Surgical Outcomes of Standardized Endoscopical Deep Medial Orbital Decompression in Dysthyroid Optic Neuropathy.

INTRODUCTION: The aim of the study was to standardize the endoscopic deep medial orbital decompression surgery for better relief of optic nerve compression in dysthyroid optic neuropathy (DON). METHODS: A total of 128 eyes from patients received the standardized endoscopic deep medial orbital decompression surgery were recruited in this study. The efficacy of the procedure was assessed at a 1-month follow-up by the best-corrected visual acuity (VA), visual field (VF), and visual evoked potential (VEP). Clinical data were collected to explore the factors that affected visual recovery. Oxygen saturation of retinal blood vessels, retinal thickness, and vessel density were measured to demonstrate the potential recovery mechanisms. RESULTS: After surgery, the ratio of extraocular muscle volume in the orbital apex to orbital apex volume significantly decreased from 44.32 ± 22.31% to 36.82 ± 12.02% (p < 0.001). 96.87% of eyes' final VA improved; average VA improved from 0.93 ± 0.73 to 0.50 ± 0.60 at 1 week (p < 0.001) and 0.40 ± 0.53 at 1 month (p < 0.001). Postoperatively, VF and VEP also improved, the oxygen saturation of retinal arteries increased, and the retinal thickness was reduced. Preoperative VA, visual impairment duration, and clinical activity score evaluation were associated with visual recovery. CONCLUSION: In this study, we standardized the endoscopic deep medial orbital decompression, of which key point was to relieve pressure in the orbital apex and achieved satisfactory visual recovery in DON patients.

Progress of Statin Therapy in the Treatment of Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a type of interstitial lung disease (ILD) characterized by the proliferation of fibroblasts and aberrant accumulation of extracellular matrix. These changes are accompanied by structural destruction of the lung tissue and the progressive decline of pulmonary function. In the past few decades, researchers have investigated the pathogenesis of IPF and sought a therapeutic approach for its treatment. Some studies have shown that the occurrence of IPF is related to pulmonary inflammatory injury; however, its specific etiology and pathogenesis remain unknown, and no effective treatment, with the exception of lung transplantation, has been identified yet. Several basic science and clinical studies in recent years have shown that statins, the traditional lipid-lowering drugs, exert significant antifibrotic effects, which can delay the progression of IPF and impairment of pulmonary function. This article is aimed at summarizing the current understanding of the pathogenesis of IPF, the progress of research on the use of statins in IPF models and clinical trials, and its main molecular targets.

Targeted resequencing showing novel common and rare genetic variants increases the risk of asthma in the Chinese Han population.

BACKGROUND: Although studies have identified hundreds of genetic variants associated with asthma risk, a large fraction of heritability remains unexplained, especially in Chinese individuals. METHODS: To identify genetic risk factors for asthma in a Han Chinese population, 211 asthma-related genes were first selected based on database searches. The genes were then sequenced for subjects in a Discovery Cohort (284 asthma patients and 205 older healthy controls) using targeted next-generation sequencing. Bioinformatics analysis and statistical association analyses were performed to reveal the associations between rare/common variants and asthma, respectively. The identified common risk variants underwent a validation analysis using a Replication Cohort (664 patients and 650 controls). RESULTS: First, we identified 18 potentially functional rare loss-of-function (LOF) variants in 21/284 (7.4%) of the asthma cases. Second, using burden tests, we found that the asthma group had nominally significant (p < 0.05) burdens of rare nonsynonymous variants in 10 genes. Third, 23 common single-nucleotide polymorphisms were associated with the risk of asthma, 7/23 (30.4%) and 9/23 (39.1%) of which were modestly significant (p < 9.1 × 10-4 ) in the Replication Cohort and Combined Cohort, respectively. According to our cumulative risk model involving the modestly associated alleles, middle- and high-risk subjects had a 2.0-fold (95% CI: 1.621-2.423, p = 2.624 × 10-11 ) and 6.0-fold (95% CI: 3.623-10.156, p = 7.086 × 10-12 ) increased risk of asthma, respectively, compared with low-risk subjects. CONCLUSION: This study revealed novel rare and common genetic risk factors for asthma, and provided a cumulative risk model for asthma risk prediction and stratification in Han Chinese individuals.

