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Purpose: To compare neonatal eye screening using the red reflex test (RRT) versus the wide-field digital imaging (WFDI) system., Methods: Prospective cohort study. Newborns (n = 380, 760 eyes) in the Maternity Ward of Irmandade Santa Casa de Misericórdia de São Paulo hospital from May to July 2014 underwent RRT by a paediatrician and WFDI performed by the authors. Wide-field digital imaging (WFDI) images were analysed by the authors. Validity of the paediatrician's RRT was assessed by unweighted kappa [κ] statistic, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV)., Results: While WFDI showed abnormalities in 130 eyes (17.1%), RRT was only abnormal in 13 eyes (1.7%). Wide-field digital imaging (WFDI) detected treatable retina pathology that RRT missed including hyphema, CMV retinitis, FEVR and a vitreous haemorrhage. The sensitivity of the paediatrician's RRT to detect abnormalities was poor at 0.77% (95% confidence interval, CI, 0.02%-4.21%) with a PPV of only 7.69% (95% CI, 1.08%-38.85%). Overall, there was no agreement between screening modalities (κ = -0.02, 95% CI, -0.05 to 0.01). The number needed to screen to detect ocular abnormalities using WFDI was 5.9 newborns and to detect treatable abnormalities was 76 newborns., Conclusion: While RRT detects gross abnormalities that preclude visualization of the retina (i.e. media opacities and very large tumours), only WFDI consistently detects subtle treatable retina and optic nerve pathology. With a higher sensitivity than the current gold standard, universal WFDI allows for early detection and management of potentially blinding ophthalmic disease missed by RRT., (© 2021 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background/objectives: Fluorescein angiography (FA) has been a pivotal tool to study the pathophysiology of retinopathy of prematurity (ROP) in vivo. We examined the course of ROP using FA in order to assess the predictive value of angiographic features., Subjects/methods: This is an observational retrospective cohort multi-center study of eyes screened for ROP with binocular indirect ophthalmoscope and with FA. All infants undergoing screening examination for ROP who had retinal vasculature limited to Zone I and posterior Zone II vascularization underwent FA between 31 and 34 weeks postmenstrual age. RetCam fundus imaging and video digital fluorescein angiography were performed in the neonatal intensive care units. Masked grading of the FA images was retrospectively conducted by two ROP expert ophthalmologists. Ten criteria that describe retinovascular and choroidal features on FA were used to assess their predictive value for development of treatment-requiring ROP., Results: A total of 98 eyes of 56 patients were included for this study. FAs of eyes of premature infants show a wide range of features either at the junction between the vascular and avascular retina and posteriorly to that. Among the angiographic features evaluated, leakage, shunts and hyperfluorescent lesions at the junction between vascular and avascular zone were predictive of the development of treatment-requiring ROP (p < 0.05), but findings in the posterior vascularized retina were not., Conclusions: FA can add to our understanding of the evolution of vascular abnormalities in the course of ROP and can help predict which eyes will go on to treatment., (© 2020. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Purpose: To study the effect of statin exposure on the progression from non-exudative to exudative age-related macular degeneration (AMD)., Methods: Retrospective cohort study of commercially insured patients diagnosed with non-exudative AMD (n = 231,888) from 2007 to 2015. Time-to-event analysis of the association between exposure to lipid-lowering medications and time from non-exudative AMD to exudative AMD diagnosis was conducted. Outcome measures included progression to exudative AMD, indicated by diagnosis codes for exudative AMD or procedural codes for intravitreal injections., Results: In the year before and after first AMD diagnosis, 11,330 patients were continuously prescribed lipid-lowering medications and 31,627 patients did not take any lipid-lowering medication. Of those taking statins, 21 (1.6%) patients were on very-high-dose lipophilic statins, 644 (47.6%) on high-dose lipophilic statins, and 689 (50.9%) on low-dose lipophilic statins. We found no statistically significant relationship between exposure to low (HR 0.89, 95% CI 0.83 to 1.38) or high-dose lipophilic statins (HR 1.12, 95% CI 0.86 to 1.45) and progression to exudative AMD. No patients taking very-high-dose lipophilic statins converted from non-exudative to exudative AMD, though this difference was not statistically significant due to the subgroup size (p = .23, log-rank test)., Conclusions: No statistically significant relationship was found between statin exposure and risk of AMD progression. Interestingly, no patients taking very-high-dose lipophilic statins progressed to exudative AMD, a finding that warrants further exploration., Competing Interests: Darius M. Moshfeghi is a co-founder with equity and serves on the board of directors of Linc, Inc a company that has developed a novel statin molecule that among other things may be targeted for AMD. Additionally, Darius M. Moshfeghi has the following conflicts of interest: 1-800 Contacts (board of directors, equity), Akceso Advisors AG (evaluation of DME market), Akebia (scientific advisory board for ROP), Alcon (data safety monitoring board for HAWK/HARRIER), Aldeyra Therapeutics (Site PI: ADX-2191-PVR-001 GUARD), Allegro (scientific advisory board), Apellis (Site PI: APL2-303 DERBY), Bayer Pharma AG (ROP imaging committee), CMEOutfitters.com (CME consultant), Cole Eye Institute (CME consultant), Congruence medical solutions (consultant), dSentz, Inc. (founder, board of directors, equity), Genentech (PROPER grant 2019), Grand Legend Technology, LTD (equity), Iconic Therapeutics (steering committee, unpaid), Irenix (scientific advisory board, unpaid), Northwell Health (grand rounds), Novartis Pharmaceuticals (data safety monitoring board for HAWK/HARRIER, KITE/KESTREL, China nAMD/DME, pediatric advisory board), Ocular Surgery News (consultant), Pr3vent (founder, board of directors, equity), Praxis UNS, Inc. (consultant), Prime Medical Education (CME consultant), Promisight, Inc. (founder, board of directors, equity), Pykus (scientific advisory board, equity), Regeneron (CME consultant, ROP steering committee, PI for ROP trial), Research to Prevent Blindness, Inc. (unrestricted departmental grant), Retina Technologies LLC (advisor, consultant), Retina Today/Pentavision (consultant), Shapiro Law Group (ROP expert witness), SLACK, Inc. (CME consultant), University of Miami (CME consultant), VersI, Inc. (founder, equity), Vindico (CME consultant), Visunex (scientific advisory board, equity. None of the other authors have any conflicts of interest to report. The above funders did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objective: Investigate whether machine learning can predict pulmonary complications (PPCs) after emergency gastrointestinal surgery in patients with acute diffuse peritonitis. Methods: This is a secondary data analysis study. We use five machine learning algorithms (Logistic regression, DecisionTree, GradientBoosting, Xgbc, and gbm) to predict postoperative pulmonary complications. Results: Nine hundred and twenty-six cases were included in this study; 187 cases (20.19%) had PPCs. The five most important variables for the postoperative weight were preoperative albumin, cholesterol on the 3rd day after surgery, albumin on the day of surgery, platelet count on the 1st day after surgery and cholesterol count on the 1st day after surgery for pulmonary complications. In the test group: the logistic regression model shows AUC = 0.808, accuracy = 0.824 and precision = 0.621; Decision tree shows AUC = 0.702, accuracy = 0.795 and precision = 0.486; The GradientBoosting model shows AUC = 0.788, accuracy = 0.827 and precision = 1.000; The Xgbc model shows AUC = 0.784, accuracy = 0.806 and precision = 0.583. The Gbm model shows AUC = 0.814, accuracy = 0.806 and precision = 0.750. Conclusion: Machine learning algorithms can predict patients' PPCs with acute diffuse peritonitis. Moreover, the results of the importance matrix for the Gbdt algorithm model show that albumin, cholesterol, age, and platelets are the main variables that account for the highest pulmonary complication weights., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Xue, Wen, Ji, Tong, Yang and Zhou.)

