Extraordinary preservation of gene collinearity over three hundred million years revealed in homosporous lycophytes.

Homosporous lycophytes (Lycopodiaceae) are a deeply diverged lineage in the plant tree of life, having split from heterosporous lycophytes (Selaginella and Isoetes) ~400 Mya. Compared to the heterosporous lineage, Lycopodiaceae has markedly larger genome sizes and remains the last major plant clade for which no chromosome-level assembly has been available. Here, we present chromosomal genome assemblies for two homosporous lycophyte species, the allotetraploid Huperzia asiatica and the diploid Diphasiastrum complanatum. Remarkably, despite that the two species diverged ~350 Mya, around 30% of the genes are still in syntenic blocks. Furthermore, both genomes had undergone independent whole genome duplications, and the resulting intragenomic syntenies have likewise been preserved relatively well. Such slow genome evolution over deep time is in stark contrast to heterosporous lycophytes and is correlated with a decelerated rate of nucleotide substitution. Together, the genomes of H. asiatica and D. complanatum not only fill a crucial gap in the plant genomic landscape but also highlight a potentially meaningful genomic contrast between homosporous and heterosporous species.

Clinical and genetic characterization of a large cohort of Chinese patients with Bietti crystalline retinopathy.

PURPOSE: To investigate the clinical and genetic characteristics for a large cohort of Chinese patients with Bietti crystalline retinopathy (BCR). METHODS: A total of 208 Chinese BCR patients from 175 families were recruited. Comprehensive clinical evaluations and genetic analysis were performed. Genotype-phenotype correlations were evaluated through statistical analysis. RESULTS: The patients' median age was 37 years (range, 20-76 years). The median best corrected visual acuity (BCVA) was 0.8 LogMAR unit (range, 2.8 to -0.12). A significant decline of BCVA was revealed in patients over 40 years old (P<0.001). Two clinical types were observed: peripheral type (type P) and central type (type C). Significantly more type C patients had a worse central visual acuity, but a more preserved retinal function (P<0.05). Molecular screening detected biallelic CYP4V2 pathogenic variants in 98.3% (172/175) of the families, including 19 novel ones. The most frequent pathogenic variant was c.802-8_810del17insGC, with the allele frequency of 55.7% (195/350), followed by c.992A>C (28/350, 8%) and c.1091-2A>G (23/350, 6.6%). BCR patients with one c.802-8_810del17insGC and one truncating variant (IVS6-8/Tru) had BCVA>1.3 LogMAR unit (Snellen equivalent<20/400) at a younger age than those with homozygous c.802-8_810del17insGC variants (homo IVS6-8) (P=0.031). CONCLUSIONS: BCR patients preserved relatively good vision before 40 years old. Two distinct clinical types of BCR were observed. BCR patients with IVS6-8/Tru had an earlier decline in visual acuity than those with homo IVS6-8. Our findings enhance the knowledge of BCR and will be helpful in patient selection for gene therapy.

The chromosome-level genome of female ginseng (Angelica sinensis) provides insights into molecular mechanisms and evolution of coumarin biosynthesis.

Coumarins are natural products with important medicinal values, and include simple coumarins, furanocoumarins and pyranocoumarins. Female ginseng (Angelica sinensis) is a renowned herb with abundant coumarins, originated in China and known for the treatment of female ailments for thousands of years. The molecular basis of simple coumarin biosynthesis in A. sinensis and the evolutionary history of the genes involved in furanocoumarin biosynthesis are largely unknown. Here, we generated the first chromosome-scale genome of A. sinensis. It has a genome size of 2.37 Gb, which was generated by combining PacBio and Hi-C sequencing technologies. The genome was predicted to contain 43 202 protein-coding genes dispersed mainly on 11 pseudochromosomes. We not only provided evidence for whole-genome duplication (WGD) specifically occurring in the Apioideae subfamily, but also demonstrated the vital role of tandem duplication for phenylpropanoid biosynthesis in A. sinensis. Combined analyses of transcriptomic and metabolomic data revealed key genes and candidate transcription factors regulating simple coumarin biosynthesis. Furthermore, phylogenomic synteny network analyses suggested prenyltransferase genes involved in furanocoumarin biosynthesis evolved independently in the Moraceae, Fabaceae, Rutaceae and Apiaceae after ζ and ε WGD. Our work sheds light on coumarin biosynthesis, and provides a benchmark for accelerating genetic research and molecular breeding in A. sinensis.

