Metabolic profiling reveals circulating biomarkers associated with incident and prevalent Parkinson's disease.

The metabolic profile predating the onset of Parkinson's disease (PD) remains unclear. We aim to investigate the metabolites associated with incident and prevalent PD and their predictive values in the UK Biobank participants with metabolomics and genetic data at the baseline. A panel of 249 metabolites was quantified using a nuclear magnetic resonance analytical platform. PD was ascertained by self-reported history, hospital admission records and death registers. Cox proportional hazard models and logistic regression models were used to investigate the associations between metabolites and incident and prevalent PD, respectively. Area under receiver operating characteristics curves (AUC) were used to estimate the predictive values of models for future PD. Among 109,790 participants without PD at the baseline, 639 (0.58%) individuals developed PD after one year from the baseline during a median follow-up period of 12.2 years. Sixty-eight metabolites were associated with incident PD at nominal significance (P < 0.05), spanning lipids, lipid constituent of lipoprotein subclasses and ratios of lipid constituents. After multiple testing corrections (P < 9 × 10-4), polyunsaturated fatty acids (PUFA) and omega-6 fatty acids remained significantly associated with incident PD, and PUFA was shared by incident and prevalent PD. Additionally, 14 metabolites were exclusively associated with prevalent PD, including amino acids, fatty acids, several lipoprotein subclasses and ratios of lipids. Adding these metabolites to the conventional risk factors yielded a comparable predictive performance to the risk-factor-based model (AUC = 0.766 vs AUC = 0.768, P = 0.145). Our findings suggested metabolic profiles provided additional knowledge to understand different pathways related to PD before and after its onset.

Epitope mapping and establishment of a blocking ELISA for mAb targeting the p72 protein of African swine fever virus.

The African swine fever virus (ASFV) has the ability to infect pigs and cause a highly contagious acute fever that can result in a mortality rate as high as 100%. Due to the viral epidemic, the pig industry worldwide has suffered significant financial setbacks. The absence of a proven vaccine for ASFV necessitates the development of a sensitive and reliable serological diagnostic method, enabling laboratories to effectively and expeditiously detect ASFV infection. In this study, four strains of monoclonal antibodies (mAbs) against p72, namely, 5A1, 4C4, 8A9, and 5E10, were generated through recombinant expression of p72, the main capsid protein of ASFV, and immunized mice with it. Epitope localization was performed by truncated overlapping polypeptides. The results indicate that 5A1 and 4C4 recognized the amino acid 20-39 aa, 8A9 and 5E10 are recognized at 263-282 aa, which is consistent with the reported 265-280 aa epitopes. Conserved analysis revealed 20-39 aa is a high conservation of the epitopes in the ASFV genotypes. Moreover, a blocking ELISA assay for detection ASFV antibody based on 4C4 monoclonal antibody was developed and assessed. The receiver-operating characteristic (ROC) was performed to identify the best threshold value using 87 negative and 67 positive samples. The established test exhibited an area under the curve (AUC) of 0.9997, with a 95% confidence interval ranging from 99.87 to 100%. Furthermore, the test achieved a diagnostic sensitivity of 100% (with a 95% confidence interval of 95.72 to 100%) and a specificity of 98.51% (with a 95% confidence interval of 92.02 to 99.92%) when the threshold was set at 41.97%. The inter- and intra-batch coefficient of variation were below 10%, demonstrating the exceptional repeatability of the method. This method can detect the positive standard serum at a dilution as high as 1:512. Subsequently, an exceptional blocking ELISA assay was established with high diagnostic sensitivity and specificity, providing a novel tool for detecting ASFV antibodies. KEY POINTS: • Four strains of ASFV monoclonal antibodies against p72 were prepared and their epitopes were identified. • Blocking ELISA method was established based on monoclonal antibody 4C4 with an identified conservative epitope. • The established blocking ELISA method has a good effect on the detection of ASFV antibody.

Mimicking bacterial infection in male mice changes sperm small RNA profiles and multigenerationally alters offspring behavior and physiology.

