences systemic and local BM cytokine production, thereby impacting HL fate.

OBJECTIVES:Microcirculatory dysfunction drives the end-organ pathophysiology of circulatory shock but is not reflected within existing clinical indices of perfusion, such as blood pressure. The choroidal vasculature of the retina can be measured non-invasively and we hypothesised that this may reflect dysfunction in other organs. We tested the feasibility of measuring the choroid in intensive care and explored associations between choroidal measurements and clinical parameters. DESIGN:A pilot study of optical coherence tomography conducted in a sample of general intensive care unit (ICU) patients. SETTING:A tertiary mixed ICU within the UK. PARTICIPANTS:15 patients were recruited. One patient was excluded following withdrawal of active treatment. 12/14 (86%) of the remaining patients had successful baseline imaging and 6 (40%) of these had follow-up imaging within intensive care. These patients had a mean age of 56.3 years, were 71% (10/14) male and mean Acute Physiology and Chronic Health Evaluation 2 (APACHE2) score on ICU admission was 20.4. OUTCOME MEASURES:Choroidal anatomy, including choroidal and suprachoroidal thickness, as well as volumetric analysis of intrachoroidal blood vessels, was assessed using automated image segmentation along with clinical, physiological and biochemical data at ICU admission and after an interval of 12-72 hours. Feasibility and safety data were assessed throughout ICU admission. RESULTS:Baseline choroidal vascular index and choroidal thickness were positively associated with fluid balance, and negatively with APACHE2 score, haematocrit and albumin content. A measurable suprachoroidal space was seen in nine (75%) patients (range 25.0-110.0 microns) and was inversely associated with heart rate. There was substantial intraindividual variation in choroidal measurements over time. There were no safety concerns. CONCLUSIONS:Measuring the choroid is feasible in patients with Intensive Care Society Level 2 or Level 3 requirements. The suprachoroidal space may be markedly enlarged in these patients. Exploratory associations with systemic variables suggest that the choroid may provide information about the microvascular function of other major organs. Size and change of choroidal measurements may reflect perfusion pressure and vascular leakage.

AIMS:To conduct the first cross-sectional epidemiological investigation of pathologic myopia (PM) in UK adults with high myopia. METHODS:Fundus photographs of 3024 highly myopic eyes (spherical equivalent refraction (SER) ≤-5.00D) from 2000 randomly sampled adults (aged 40-70 years) in the UK Biobank were double graded by an ophthalmic reading centre using the Meta-analysis for Pathologic Myopia framework. Adjudication was performed by one of two retinal specialists. Multivariable mixed-effects logistic regression was used to explore potential risk factors and fundus biomarkers-initially adjusting for SER, age and sex, before including these and other variables with p<0.10 in a single model. RESULTS:PM was present in 1138 of 3006 gradable fundus photographs, with 41.7% (95% CI 39.5% to 43.9%) of participants affected in at least one eye graded. Most eyes with PM exhibited diffuse chorioretinal atrophy (97.4%), while the more severe stages-patchy chorioretinal atrophy and macular atrophy-were observed in only 24 and 5 eyes, respectively. 13 eyes had 'plus' lesions or suspected staphyloma. Factors independently associated with increased odds of PM (all p<0.05) included decreasing SER (adjusted OR: 0.22, 95% CI 0.15 to 0.32), older age (2.20, 1.63 to 2.97), female sex (1.87, 1.12 to 3.12), lower deprivation (0.73, 0.56 to 0.94), white ethnicity (52.3, 17.3 to 158.3), lower retinal arteriovenous ratio (0.47, 0.37 to 0.58), increased retinal vascular complexity (4.60, 3.16 to 6.70) and a relatively horizontal disc orientation (2.98, 1.88 to 4.72). None of the explored modifiable lifestyle or health-related variables were associated with PM. CONCLUSIONS:PM prevalence is high among mid-life adults with high myopia in the UK Biobank, although most cases are relatively mild (diffuse chorioretinal atrophy). The only modifiable risk factor identified is myopia severity.