Development and validation of explainable machine-learning models for carotid atherosclerosis early screening.

BACKGROUND: Carotid atherosclerosis (CAS), an important factor in the development of stroke, is a major public health concern. The aim of this study was to establish and validate machine learning (ML) models for early screening of CAS using routine health check-up indicators in northeast China. METHODS: A total of 69,601 health check-up records from the health examination center of the First Hospital of China Medical University (Shenyang, China) were collected between 2018 and 2019. For the 2019 records, 80% were assigned to the training set and 20% to the testing set. The 2018 records were used as the external validation dataset. Ten ML algorithms, including decision tree (DT), K-nearest neighbors (KNN), logistic regression (LR), naive Bayes (NB), random forest (RF), multiplayer perceptron (MLP), extreme gradient boosting machine (XGB), gradient boosting decision tree (GBDT), linear support vector machine (SVM-linear), and non-linear support vector machine (SVM-nonlinear), were used to construct CAS screening models. The area under the receiver operating characteristic curve (auROC) and precision-recall curve (auPR) were used as measures of model performance. The SHapley Additive exPlanations (SHAP) method was used to demonstrate the interpretability of the optimal model. RESULTS: A total of 6315 records of patients undergoing carotid ultrasonography were collected; of these, 1632, 407, and 1141 patients were diagnosed with CAS in the training, internal validation, and external validation datasets, respectively. The GBDT model achieved the highest performance metrics with auROC of 0.860 (95% CI 0.839-0.880) in the internal validation dataset and 0.851 (95% CI 0.837-0.863) in the external validation dataset. Individuals with diabetes or those over 65 years of age showed low negative predictive value. In the interpretability analysis, age was the most important factor influencing the performance of the GBDT model, followed by sex and non-high-density lipoprotein cholesterol. CONCLUSIONS: The ML models developed could provide good performance for CAS identification using routine health check-up indicators and could hopefully be applied in scenarios without ethnic and geographic heterogeneity for CAS prevention.

Inhibitory receptor CD47 binding to plasma TSP1 suppresses NK-cell IFN-γ production via activating the JAK/STAT3 pathway during HIV infection.

BACKGROUND: Natural killer (NK) cells play an important first-line role against tumour and viral infections and are regulated by inhibitory receptor expression. Among these inhibitory receptors, the expression, function, and mechanism of cluster of differentiation 47 (CD47) on NK cells during human immunodeficiency virus (HIV) infection remain unclear. METHODS: Fresh peripheral blood mononuclear cells (PBMCs) were collected from people living with HIV (PLWH) and HIV negative controls (NC) subjects. Soluble ligand expression levels of CD47 were measured using ELISA. HIV viral proteins or Toll-like receptor 7/8 (TLR7/8) agonist was used to investigate the mechanisms underlying the upregulation of CD47 expression. The effect of CD47 on NK cell activation, proliferation, and function were evaluated by flow cytometry. RNA-seq was used to identify downstream pathways for CD47 and its ligand interactions. A small molecule inhibitor was used to restore the inhibition of NK cell function by CD47 signalling. RESULTS: CD47 expression was highly upregulated on the NK cells from PLWH, which could be due to activation of the Toll-like receptor 7/8 (TLR7/8) pathway. Compared with NC subjects, PLWH subjects exhibited elevated levels of CD47 ligands, thrombospondin-1 (TSP1), and counter ligand signal regulatory protein-α (SIRPα). The TSP1-CD47 axis drives the suppression of interferon gamma (IFN-γ) production and the activation of the Janus kinase signal transducer and activator of transcription (JAK-STAT) pathway in NK cells. After treatment with a STAT3 inhibitor, the NK cells from PLWH showed significantly improved IFN-γ production. CONCLUSIONS: The current data indicate that the binding of the inhibitory receptor CD47 to plasma TSP1 suppresses NK cell IFN-γ production by activating the JAK/STAT3 pathway during HIV infection. Our results suggest that CD47 and its related signalling pathways could be targets for improving NK cell function in people living with HIV.

First complete-genome documentation of HIV-1 intersubtype superinfection with transmissions of diverse recombinants over time to five recipients.