Paternal pre-conceptual exposures, including stress, diet, substance abuse, parasite infection, and viral immune activation via Poly I:C, have been reported to influence the brains and behavior of offspring through sperm epigenetic changes. However, the effects of paternal (F0) pre-conceptual exposure to bacterial-induced immune activation on the behavior and physiology of F1 and F2 generations remain unexplored. We examined this using C57BL/6J mice. Eight-week-old males (F0) received a single intraperitoneal injection of the bacterial mimetic lipopolysaccharide (LPS: 5 mg/kg) or 0.9 % saline (vehicle control) before mating with naïve females at four weeks post-injection. Comprehensive behavioral assessments were conducted to investigate anxiety, social behaviors, depressive-like behaviors and cognition in both the F1 and F2 generations within the age range of 8 to 14 weeks. Results demonstrated that only female offspring of LPS-exposed fathers exhibited reduced anxiety levels in the light/dark box, large open field, and novelty-suppressed feeding test. These F1 female offspring also exhibited heightened sociability in the 3-chambered social interaction test and a reduced preference for saccharin in the saccharin preference test. Additionally, the F1 male offspring of LPS-challenged males demonstrated an increased total distance traveled in the light/dark box and a longer distance covered in the light zone. They also exhibited diminished preference for social novelty in the 3-chambered social interaction test and an elevated novel arm preference index in the Y-maze. In the F2 generation, male descendants of LPS-treated fathers showed reduced latency to feed in the novelty-suppressed feeding test. Additionally, the F2 generation of LPS-challenged fathers, but not the F1 generation, displayed enhanced immune response in both sexes after an acute LPS immune challenge (5 mg/kg). Analysis of sperm small noncoding RNA profiles from LPS-treated F0 mice revealed significant changes at 4 weeks after administration of LPS. These changes included three microRNAs, eight PIWI-interacting RNAs, and two transfer RNAs, exhibiting significant upregulation (mmu-miR-146a-5p, mmu-piR-27082 and mmu-piR-29102) or downregulation (mmu-miR-5110, mmu-miR-467e-3p, mmu-piR-22583, mmu-piR-23548, mmu-piR-36341, mmu-piR-50293, mmu-piR-16583, mmu-piR-36507, Mus_musculus_tRNA-Ile-AAT-2-1 and Mus_musculus_tRNA-Tyr-GTA-1-1). Additionally, we detected 52 upregulated small noncoding RNAs (including 9 miRNAs, 41 piRNAs, and 2 tRNAs) and 7 downregulated small noncoding RNAs (3 miRNAs, 3 piRNAs, and 1 tRNA) in the sperm of F1 offspring from LPS-treated males. These findings provide compelling evidence for the involvement of epigenetic mechanisms in the modulation of brain function and immunity, and associated behavioral and immunological traits, across generations, in response to bacterial infection.

Antidiabetic action of the Chinese formula Shouhuitongbian and the underlying mechanism associated with alteration of gut microbiota.

BACKGROUND: The prevalence and incidence of type 2 diabetes mellitus (T2DM) have dramatically increased. The intestinal flora and its derived metabolites are demonstrated to play vital roles in the etiology and onset of T2DM. Shouhuitongbian (SHTB) is a traditional Chinese formula to treat constipation. SHTB is composed of seven herbs and components of Colla corii asini (CCA) that are obtained from the hide of Equus asinus L.. Some of herbs in SHTB such as Aloe vera (L.) Burm.f., Cassia obtusifolia L., fruits of Lycium barbarum L., and Citrus aurantium L. have shown to improve insulin resistance (IR) and T2DM in early reports. We hypothesized that SHTB composed of these herbs has antidiabetic effects. The antidiabetic efficacy and mechanism of action of SHTB have not been previously reported. HYPOTHESIS/PURPOSE: To demonstrate the antidiabetic effect and elucidate the underlying mechanisms of SHTB from the perspective of gut microbiota. STUDY DESIGN: The main compounds were identified and quantified by high-performance liquid chromatography (HPLC)-mass spectrometry analysis. High fat diet (HFD)-fed mice and db/db mice were used to assess the antidiabetic effects and the mechanism of SHTB. The underlying mechanisms were evaluated by enzyme-linked immunosorbent assay (ELISA), western blot analysis, quantitative real time polymerase chain reaction (qPCR) analysis, 16S rRNA high-throughput sequencing, and targeted metabolome analysis. METHODS: HFD-fed mice and db/db mice were orally treated with the standard positive drug metformin (100 mg/kg/d) and with SHTB (200 and 100 mg/kg/d), which was chemically characterized according to the European Medicine Agency (EMA) guidelines. The beneficial effects of SHTB were studied by homeostasis model assessment of insulin resistance (HOMA-IR) index, oral glucose tolerance test (OGTT), insulin tolerance test (ITT), total cholesterol (T-CHO), triglyceride (TG), and inflammation. Subsequently, 16S rDNA-based high-throughput pyrosequencing and GC-MS-based targeted metabolomics profiling were performed to analyze the gut microbiota composition and metabolites profile in the gut, respectively. Moreover, the mammalian target of rapamycin complex 1 (mTORC1) / insulin receptor substrate 1 (IRS-1) / phosphoinositide 3-kinase (PI3K) / protein kinase B (AKT) pathway was evaluated via qPCR and western blot. RESULTS: Chemically characterized SHTB, in which six markers were quantified, effectively alleviated glucose intolerance and IR, ameliorated lipid metabolism dysfunction, and reduced inflammation. In addition, 16S rDNA sequencing found that SHTB reshaped the composition of intestinal flora, as indicated by the enrichment of Akkermansia and Parabacteroides in both HFD-fed and db/db mice. Moreover, SHTB enhanced the intestinal production of short-chain fatty acids (SCFAs) and branched short-chain fatty acids (BSCFAs), and reduced the levels of the fecal and circulating branched-chain amino acids (BCAAs). The IRS-1/PI3K/AKT signaling pathway was upregulated after treatment with SHTB. CONCLUSION: Orally administration of SHTB effectively improved IR and reduced hyperglycemia in mice. Treatment with SHTB regulated the gut BCAAs-mTORC1/IRS-1/PI3K/AKT axis by enhancing the BCAAs catabolism in the gut, which attenuated the deleterious effect of BCAAs on the IRS-1 signaling pathway.