The retinal vasculature pathophysiological changes in vision recovery after treatment for indirect traumatic optic neuropathy patients.

PURPOSE: To evaluate the retinal vasculature pathophysiological changes of indirect traumatic optic neuropathy (ITON) patients after effective surgery. METHODS: Monocular ITON patients who underwent endoscopic trans-ethmosphenoid optic canal decompression (ETOCD) or conservative treatments in Zhongshan Ophthalmic Center from January 2017 to June 2020 were recruited. Visual acuity (VA), visual evoked potential (VEP), oxygen saturation of retinal blood vessels (SO2), and optical coherence tomography angiography (OCT-A) were measured. All patients were followed up at least 3 months after treatments. RESULTS: A total of 95 ITON patients were recruited, including 77 patients who underwent ETOCD and 18 patients who underwent conservative treatments. After treatments, more patients received ETOCD (59/77 = 76.6%) presented with improved VA compared with the patients with conservative treatments (6/18 = 33.3%). Compared with the pre-therapeutic measurements, VEP were significantly improved after surgery in ETOCD-treated patients (P < 0.05). Latent periods of P1 and N2, as well as amplitude of P2 of VEP parameters, showed more sensitive to vision recovery (P < 0.05). Retinal artery SO2 and the differences between arteries and veins were improved in ETOCD-treated patients (P < 0.05). Meanwhile, with OCT-A examination, the retinal thickness and retinal vessel density were notably better in ETOCD-treated patients after surgery than that in patients received conservative treatments (P < 0.05). CONCLUSIONS: Vision recovery after effective treatment of ITON patients was associated with the increased oxygen saturation of retinal vessels, better availability of oxygen in the retina, greater vessel density, and thicker retinas, which might further underlie the vasculature mechanism of vision recovery in ITON patients.

A nonsynonymous polymorphism (rs117179004, T392M) of hyaluronidase 1 (HYAL1) is associated with increased risk of idiopathic pulmonary fibrosis in Southern Han Chinese.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a genetic heterogeneous disease with high mortality and poor prognosis. Hyaluronidase 1 (HYAL1) was found to be upregulated in fibroblasts from IPF patients, and overexpression of HYAL1 could prevent human fetal lung fibroblast proliferation. However, the genetic correlation between the HYAL1 and IPF or connective tissue diseases related interstitial lung disease (CTD-ILD) has not been determined. METHODS: A two-stage study was conducted in Southern Han Chinese population. We sequenced the coding regions and flanking regulatory regions of HYAL1 in stage one (253 IPF cases and 125 controls). A statistically significant variant was further genotyped in stage two (162 IPF cases, 182 CTD-ILD cases, and 225 controls). RESULTS: We identified a nonsynonymous polymorphism (rs117179004, T392M) significantly associated with increased IPF risk (dominant model: OR = 2.239, 95% CI = 1.212-4.137, p = 0.010 in stage one; OR = 2.383, 95% CI = 1.376-4.128, p = 0.002 in stage two). However, we did not observe this association in CTD-ILD (OR = 1.401, 95% CI = 0.790-2.485, p = 0.248). CONCLUSION: Our findings suggest that the nonsynonymous polymorphism (rs117179004, T392M) may confer susceptibility to IPF in Southern Han Chinese, but is not associated with susceptibility to CTD-ILD.

Curcumin protects BEAS­2B cells from PM2.5­induced oxidative stress and inflammation by activating NRF2/antioxidant response element pathways.

Fine particulate matter (PM2.5) with an average aerodynamic diameter of <2.5 µm can cause severe lung injury. Oxidative stress and inflammation are considered the main outcomes of PM2.5 exposure. Curcumin is a well­known antioxidant; however, its effect on PM2.5­induced oxidative injury in airway epithelial cells remains unclear. In the present study, it was demonstrated that pre­treatment with curcumin significantly reduced the PM2.5­induced apoptosis of BEAS­2B human bronchial epithelial cells by decreasing the level of intercellular reactive oxygen species. Western blot analysis revealed that curcumin increased the expression of nuclear factor erythroid 2­related factor 2 (NRF2) and regulated the transcription of downstream genes, particularly those encoding antioxidant enzymes. Moreover, curcumin reduced the PM2.5­induced expression and production of inflammatory factors, and induced the expression of the anti­inflammatory factors, interleukin (IL)­5 and IL­13. Taken together, the present study demonstrates that curcumin protects BEAS­2B cells against PM2.5­induced oxidative damage and inflammation, and prevents cell apoptosis by increasing the activation of NRF2­related pathways. It is thus suggested that curcumin may be a potential compound for use in the prevention of PM2.5­induced tissue injury.