Human immunodeficiency virus type 1 (HIV-1) recombinants in the world are believed to be generated through recombination between distinct HIV-1 strains among coinfection or superinfection cases. However, direct evidence to support transmission of HIV-1 recombinants from a coinfected/superinfected donor to putative recipient is lacking. Here, we report on the origin and evolutionary relationship between a set of recombinants from a CRF01_AE/CRF07_BC superinfected putative donor and diverse CRF01_AE/CRF07_BC recombinants from five putative recipients. Interviews on sociodemographic characteristics and sexual behaviors for these six HIV-1-infected men who have sex with men showed that they had similar ways of partner seeking: online dating sites and social circles. Phylogenetic and recombination analyses demonstrated that the near-full-length genome sequences from six patients formed a monophyletic cluster different from known HIV-1 genotypes in maximum likelihood phylogenetic trees, were all composed of CRF01_AE and CRF07_BC fragments with two common breakpoints on env, and shared 4-7 breakpoints with each other. Moreover, 3' half-genomes of recombinant strains from five recipients had identical/similar recombinant structures with strains at longitudinal samples from the superinfected donor. Recombinants from the donor were paraphyletic, whereas five recipients were monophyletic or polyphyletic in the maximum clade credibility tree. Bayesian analyses confirmed that the estimated time to the most recent common ancestor (tMRCA) of CRF01_AE and CRF07_BC strains of the donor was 2009.2 and 2010.7, respectively, and all were earlier than the emergence of recombinants from five recipients. Our results demonstrated that the closely related unique recombinant forms of HIV-1 might be the descendent of a series of recombinants generated gradually in a superinfected patient. This finding highlights the importance of early initiation of antiretroviral therapy as well as tracing and testing of partners in patients with multiple HIV-1 infection.

Molecular Network Analysis Discloses the Limited Contribution to HIV Transmission for Patients with Late HIV Diagnosis in Northeast China.

In the "treat all" era, the high rate of late HIV diagnosis (LHD) worldwide remains an impediment to ending the HIV epidemic. In this study, we analyzed LHD in newly diagnosed people living with HIV (PLWH) and its impact on HIV transmission in Northeast China. Sociodemographic information, baseline clinical data, and plasma samples obtained from all newly diagnosed PLWH in Shenyang, the largest city in Northeast China, between 2016 and 2019 were evaluated. Multivariate logistic regression analysis was performed to identify risk factors associated with LHD. A molecular network based on the HIV pol gene was constructed to assess the risk of HIV transmission with LHD. A total of 2882 PLWH, including 882 (30.6%) patients with LHD and 1390 (48.2%) patients with non-LHD, were enrolled. The risk factors for LHD were older age (≥ 30 years: p < .01) and diagnosis in the general population through physical examination (p < .0001). Moreover, the molecular network analysis revealed that the clustering rate (p < .0001), the fraction of individuals with ≥ 4 links (p = .0847), and the fraction of individuals linked to recent HIV infection (p < .0001) for LHD were significantly or marginally significantly lower than those recorded for non-LHD. Our study indicates the major risk factors associated with LHD in Shenyang and their limited contribution to HIV transmission, revealing that the peak of HIV transmission of LHD at diagnosis may have been missed. Early detection, diagnosis, and timely intervention for LHD may prevent HIV transmission.

A longitudinal analysis of immune escapes from HLA-B*13-restricted T-cell responses at early stage of CRF01_AE subtype HIV-1 infection and implications for vaccine design.

BACKGROUND: Identifying immunogens which can elicit effective T cell responses against human immunodeficiency virus type 1 (HIV-1) is important for developing a T-cell based vaccine. It has been reported that human leukocyte antigen (HLA)-B*13-restricted T-cell responses contributed to HIV control in subtype B' and C infected individuals. However, the kinetics of B*13-restricted T-cell responses, viral evolution within epitopes, and the impact on disease progression in CRF01_AE subtype HIV-1-infected men who have sex with men (MSM) are not known. RESULTS: Interferon-γ ELISPOT assays and deep sequencing of viral RNAs were done in 14 early HLA-B*13-positive CRF01_AE subtype HIV-1-infected MSM. We found that responses to RQEILDLWV (Nef106-114, RV9), GQMREPRGSDI (Gag226-236, GI11), GQDQWTYQI (Pol487-498, GI9), and VQNAQGQMV (Gag135-143, VV9) were dominant. A higher relative magnitude of Gag-specific T-cell responses, contributed to viral control, whereas Nef-specific T-cell responses were associated with rapid disease progression. GI11 (Gag) was conserved and strong GI11 (Gag)-specific T-cell responses showed cross-reactivity with a dominant variant, M228I, found in 3/12 patients; GI11 (Gag)-specific T-cell responses were positively associated with CD4 T-cell counts (R = 0.716, P = 0.046). Interestingly, the GI9 (Pol) epitope was also conserved, but GI9 (Pol)-specific T-cell responses did not influence disease progression (P > 0.05), while a D490G variant identified in one patient did not affect CD4 T-cell counts. All the other epitopes studied [VV9 (Gag), RQYDQILIEI (Pol113-122, RI10), HQSLSPRTL (Gag144-152, HL9), and RQANFLGRL (Gag429-437, RL9)] developed escape mutations within 1 year of infection, which may have contributed to overall disease progression. Intriguingly, we found early RV9 (Nef)-specific T-cell responses were associated with rapid disease progression, likely due to escape mutations. CONCLUSIONS: Our study strongly suggested the inclusion of GI11 (Gag) and exclusion of RV9 (Nef) for T-cell-based vaccine design for B*13-positive CRF01_AE subtype HIV-1-infected MSM and high-risk individuals.