Abstract Background Bipolar disorder and depression are associated with structural and functional changes in the retina, including a thinner retinal nerve fibre layer (RNFL). Lithium is widely considered the most effective treatment for bipolar disorder, but its mechanism of action is not fully understood. We assessed research looking at the effect of lithium on structural or functional retinal outcomes in humans. Methods Searches using the terms ‘Lithium’ AND ‘retina’ were carried out to identify peer reviewed studies assessing the impact of lithium on retinal structure or function. These included those with or without a control group comparison, pre- and post- lithium comparisons and observational studies. There were no exclusions based on the quantity or preparation of lithium administered, or the length of administration. Risk of bias was assessed using the Joanna Briggs Institute (JBI) critical appraisal tool for Analytical Cross Sectional Studies, and a narrative synthesis and tabulated summary of the included studies was completed. Results Seven studies assessing structural outcomes and 10 reporting functional ones were identified, all highly heterogenous and with multiple limitations. Structural outcomes were derived exclusively from optical coherence tomography (OCT) with retinal nerve fibre layer (RNFL) being the most common measurement. There was no evidence of differences in the RNFL between participants with bipolar disorder taking lithium and healthy controls in two larger studies. In six studies looking at differences in those with bipolar disorder taking lithium and those taking valproate, two showed no signs of difference and four showed evidence of thicker RNFL in the lithium group. Studies reporting functional outcomes reported a statistically significant effect of lithium on at least one functional measure, derived from electrooculography, electroretinography, and dark adaptation thresholds. Conclusions Current evidence suggests that lithium is likely to have an effect on the retina but limitations in all studies mean better designed and adequately powered prospective studies are required. Registration PROSPERO database (Number-CRD42024516635).

The digitalisation of health data has helped drive initiatives like the Scottish Collaborative Optometry-Ophthalmology Network eResearch (SCONe), which links retinal images from community optometry practices with other routinely collected health data to enhance disease detection. As data-driven approaches expand throughout the healthcare system, patient and public involvement and engagement (PPIE) is increasingly recognised as essential for improving the quality, relevance, and acceptability of health research. However, despite growing endorsement, challenges remain, including inconsistent terminology, varying levels of involvement, limited implementation guidance, and a lack of evidence on its impact. These challenges are even more pronounced in data science, particularly within large-scale research, where PPIE is often underreported, leaving the field without a clear framework for meaningful implementation. This article offers a reflective account of the challenges and barriers encountered by SCONe in developing a PPIE strategy. By documenting this process, it provides insights into the complexities of implementing PPIE in large research consortia and offers practical guidance for future initiatives seeking to enhance the impact and relevance of public partnerships in large scale data science research.

Importance:Myocardial fibrosis burden has been associated with adverse clinical outcomes in symptomatic patients with aortic stenosis. Objective:To determine whether midwall myocardial fibrosis burden is associated with adverse clinical outcomes in asymptomatic patients and whether those with more fibrosis derive greater benefit from early intervention. Design, Setting, and Participants:This post hoc analysis of a randomized clinical trial was conducted between August 2017 and October 2022. The trial took place at 24 cardiac centers across the United Kingdom and Australia. Participants included asymptomatic patients with severe aortic stenosis and midwall fibrosis on cardiac magnetic resonance. These data were analyzed from October 2024 through June 2025. Intervention:Early intervention with transcatheter or surgical aortic valve replacement. Main Outcomes and Measures:Primary outcome was all-cause death or unplanned aortic stenosis-related hospitalization. Secondary outcomes included the individual components of the primary outcome. Results:In 224 trial participants (mean [SD] age, 73 [9] years; 63 women and 161 men, and mean [SD] aortic valve peak velocity 4.3 [0.5] m per second) with a median follow-up of 42 months, fibrosis burden (per 1% increase) was associated with an increase in the primary end point (hazard ratio [HR], 1.23; 95% CI, 1.08-1.37) and its component of unplanned aortic stenosis-related hospitalizations (HR, 1.22; 95% CI, 1.03-1.40) but not all-cause death (HR, 1.17; 95% CI, 0.98-1.35). There were no interactions between randomization arm and the midwall fibrosis burden for the primary (P for interaction = .39) or secondary end points. In patients with high fibrosis burden above the median, the primary end point occurred in 12 of 59 (20%) of those randomized to early intervention and 17 of 53 (32%) of those randomized to guideline-directed conservative management (HR, 0.62; 95% CI, 0.29-1.28). For the individual components, all-cause death occurred in 9 (15%) and 10 (19%) patients, respectively (HR, 0.84; 95% CI, 0.33-2.07), and unplanned aortic stenosis-related hospitalization in 4 (7%) and 13 (25%) patients respectively (HR, 0.27; 95% CI, 0.08-0.77). In patients with low fibrosis burden below the median, there were no differences in the primary outcome (HR, 1.05; 95% CI, 0.39-2.86) or its components between intervention groups. Conclusions and Relevance:In this study, in asymptomatic patients with severe aortic stenosis, higher midwall fibrosis burden was associated with adverse outcomes. There was no demonstrable heterogeneity by the degree of midwall fibrosis for the treatment effects of early surgical or transcatheter aortic valve replacement compared to clinical surveillance. Trial Registration:ClinicalTrials.gov Identifier: NCT03094143.

