Sex differences in the relationships between macronutrients and all-cause mortality in individuals with metabolically unhealthy overweight/obesity.

This study investigates sex differences in the effects of macronutrient quantity, quality, and timing on mortality in metabolically unhealthy overweight/obesity (MUO) populations. The study included 18,345 participants, including 9204 men and 9141 women. The Cox proportional risk model and isocaloric substitution effects were used to examine the association of macronutrient intake and subtype with all-cause mortality in the MUO populations. After adjusting for the potential covariates, The risk of all-cause mortality was elevated in men in the highest 25% percentile of poor-quality carbohydrates compared with men in the lowest quartile (odds ratio [OR]: 2.04; 95% confidence interval [CI], 1.40-2.98). Compared with women in the lowest quartile, the risk of all-cause mortality for women in the highest 25% percentile for high-quality carbohydrates (OR: 0.74; 95% CI, 0.55-0.99) and unsaturated fatty acids (OR: 0.54; 95% CI, 0.32-0.93) were decreased. In women, replacing low-quality carbohydrates with high-quality carbohydrates on an isocaloric basis reduces the risk of all-cause mortality by approximately 9%. We find that different macronutrient consumption subtypes are associated with all-cause mortality in MUO populations, with differential effects between men and women, and that the risk of all-cause mortality is influenced by macronutrient quality and meal timing.

Stem cell factor protects against chronic ischemic retinal injury by modulating on neurovascular unit.

Retinal ischemia is a significant factor in various vision-threatening diseases, but effective treatments are currently lacking. This study explores the potential of stem cell factor (SCF) in regulating the neurovascular unit as a therapeutic intervention for retinal ischemic diseases. A chronic retinal ischemia model was established in Brown Norway rats using bilateral common carotid artery occlusion (BCCAO). Subsequent SCF treatment resulted in a remarkable recovery of retinal function, as indicated by electroretinogram, light/dark transition test, and optokinetic head tracking test results. Histological examination demonstrated a significant increase in the number of retinal neurons and an overall thickening of the retina. Immunofluorescence confirmed these findings and further demonstrated that SCF treatment regulated retinal remodeling. Notably, SCF treatment ameliorated the disrupted expression of synaptic markers in the control group's BCCAO rats and suppressed the activation of Müller cells and microglia. Retinal whole-mount analysis revealed a significant improvement in the abnormalities in retinal vasculature following SCF treatment. Transcriptome sequencing analysis revealed that SCF-induced transcriptome changes were closely linked to the Wnt7 pathway. Key members of the Wnt7 pathway, exhibited significant upregulation following SCF treatment. These results underscore the protective role of SCF in the neurovascular unit of retinal ischemia rats by modulating the Wnt7 pathway. SCF administration emerges as a promising therapeutic strategy for retinal ischemia-related diseases, offering potential avenues for future clinical interventions.

Protein Coronas on Functionalized Nanoparticles Enable Quantitative and Precise Large-Scale Deep Plasma Proteomics.

Background: The wide dynamic range of circulating proteins coupled with the diversity of proteoforms present in plasma has historically impeded comprehensive and quantitative characterization of the plasma proteome at scale. Automated nanoparticle (NP) protein corona-based proteomics workflows can efficiently compress the dynamic range of protein abundances into a mass spectrometry (MS)-accessible detection range. This enhances the depth and scalability of quantitative MS-based methods, which can elucidate the molecular mechanisms of biological processes, discover new protein biomarkers, and improve comprehensiveness of MS-based diagnostics. Methods: Investigating multi-species spike-in experiments and a cohort, we investigated fold-change accuracy, linearity, precision, and statistical power for the using the Proteograph™ Product Suite, a deep plasma proteomics workflow, in conjunction with multiple MS instruments. Results: We show that NP-based workflows enable accurate identification (false discovery rate of 1%) of more than 6,000 proteins from plasma (Orbitrap Astral) and, compared to a gold standard neat plasma workflow that is limited to the detection of hundreds of plasma proteins, facilitate quantification of more proteins with accurate fold-changes, high linearity, and precision. Furthermore, we demonstrate high statistical power for the discovery of biomarkers in small- and large-scale cohorts. Conclusions: The automated NP workflow enables high-throughput, deep, and quantitative plasma proteomics investigation with sufficient power to discover new biomarker signatures with a peptide level resolution.