C6orf120 gene knockout in rats mitigates concanavalin A­induced autoimmune hepatitis via regulating NKT cells.

OBJECTIVE: To elucidate the role of the functional unknown gene C6orf120 in the pathogenesis of AIH and its mechanism of action, using C6orf120 knockout rats. METHODS: An autoimmune hepatitis model was established with 35 mg/kg intravenous injection of concanavalin A (Con A) in C6orf120-knockout (C6orf120-/-) and wild-type (WT) rats. Rats were sacrificed after administering Con A for 0, 12, and 24 h. The peripheral blood, liver, spleen, and mesenteric lymph nodes were collected for follow-up studies. RESULTS: C6orf120 knockout significantly decreased the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and improved the histological damage in Con A-induced autoimmune liver injury.Loss of C6orf120 function significantly increased the frequency of CD3+ CD161+ NKT cells in the peripheral blood, liver, and spleen; downregulated the expression of CD314 (NKG2D) in the liver, spleen, and mesenteric lymph nodes; reduced the expression of inflammatory cytokines and chemokines; and suppressed the mRNA and protein expression of Fas and FasL in the liver. Additionally, C6orf120 knockout significantly downregulated the expression of p-JAK1, p-JAK2, p-STAT1, and p-STAT3 in liver tissue. CONCLUSION: The protective effect of C6orf120 knockout against Con A-induced hepatitis may be due to the inhibition of NKT cell activation, restriction of cytokine and chemokine activities, inhibition of JAK-STAT and Fas/FasL signaling pathway activation, and reduction in liver inflammation and hepatocyte apoptosis.

Outcomes of persistent low-level viremia among HIV patients on antiretroviral therapy: A prospective cohort study.

INTRODUCTION: We aimed to investigate the relationship between low-level viremia (LLV) and virological failure (VF), death, and non-AIDS events (NAEs). METHODS: A prospective cohort study of people living with HIV (PLHIV) on antiretroviral therapy (ART) was conducted from 2011-2018 at an HIV clinic in Shenyang, China. The incidence of VF and the mortality and NAEs due to LLV were assessed. Cox proportional hazards regression was performed to investigate risk factors for VF, mortality, and NAEs. RESULTS: In total, 1288 patients, contributing 3915 person-years of follow-up (median follow-up, 2.5 years [interquartile range: 2-4 years]), were enrolled. Thirty-one patients (2.4%) experienced VF, 5 (0.4%) died, and 38 (3.0%) experienced NAEs. The risk of VF was significantly increased among patients with a viral load (VL) of 200-499 copies/mL (adjusted hazard ratio [aHR]: 14.92, 95% confidence interval [CI]: 5.92-37.60) or 500-999 copies/mL (aHR: 13.68, 95% CI: 3.61-51.87), but not among patients with a VL of 50-199 copies/mL (aHR: 3.10, 95% CI: 0.86-11.09). The risk of NAEs was significantly increased among patients with LLV (aHR: 7.33, 95% CI: 3.73-14.42). Compared to no LLV, a VL of 50-199 copies/mL (aHR: 4.11, 95% CI: 1.73-9.74), 200-499 copies/mL (aHR: 18.31, 95% CI: 6.66-50.33), and 500-999 copies/mL (aHR: 21.34, 95% CI: 5.69-80.01) showed higher risk of NAEs. CONCLUSION: Low-level viremia was associated with VF and NAEs. Patients with LLV, especially those with a VL ≥200 copies/mL, may need more frequent VL testing and NAE screening.