Bone marrow adipose tissue is a distinct adipose subtype comprising more than 10% of fat mass in healthy humans. However, the functions and pathophysiological correlates of this tissue are unclear, and its genetic determinants remain unknown. Here, we use deep learning to measure bone marrow adiposity in the femoral head, total hip, femoral diaphysis, and spine from MRI scans of approximately 47,000 UK Biobank participants, including over 41,000 white and over 6300 non-white participants. We then establish the heritability and genome-wide significant associations for bone marrow adiposity at each site. Our meta-GWAS in the white population finds 67, 147, 134, and 174 independent significant single nucleotide polymorphisms, which map to 54, 90, 43, and 100 genes for the femoral head, total hip, femoral diaphysis, and spine, respectively. Transcriptome-wide association studies, colocalization analyses, and sex-stratified meta-GWASes in the white participants further resolve functional and sex-specific genes associated with bone marrow adiposity at each site. Finally, we perform a multi-ancestry meta-GWAS to identify genes associated with bone marrow adiposity across the different bone regions and across ancestry groups. Our findings provide insights into BMAT formation and function and provide a basis to study the impact of BMAT on human health and disease.

Motor neuron disease (MND) is a rapidly progressive neurodegenerative disorder characterised by motor neuron death resulting in limb and bulbar paralysis with death from respiratory failure within 2-3 years of diagnosis in most individuals. The commonest subtype, accounting for 80% of individuals, is amyotrophic lateral sclerosis (ALS). There is an urgent need for sensitive and specific biomarkers for diagnosis and disease monitoring. Recent studies suggest retinal abnormalities may arise in MND offering the opportunity for retinal imaging as a non-invasive and scalable biomarker. We conducted a systematic review and narrative summary of studies evaluating retinal imaging modalities (optical coherence tomography [OCT], fundus photography, scanning laser ophthalmoscopy and OCT angiography) in adults with MND. We identified 18 studies in the 25 years between 2000–2024. Most studies reported thinning in the retinal nerve fibre layer, nuclear layers, and choroid in MND compared to healthy controls with a few reporting thickening or vascular changes. Nine studies linked retinal measures to disease severity or duration. Preliminary data support the potential utility of retinal imaging in MND with the need for larger longitudinal studies to investigate further.

Bone marrow adiposity changes in diverse diseases, but the full scope of these, and whether they are directly influenced by marrow adiposity, remains unknown. To address this, we previously measured the bone marrow fat fraction of the femoral head, total hip, femoral diaphysis, and spine of over 48,000 UK Biobank participants. Here, we first use these data for PheWAS to identify diseases associated with marrow adiposity at each site. This reveals associations with 47 incident diseases across 12 disease categories, including osteoporosis, fracture, type 2 diabetes, cardiovascular diseases, cancers, and other conditions that burden public health worldwide. Intriguingly, type 2 diabetes associates positively with spine bone marrow adiposity but negatively with marrow adiposity at femoral sites. We then establish PRSs based on bone-marrow-fat-fraction-associated SNPs and use PRS-PheWAS and Mendelian randomization to explore causal associations between marrow adiposity and disease. PRS-PheWAS reveals that genetic predisposition to increased marrow adiposity is positively associated with osteoporosis and fractures. Mendelian randomization further suggests that increased marrow adiposity at the diaphysis and total hip is causally associated with osteoporosis. Our findings substantially advance understanding of how marrow adiposity impacts human health and highlight its potential as a biomarker and/or therapeutic target for diverse human diseases.