Translational Relevance: Mitochondria are viable therapeutic targets for a broad spectrum of ocular diseases.

Purpose: To determine if fluorescein angiographic (FA) findings after intravitreal ranibizumab (IVR) for retinopathy of prematurity (ROP) conform to a class effect previously described with bevacizumab., Methods: Single-center retrospective case series of all infants treated with 0.2 mg (0.02 mL) IVR for Type 1 ROP from July 2016 to November 2018. FA were obtained at 40, 52, 62, and 72 weeks of postmenstrual age (PMA) using wide-angle photography. FA images were analyzed and the peripheral avascular areas measured with ImageJ using a reference disc diameter (DD). Based on the extent of the avascular area and tortuosity of the retinal vessels all eyes were classified into four categories: complete vascular maturity (vascularization within 2 DD of the ora serrata), VAA (avascular area >2 DD of the ora serrata), VAT (avascular area >2 DD of the ora serrata and posterior tortuosity), and reactivation (recurrence of stage disease)., Results: About 13 infants were enrolled and 24 eyes were available in this study. None of the eyes reached complete vascular maturity at an average PMA of 60 weeks, 7 (29%) eyes presented with VAA, 8 (33%) with VAT, and 9 (37.5%) reactivated. The reactivated eyes presented with the largest area of peripheral ischemia, followed by the VAT and then the VAA groups ( p  = 0.02)., Conclusion: IVR conforms to the previously described regression patterns following intravitreal bevacizumab for ROP indicative of a class effect. Follow-up using FA might help to optimize the management of these infants after injection of the drug.