The Inflammatory Factors Associated with Disease Severity to Predict COVID-19 Progression.

Coronavirus disease 2019 (COVID-19) is associated with immune dysregulation and cytokine storm. Exploring the immune-inflammatory characteristics of COVID-19 patients is essential to reveal pathogenesis and predict progression. In this study, COVID-19 patients showed decreased CD3+, CD4+, and CD8+ T cells but increased neutrophils in circulation, exhibiting upregulated neutrophil-to-lymphocyte and neutrophil-to-CD8+ T cell ratio. IL-6, TNF-α, IL-1ß, IL-18, IL-12/IL-23p40, IL-10, Tim-3, IL-8, neutrophil extracellular trap-related proteinase 3, and S100A8/A9 were elevated, whereas IFN-γ and C-type lectin domain family 9 member A (clec9A) were decreased in COVID-19 patients compared with healthy controls. When compared with influenza patients, the expressions of TNF-α, IL-18, IL-12/IL-23p40, IL-8, S100A8/A9 and Tim-3 were significantly increased in critical COVID-19 patients, and carcinoembryonic Ag, IL-8, and S100A8/A9 could serve as clinically available hematologic indexes for identifying COVID-19 from influenza. Moreover, IL-6, IL-8, IL-1ß, TNF-α, proteinase 3, and S100A8/A9 were increased in bronchoalveolar lavage fluid of severe/critical patients compared with moderate patients, despite decreased CD4+ T cells, CD8+ T cells, B cells, and NK cells. Interestingly, bronchoalveolar IL-6, carcinoembryonic Ag, IL-8, S100A8/A9, and proteinase 3 were found to be predictive of COVID-19 severity and may serve as potential biomarkers for predicting COVID-19 progression and potential targets in therapeutic intervention of COVID-19.

Establishment of a Rapid Lesion-Controllable Retinal Degeneration Monkey Model for Preclinical Stem Cell Therapy.

BACKGROUND: Retinal degenerative disorders (RDs) are the main cause of blindness without curable treatment. Our previous studies have demonstrated that human-induced pluripotent stem cells can differentiate into retinal organoids with all subtypes of retina, which provides huge promise for treating these diseases. Before these methods can be realized, RD animal models are required to evaluate the safety and efficacy of stem cell therapy and to develop the surgical tools and procedures for cell transplantation in patients. This study involved the development of a monkey model of RD with controllable lesion sites, which can be rapidly prepared for the study of preclinical stem cell therapy among other applications. METHODS: Sodium nitroprusside (SNP) in three doses was delivered into the monkey eye by subretinal injection (SI), and normal saline was applied as control. Structural and functional changes of the retinas were evaluated via multimodal imaging techniques and multifocal electroretinography (mfERG) before and after the treatment. Histological examination was performed to identify the target layer of the affected retina. The health status of monkeys was monitored during the experiment. RESULTS: Well-defined lesions with various degrees of retinal degeneration were induced at the posterior pole of retina as early as 7 days after SNP SI. The damage of SNP was dose dependent. In general, 0.05 mM SNP caused mild structural changes in the retina; 0.1 mM SNP led to the loss of outer retinal layers, including the outer plexiform layer (OPL), outer nuclear layer (ONL), and retinal pigment epithelium (RPE); while 0.2 mM SNP impacted the entire layer of the retina and choroid. MfERG showed reduced amplitude in the damaged region. The structural and functional damages were not recovered at 7-month follow-up. CONCLUSION: A rapidly induced lesion site-controllable retinal degeneration monkey model was established by the subretinal administration of SNP, of which the optimal dose is 0.1 mM. This monkey model mimics the histological changes of advanced RDs and provides a valuable platform for preclinical assessment of stem cell therapy for RDs.