Rapid HIV Progression Is Associated with Extensive Ongoing Somatic Hypermutation.

The Ab response to HIV is of great interest, particularly in the context of a protective vaccine and broadly neutralizing Abs, but research is typically geared toward elite controllers because of their ability to successfully control the virus. In this study, we studied the evolution of the Ab repertoire over the first year of HIV infection in people classified as rapid progressors (RP) compared with typical progressors. HIV RPs are an important yet understudied group of HIV patients classified by a rapid decline in CD4 counts and accelerated development of AIDS. We found that the global IgG somatic hypermutation load negatively correlated with disease progression, possibly because of exaggerated isotype switching of unmutated sequences in patients with low CD4 counts. We measured Ab sequence evolution over time using longitudinal samples taken during the early stages of infection and 1 year postinfection. Within clonal lineages spanning both timepoints, visit 2-derived sequences harbored considerably more mutations than their visit 1 relatives. Despite extensive ongoing somatic hypermutation, the initially strong signs of Ag selection pressure observed in visit 1-derived sequences decayed by visit 2. These data suggest that excessive immune activation in RPs leads to a hyperactive B cell response that fails to confer protection.

Automated detection of severe diabetic retinopathy using deep learning method.

PURPOSE: The purpose of this study is to develop and validate the intelligent diagnosis of severe DR with lesion recognition based on color fundus photography. METHODS: The Kaggle public dataset for DR grading is used in the project, including 53,576 fundus photos in the test set, 28,101 in the training set, and 7,025 in the validation set. We randomly select 4,192 images for lesion annotation. Inception V3 structure is adopted as the classification algorithm. Both 299 × 299 pixel images and 896 × 896 pixel images are used as the input size. ROC curve, AUC, sensitivity, specificity, and their harmonic mean are used to evaluate the performance of the models. RESULTS: The harmonic mean and AUC of the model of 896 × 896 input are higher than those of the 299 × 299 input model. The sensitivity, specificity, harmonic mean, and AUC of the method with 896 × 896 resolution images as input for severe DR are 0.925, 0.907, 0.916, and 0.968, respectively. The prediction error mainly occurs in moderate NPDR, and cases with more hard exudates and cotton wool spots are easily predicted as severe cases. Cases with preretinal hemorrhage and vitreous hemorrhage are easily identified as severe cases, and IRMA is the most difficult lesion to recognize. CONCLUSIONS: We have studied the intelligent diagnosis of severe DR based on color fundus photography. This artificial intelligence-based technology offers a possibility to increase the accessibility and efficiency of severe DR screening.

Role of triglycerides as a predictor of autoimmune hepatitis with cirrhosis.

BACKGROUND: Metabolism-related indicators have been suggested as possible prognostic indicators of liver disease in recent relevant studies, but their value in predicting autoimmune hepatitis (AIH) cirrhosis is unclear. This study evaluated the role of lipid levels in determining the prognosis of AIH-related cirrhosis. METHODS: We retrospectively included 345 patients with AIH who were initially diagnosed at Beijing Ditan Hospital from 2010-2019, and ultimately screened 196 patients who met the criteria. A logistic regression analysis was performed to screen factors associated with cirrhosis. Kaplan-Meier (KM) curves were constructed to analyze the effects of different triglyceride (TG) levels on the survival of patients with cirrhosis. A restricted cubic spline fitted Cox regression model was used to analyze the nonlinear relationship between serum TG levels and patient prognosis. RESULTS: Patients with AIH cirrhosis have lower TG levels than those without cirrhosis. Lower serum TG levels correlated with the severity of cirrhosis. The survival analysis showed that TG levels were associated with the overall survival of patients with AIH, as a lower 5-year survival rate (log-rank P<0.05) was observed for patients in the TG≤0.95 mmol/L group (hazard ratio (HR)=3.79, 95% CI: 1.528-9.423). In addition, lower TG levels were associated with a higher incidence of death in patients with AIH cirrhosis. The risk of death gradually increased for the interval of TG levels of 0.5-0.8 mmol/L (P for nonlinearity<0.001), and the hazard ratio per standard deviation increase in the TG level was 0.97 (95% CI: 0.94-0.99). The plot showed a U-shaped relationship between TG levels and the survival of patients with decompensated cirrhosis. The risk ratio progressively decreased with lower TG levels (P for nonlinearity=0.002). Below 0.6 mmol/L, the probability of TG risk per standard deviation prediction was 1.49 (95% CI: 1.00-2.24). CONCLUSION: Serum TG levels are closely related to the disease severity and overall survival of patients with AIH cirrhosis and may be used as a new indicator of advanced liver disease and long-term prognosis.