Both environmental stress and immune challenge can induce abnormal neurobehavior. However, the impact of chronic stress on immune challenge-related neurobehavioral abnormalities is still controversial. Hence, we aimed to investigate the effects of chronic stress on immune challenge-related neurobehavioral abnormalities and explore the possible underlying mechanisms. During the first set of experiments, mice were reared under normal condition (NC) or chronic stress (CS) for 4 consecutive weeks. They were allocated to the following four groups: NC + normal saline (NS) group, CS + NS group, NC + lipopolysaccharide (LPS) group, and CS + LPS group. Open field, elevated plus maze, fear conditioning, novel object recognition, and forced swimming tests were performed, and their tissues were harvested. During the second set of experiments, after rearing the mice under the above conditions for 3 weeks, microelectrodes were implanted into the CA1 of the hippocampus. After recovery for 1 week under the respective environmental conditions, the mice were allocated to four groups, as in the first experiments. The basal (home cage) and task (fear conditioning)-related local field potential (LFP) were recorded. In the present study, LPS significantly induced a decrease in the freezing to context and discrimination ratio. However, only the freezing to context was further reduced by prior chronic stress. This suggested that chronic stress worsened fear memory impairment induced by acute LPS challenge. Consistent with the change in fear memory, LPS significantly decreased the expression of PV in the CA1, which was further downregulated by prior chronic stress. On the other hand, LPS inhibited the power of both basal and task-related θ oscillations in the CA1. Only the task-related θ power was further decreased by chronic stress. In conclusion, our study showed that the phenotypic loss of PV interneurons and the decrease in the power of the θ oscillation in the CA1 aggravated by chronic stress may mediate, at least in part, the deterioration of fear memory impairment induced by LPS., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Optic disc pits frequently lead to visual deterioration due to macular retinoschisis or serous retinal detachment. Here, we report a case of optic disc pit-associated macular retinoschisis due to intraretinal fluid accumulation that resolved with improvement in visual acuity after treatment with topical dorzolamide., Case Description: A 56-year-old otherwise healthy female with no ocular history presented with 2 weeks of slowly worsening blurry vision in her right eye. Visual acuity was 20/30 in the right eye. Posterior segment examination revealed posterior vitreous detachment, an optic disc pit at 9 o'clock, macular edema and foveoschisis with fluid extending from the optic nerve, and a normal peripheral retina. Optical coherence tomography imaging of the macula showed central subfield thickness of 526 µm. The patient preferred no surgical intervention, so topical dorzolamide 2% three times daily was initiated. Over the next 2 years, the central subfield thickness steadily declined from 526 to 262 µm, and her vision improved to 20/20 with improvement in the macular retinoschisis., Conclusion: Our report presents a case of resolution of optic disc pit-associated macular retinoschisis due to intraretinal fluid accumulation with possible role for dorzolamide as a potential treatment option.