Evaluation of the efficacy and safety of intravenous remdesivir in adult patients with severe COVID-19: study protocol for a phase 3 randomized, double-blind, placebo-controlled, multicentre trial.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by a novel corinavirus (later named SARS-CoV-2 virus), was fistly reported in Wuhan, Hubei Province, China towards the end of 2019. Large-scale spread within China and internationally led the World Health Organization to declare a Public Health Emergency of International Concern on 30th January 2020. The clinical manifestations of COVID-19 virus infection include asymptomatic infection, mild upper respiratory symptoms, severe viral pneumonia with respiratory failure, and even death. There are no antivirals of proven clinical efficacy in coronavirus infections. Remdesivir (GS-5734), a nucleoside analogue, has inhibitory effects on animal and human highly pathogenic coronaviruses, including MERS-CoV and SARS-CoV, in in vitro and in vivo experiments. It is also inhibitory against the COVID-19 virus in vitro. The aim of this study is to assess the efficacy and safety of remdesivir in adult patients with severe COVID-19. METHODS: The protocol is prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. This is a phase 3, randomized, double-blind, placebo-controlled, multicentre trial. Adults (≥ 18 years) with laboratory-confirmed COVID-19 virus infection, severe pneumonia signs or symptoms, and radiologically confirmed severe pneumonia are randomly assigned in a 2:1 ratio to intravenously administered remdesivir or placebo for 10 days. The primary endpoint is time to clinical improvement (censored at day 28), defined as the time (in days) from randomization of study treatment (remdesivir or placebo) until a decline of two categories on a six-category ordinal scale of clinical status (1 = discharged; 6 = death) or live discharge from hospital. One interim analysis for efficacy and futility will be conducted once half of the total number of events required has been observed. DISCUSSION: This is the first randomized, placebo-controlled trial in COVID-19. Enrolment began in sites in Wuhan, Hubei Province, China on 6th February 2020. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04257656. Registered on 6 February 2020.

Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial.

BACKGROUND: No specific antiviral drug has been proven effective for treatment of patients with severe coronavirus disease 2019 (COVID-19). Remdesivir (GS-5734), a nucleoside analogue prodrug, has inhibitory effects on pathogenic animal and human coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro, and inhibits Middle East respiratory syndrome coronavirus, SARS-CoV-1, and SARS-CoV-2 replication in animal models. METHODS: We did a randomised, double-blind, placebo-controlled, multicentre trial at ten hospitals in Hubei, China. Eligible patients were adults (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, with an interval from symptom onset to enrolment of 12 days or less, oxygen saturation of 94% or less on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less, and radiologically confirmed pneumonia. Patients were randomly assigned in a 2:1 ratio to intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2-10 in single daily infusions) or the same volume of placebo infusions for 10 days. Patients were permitted concomitant use of lopinavir-ritonavir, interferons, and corticosteroids. The primary endpoint was time to clinical improvement up to day 28, defined as the time (in days) from randomisation to the point of a decline of two levels on a six-point ordinal scale of clinical status (from 1=discharged to 6=death) or discharged alive from hospital, whichever came first. Primary analysis was done in the intention-to-treat (ITT) population and safety analysis was done in all patients who started their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04257656. FINDINGS: Between Feb 6, 2020, and March 12, 2020, 237 patients were enrolled and randomly assigned to a treatment group (158 to remdesivir and 79 to placebo); one patient in the placebo group who withdrew after randomisation was not included in the ITT population. Remdesivir use was not associated with a difference in time to clinical improvement (hazard ratio 1·23 [95% CI 0·87-1·75]). Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less (hazard ratio 1·52 [0·95-2·43]). Adverse events were reported in 102 (66%) of 155 remdesivir recipients versus 50 (64%) of 78 placebo recipients. Remdesivir was stopped early because of adverse events in 18 (12%) patients versus four (5%) patients who stopped placebo early. INTERPRETATION: In this study of adult patients admitted to hospital for severe COVID-19, remdesivir was not associated with statistically significant clinical benefits. However, the numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies. FUNDING: Chinese Academy of Medical Sciences Emergency Project of COVID-19, National Key Research and Development Program of China, the Beijing Science and Technology Project.