A nomogram for predicting paradoxical immune reconstitution inflammatory syndrome associated with cryptococcal meningitis among HIV-infected individuals in China.

BACKGROUND: Cryptococcal meningitis (CM) associated immune reconstitution inflammatory syndrome (CM-IRIS) is the second most common complication in HIV-infected individuals with cryptococcal meningitis, with a reported mortality rate ranging from 8 to 30%. Given the devastating consequences of CM-IRIS related intracranial neuroinflammation and its challenging in diagnosis, we conducted a study to explore the risk factors and the occurrence of paradoxical CM-IRIS in HIV-infected patients, which is of great value for prevention and clinical management. METHODS: We conducted a retrospective cohort study to identify the indicators associated with paradoxical CM-IRIS among 86 HIV-infected patients with CM using univariate and multivariate cox analysis. A nomogram was constructed using selected variables to evaluate the occurrence of paradoxical CM-IRIS at 6 months and 12 months after ART initiation. The discrimination and calibration of the nomogram were assessed by concordance index (C-index) and calibration plots. Decision curves analysis (DCA) were used to evaluate clinical effectiveness of the nomogram. Subsequently, to help clinicians recognize patients at high risk faster, patients were divided into high-risk and low-risk groups according to the best cutoff point identified by X-tile. RESULTS: Of 86 AIDS patients with CM, 22.1% experienced paradoxical CM-IRIS at a median of 32 days after antiretroviral therapy (ART) initiation. The occurrence of paradoxical CM-IRIS was associated with age, ART initiation within 4 weeks of antifungal treatment, a four-fold increase in CD4 T cell counts, C-reactive protein levels, and hemoglobin levels independently. These five variables were further used to construct a predictive nomogram. The C-index (0.876) showed the favorable discriminative ability of the nomogram. The calibration plot revealed a high consistency between the predicted and actual observations. DCA showed that the nomogram was clinically useful. Risk stratification based on the total score of the nomogram showed well-differentiated in the high-risk and low-risk groups. Clinicians should pay attention to patients with total points high than 273. CONCLUSIONS: We identified the predictive factors of paradoxical CM-IRIS and constructed a nomogram to evaluate the occurrence of paradoxical CM-IRIS in 6 months and 12 months. The nomogram represents satisfactory performance and might be applied clinically to the screening and management of high-risk patients.

Recurrent vitreous opacity caused by intraocular Toxocara larva: a case report and literature review.

BACKGROUND: Toxocara larva entity has seldom been reported on the surface of the retina. We report on an unusual case of recurrent vitreous opacity caused by intraocular Toxocara larva after vitrectomy. CASE PRESENTATION: A 34-year-old male was referred to our clinic with a 6-month history of decreased visual acuity in the right eye characterized as red, painless, and progressive. Optos fundus photograph showed optic disc elevation with granuloma, and proliferative membrane starting from the optic disc and running towards the superior temporal retina due to the movement of a Toxocara larva, which was covered by the proliferative membrane in the superior temporal retina. Since it adhered closely to the retina, the lesion in the superior temporal retina was not removed to avoid induction of an iatrogenic retinal break and the larva was not found during the first diagnostic pars plana vitrectomy. Intraocular Anti-Toxocara IgG was 45.53U (< 3, enzyme-linked immunosorbent assay (ELISA)), and the Goldmann-Witmer coefficient was 8.55, confirming the diagnosis of ocular toxocariasis. After this operation, visual acuity improved to 20/200. However, vitreous opacity worsened again, and the proliferative membrane expanded around the Toxocara larva three weeks after the operation. Toxocara larva was found and removed in the superior temporal region during the second operation. His visual acuity improved to 20/100, vitreous opacity disappeared, and the retina was stable two months after the second operation. CONCLUSION: It is advisable to remove suspected Toxocara larva to prevent the reoccurrence of ocular toxocariasis.

Analysis of Influencing Factors of Unplanned Readmission in Patients With Acute Coronary Syndrome Within 30 Days After PCI.