Comparison of Ophthalmic Artery Morphological Characteristics and Retinal Vessel Diameter for Identifying Ocular Ischemic Syndrome.

Purpose: To investigate the morphological characteristics of the ophthalmic artery (OA) and retinal vessels in ocular ischemic syndrome (OIS) and to compare their ability to identify OIS. Methods: This cross-sectional observational study included 21 patients with unilateral OIS and 17 controls matched for age, sex, degree of internal carotid artery (ICA) stenosis, and cerebral collateral patency. This study used a three-dimensional reconstruction based on computed tomographic angiography to measure the morphological characteristics of the OA and the ICA. Quantitative measurements of retinal vessel diameter were performed using the Integrative Vessel Analysis software. Receiver operating characteristic (ROC) curve analysis was performed to assess the ability of the OA diameter and the central retinal artery equivalent (CRAE) to identify OIS. Results: The diameter of the OA (odds ratio = 0.001; P = 0.001) and the CRAE (odds ratio = 0.951; P = 0.028) were significantly associated with the presence of OIS after adjusting for age, sex, and the degree of the ICA stenosis. The areas under the curve for the OA diameter and the CRAE were, respectively, 0.871 (P < 0.001) and 0.744 (P = 0.017) according to the ROC curves analysis. Conclusions: The OA diameter measurement identified OIS better than CRAE measurement. The OA may reflect the changes in ocular blood supply in patients with OIS earlier than retinal vessels. The OA of eyes with OIS may undergo arterial wall remodeling, leading to a decrease in OA diameter and further reduction in blood flow.

Blood flow perfusion in visual pathway detected by arterial spin labeling magnetic resonance imaging for differential diagnosis of ocular ischemic syndrome.

Background: Ocular ischemic syndrome (OIS), attributable to chronic hypoperfusion caused by marked carotid stenosis, is one of the important factors that cause ocular neurodegenerative diseases such as optic atrophy. The current study aimed to detect blood flow perfusion in a visual pathway by arterial spin labeling (ASL) and magnetic resonance imaging (MRI) for the differential diagnosis of OIS. Methods: This diagnostic, cross-sectional study at a single institution was performed to detect blood flow perfusion in a visual pathway based on 3D pseudocontinuous ASL (3D-pCASL) using 3.0T MRI. A total of 91 participants (91 eyes) consisting of 30 eyes with OIS and 61 eyes with noncarotid artery stenosis-related retinal vascular diseases (39 eyes with diabetic retinopathy and 22 eyes with high myopic retinopathy) were consecutively included. Blood flow perfusion values in visual pathways derived from regions of interest in ASL images, including the retinal-choroidal complex, the intraorbital segments of the optic nerve, the tractus optics, and the visual center, were obtained and compared with arm-retinal circulation time and retinal circulation time derived from fundus fluorescein angiography (FFA). Receiver operating characteristic (ROC) curve analyses and the intraclass correlation coefficient (ICC) were performed to evaluate the accuracy and consistency. Results: Patients with OIS had the lowest blood flow perfusion values in the visual pathway (all p < 0.05). The relative intraorbital segments of optic nerve blood flow values at post-labeling delays (PLDs) of 1.5 s (area under the curve, AUC = 0.832) and the relative retinal-choroidal complex blood flow values at PLDs of 2.5 s (AUC = 0.805) were effective for the differential diagnosis of OIS. The ICC of the blood flow values derived from the retinal-choroidal complex and the intraorbital segments of the optic nerve between the two observers showed satisfactory concordance (all ICC > 0.932, p < 0.001). The adverse reaction rates of ASL and FFA were 2.20 and 3.30%, respectively. Conclusion: 3D-pCASL showed that the participants with OIS had lower blood flow perfusion values in the visual pathway, which presented satisfactory accuracy, reproducibility, and safety. It is a noninvasive and comprehensive differential diagnostic tool to assess blood flow perfusion in a visual pathway for the differential diagnosis of OIS.