To describe a database of longitudinally graded telemedicine retinal images to be used as a comparator for future studies assessing grader recall bias and ability to detect typical progression (e.g. International Classification of Retinopathy of Prematurity (ICROP) stages) as well as incremental changes in retinopathy of prematurity (ROP). Cohort comprised of retinal images from 84 eyes of 42 patients who were sequentially screened for ROP over 6 consecutive weeks in a telemedicine program and then followed to vascular maturation or treatment, and then disease stabilization. De-identified retinal images across the 6 weekly exams (2520 total images) were graded by an ROP expert based on whether ROP had improved, worsened, or stayed the same compared to the prior week's images, corresponding to an overall clinical "gestalt" score. Subsequently, we examined which parameters might have influenced the examiner's ability to detect longitudinal change; images were graded by the same ROP expert by image view (central, inferior, nasal, superior, temporal) and by retinal components (vascular tortuosity, vascular dilation, stage, hemorrhage, vessel growth), again determining if each particular retinal component or ROP in each image view had improved, worsened, or stayed the same compared to the prior week's images. Agreement between gestalt scores and view, component, and component by view scores was assessed using percent agreement, absolute agreement, and Cohen's weighted kappa statistic to determine if any of the hypothesized image features correlated with the ability to predict ROP disease trajectory in patients. The central view showed substantial agreement with gestalt scores (κ = 0.63), with moderate agreement in the remaining views. Of retinal components, vascular tortuosity showed the most overall agreement with gestalt (κ = 0.42-0.61), with only slight to fair agreement for all other components. This is a well-defined ROP database graded by one expert in a real-world setting in a masked fashion that correlated with the actual (remote in time) exams and known outcomes. This provides a foundation for subsequent study of telemedicine's ability to longitudinally assess ROP disease trajectory, as well as for potential artificial intelligence approaches to retinal image grading, in order to expand patient access to timely, accurate ROP screening.

Lung adenocarcinoma is the most common subtype of non-small cell lung cancer, and platelet receptor-related genes are related to its occurrence and progression. A new prognostic indicator based on platelet receptor-related genes was developed with multivariate COX analysis. Prognostic markers based on platelet-related risk score perform moderately in prognosis prediction. The functional annotation of this risk model in high-risk patients shows that the pathways related to cell cycle, glycolysis and platelet-derived related factors are rich. It is worth noting that somatic mutation analysis shows that TTN and MUC16 have higher mutation burdens in high-risk patients. Moreover, the differential genes of high- and low-risk groups are regulated by copy number variation and miRNA. And we provide a free online nomogram web tool based on clinical factors and the risk score (https://wsxzaq.shinyapps.io/wsxzaq&#95;nomogram/). The score has been verified among three independent external cohorts (GSE13213, GSE68465 and GSE72094), and is still an independent risk factor for lung adenocarcinoma. In addition, among the other 6 cancers, the OS prognosis of high and low-risk groups of PRS is different (P < 0.05). Our research results have screened multiple platelet differential genes with clinical significance and constructed a meaningful prognostic risk score (PRS).

Abstract: Chronic neuropathic pain is frequently accompanied by memory impairment, yet the underlying mechanisms remain unclear. Here, we showed that mice displayed memory impairment starting at 14 days and lasting for at least 21 days after chronic constriction injury (CCI) of unilateral sciatic nerve in mice. Systemic administration of the pan histone deacetylase (HDAC) inhibitor sodium butyrate attenuated this memory impairment. More specifically, we found that hippocampus HDAC3 was involved in this process because the levels of its mRNA and protein increased significantly in the hippocampus at 14 and 21 days after CCI, but not sham surgery. Systemic administration of the selective HDAC3 antagonist RGFP966 attenuated CCI-induced memory impairment, improved hippocampal long-term potentiation impairment, and rescued reductions of dendritic spine density and synaptic plasticity-associated protein in the hippocampus. In addition, HDAC3 overexpression in the hippocampus led to memory impairment without affecting basal nociceptive responses in naive mice. Our findings suggest that HDAC3 contributes to memory impairment after CCI by impairing synaptic plasticity in hippocampus. Histone deacetylase 3 might serve as a potential molecular target for therapeutic treatment of memory impairment under neuropathic pain conditions., (Copyright © 2020 International Association for the Study of Pain.)

Sepsis-associated encephalopathy (SAE) is a clinical syndrome of brain dysfunction secondary to sepsis, which is characterized by long-term neurocognitive deficits such as memory, attention, and executive dysfunction. However, the mechanisms underlying SAE remain unclear. By using transcriptome sequencing approach, we showed that hippocampal S100A9 was significantly increased in sepsis induced by cecal ligation and puncture (CLP) or lipopolysaccharide (LPS) challenge. Thus, we used S100A9 inhibitor Paquinimod to study the role of S100A9 in cognitive impairments in CLP-induced and LPS-induced mice models of SAE. Sepsis survivor mice underwent behavioral tests or the hippocampal tissues subjected to Western blotting, real-time quantitative PCR, and immunohistochemistry. Our results showed that CLP-induced and LPS-induced memory impairments were accompanied with increased expressions of hippocampal microglia Iba1 and CD86 (M1 markers), but reduced expression of Arg1 (M2 marker). Notably, S100A9 inhibition significantly improved the survival rate and learning and memory impairments in sepsis survivors, with a shift from M1 to M2 phenotype. Taken together, our study suggests that S100A9 upregulation might contribute to learning and memory impairments by promoting microglia M1 polarization in sepsis survivors, whereas S100A9 inhibition might provide a potential therapeutic target for SAE.

