A Deep-Learning Algorithm to Predict Short-Term Progression to Geographic Atrophy on Spectral-Domain Optical Coherence Tomography

IMPORTANCE: The identification of patients at risk of progressing from intermediate age-related macular degeneration (iAMD) to geographic atrophy (GA) is essential for clinical trials aimed at preventing disease progression. DeepGAze is a fully automated and accurate convolutional neural network-based deep learning algorithm for predicting progression from iAMD to GA within 1 year from spectral-domain optical coherence tomography (SD-OCT) scans. OBJECTIVE: To develop a deep-learning algorithm based on volumetric SD-OCT scans to predict the progression from iAMD to GA during the year following the scan. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included participants with iAMD at baseline and who either progressed or did not progress to GA within the subsequent 13 months. Participants were included from centers in 4 US states. Data set 1 included patients from the Age-Related Eye Disease Study 2 AREDS2 (Ancillary Spectral-Domain Optical Coherence Tomography) A2A study (July 2008 to August 2015). Data sets 2 and 3 included patients with imaging taken in routine clinical care at a tertiary referral center and associated satellites between January 2013 and January 2023. The stored imaging data were retrieved for the purpose of this study from July 1, 2022, to February 1, 2023. Data were analyzed from May 2021 to July 2023. EXPOSURE: A position-aware convolutional neural network with proactive pseudointervention was trained and cross-validated on Bioptigen SD-OCT volumes (data set 1) and validated on 2 external data sets comprising Heidelberg Spectralis SD-OCT scans (data sets 2 and 3). MAIN OUTCOMES AND MEASURES: Prediction of progression to GA within 13 months was evaluated with area under the receiver-operator characteristic curves (AUROC) as well as area under the precision-recall curve (AUPRC), sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. RESULTS: The study included a total of 417 patients: 316 in data set 1 (mean [SD] age, 74 [8]; 185 [59%] female), 53 in data set 2, (mean [SD] age, 83 [8]; 32 [60%] female), and 48 in data set 3 (mean [SD] age, 81 [8]; 32 [67%] female). The AUROC for prediction of progression from iAMD to GA within 1 year was 0.94 (95% CI, 0.92-0.95; AUPRC, 0.90 [95% CI, 0.85-0.95]; sensitivity, 0.88 [95% CI, 0.84-0.92]; specificity, 0.90 [95% CI, 0.87-0.92]) for data set 1. The addition of expert-annotated SD-OCT features to the model resulted in no improvement compared to the fully autonomous model (AUROC, 0.95; 95% CI, 0.92-0.95; P = .19). On an independent validation data set (data set 2), the model predicted progression to GA with an AUROC of 0.94 (95% CI, 0.91-0.96; AUPRC, 0.92 [0.89-0.94]; sensitivity, 0.91 [95% CI, 0.74-0.98]; specificity, 0.80 [95% CI, 0.63-0.91]). At a high-specificity operating point, simulated clinical trial recruitment was enriched for patients progressing to GA within 1 year by 8.3- to 20.7-fold (data sets 2 and 3). CONCLUSIONS AND RELEVANCE: The fully automated, position-aware deep-learning algorithm assessed in this study successfully predicted progression from iAMD to GA over a clinically meaningful time frame. The ability to predict imminent GA progression could facilitate clinical trials aimed at preventing the condition and could guide clinical decision-making regarding screening frequency or treatment initiation

Contribution of abdominal adiposity to age-related differences in insulin sensitivity and plasma lipids in healthy nonobese women