Cerebral small vessel disease (cSVD) is characterised by white matter hyperintensities (WMH) and contributes to stroke and dementia. Cerebrovascular reactivity (CVR) declines with worsening cSVD but estimates of CVR from brain scans give limited information about the coordination of individual arterioles or venules. Retinovascular reactivity can provide separate data about arterioles and venules, but it is not known if retinovascular reactivity correlates with CVR in people with cSVD. We aimed to assess retinal vascular reactivity in people with cSVD and explore associations with WMH and CVR in a cross-sectional study. Participants had retinal photographs and magnetic resonance brain imaging (MRI) before and during inhalation of 6% CO 2 in air. We recruited 60 participants. 48 provided analysable retinal vessel reactivity data. Retinal arteriole/venule ratio was inversely related to WMH severity (adjusted R2 = 0.47 β–5.2 95%CI–7.9 to −2.5) and directly related to CVR (adjusted R2 = 0.21 β0.15 95%CI 0.04 to 0.25). In general, participants whose arteriole/venule ratio increased with CO 2 had milder WMH and higher (better) CVR, while participants whose arteriole/venule ratio decreased had more severe WMH and lower (worse) CVR. Retinovascular reactivity to CO 2 inhalation in people with cSVD suggests loss of normal arteriovenous coordination and inefficient perfusion of the capillary bed.

Importance:As on-axis metrics, spherical equivalent refraction (SER) and axial length (AL) are limited in capturing individual-level differences in posterior segment anatomy. Objective:To propose a fundus-level metric-fundus refraction offset (FRO)-and investigate its association with ocular parameters derived from optical coherence tomography (OCT). Design, Setting, and Participants:This cross-sectional, population-based study used data from 45 180 healthy eyes in the UK Biobank (2009-2010). Fundus photographs from a random subset (70%) were used to train a deep learning model to predict SER, with the goal of developing a model that learned to capture the nonpathological variations in fundus appearance from -15.50 D to 9.25 D. The trained model was applied to the remaining subset (internal unseen set) to derive FRO for each eye. FRO was also computed for an external dataset (the Caledonian cohort, 2023-2024) with enhanced depth imaging OCT and AL data for 152 right eyes. Data were analyzed from July to November 2024. Exposure:FRO, defined as the error in fundus-predicted SER. A more negative FRO indicated a more myopic-looking fundus than typical for an eye with the same SER. Main Outcomes and Measures:The association between FRO and macular thickness (MT) was tested using linear mixed-effects regression in the internal unseen set, controlling for SER, age, sex, and race. In the external dataset, the associations of FRO with choroidal area, choroidal vascularity index (CVI), and MT were examined using linear fixed-effects regression, controlling for SER (and subsequently AL) and other aforementioned covariates. Results:High-quality OCT data were available from 9524 eyes in the internal unseen set and 152 eyes in the external dataset among individuals with a mean (SD) age of 54.5 (8.2) years and 19.3 (3.8) years, respectively. In the internal unseen set, a more negative FRO was independently associated with lower MT (β, 0.64; 95% CI, 0.37-0.90; P < .001). A similar association was observed in the external dataset-whether adjusted for SER (β, 2.45; 95% CI, 0.64-4.26; P = .008) or AL (β, 2.09; 95% CI, 0.28-3.91; P = .02). Additionally, CVI decreased as FRO became more negative-both in the SER-adjusted (β, 0.01; 95% CI, 0.01-0.02; P < .001) and AL-adjusted (β, 0.01, 95% CI, 0.004-0.02; P = .001) analyses. Conclusion and Relevance:In this study, FRO reflected the individual-level mismatch between SER (or AL) and the anatomical severity of ametropia. This may have prognostic relevance for personalized risk prediction of myopia and its complications.

IntroductionDifferent regions of the small ruminant lung exhibit variable susceptibility to specific lung pathologies. Such susceptibility may be reflected in regional lung radiomic features extracted from computed tomography (CT) images. In this study, we investigated whether region-specific variation in radiomic features exists in ovine lungs and whether these features remain stable over time.MethodsThoracic CT image datasets from 30 young adult sheep were subject to an image segmentation protocol directed at partitioning the lung into individual lobar and sub-lobar segments for radiomic feature analysis. After identifying and removing unstable, non-reproducible, and highly correlated features, 22 features remained and were used as input for principal component (PC) analysis.ResultsThe significance of segment-related influence on PC scores was determined and visualised. For six sheep, successive CT images were acquired at monthly intervals for a period of 9 months in order to assess time-dependent variation in radiomic features. The results indicated that there was a significant difference in radiomic features derived from different lung segments. Visualisation of PC scores highlighted differences between caudodorsal and cranioventral lung, between lobar and sub-lobar segments, and suggested a bias towards one lung or the other. Significant changes in PC scores occurred over time. With few exceptions, largely similar changes occurred across all segments in this regard.DiscussionOverall, our results indicate that although sheep lung radiomic features are influenced by the lung segment of origin, their variation over time is largely consistent throughout the lung. Such influence should be borne in mind when interpreting radiomic features and their changes over time.