Therapeutic potential to target sialylation and SIGLECs in neurodegenerative and psychiatric diseases.

Sialic acids, commonly found as the terminal carbohydrate on the glycocalyx of mammalian cells, are pivotal checkpoint inhibitors of the innate immune system, particularly within the central nervous system (CNS). Sialic acid-binding immunoglobulin-like lectins (SIGLECs) expressed on microglia are key players in maintaining microglial homeostasis by recognizing intact sialylation. The finely balanced sialic acid-SIGLEC system ensures the prevention of excessive and detrimental immune responses in the CNS. However, loss of sialylation and SIGLEC receptor dysfunctions contribute to several chronic CNS diseases. Genetic variants of SIGLEC3/CD33, SIGLEC11, and SIGLEC14 have been associated with neurodegenerative diseases such as Alzheimer's disease, while sialyltransferase ST8SIA2 and SIGLEC4/MAG have been linked to psychiatric diseases such as schizophrenia, bipolar disorders, and autism spectrum disorders. Consequently, immune-modulatory functions of polysialic acids and SIGLEC binding antibodies have been exploited experimentally in animal models of Alzheimer's disease and inflammation-induced CNS tissue damage, including retinal damage. While the potential of these therapeutic approaches is evident, only a few therapies to target either sialylation or SIGLEC receptors have been tested in patient clinical trials. Here, we provide an overview of the critical role played by the sialic acid-SIGLEC axis in shaping microglial activation and function within the context of neurodegeneration and synaptopathies and discuss the current landscape of therapies that target sialylation or SIGLECs.

Deep neural network-estimated age using optical coherence tomography predicts mortality.

The concept of biological age has emerged as a measurement that reflects physiological and functional decline with ageing. Here we aimed to develop a deep neural network (DNN) model that predicts biological age from optical coherence tomography (OCT). A total of 84,753 high-quality OCT images from 53,159 individuals in the UK Biobank were included, among which 12,631 3D-OCT images from 8,541 participants without any reported medical conditions at baseline were used to develop an age prediction model. For the remaining 44,618 participants, OCT age gap, the difference between the OCT-predicted age and chronological age, was calculated for each participant. Cox regression models assessed the association between OCT age gap and mortality. The DNN model predicted age with a mean absolute error of 3.27 years and showed a strong correlation of 0.85 with chronological age. After a median follow-up of 11.0 years (IQR 10.9-11.1 years), 2,429 deaths (5.44%) were recorded. For each 5-year increase in OCT age gap, there was an 8% increased mortality risk (hazard ratio [HR] = 1.08, CI:1.02-1.13, P = 0.004). Compared with an OCT age gap within ± 4 years, OCT age gap less than minus 4 years was associated with a 16% decreased mortality risk (HR = 0.84, CI: 0.75-0.94, P = 0.002) and OCT age gap more than 4 years showed an 18% increased risk of death incidence (HR = 1.18, CI: 1.02-1.37, P = 0.026). OCT imaging could serve as an ageing biomarker to predict biological age with high accuracy and the OCT age gap, defined as the difference between the OCT-predicted age and chronological age, can be used as a marker of the risk of mortality.