WSTĘP. Autorzy sprawdzili słuszność hipotezy zakładającej, że związany z wiekiem przyrost tkanki tłuszczowej trzewnej odpowiada częściowo za ujemny wpływ na insulinowrażliwość i profil lipidowy u kobiet bez otyłości. MATERIAŁ I METODY. Bezpośrednio oceniono: powierzchnię podskórnej i trzewnej tkanki tłuszczowej (tomografia komputerowa), zużycie glukozy (badanie metodą hiperinsulinowej/euglikemicznej klamry metabolicznej), elementy składowe organizmu (metoda absorpcjometrii promieniami X dwoistej energii), profil lipidowy oraz maksymalne zużycie tlenu (VO2max) u 178 kobiet bez otyłości, zakwalifikowanych do odpowiednich grup wiekowych: grupa 1 - 28 &plusmn; 4 lata (n = 88); grupa 2 - 46 &plusmn; 2 lata (n = 38); grupa 3 - 53 &plusmn; 2 lata (n = 31); grupa 4 - 67 &plusmn; 6 lat (n = 21). WYNIKI. Powierzchnia trzewnej tkanki tłuszczowej zwiększa się wraz z wiekiem (2,36 cm2 rocznie, p < 0,0001). Zanotowano związany z wiekiem wzrost stężenia cholesterolu całkowitego (p < 0,0003), triglicerydów (p < 0,0009), cholesterolu frakcji LDL (p < 0,027) i stosunku stężenia cholesterolu całkowitego do cholesterolu frakcji HDL (p < 0,042). Obserwowane różnice w insulinowrażliwości także wiązały się z wiekiem, jednakże w tym przypadku zależność była odmienna. Insulinowrażliwość, wyrażona jako całkowita lub przeliczona na kilogram beztłuszczowej masy ciała, była najniższa w grupie 4, ale nie różniła się istotnie między grupami 1, 2 i 3. Po analizie statystycznej, uwzględniającej powierzchnię tkanki tłuszczowej trzewnej, niższa insulinowrażliwość utrzymywała się, jednocześnie, relatywnie zmniejszyła się różnica w porównaniu z pozostałymi grupami. Wpływ zawartości trzewnej tkanki tłuszczowej na związane z wiekiem zmiany profilu lipidowego był silniejszy. Różnice w powierzchni trzewnej i głębokiej podskórnej tkanki tłuszczowej znosiły wpływ wieku na stężenie cholesterolu całkowitego, triglicerydów i cholesterolu frakcji LDL. Nie obserwowano natomiast wpływu wartości VO2max lub aktywnego wypoczynku na zależne od wieku zmiany w insulinowrażliwości bądź profilu lipidowym. WNIOSKI. 1) Wraz z wiekiem zwiększa się powierzchnia trzewnej tkanki tłuszczowej, podczas gdy zmniejszenie insulinowrażliwości obserwuje się tylko u kobiet starszych; 2) Związane z wiekiem różnice w trzewnej tkance tłuszczowej tylko w niewielkim stopniu odpowiadają za spadek insulinowrażliwości u kobiet bez otyłości; 3) Niepożądane zmiany profilu lipidowego w dużym stopniu wiążą się z zależnym od wieku przyrostem trzewnej tkanki tłuszczowej.INTRODUCTION. We examined the hypothesis that an age-related increase in the compartments of visceral fat would account, in part, for the deleterious changes in insulin sensitivity and blood lipid profile in nonobese women. MATERIAL AND METHODS. We directly assessed visceral and subcutaneous abdominal adipose tissue areas (computed tomography), glucose disposal (hyperinsulinemic-euglycemic clamp), body composition (dual energy X-ray absorptiometry), blood-lipid profile, and aerobic fitness (VO2max) in 178 nonobese women categorized into four age groups: group 1, 28 &plusmn; 4 years, n = 88; group 2, 46 &plusmn; 2 years, n = 38; group 3, 53 &plusmn; 2 years, n = 31; and group 4, 67 &plusmn; 6 years, n = 21. RESULTS. Visceral abdominal adipose tissue area increased with age (2.36 cm2 per year, P < 0.0001). We noted an age-related increase in total cholesterol (P < 0.0003), triglycerides (P < 0.0009), LDL cholesterol (P < 0.027), and the ratio of total cholesterol to HDL cholesterol (P < 0.042). However, agerelated changes in insulin sensitivity exhibited a different age-related pattern. That is, insulin sensitivity, expressed on an absolute basis or indexed per kilogram of fat-free mass, was lowest in group 4 but was not significantly different among groups 1, 2, and 3. After statistical control for visceral fat, lower insulin sensitivity persisted in group 4, although differences were diminished relative to other groups. However, the effect of visceral fat on agerelated changes in the blood-lipid profile was stronger. That is, differences in visceral and deep subcutaneous adipose tissue area abolished age-related differences in total cholesterol, triglycerides, and LDL cholesterol. No independent effects of VO2max or leisure-time physical activity on age-related changes in insulin sensitivity or on the blood-lipid profile were noted. CONCLUSIONS. We conclude that 1) visceral fat shows an increase with advancing age, whereas a decrease in insulin sensitivity was noted only in older women; 2) age-related differences in visceral fat explain only a modest part of the decline in insulin sensitivity in nonobese women; and 3) unfavorable changes in plasma lipids were strongly associated with the age-related increase in visceral abdominal adipose tissue