Functionally distinct BMP1 isoforms show an opposite pattern of abundance in plasma from non-small cell lung cancer subjects and controls.

Advancements in deep plasma proteomics are enabling high-resolution measurement of plasma proteoforms, which may reveal a rich source of novel biomarkers previously concealed by aggregated protein methods. Here, we analyze 188 plasma proteomes from non-small cell lung cancer subjects (NSCLC) and controls to identify NSCLC-associated protein isoforms by examining differentially abundant peptides as a proxy for isoform-specific exon usage. We find four proteins comprised of peptides with opposite patterns of abundance between cancer and control subjects. One of these proteins, BMP1, has known isoforms that can explain this differential pattern, for which the abundance of the NSCLC-associated isoform increases with stage of NSCLC progression. The presence of cancer and control-associated isoforms suggests differential regulation of BMP1 isoforms. The identified BMP1 isoforms have known functional differences, which may reveal insights into mechanisms impacting NSCLC disease progression.

Circular RNA in Retina: A Potential Biomarker and Therapeutic Target.

Circular RNA (circRNA) is a newly discovered noncoding RNA, which forms a closed ring with more than 200 bases in length. CircRNA is formed by back splicing of precursor RNA, and its expression abundance in body fluid is up to 10 times that of homologous linear transcripts. Recently, novel activities for circRNA in various diseases have emerged, ranging from cancer therapy and neurodegenerative diseases. Here, we reviewed the literature on the biogenesis of circRNA and its relationship with retinal diseases in recent years. We first described the mechanism, existing form and main function of circRNA. Next, we also pinpoint that circRNA has great value in the diagnosis and treatment of retinal diseases represented by retinoblastoma, retinal degeneration, and diabetic retinopathy. By this review, we hope to explore more possibilities of circRNA in clinical diagnosis and treatment.

B Cells Promote T Cell Immunosenescence and Mammalian Aging Parameters.

A dysregulated adaptive immune system is a key feature of aging, and is associated with age-related chronic diseases and mortality. Most notably, aging is linked to a loss in the diversity of the T cell repertoire and expansion of activated inflammatory age-related T cell subsets, though the main drivers of these processes are largely unknown. Here, we find that T cell aging is directly influenced by B cells. Using multiple models of B cell manipulation and single-cell omics, we find B cells to be a major cell type that is largely responsible for the age-related reduction of naive T cells, their associated differentiation towards pathogenic immunosenescent T cell subsets, and for the clonal restriction of their T cell receptor (TCR). Accordingly, we find that these pathogenic shifts can be therapeutically targeted via CD20 monoclonal antibody treatment. Mechanistically, we uncover a new role for insulin receptor signaling in influencing age-related B cell pathogenicity that in turn induces T cell dysfunction and a decline in healthspan parameters. These results establish B cells as a pivotal force contributing to age-associated adaptive immune dysfunction and healthspan outcomes, and suggest new modalities to manage aging and related multi-morbidity.

Value of Combined Diagnosis for Choroidal Lymphoma: A Case Report.

Intraocular lymphoma (IOL) comprises a group of malignant tumours originating from lymphohematopoietic tissues that have a poor prognosis. These tumours predominantly occur in the vitreous and retina but are rarely found in the choroid. A few case reports and case series of choroidal lymphoma (CL) have been reported in the literature. CL is prone to misdiagnosis and incorrect treatment because it often mimics other intraocular diseases such as uveitis. This may seriously affect localisation of the primary lesion and delay treatment, which may even affect the patient's survival. Herein, we report a case of CL and propose the combination of characteristic ophthalmic imaging with systemic imaging and aqueous humour detection to establish a robust basis for the early diagnosis of CL.