OBJECTIVE: The purpose of this study is to identify the influencing factors of unplanned readmission in patients with the acute coronary syndrome (ACS) within 30 days after percutaneous coronary intervention (PCI). METHODS: From November 1, 2018, to October 31, 2019, the clinical data of 1277 patients with acute coronary syndrome and percutaneous coronary intervention retrospectively were collected. After screening by exclusion and rejection criteria, a total of 936 patients finally entered the study. Patients were divided into the readmission group (57 cases) and the non-readmission group (879 cases), according to whether unplanned readmission occurred within 30 days after PCI. To analyze the influence of patients' age, past disease history, medication history, laboratory data, vascular diseases, and other factors on readmission and the clinical characteristics of readmission patients. RESULTS: Fifty-seven patients had unplanned readmission within 30 days, and the readmission rate was 6.09%. The clinical features of readmission patients are older age, longer hospitalization days, more emergency percutaneous coronary intervention, more patients with diabetes history, and more patients diagnosed with ST-segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction. Logistic regression analysis revealed that smoking index, number of diseased vessels, ACEF score, diabetes, and PCI status were the influencing factors of unplanned readmission of ACS patients within 30 days after PCI. CONCLUSION: Smoking index, number of diseased vessels, ACEF score, diabetes, and PCI status are the influencing factors of unplanned readmission within 30 days after percutaneous coronary intervention for patients with acute coronary syndrome.

Impact of HIV-1 CRF55_01B infection on the evolution of CD4 count and plasma HIV RNA load in men who have sex with men prior to antiretroviral therapy.

BACKGROUND: CRF55_01B is a newly identified HIV-1 circulating recombinant form originated from MSM in China. However, its impact on the disease progression and transmission risk has not been investigated. This study aimed to determine the impact of CRF55_01B infection on viral dynamics and immunological status so as to provide scientific evidence for further control and prevention effort on CRF55_01B. Linear mixed effect models were applied to evaluate CD4 cell count decline and viral load increase by subtype. RESULTS: Of the 3418 blood samples, 1446 (42.3%) were CRF07_BC, 1169 (34.2%) CRF01_AE, 467 (13.7%) CRF55_01B, 249 (7.3%) type B, and 87 (2.5%) other subtypes (CRF_08BC, CRF_01B, C). CRF55_01B had become the third predominant strain since 2012 in Shenzhen, China. CRF55_01B-infected MSM showed lower median of CD4 count than CRF07_BC-infected MSM (349.5 [IQR, 250.2-474.8] vs. 370.0 [IQR, 278.0-501.0], P < 0.05). CRF55_01B infection was associated with slower loss of CD4 count than CRF01_AE (13.6 vs. 23.3 [cells/µl]¹/²/year, P < 0.05)among MSM with initial CD4 count of 200-350 cells/µl. On the other hand, those infected with CRF55_01B showed higher median plasma HIV RNA load (5.4 [IQR, 5.0-5.9]) than both CRF01_AE (5.3 [IQR, 4.8-5.7], P < 0.05) and CRF07_BC (5.0 log10 [IQR, 4.5-5.5], P < 0.001) at the initiation of antiretroviral therapy. Furthermore, the annual increasing rate of viral load for CRF55_01B infection was significantly higher than that of CRF07_BC (2.0 vs. 0.7 log10 copies/ml/year, P < 0.01). CONCLUSIONS: The relatively lower CD4 count and faster increase of plasma HIV RNA load of CRF55_01B-infected MSM without antiretroviral therapy suggest that CRF55_01B may lead to longer asymptomatic phase and higher risk of HIV transmission. Strengthened surveillance, tailored prevention strategies and interventions, and in-depth research focusing on CRF55_01B are urgently needed to forestall potential epidemic.

The inhibitory receptor Tim-3 fails to suppress IFN-γ production via the NFAT pathway in NK-cell, unlike that in CD4+ T cells.

BACKGROUND: T cell immunoglobulin and mucin domain-containing-3 (Tim-3) is a negative regulator expressed on T cells, and is also expressed on natural killer (NK) cells. The function of Tim-3 chiefly restricts IFNγ-production in T cells, however, the impact of Tim-3 on NK cell function has not been clearly elucidated. RESULTS: In this study, we demonstrated down-regulation of Tim-3 expression on NK cells while Tim-3 is upregulated on CD4+ T cells during HIV infection. Functional assays indicated that Tim-3 mediates suppression of CD107a degranulation in NK cells and CD4+ T cells, while it fails to inhibit the production of IFN-γ by NK cells. Analyses of downstream pathways using an antibody to block Tim-3 function demonstrated that Tim-3 can inhibit ERK and NFκB p65 signaling; however, it failed to suppress the NFAT pathway. Further, we found that the NFAT activity in NK cells was much higher than that in CD4+ T cells, indicating that NFAT pathway is important for promotion of IFN-γ production by NK cells. CONCLUSIONS: Thus, our data show that the expression of Tim-3 on NK cells is insufficient to inhibit IFN-γ production. Collectively, our findings demonstrate a potential mechanism of Tim-3 regulation of NK cells and a target for HIV infection immunotherapy.