YOLO-DRS: A Bioinspired Object Detection Algorithm for Remote Sensing Images Incorporating a Multi-Scale Efficient Lightweight Attention Mechanism.

Bioinspired object detection in remotely sensed images plays an important role in a variety of fields. Due to the small size of the target, complex background information, and multi-scale remote sensing images, the generalized YOLOv5 detection framework is unable to obtain good detection results. In order to deal with this issue, we proposed YOLO-DRS, a bioinspired object detection algorithm for remote sensing images incorporating a multi-scale efficient lightweight attention mechanism. First, we proposed LEC, a lightweight multi-scale module for efficient attention mechanisms. The fusion of multi-scale feature information allows the LEC module to completely improve the model's ability to extract multi-scale targets and recognize more targets. Then, we propose a transposed convolutional upsampling alternative to the original nearest-neighbor interpolation algorithm. Transposed convolutional upsampling has the potential to greatly reduce the loss of feature information by learning the feature information dynamically, thereby reducing problems such as missed detections and false detections of small targets by the model. Our proposed YOLO-DRS algorithm exhibits significant improvements over the original YOLOv5s. Specifically, it achieves a 2.3% increase in precision (P), a 3.2% increase in recall (R), and a 2.5% increase in mAP@0.5. Notably, the introduction of the LEC module and transposed convolutional results in a respective improvement of 2.2% and 2.1% in mAP@0.5. In addition, YOLO-DRS only increased the GFLOPs by 0.2. In comparison to the state-of-the-art algorithms, namely YOLOv8s and YOLOv7-tiny, YOLO-DRS demonstrates significant improvements in the mAP@0.5 metrics, with enhancements ranging from 1.8% to 7.3%. It is fully proved that our YOLO-DRS can reduce the missed and false detection problems of remote sensing target detection.

Role of Caveolin-1 on the molybdenum and cadmium exposure induces pulmonary ferroptosis and fibrosis in the sheep.

Molybdenum (Mo) is an essential trace element that exists in all tissues of the human body, but excessive Mo intake has a toxic effect. Cadmium (Cd) is a widely known and harmful heavy metal that exists in the environment. Although studies on Mo and Cd are available, it is still unknown how the combination of Mo and Cd causes pulmonary injury. Forty-eight sheep that were 2 months old were chosen and randomly separated into four groups as follows: Control group, Mo group, Cd group, and Mo + Cd group. The experiment lasted 50 days. The results showed that Mo and/or Cd caused significant pathological damage and oxidative stress in the lungs of sheep. Moreover, Mo and/or Cd exposure could downregulate the expression levels of xCT (SLC7A11 and SLC3A2), GPX4 and FTH-1 and upregulate the expression levels of PTGS2 and NCOA4, which led to iron overload and ferroptosis. Ferroptosis induced Wnt/ß-catenin-mediated fibrosis by elevating the expression levels of Caveolin-1 (CAV-1), Wnt 1, Wnt3a, ß-catenin (CTNNB1), TCF4, Cyclin D1, mmp7, α-SMA (ACTA2), Collagen 1 (COL1A1) and Vimentin. These changes were particularly noticeable in the Mo and Cd combination group. In conclusion, these data demonstrated that Mo and/or Cd exposure led to lung ferroptosis by inhibiting the SLC7A11/GSH/GPX4 axis, which in turn increases CAV-1 expression and subsequently activates the Wnt/ß-catenin pathway, leading to fibrosis in sheep lungs.

The Association of Retinal age gap with metabolic syndrome and inflammation.

BACKGROUND: Metabolic syndrome (MetS) is a clustering of cardiometabolic components, posing tremendous burdens in the aging society. Retinal age gap has been proposed as a robust biomarker associated with mortality and Parkinson's disease. Although MetS and chronic inflammation could accelerate the aging process and increase the risk of mortality, the association of the retinal age gap with MetS and inflammation has not been examined yet. METHODS: Retinal age gap (retina-predicted age minus chronological age) was calculated using a deep learning model. MetS was defined as the presence of three or more of the following: central obesity, hypertension, dyslipidemia, hypertriglyceridemia, and hyperglycemia. Inflammation index was defined as a high-sensitivity C-reactive protein level above 3.0 mg/L. Logistic regression models were used to examine the associations of retinal age gaps with MetS and inflammation. RESULTS: We found that retinal age gap was significantly associated with MetS and inflammation. Specifically, compared to participants with retinal age gaps in the lowest quartile, the risk of MetS was significantly increased by 10% and 14% for participants with retinal age gaps in the third and fourth quartile (odds ratio [OR]:1.10; 95% confidence interval [CI], 1.01,1.21;, p = .030; OR: 1.14, 95% CI, 1.03,1.26; p = .012, respectively). Similar trends were identified for the risk of inflammation and combined MetS and inflammation. CONCLUSION: We found that retinal age gaps were significantly associated with MetS as well as inflammation. Given the noninvasive and cost-effective nature and the efficacy of the retinal age gap, it has great potential to be used as a screening tool for MetS in large populations.