Enhanced Competition at the Nano-Bio Interface Enables Comprehensive Characterization of Protein Corona Dynamics and Deep Coverage of Proteomes.

Introducing engineered nanoparticles (NPs) into a biofluid such as blood plasma leads to the formation of a selective and reproducible protein corona at the particle-protein interface, driven by the relationship between protein-NP affinity and protein abundance. This enables scalable systems that leverage protein-nano interactions to overcome current limitations of deep plasma proteomics in large cohorts. Here the importance of the protein to NP-surface ratio (P/NP) is demonstrated and protein corona formation dynamics are modeled, which determine the competition between proteins for binding. Tuning the P/NP ratio significantly modulates the protein corona composition, enhancing depth and precision of a fully automated NP-based deep proteomic workflow (Proteograph). By increasing the binding competition on engineered NPs, 1.2-1.7× more proteins with 1% false discovery rate are identified on the surface of each NP, and up to 3× more proteins compared to a standard plasma proteomics workflow. Moreover, the data suggest P/NP plays a significant role in determining the in vivo fate of nanomaterials in biomedical applications. Together, the study showcases the importance of P/NP as a key design element for biomaterials and nanomedicine in vivo and as a powerful tuning strategy for accurate, large-scale NP-based deep proteomic studies.

The G allele of the IGF1 rs2162679 SNP is a potential protective factor for any myopia: Updated systematic review and meta-analysis.

BACKGROUND: The insulin-like growth factor 1 (IGF1) gene is located within the myopia-associated MYP3 interval, which suggests it may play an important role in the progression of myopia. However, the association between IGF1 SNPs and any myopia is rarely reported. METHODS: A comprehensive literature search was conducted on studies published up to July 22, 2021 in PubMed, EMBASE, CBM, COCHRANE, CNKI, WANFANG and VIP databases. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for single-nucleotide polymorphisms (SNPs) that have been evaluated in at least three studies. RESULTS: Nine studies involving 4596 subjects with any myopia and 4950 controls examined 25 SNPs in IGF1 gene, among which seven SNPs were included in this meta-analysis. Significant associations were not found in any genetic models between rs6214, rs12423791, rs5742632, rs10860862, rs5742629 and any myopia. Rs2162679 was suggestively associated with any myopia in the codominant model (GA vs. AA: OR = 0.87, 95% CI: 0.76-1.00) and the dominant model (GG+GA vs. AA: OR = 0.88, 95% CI = 0.78-1.00). CONCLUSION: Meta-analysis of updated data reveals that the G allele of the IGF1 rs2162679 SNP is a potential protective factor for any myopia, which is worth further researches.

Restoration of DNA repair mitigates genome instability and increases productivity of Chinese hamster ovary cells.

Chinese hamster ovary (CHO) cells are the primary host for manufacturing of therapeutic proteins. However, productivity loss is a major problem and is associated with genome instability, as chromosomal aberrations reduce transgene copy number and decrease protein expression. We analyzed whole-genome sequencing data from 11 CHO cell lines and found deleterious single-nucleotide variants in DNA repair genes. Comparison with primary Chinese hamster cells confirmed DNA repair to be compromised in CHO. Correction of key DNA repair genes by single-nucleotide variant reversal or expression of intact complementary DNAs successfully improved DNA repair and mitigated karyotypic instability. Moreover, overexpression of intact copies of LIG4 and XRCC6 in a CHO cell line expressing secreted alkaline phosphatase mitigated transgene copy loss and improved protein titer retention. These results show that correction of DNA repair genes yields improvements in genome stability in CHO, and provide new opportunities for cell line development for sustainable protein expression.