Introduction: Presenilin enhancer2 (Pen-2) is an essential subunit of γ-secretase, which is a key protease responsible for the cleavage of amyloid precursor protein (APP) and Notch. Mutations on Pen-2 cause familial Alzheimer disease (AD). However, it remains unknown whether Pen-2 regulates neuronal survival and neuroinflammation in the adult brain., Methods: Forebrain neuron-specific Pen-2 conditional knockout (Pen-2 cKO) mice were generated for this study. Pen-2 cKO mice expressing Notch1 intracellular domain (NICD) conditionally in cortical neurons were also generated., Results: Loss of Pen-2 causes astrogliosis followed by age-dependent cortical atrophy and neuronal loss. Loss of Pen-2 results in microgliosis and enhanced inflammatory responses in the cortex. Expression of NICD in Pen-2 cKO cortices ameliorates neither neurodegeneration nor neuroinflammation., Conclusions: Pen-2 is required for neuronal survival in the adult cerebral cortex. The Notch signaling may not be involved in neurodegeneration caused by loss of Pen-2., (© 2020 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Background: Several predictors have been shown to be independently associated with chronic postsurgical pain for gastrointestinal surgery, but few studies have investigated the factors associated with acute postsurgical pain (APSP). The aim of this study was to identify the predictors of APSP intensity and severity through investigating demographic, psychological, and clinical variables., Methods: We performed a prospective cohort study of 282 patients undergoing gastrointestinal surgery to analyze the predictors of APSP. Psychological questionnaires were assessed 1 day before surgery. Meanwhile, demographic characteristics and perioperative data were collected. The primary outcomes are APSP intensity assessed by numeric rating scale (NRS) and APSP severity defined as a clinically meaningful pain when NRS ≥4. The predictors for APSP intensity and severity were determined using multiple linear regression and multivariate logistic regression, respectively., Results: 112 patients (39.7%) reported a clinically meaningful pain during the first 24 hours postoperatively. Oral morphine milligram equivalent (MME) consumption ( β 0.05, 95% CI 0.03-0.07, p < 0.001), preoperative anxiety ( β 0.12, 95% CI 0.08-0.15, p < 0.001), and expected postsurgical pain intensity ( β 0.12, 95% CI 0.06-0.18, p < 0.001) were positively associated with APSP intensity. Furthermore, MME consumption (OR 1.15, 95% CI 1.10-1.21, p < 0.001), preoperative anxiety (OR 1.33, 95% CI 1.21-1.46, p < 0.001), and expected postsurgical pain intensity (OR 1.36, 95% CI 1.17-1.57, p < 0.001) were independently associated with APSP severity., Conclusion: These results suggested that the predictors for APSP intensity following gastrointestinal surgery included analgesic consumption, preoperative anxiety, and expected postsurgical pain, which were also the risk factors for APSP severity., Competing Interests: The authors declare that they have no conflicts of interest regarding the publication of this paper., (Copyright © 2021 Qing-Ren Liu et al.)

To explore the predictive performance of machine learning on the recurrence of patients with gastric cancer after the operation. The available data is divided into two parts. In particular, the first part is used as a training set (such as 80% of the original data), and the second part is used as a test set (the remaining 20% of the data). And we use fivefold cross-validation. The weight of recurrence factors shows the top four factors are BMI, Operation time, WGT and age in order. In training group:among the 5 machine learning models, the accuracy of gbm was 0.891, followed by gbm algorithm was 0.876; The AUC values of the five machine learning algorithms are from high to low as forest (0.962), gbm (0.922), GradientBoosting (0.898), DecisionTree (0.790) and Logistic (0.748). And the precision of the forest is the highest 0.957, followed by the GradientBoosting algorithm (0.878). At the same time, in the test group is as follows: the highest accuracy of Logistic was 0.801, followed by forest algorithm and gbm; the AUC values of the five algorithms are forest (0.795), GradientBoosting (0.774), DecisionTree (0.773), Logistic (0.771) and gbm (0.771), from high to low. Among the five machine learning algorithms, the highest precision rate of Logistic is 1.000, followed by the gbm (0.487). Machine learning can predict the recurrence of gastric cancer patients after an operation. Besides, the first four factors affecting postoperative recurrence of gastric cancer were BMI, Operation time, WGT and age.