Association of polysialic acid serum levels with schizophrenia spectrum and bipolar disorder-related structural brain changes and hospitalization.

Expression of polysialic acid (polySia) in the adult brain is enriched in areas of continuous neurogenesis and plasticity such as the hippocampus. Genome-wide association studies identified variants of glycosylation enzyme-encoding genes, required for the generation of polySia, to be associated with the development of schizophrenia and bipolar disorder. Here, we report that serum levels of polySia are increased in patients with schizophrenia spectrum disorder compared to patients with major depressive disorders or demographically matched healthy controls. Furthermore, elevated polySia serum levels are associated with structural hippocampal gray matter decline in schizophrenia spectrum and bipolar disorder. In patients with schizophrenia spectrum disorder, polySia serum levels correlate with the number, duration of disease-related hospitalizations, early retirement and medical leave as estimators of detrimental long-term disease trajectories. Our data show that polySia serum levels are linked to structural hippocampal brain changes in schizophrenia spectrum and bipolar disorders, and suggest a contribution of polySia to the pathophysiology of these diseases.

Effects of Blood Pressure and Arterial Stiffness on Retinal Neurodegeneration: Cross-Sectional and Longitudinal Evidence From UK Biobank and Chinese Cohorts.

BACKGROUND: Hypertension might be a modifiable risk factor for neurodegeneration diseases. However, the associations between blood pressure (BP), arterial stiffness index and retinal neurodegeneration remain unclear. METHODS: This study used cross-sectional data from the United Kingdom BioBank (UKB) and longitudinal data from the Chinese Ocular Imaging Project (COIP). The macular ganglion cell-inner plexiform layer thickness (mGCIPLT) and macular retinal nerve fiber layer thickness were measured using spectral domain optical coherence tomography imaging. Swept-source optical coherence tomography was performed to obtain the longitudinal trajectory of the mGCIPLT and peripapillary retinal nerve fiber layer thickness in the COIP cohort. Multivariable linear models were used to analyze the associations between BP and retinal measurements. RESULTS: In a cross-sectional analysis of 22 801 participants from UKB, thinner mGCIPLT was related to higher systolic BP (ß: -0.103 [-0.146 to -0.061]; P<0.001), and higher diastolic BP (ß: -0.191 [-0.265 to -0.117]; P<0.001), and was significantly associated with higher mean arterial pressure (ß: -0.174 [-0.238 to -0.109]; P<0.001) and higher mean pulse pressure (ß: -0.080 [-0.139 to -0.020]; P=009). In a longitudinal analysis of 2012 eligible COIP participants, higher levels of baseline systolic BP, diastolic BP, mean arterial pressure, and mean pulse pressure were associated with faster thinning in mGCIPLT and peripapillary retinal nerve fiber layer thickness (all P<0.001). The strongest association was the effect of mean arterial pressure on mGCIPLT (ß: -0.118 [-0.175 to -0.061]; P<0.001). The results of the analysis of macular retinal nerve fiber layer thickness and peripapillary retinal nerve fiber layer thickness were consistent with those of mGCIPLT. CONCLUSIONS: BP levels were independently and consistently associated with various retinal neurodegenerative exacerbations.

Retinal age gap as a predictive biomarker for mortality risk.

AIM: To develop a deep learning (DL) model that predicts age from fundus images (retinal age) and to investigate the association between retinal age gap (retinal age predicted by DL model minus chronological age) and mortality risk. METHODS: A total of 80 169 fundus images taken from 46 969 participants in the UK Biobank with reasonable quality were included in this study. Of these, 19 200 fundus images from 11 052 participants without prior medical history at the baseline examination were used to train and validate the DL model for age prediction using fivefold cross-validation. A total of 35 913 of the remaining 35 917 participants had available mortality data and were used to investigate the association between retinal age gap and mortality. RESULTS: The DL model achieved a strong correlation of 0.81 (p<0·001) between retinal age and chronological age, and an overall mean absolute error of 3.55 years. Cox regression models showed that each 1 year increase in the retinal age gap was associated with a 2% increase in risk of all-cause mortality (hazard ratio (HR)=1.02, 95% CI 1.00 to 1.03, p=0.020) and a 3% increase in risk of cause-specific mortality attributable to non-cardiovascular and non-cancer disease (HR=1.03, 95% CI 1.00 to 1.05, p=0.041) after multivariable adjustments. No significant association was identified between retinal age gap and cardiovascular- or cancer-related mortality. CONCLUSIONS: Our findings indicate that retinal age gap might be a potential biomarker of ageing that is closely related to risk of mortality, implying the potential of retinal image as a screening tool for risk stratification and delivery of tailored interventions.