Choroid Development and Feasibility of Choroidal Imaging in the Preterm and Term Infants Utilizing SD-OCT

To determine whether choroidal imaging is feasible in preterm and term infants using an 840-nm portable spectral domain optical coherence tomography (SD-OCT) system without the use of enhanced-depth imaging techniques and to assess choroidal development by comparing choroidal thickness of preterm infants, term infants, and adults

Transcriptomic Analysis of Chronic Hepatitis B and C and Liver Cancer Reveals MicroRNA-Mediated Control of Cholesterol Synthesis Programs

ABSTRACT Chronic hepatitis B (CHB), chronic hepatitis C (CHC), and associated hepatocellular carcinoma (HCC) are characterized by cholesterol imbalance and dyslipidemia; however, the key regulatory drivers of these phenotypes are incompletely understood. Using gene expression microarrays and high-throughput sequencing of small RNAs, we performed integrative analysis of microRNA (miRNA) and gene expression in nonmalignant and matched cancer tissue samples from human subjects with CHB or CHC and HCC. We also carried out follow-up functional studies of specific miRNAs in a cell-based system. These studies led to four major findings. First, pathways affecting cholesterol homeostasis were among the most significantly overrepresented among genes dysregulated in chronic viral hepatitis and especially in tumor tissue. Second, for each disease state, specific miRNA signatures that included miRNAs not previously associated with chronic viral hepatitis, such as miR-1307 in CHC, were identified. Notably, a few miRNAs, including miR-27 and miR-224, were components of the miRNA signatures of all four disease states: CHB, CHC, CHB-associated HCC, and CHC-associated HCC. Third, using a statistical simulation method (miRHub) applied to the gene expression data, we identified candidate master miRNA regulators of pathways controlling cholesterol homeostasis in chronic viral hepatitis and HCC, including miR-21, miR-27, and miR-33. Last, we validated in human hepatoma cells that both miR-21 and miR-27 significantly repress cholesterol synthesis and that miR-27 does so in part through regulation of the gene that codes for the rate-limiting enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase ( HMGCR ). IMPORTANCE Hepatitis B virus (HBV) and hepatitis C virus (HCV) are phylogenetically unrelated hepatotropic viruses that persistently infect hundreds of millions of people world-wide, often leading to chronic liver disease and hepatocellular carcinoma (HCC). Chronic hepatitis B (CHB), chronic hepatitis C (CHC), and associated HCC often lead to cholesterol imbalance and dyslipidemia. However, the regulatory mechanisms underlying the dysregulation of lipid pathways in these disease states are incompletely understood. MicroRNAs (miRNAs) have emerged as critical modulators of lipid homeostasis. Here we use a blend of genomic, molecular, and biochemical strategies to identify key miRNAs that drive the lipid phenotypes of chronic viral hepatitis and HCC. These findings provide a panoramic view of the miRNA landscape in chronic viral hepatitis, which could contribute to the development of novel and more-effective miRNA-based therapeutic strategies

Optics and Quantum Electronics

Contains table of contents for Section 3 and reports on twenty research projects.Charles S. Draper Laboratories Contract DL-H-467138Joint Services Electronics Program Contract DAAL03-92-C-0001Joint Services Electronics Program Grant DAAH04-95-1-0038U.S. Air Force - Office of Scientific Research Contract F49620-91-C-0091MIT Lincoln LaboratoryNational Science Foundation Grant ECS 90-12787Fujitsu LaboratoriesNational Center for Integrated PhotonicsHoneywell Technology CenterU.S. Navy - Office of Naval Research (MFEL) Contract N00014-94-1-0717U.S. Navy - Office of Naval Research (MFEL) Grant N00014-91-J-1956National Institutes of Health Grant NIH-5-R01-GM35459-09U.S. Air Force - Office of Scientific Research Grant F49620-93-1-0301MIT Lincoln Laboratory Contract BX-5098Electric Power Research Institute Contract RP3170-25ENEC