Systematic review of the efficacy and safety of stage I or II IOL implantation in patients with diabetic retinopathy.

BACKGROUND: Intraocular lens (IOL) implantation is required after vitrectomy combined with cataract surgery in diabetic retinopathy patients. However, the question of whether an IOL should be implanted in stage I after vitrectomy or stage II during silicone oil filling has been controversial, and there has been no systematic review of this clinical issue. METHODS: WanFang, SinoMed CNKI, VIP, PubMed, Embase, and Cochrane Library databases were systematically searched for relevant studies. The deadline was May 8, 2021. All studies of stage I or II IOL implantation in patients with diabetes who underwent vitrectomy were included. Revman 5.3 software was used for the meta-analysis. RESULTS: Four studies, involving 253 eyes, were included. This study analyzed the literature with a common outcome index by meta-analysis and systematically evaluated the literature without a common outcome index. Four studies compared the efficacy and safety of the 2 sequential surgical methods in patients with diabetic retinopathy. The results of the meta-analysis showed that there was no significant difference in the efficacy and safety of stage II IOL implantation when compared with stage I IOL implantation (P > .05). One study showed that stage II cataract surgery with oil extraction resulted in better postoperative visual acuity and fewer complications than stage I cataract surgery with vitrectomy. One study showed that stage II IOL implantation during oil extraction had better postoperative visual acuity than stage I IOL implantation during vitrectomy without increasing surgical complications. CONCLUSION: Vitrectomy combined with stage II IOL implantation is safer and more effective than stage I in patients with diabetic retinopathy; however, more clinical studies are needed to verify this.

An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging.

While many diseases of aging have been linked to the immunological system, immune metrics capable of identifying the most at-risk individuals are lacking. From the blood immunome of 1,001 individuals aged 8-96 years, we developed a deep-learning method based on patterns of systemic age-related inflammation. The resulting inflammatory clock of aging (iAge) tracked with multimorbidity, immunosenescence, frailty and cardiovascular aging, and is also associated with exceptional longevity in centenarians. The strongest contributor to iAge was the chemokine CXCL9, which was involved in cardiac aging, adverse cardiac remodeling and poor vascular function. Furthermore, aging endothelial cells in human and mice show loss of function, cellular senescence and hallmark phenotypes of arterial stiffness, all of which are reversed by silencing CXCL9. In conclusion, we identify a key role of CXCL9 in age-related chronic inflammation and derive a metric for multimorbidity that can be utilized for the early detection of age-related clinical phenotypes.

Calibrating predictive model estimates in a distributed network of patient data.

BACKGROUND: Protecting the privacy of patient data is an important issue. Patient data are typically protected in local health systems, but this makes integration of data from different healthcare systems difficult. To build high-performance predictive models, a large number of samples are needed, and performance measures such as calibration and discrimination are essential. While distributed algorithms for building models and measuring discrimination have been published, distributed algorithms to measure calibration and recalibrate models have not been proposed. OBJECTIVE: Recalibration models have been shown to improve calibration, but they have not been proposed for data that are distributed in various health systems, or "sites". Our goal is to measure calibration performance and build a global recalibration model using data from multiple health systems, without sharing patient-level data. MATERIALS AND METHODS: We developed a distributed smooth isotonic regression recalibration model and extended established calibration measures, such as Hosmer-Lemeshow Tests, Expected Calibration Error, and Maximum Calibration Error in a distributed manner. RESULTS: Experiments on both simulated and clinical data were conducted, and the recalibration results produced by a traditional (ie, centralized) versus a distributed smooth isotonic regression were compared. The results were exactly the same. DISCUSSION: Our algorithms demonstrated that calibration can be improved and measured in a distributed manner while protecting data privacy, albeit at some cost in terms of computational efficiency. It also gives researchers who may have too few instances in their own institutions a method to construct robust recalibration models. CONCLUSION: Preserving data privacy and improving model calibration are both important to advancing predictive analysis in clinical informatics. The algorithms alleviate the difficulties in model building across sites.