Self-reported cataract surgery and 10-year all-cause and cause-specific mortality: findings from the National Health and Nutrition Examination Survey.

PURPOSE: To investigate the association of self-reported cataract surgery with all-cause and cause-specific mortality using a large-scale population-based sample. METHODS: Data from the 1999-2008 cycles of the National Health and Nutrition Examination Survey were used. A self-reported history of cataract surgery was considered a surrogate for the presence of clinically significant cataract surgery. Mortality data were ascertained from National Death Index records. Hazard ratios (HRs) and 95% confidence intervals (CIs) for survival were estimated using Cox proportional hazards regression models. RESULTS: A total of 14 918 participants were included in the analysis. During a median follow-up of 10.8 (Interquartile range, IQR, 8.25-13.7) years, 3966 (19.1%) participants died. Participants with self-reported cataract surgery were more likely to die from all causes and specific causes (vascular disease, cancer, accident, Alzheimer's disease, respiratory disease, renal disease and others) compared with those without (all Ps <0.05). The association between self-reported cataract surgery and all-cause mortality remained significant after multiple adjustments (HR=1.13; 95% CI 1.01 to 1.26). For cause-specific mortality, multivariable Cox models showed that self-reported cataract surgery predicted a 36% higher risk of vascular-related mortality (HR=1.36; 95% CI 1.01 to 1.82). The association with other specific causes of mortality did not reach statistical significance after multiple adjustments. CONCLUSIONS: This study found significant associations of self-reported cataract surgery with all-cause and vascular mortalities. Our findings provide potential insights into the pathogenic pathways underlying cataract.

Parapapillary Choroidal Microvasculature Predicts Diabetic Retinopathy Progression and Diabetic Macular Edema Development: A Three-Year Prospective Study.

PURPOSE: To determine the predictive value of the microcirculation of the optic nerve head by swept-source optical coherence tomography angiography for identifying individuals with high risk of diabetic retinopathy (DR) progression and diabetic macular edema (DME) development. DESIGN: Prospective observational cohort study. METHODS: A total of 946 patients (1879 eyes) with type 2 diabetes mellitus were recruited who had no DR or mild nonproliferative DR at baseline, and no DME. All subjects underwent 3 × 3 mm swept-source optical coherence tomography angiography centered on the optic nerve head to generate angiograms in 4 layers: radial peripapillary plexus, superficial retinal capillary plexus (SCP), deep retinal capillary plexus, and choriocapillaris (CC). The CC flow deficit percentage (CC FD%), vessel density (VD), and perfusion density (PD) were quantified. RESULTS: During the 3 consecutive years of follow-up, 312 eyes (16.60%) experienced DR progression and 115 eyes (6.12%) developed DME. The DR progression was related to a lower VD of the SCP (relative risk per standard deviation decrease, 95% confidence interval): 1.30, 1.14-1.48; P < .001), a lower PD of the SCP (1.41, 1.24-1.60; P < .001), a lower VD of the radial peripapillary plexus (1.23, 1.08-1.40; P = .002), and an elevated CC FD% (1.62, 1.40-1.88; P < .001). The DME occurrence was associated with a lower VD of SCP (1.35, 1.09-1.66; P = .005), a lower PD of SCP (1.29, 1.05-1.59; P = .016), and a higher CC FD% (1.29, 1.03-1.61; P < .001). The CC FD% significantly improved the predictive power, with the increase of the C-statistic for DR progression and DME occurrence by 3.83% (P = .002) and 5.24% (P < .001), respectively. CONCLUSIONS: This study provides the first longitudinal evidence suggesting that peripapillary CC FD% can improve the prediction of DR progression and DME development beyond traditional risk factors.

Choriocapillaris Flow Deficit as a Biomarker for Diabetic Retinopathy and Diabetic Macular Edema: 3-Year Longitudinal Cohort.