A novel FoxM1-PSMB4 axis contributes to proliferation and progression of cervical cancer.

The abnormally high activity of the proteasome system is closely related to the occurrence and development of various tumors. PSMB4 is a non-catalytic subunit for the proteasome assembly. Although the reports from genetic screening have demonstrated it's a driver gene for cell growth in several types of solid tumor, its expression pattern and regulatory mechanisms in malignant diseases are still elusive. Here, we found that PSMB4 is overexpressed in cervical cancer tissues. And knockdown of PSMB4 significantly inhibited cervical cancer cell proliferation. The mechanistic study revealed that FoxM1, a master regulator of cell division, binds directly to the promoter region of PSMB4 and regulates the PSMB4 expression in the mRNA level. In addition, the data analysis from TCGA showed a positive correlation between FxoM1 and PSMB4 in cervical cancer. Furthermore, the loss of functional and rescue experiments confirmed that PSMB4 is required for FoxM1-driven cervical cancer cell proliferation. Collectively, our study explains the phenomenon of dysregulated expression of PSMB4 in cervical cancer tissues and verifies its driver effect on cancer cell proliferation. More importantly, it highlights a FoxM1-PSMB4 axis could be a potential target for the treatment of cervical cancer.

WWP2 regulates proliferation of gastric cancer cells in a PTEN-dependent manner.

WW domain containing E3 Ub-protein ligase 2 (WWP2) plays an important role in tumor progression as an E3 ligase of PTEN. Here, we investigated the role of WWP2 in gastric cancer (GC). We found that WWP2 is overexpressed in GC tissues, which is closely related to poor prognosis of GC patients. Using a WWP2-shRNA lentivirus expressing system, we established WWP2 stable-knockdown GC cell lines and found that knockdown of WWP2 inhibits the proliferation of GC cells both in vitro and in vivo. Also, WWP2 silencing induced the up-regulation of PTEN protein level and down-regulation of AKT phosphorylation level. We further investigated the role of PTEN in this regulating process by performing rescue assay and found that PTEN is essential for WWP2-mediated regulation of GC cells proliferation. Taken together, our results demonstrated that WWP2 promotes proliferation of GC cells by downregulating PTEN, which may provide new therapeutic targets for GC.

Correction to: Automatic differentiation of Glaucoma visual field from non-glaucoma visual field using deep convolutional neural network.

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Novel BEST1 mutations and special clinical characteristics of autosomal recessive bestrophinopathy in Chinese patients.

PURPOSE: The aim of this study was to describe the genetic and clinical characteristics of Chinese patients with autosomal recessive bestrophinopathy (ARB). METHODS: This study presents a retrospective observational case series. Twenty-one ARB patients and 25 clinically healthy family members were recruited. The coding regions and adjacent intronic regions of BEST1 were analysed via Sanger sequencing. Clinical examinations, including ultrasound biomicroscopy, A-scan, optical coherence tomography, fundus autofluorescence, fundus fluorescein angiography (FFA), indocyanine green angiography (ICGA) and visual electrophysiology, were reviewed. RESULTS: Six novel mutations (c.380C>T, p.T127M; c.397A>G, p.N133D; c.500A>G, p.E167G; c.817G>A, p.V273M; c.174_176del, p.Q58del; and c.950_955del, p.S318_L319) and 8 previously reported mutations were identified. The p.R255W mutation had the highest frequency in our cohort. Twenty patients had serous retinal detachment with multifocal subretinal vitelliform deposits in the posterior poles. One patient exhibited chorioretinal atrophy. FFA revealed peripheral vascular leakage in 10 patients, and ICGA revealed hyperfluorescent spots in 8 patients. Visual electrophysiology was abnormal in all patients. Fifteen patients with angle closure (AC) or angle-closure glaucoma (ACG) had shallower anterior chambers and shorter axial lengths than the patients with open angle, contributing to their risk of developing AC/ACG. One patient developed AC during the 7-year follow-up period. The misdiagnosis and missed rates were 35.3% and 58.8%, respectively. CONCLUSION: The six novel mutations and high frequency of p.R255W suggest ethnical differences in the BEST1 mutation spectrum among Chinese patients. BEST1 gene screening and detailed clinical examinations help establishing a diagnosis of ARB. Clinical evaluations of the risk of developing AC/ACG are recommended for ARB patients.