Modeling Predictive Age-Dependent and Age-Independent Symptoms and Comorbidities of Patients Seeking Treatment for COVID-19: Model Development and Validation Study.

BACKGROUND: The COVID-19 pandemic continues to ravage and burden hospitals around the world. The epidemic started in Wuhan, China, and was subsequently recognized by the World Health Organization as an international public health emergency and declared a pandemic in March 2020. Since then, the disruptions caused by the COVID-19 pandemic have had an unparalleled effect on all aspects of life. OBJECTIVE: With increasing total hospitalization and intensive care unit admissions, a better understanding of features related to patients with COVID-19 could help health care workers stratify patients based on the risk of developing a more severe case of COVID-19. Using predictive models, we strive to select the features that are most associated with more severe cases of COVID-19. METHODS: Over 3 million participants reported their potential symptoms of COVID-19, along with their comorbidities and demographic information, on a smartphone-based app. Using data from the >10,000 individuals who indicated that they had tested positive for COVID-19 in the United Kingdom, we leveraged the Elastic Net regularized binary classifier to derive the predictors that are most correlated with users having a severe enough case of COVID-19 to seek treatment in a hospital setting. We then analyzed such features in relation to age and other demographics and their longitudinal trend. RESULTS: The most predictive features found include fever, use of immunosuppressant medication, use of a mobility aid, shortness of breath, and severe fatigue. Such features are age-related, and some are disproportionally high in minority populations. CONCLUSIONS: Predictors selected from the predictive models can be used to stratify patients into groups based on how much medical attention they are expected to require. This could help health care workers devote valuable resources to prevent the escalation of the disease in vulnerable populations.

Late-phase hypercyanescence during indocyanine green angiography for assessment of myopic choroidal neovascularization.

PURPOSE: Indocyanine green angiography (ICGA) is a major diagnostic modality but the clinical implications of specific staining patterns in active myopic choroidal neovascularization (mCNV) are unclear. We examined the associations of ICGA cyanofluorescence patterns with disease characteristics and response to an as-needed intravitreal ranibizumab (IVR) treatment regimen among active mCNV patients. METHODS: Twenty-four subjects with active mCNV treated by IVR were enrolled in this retrospective cohort study. Information from medical records were reviewed, including best corrected visual acuity (BCVA), fluorescein angiography (FA) findings, ICGA cyanofluorescence patterns, and spectral-domain OCT (SD-OCT) results. The CNV lesion size, CNV thickness, and central retinal thickness (CRT) were measured from these images. RESULTS: Two staining patterns were identified on late-phase ICGA images, hypercyanescence (9/24, 37.5%) and non-hypercyanescence (15/24, 62.5%). There were no differences in baseline BCVA, CNV thickness, and CRT between ICGA pattern groups; however, the hypercyanescence group demonstrated a larger CNV lesion size (p = 0.035) and required more IVR injections than the non-hypercyanescence group (2.67 ± 1.58 vs 1.07 ± 0.27, p = 0.016), while the non-hypercyanescence group demonstrated better final BCVA improvement (p = 0.041). Hypercyanescence could be divided into two types, a uniform type and rim type. A pseudopodia-like protrusion of CNV enlargement with a rim-enhanced type hypercyanescence at the protrusion rim was predictive of required retreatment. CONCLUSIONS: Hypercyanescence on late-phase ICGA may assist in identifying more active mCNV requiring intensive treatment.

WITHDRAWN: Exosomes derived from BDNF-expressing 293T attenuate ischemic retinal injury in vitro and in vivo.

This paper was originally published in Aging Advance Online Publications on November 29, 2020. In compliance with Aging's withdrawal policy, the paper was withdrawn in its entirety. It will not appear in Aging internal or any external indexes or archives.