PURPOSE: To investigate the relationship between choriocapillaris flow deficit percentage (CC FD%) by swept-source optical coherence tomography angiography (SS-OCTA) and 3-year risk of diabetic retinopathy (DR) progression and diabetic macular edema (DME) development. DESIGN: Prospective, observational cohort study. METHODS: A total of 903 participants with type 2 diabetes mellitus (T2DM) without DR or with mild nonproliferative DR (NPDR) free of DME at baseline were followed up annually for 3 years. All participants underwent standard 7-field fundus photography and spectral-domain OCT. SS-OCTA was used for retinal and choriocapillaris imaging and 3 × 3-mm2 macular CC FD% was quantified. Univariate and multivariate logistic models were used to evaluate the association between CC FD% and 2 or more steps of DR progression and DME development. The additional predictive value of CC FD% for outcome events was assessed using C statistic, net reclassification index (NRI), and integrated discrimination improvement index (IDI). RESULTS: Over 3 years, 295 of 1805 eyes (16.34%) developed DR progression, and 118 eyes (6.54%) developed DME. A higher average CC FD% was correlated with DR progression (odds ratio [OR], 3.41 per SD increase, 95% CI: 2.65-4.39, P < .001) and DME development (OR, 1.37 per SD increase, 95% CI: 1.06-1.77, P = .016) after adjusting for confounders. In the ETDRS regions, increased CC FD% in all fields was associated with DR progression; however, increased CC FD% in the inferior field was associated with DME development. Compared with the models based on established risk factors, the addition of average CC FD% significantly improved the C statistics for DR progression (0.712 to 0.777, P < .001) and DME occurrence (0.743 to 0.773, P = .044). The estimated NRIs and IDIs (all >0) indicated that the addition of CC FD% led to a significant improvement in the discriminative performance for end points. CONCLUSION: CC FD% is independently associated with DR progression and DME development in the Chinese T2DM population and provides incremental predictive value beyond traditional risk factors and retinal microvascular parameters. Further inclusion of CC FD% in DR prediction models helps guide population-based screening and personalized management.

Rates of Choroidal and Neurodegenerative Changes Over Time in Diabetic Patients Without Retinopathy: A 3-Year Prospective Study.

PURPOSE: To evaluate the longitudinal changes of retinal neurodegeneration and choroidal thickness in diabetic patients with and without diabetic retinopathy (DR). DESIGN: Prospective observational cohort study. METHODS: This prospective observational cohort study recruited type 2 diabetic patients from a community registry in Guangzhou. All participants underwent annual ocular examinations via swept-source optical coherence tomography that obtained choroid thickness (CT), retinal thickness (RT), and ganglion cell-inner plexiform layer (GC-IPL) thickness. The changes in GC-IPL, CT, and RT between patients who developed incident DR (IDR) or remained non-DR (NDR) were compared during a 3-year follow-up. RESULTS: Among 924 patients, 159 (17.2%) patients developed IDR within the 3-year follow-up. A reduction in GC-IPL, RT, and CT was observed in NDR and IDR; however, CT thinning in patients with IDR was significantly accelerated, with an average CT reduction of -6.98 (95% CI: -8.26, -5.71) µm/y in patients with IDR and -3.98 (95% CI: -4.60, -3.36) µm/y in NDR patients (P < .001). Reductions in average GC-IPL thickness over 3 years were -0.97 (95% CI: -1.24, -0.70) µm/y in patients with IDR and -0.76 (95% CI: -0.82, -0.70) µm/y in NDR patients (P = .025). After adjusting for confounding factors, the average CT and GC-IPL thinning were significantly faster in patients with IDR compared with those who remained NDR by 2.09 µm/y (95% CI: 1.01, 3.16; P = .004) and -0.29 µm/y (95% CI: -0.49, -0.09; P = .004), respectively. The RT in the IDR group increased, whereas the RT in the NDR group decreased over time, with the adjusted difference of 2.09 µm/y (95% CI: 1.01, 3.16; P < .001) for central field RT. CONCLUSIONS: The rate of retinal neurodegeneration and CT thinning were significantly different between the eyes that developed IDR and remained NDR during the 3-year follow-up, but both groups observed thickness reduction. This indicates that GC-IPL and CTs may decrease before the clinical manifestations of DR.

A new clam shrimp (Branchiopoda: Diplostraca: Spinicaudata) from the Upper Jurassic in the Jiyuan Basin, China and its biostratigraphic significance.