Cigarette Smoke Extract Promotes TIM4 Expression in Murine Dendritic Cells Leading to Th2 Polarization through ERK-Dependent Pathways.

Smoking is considered to be the main source of indoor pollution, and it has been identified as an important environmental factor contributing to asthma onset. We know that T helper 2 (Th2) response plays a crucial role in the process of asthma disease. We have investigated the reaction of cigarette smoke extract (CSE) on Th polarization which is controlled by dendritic cells (DCs). Stimulated by CSE, immature DCs from murine bone marrow showed upregulated levels of TIM4. Cocultured with CD4+ T cells, stimulated DCs increased the ratio of IL-4+ versus IFN-γ+ of CD4+ T cells. This suggests a differentiation towards Th2 response. Moreover, antibodies against TIM4 reversed the upexpression of the IL-4+/IFN-γ+ ratio provoked by CSE, indicating that the Th2 polarization which was induced by CSE is via TIM4 mechanisms. CSE could activate mitogen-activated protein kinase pathways like ERK and p38. Upregulation of TIM4 expression by CSE stimulation was found to be inhibited by an ERK inhibitor but not p38 and JNK. In conclusion, DC-induced Th2 polarization is a hallmark of CSE allergy, and this aspect can be explained by CSE-induced TIM4 expression.

Automatic differentiation of Glaucoma visual field from non-glaucoma visual filed using deep convolutional neural network.

BACKGROUND: To develop a deep neural network able to differentiate glaucoma from non-glaucoma visual fields based on visual filed (VF) test results, we collected VF tests from 3 different ophthalmic centers in mainland China. METHODS: Visual fields obtained by both Humphrey 30-2 and 24-2 tests were collected. Reliability criteria were established as fixation losses less than 2/13, false positive and false negative rates of less than 15%. RESULTS: We split a total of 4012 PD images from 1352 patients into two sets, 3712 for training and another 300 for validation. There is no significant difference between left to right ratio (P = 0.6211), while age (P = 0.0022), VFI (P = 0.0001), MD (P = 0.0039) and PSD (P = 0.0001) exhibited obvious statistical differences. On the validation set of 300 VFs, CNN achieves the accuracy of 0.876, while the specificity and sensitivity are 0.826 and 0.932, respectively. For ophthalmologists, the average accuracies are 0.607, 0.585 and 0.626 for resident ophthalmologists, attending ophthalmologists and glaucoma experts, respectively. AGIS and GSS2 achieved accuracy of 0.459 and 0.523 respectively. Three traditional machine learning algorithms, namely support vector machine (SVM), random forest (RF), and k-nearest neighbor (k-NN) were also implemented and evaluated in the experiments, which achieved accuracy of 0.670, 0.644, and 0.591 respectively. CONCLUSIONS: Our algorithm based on CNN has achieved higher accuracy compared to human ophthalmologists and traditional rules (AGIS and GSS2) in differentiation of glaucoma and non-glaucoma VFs.

Targeted resequencing reveals genetic risks in patients with sporadic idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a genetic heterogeneous disease with high mortality and poor prognosis. However, a large fraction of genetic cause remains unexplained, especially in sporadic IPF (∼80% IPF). By systemically reviewing related literature and potential pathogenic pathways, 92 potentially IPF-related genes were selected and sequenced in genomic DNAs from 253 sporadic IPF patients and 125 matched health controls using targeted massively parallel next-generation sequencing. The identified risk variants were confirmed by Sanger sequencing. We identified two pathogenic and 10 loss-of-function (LOF) candidate variants, accounting for 4.74% (12 out of 253) of all the IPF cases. In burden tests, rare missense variants in three genes (CSF3R, DSP, and LAMA3) were identified that have a statistically significant relationship with IPF. Four common SNPs (rs3737002, rs2296160, rs1800470, and rs35705950) were observed to be statistically associated with increased risk of IPF. In the cumulative risk model, high risk subjects had 3.47-fold (95%CI: 2.07-5.81, P = 2.34 × 10-6 ) risk of developing IPF compared with low risk subjects. We drafted a comprehensive map of genetic risks (including both rare and common candidate variants) in patients with IPF, which could provide insights to help in understanding mechanisms, providing genetic diagnosis, and predicting risk for IPF.