Comparative Circulation Dynamics of the Five Main HIV Types in China.

The HIV epidemic in China accounts for 3% of the global HIV incidence. We compared the patterns and determinants of interprovincial spread of the five most prevalent circulating types. HIV pol sequences sampled across China were used to identify relevant transmission networks of the five most relevant HIV-1 types (B and circulating recombinant forms [CRFs] CRF01_AE, CRF07_BC, CRF08_BC, and CRF55_01B) in China. From these, the dispersal history across provinces was inferred. A generalized linear model (GLM) was used to test the association between migration rates among provinces and several measures of human mobility. A total of 10,707 sequences were collected between 2004 and 2017 across 26 provinces, among which 1,962 are newly reported here. A mean of 18 (minimum and maximum, 1 and 54) independent transmission networks involving up to 17 provinces were identified. Discrete phylogeographic analysis largely recapitulates the documented spread of the HIV types, which in turn, mirrors within-China population migration flows to a large extent. In line with the different spatiotemporal spread dynamics, the identified drivers thereof were also heterogeneous but are consistent with a central role of human mobility. The comparative analysis of the dispersal dynamics of the five main HIV types circulating in China suggests a key role of large population centers and developed transportation infrastructures as hubs of HIV dispersal. This advocates for coordinated public health efforts in addition to local targeted interventions.IMPORTANCE While traditional epidemiological studies are of great interest in describing the dynamics of epidemics, they struggle to fully capture the geospatial dynamics and factors driving the dispersal of pathogens like HIV as they have difficulties capturing linkages between infections. To overcome this, we used a discrete phylogeographic approach coupled to a generalized linear model extension to characterize the dynamics and drivers of the across-province spread of the five main HIV types circulating in China. Our results indicate that large urbanized areas with dense populations and developed transportation infrastructures are facilitators of HIV dispersal throughout China and highlight the need to consider harmonized country-wide public policies to control local HIV epidemics.

Integrated analysis of lncRNA, miRNA and mRNA profiles reveals potential lncRNA functions during early HIV infection.

BACKGROUND: Long noncoding RNAs (lncRNAs) can regulate gene expression in a cis-regulatory fashion or as "microRNA sponges". However, the expression and functions of lncRNAs during early human immunodeficiency virus (HIV) infection (EHI) remain unclear. METHODS: 3 HAART-naive EHI patients and 3 healthy controls (HCs) were recruited in this study to perform RNA sequencing and microRNA (miRNA) sequencing. The expression profiles of lncRNAs, mRNAs and miRNAs were obtained, and the potential roles of lncRNAs were analysed based on discovering lncRNA cis-regulatory target mRNAs and constructing lncRNA-miRNA-mRNA competing endogenous RNA (ceRNA) networks. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on 175 lncRNA-associated differentially expressed (DE) mRNAs to investigate the potential functions of DE lncRNAs in ceRNA networks. RESULTS: A total of 242 lncRNAs, 1240 mRNAs and 21 mature known miRNAs were determined as differentially expressed genes in HAART-naive EHI patients compared to HCs. Among DE lncRNAs, 44 lncRNAs were predicted to overlap with 41 target mRNAs, and 107 lncRNAs might regulate their nearby DE mRNAs. Two DE lncRNAs might regulate their cis-regulatory target mRNAs BTLA and ZAP70, respectively, which were associated with immune activation. In addition, the ceRNA networks comprised 160 DE lncRNAs, 21 DE miRNAs and 175 DE mRNAs. Seventeen DE lncRNAs were predicted to regulate HIF1A and TCF7L2, which are involved in the process of HIV-1 replication. Twenty DE lncRNAs might share miRNA response elements (MREs) with FOS, FOSB and JUN, which are associated with both immune activation and HIV-1 replication. CONCLUSIONS: This study revealed that lncRNAs might play a critical role in HIV-1 replication and immune activation during EHI. These novel findings are helpful for understanding of the pathogenesis of HIV infection and provide new insights into antiviral therapy.