A new spinicaudatan species Triglypta jiyuanensis Liao & Huang sp. nov. is described from the Upper Jurassic Maao Formation in the Jiyuan Basin, northwestern Henan Province, China. The carapace of the new species is ornamented with punctae, linear arrangements of punctae, and radial lirae. The new species differs from those of the early Triglypta forms from the Middle Jurassic but closely resembles T. jianchangensis Wang, 2014 from the Upper Jurassic Tiaojishan Formation of western Liaoning Province. Our study provides new biostratigraphic evidence supporting that the Maao and Tiaojishan formations can be correlated. Moreover, we suggest that the Yangshuzhuang Formation in the Jiyuan Basin could correlate to the Haifanggou and the Longmen formations in the Yanliao area.

PROGRESSIVE PERIPAPILLARY CHOROID THINNING AND RETINAL NEURODEGENERATION IN PATIENTS WITH DIABETES: A 3-Year Cohort Study.

PURPOSE: To investigate longitudinal changes in peripapillary choroidal thickness (pCT) and retinal nerve fiber thickness (pRNFLT) in patients with Type 2 diabetes mellitus. METHODS: This was a prospective observational cohort study. Patients with Type 2 diabetes mellitus without diabetic retinopathy (DR) at baseline were recruited, followed up for three years, and further divided into an incident DR group and a non-DR group according to the outcome. The pCT and pRNFLT were measured through swept-source optical coherence tomography at 1-year interval, and the mean rates of pCT and pRNFLT thinning were compared between the DR groups. RESULTS: A total of 682 patients (682 eyes) were included in the final analysis. After 3-years follow-up, 122 (17.89%) developed DR. Both pCT and pRNFLT progressively thinned (-2.37 [-2.80 to -1.95] µm/year; -0.40 [-0.55 to -0.25] µm/year, respectively, P < 0.05) and accelerated thinning was observed in the incident DR group. The rates of pCT thinning (-3.92 [-4.96 to -2.88] µm/year, -2.03 [-2.49 to -1.57] µm/year, respectively) and pRNFLT loss (-1.03 [-1.31 to -0.76] µm/year, -0.26 [-0.43 to -0.09] µm/year, respectively) in the incident DR group were 1.93 and 3.96 times faster than those in the non-DR group, respectively. In addition, pCT and pRNFLT thinning were negatively related in Type 2 diabetes mellitus population, and faster pCT thinning indicated slower pRNFLT loss. CONCLUSION: Patients with Type 2 diabetes mellitus were at a higher risk of developing DR when accelerated pCT and pRNFLT thinning were present, indicating that heavier choroidal damage and retinal neurodegeneration precede clinical DR. The pCT and pRNFLT have the potential to serve as novel sensitive biomarkers of preclinical and early DR.

Rates of choroidal loss and ganglion cell-inner plexiform layer thinning in type 2 diabetes mellitus and healthy individuals: a 2-year prospective study.

AIMS: To investigate longitudinal choroid and ganglion cell-inner plexiform layer (GCIPL) changes in type 2 diabetes mellitus (T2DM) patients and healthy populations across 2 years. METHODS: This prospective cohort study included T2DM patients and healthy controls. T2DM patients were divided into mild non-proliferative diabetic retinopathy (NPDR) or non-DR (NDR) groups. Macular choroidal and GCIPL thickness was measured using swept-source optical coherence tomography at baseline and follow-up after 2 years. A linear-mixed effect model compared rates of change in choroidal and GCIPL thicknesses between the three groups. RESULTS: 895 T2DM patients (770 in the NDR group and 125 in the NPDR group) and 847 healthy controls were included. Following 2 years, choroidal thinning occurred at a rate of -7.7±9.2 µm/year, -8.1±8.7 µm/year and -5.2±8.1 µm/year in NDR, NPDR and control groups, respectively (p<0.001). GCIPL loss occurred quickest in NPDR patients (-0.97±0.97 µm/year), followed by NDR (-0.91±0.89 µm/year) and the control group (-0.04±0.55 µm/year) (p<0.001). Following multivariate adjustment, choroidal thinning was -2.04 µm/year (95% CI: -4.05 to -0.03; p=0.047) and -1.95 µm/year (95% CI: -3.14 to -0.75; p=0.001) faster in NPDR and NDR groups than in the control group, respectively, and GCIPL thinning was -1.02 µm/year (95% CI: -1.19 to -0.84; p<0.001) and -0.88 µm/year (95% CI: -0.98 to -0.78; p<0.001) faster in the NPDR and NDR groups than in the control group, respectively. CONCLUSION: Progressive choroidal and GCIPL thinning occurs in healthy individuals and T2DM patients; however, T2DM undergoes accelerated choroidal and GCIPL loss in NPDR patients.