Correction to: Electroretinogram evaluation for the treatment of proliferative diabetic retinopathy by short-pulse pattern scanning laser panretinal photocoagulation.

The published online version contains incorrect data in Table 2 caption. Argon should not be mentioned in the caption as this is not used in this paper.

Electroretinogram evaluation for the treatment of proliferative diabetic retinopathy by short-pulse pattern scanning laser panretinal photocoagulation.

Panretinal photocoagulation (PRP) is a standard method for proliferative diabetic retinopathy (PDR) treatment. However, conventional PRP usually significantly damages the retinal structure and vision. Retinal pattern scanning laser (PASCAL) photocoagulation has emerged as a new technique with fewer complications for the treatment of retinal disorders. This study compares the therapeutic effects of short-pulse PASCAL to conventional single-spot PRP for PDR. Fifty-two PDR patients (104 eyes) were randomly assigned into a short-pulse PASCAL-PRP treatment (SP) group and a conventional PRP treatment (TP) group. The best corrected visual acuity (BCVA) and full-field flash electroretinogram (ERG) data were evaluated before and after the two treatments. The BCVA data between before and after the PRP treatments did not show any significant difference. After the PRP treatment, the b-wave amplitude (b-A) in the dark-adapted 3.0 ERG (p = 0.0005) and the amplitude in the light-adapted 3.0 flicker ERG (p = 0.009) were significantly higher in the SP group compared with that of the TP group. In addition, after the PRP treatment, the a-wave implicit time (a-T) of light-adapted 3.0 ERG prolonged significantly in the TP group compared to the SP group. Compared with the parameters before the treatments, the a-A and b-A under dark-adapted 3.0 ERG and the b-A under the light-adapted 3.0 ERG in both TP and SP groups after the treatments decreased significantly (p < 0.05). Short-pulse PASCAL-PRP significantly attenuated partial vision damage compared to conventional PRP, although it still caused limited retinal injury and mild reduction in retinal function. These findings suggest that short-pulse PASCAL-PRP is a promising technique for PDR treatment.

Increased Circulating Autoantibodies Levels of IgG, IgA, IgM Against Cytokeratin 18 and Cytokeratin 19 in Chronic Obstructive Pulmonary Disease.

BACKGROUND AND AIMS: Autoimmune processes are involved in the progression of chronic obstructive pulmonary disease (COPD). Autoantibodies against cytokeratin 18 (CK18) and cytokeratin 19 (CK19) could be associated with lung injury. We undertook this study to investigate the role of these autoantibodies against CK18 and CK19 in the development of COPD. METHODS AND RESULTS: We used blood samples from 228 COPD patients or 136 healthy controls and male C57BL/6j mice as experimental subjects to analyze the serum autoantibody levels against CK18 or CK19 autoantigen by enzyme-linked immunosorbent assay (ELISA). We found that the circulating autoantibody levels of IgG, IgA, IgM against CK18 and CK19 were elevated in patients with COPD compared with healthy controls, which were increased gradually as the severity of the disease increases, especially in GOLD III and GOLD IV with the exception of anti-CK19 IgG and anti-CK18 IgA autoantibodies. Moreover, we observed that the serum levels of anti-CK18 and anti-CK19 IgG autoantibodies were higher in mice exposed to cigarette smoke compared with mice exposed to room air for 6 months and 9 months. Additionally, we identified the distribution of antibodies and the presence of autoantibodies (IgG) against CK18 and CK19 in the damaged lung tissues of mice. CONCLUSIONS: Increased circulating autoantibodies against CK18 and CK19 are closely related to the progression of COPD, which play an important role in the process of lung injury in COPD, suggesting that it is promising for anti-CK18 and anti-CK19 autoantibodies to serve as a tool to monitor lung damage and guide treatment.