Human and mouse neuroinflammation markers in Niemann‐Pick disease, type C1

Niemann‐Pick disease, type C1 (NPC1) is an autosomal recessive lipid storage disorder in which a pathological cascade, including neuroinflammation occurs. While data demonstrating neuroinflammation is prevalent in mouse models, data from NPC1 patients is lacking. The current study focuses on identifying potential markers of neuroinflammation in NPC1 from both the Npc1 mouse model and NPC1 patients. We identified in the mouse model significant changes in expression of genes associated with inflammation and compared these results to the pattern of expression in human cortex and cerebellar tissue. From gene expression array analysis, complement 3 (C3) was increased in mouse and human post‐mortem NPC1 brain tissues. We also characterized protein levels of inflammatory markers in cerebrospinal fluid (CSF) from NPC1 patients and controls. We found increased levels of interleukin 3, chemokine (C‐X‐C motif) ligand 5, interleukin 16 and chemokine ligand 3 (CCL3), and decreased levels of interleukin 4, 10, 13 and 12p40 in CSF from NPC1 patients. CSF markers were evaluated with respect to phenotypic severity. Miglustat treatment in NPC1 patients slightly decreased IL‐3, IL‐10 and IL‐13 CSF levels; however, further studies are needed to establish a strong effect of miglustat on inflammation markers. The identification of inflammatory markers with altered levels in the cerebrospinal fluid of NPC1 patients may provide a means to follow secondary events in NPC1 disease during therapeutic trials.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147148/1/jimd0083.pd

Optics and Quantum Electronics

Contains table of contents for Section 3 and reports on eighteen research projects.Defense Advanced Research Projects Agency/MIT Lincoln Laboratory Contract MDA972-92-J-1038Joint Services Electronics Program Grant DAAH04-95-1-0038National Science Foundation Grant ECS 94-23737U.S. Air Force - Office of Scientific Research Contract F49620-95-1-0221U.S. Navy - Office of Naval Research Grant N00014-95-1-0715MIT Center for Material Science and EngineeringNational Center for Integrated Photonics Technology Contract DMR 94-00334National Center for Integrated Photonics TechnologyU.S. Navy - Office of Naval Research (MFEL) Contract N00014-94-1-0717National Institutes of Health Grant 9-R01-EY11289MIT Lincoln Laboratory Contract BX-5098Electric Power Research Institute Contract RP3170-25ENEC

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

The chemotherapeutic agent doxorubicin (DOX) has significantly increased survival rates of pediatric and adult cancer patients. However, 10% of pediatric cancer survivors will 10–20 years later develop severe dilated cardiomyopathy (DCM), whereby the exact molecular mechanisms of disease progression after this long latency time remain puzzling. We here revisit the hypothesis that elevated apoptosis signaling or its increased likelihood after DOX exposure can lead to an impairment of cardiac function and cause a cardiac dilation. Based on recent literature evidence, we first argue why a dilated phenotype can occur when little apoptosis is detected. We then review findings suggesting that mature cardiomyocytes are protected against DOX-induced apoptosis downstream, but not upstream of mitochondrial outer membrane permeabilisation (MOMP). This lack of MOMP induction is proposed to alter the metabolic phenotype, induce hypertrophic remodeling, and lead to functional cardiac impairment even in the absence of cardiomyocyte apoptosis. We discuss findings that DOX exposure can lead to increased sensitivity to further cardiomyocyte apoptosis, which may cause a gradual loss in cardiomyocytes over time and a compensatory hypertrophic remodeling after treatment, potentially explaining the long lag time in disease onset. We finally note similarities between DOX-exposed cardiomyocytes and apoptosis-primed cancer cells and propose computational system biology as a tool to predict patient individual DOX doses. In conclusion, combining recent findings in rodent hearts and cardiomyocytes exposed to DOX with insights from apoptosis signal transduction allowed us to obtain a molecularly deeper insight in this delayed and still enigmatic pathology of DC