Background: Accumulating evidence has demonstrated that aging is associated with an exaggerated response to surgical trauma together with cognitive impairments. This has significant implications for the development of clinical phenotype such as perioperative neurocognitive disorders (PND), which is a common complication following surgery, especially for the elderly. However, the mechanism by which aging brain is vulnerable to surgical trauma remains to be elucidated., Objective: To test whether age-related alterations in hippocampal network activities contribute to increased risk of PND following surgery., Methods: Thirty-two adult and seventy-two aged male C57BL/6 mice undergone sevoflurane anesthesia and exploratory laparotomy were used to mimic human abdominal surgery. For the interventional study, mice were treated with minocycline. Behavioral tests were performed post-surgery with open field, novel object recognition and fear conditioning tests, respectively. The brain tissues were then harvested and subjected to biochemistry studies. Local field potential (LFP) recording was performed in another separate experiment., Results: Aged mice displayed signs of neuroinflammation, as reflected by significantly increased proinflammatory mediators in the hippocampus. Also, aged mice displayed persistently decreased oscillation activities under different conditions, both before and after surgery. Further correlation analysis suggested that theta power was positively associated with time with novel object, while γ oscillation activity was positively associated with freezing time to context. Of note, downregulation of neuroinflammation by microglia inhibitor minocycline reversed some of these abnormities., Conclusion: Our study highlights that age-related hippocampal oscillation dysregulation increases the risk of PND incidence, which might provide diagnostic/prognostic biomarkers for PND and possible other neurodegenerative diseases.

Long-lasting pain can induce depression, which seriously affects life quality of the patients, but little is known about the underlying mechanism. Chronic neuropathic pain can modulate DNA methylation in target genes related to neuroplasticity and mood regulation, which was induced by DNA methyltransferases (DNMTs). Methylation changes of brain-derived neurotrophic factor (Bdnf) in the hippocampus are critical for neuropathic pain and depression. Thus, we hypothesized that DNMTs are required for depression genesis, probably by repressing hippocampus Bdnf gene expression in rats with neuropathic pain, which can be rescued by ketamine. In the present study, rats were randomly subjected to spared nerve injury (SNI) or sham surgery. SNI upregulated DNMTs and downregulated Bdnf and exon I in the hippocampus and induced depression behaviors, whereas blocking the upregulation of DNMTs with RG108 alleviated SNI-induced depression by up-regulation of the expression of Bdnf and exon I. In addition, we showed that a single dose of ketamine could ameliorate SNI-induced depression-like behaviors, which was related to normalization of DNMTs and Bdnf. In conclusion, our study suggested that DNMTs-induced decreased expression of Bdnf may induce the comorbid of pain and depression, which can be prevented by ketamine., (Copyright © 2020. Published by Elsevier Inc.)

Purpose: To evaluate the efficacy and safety of iTEAR, a novel, portable, sonic external neuromodulation device, for the treatment of dry eye disease (DED)., Methods: This was a multicenter, open-label, single-arm clinical trial that included adult patients with DED with a Schirmer score of ≤10 mm in at least one eye. Enrolled subjects were instructed to apply the study device at least twice per day for 30 seconds bilaterally to the external nasal nerve. After the initial baseline visit, patients were followed up at days 3, 14, 30, 90, and 180. The primary efficacy endpoint was the Schirmer index (change from unstimulated to stimulated tear production as measured by the Schirmer test) at day 30. The major secondary endpoint was the change in symptoms of DED at day 30 evaluated using the Ocular Surface Disease Index (OSDI)., Results: A total of 101 subjects evaluated at day 30 had a mean Schirmer index of 9.4 mm (95% confidence interval [CI], 7.4-11.3), and the baseline OSDI improved by an average of 14.4 (95% CI, 11.1-17.7). Both endpoints were highly statistically and clinically significant at all time points. There were two mild unanticipated adverse events definitely related to the device., Conclusions: The safety and efficacy of the iTEAR device observed in this study support its indication for treating DED., Translational Relevance: Neurostimulation has the potential to improve signs and symptoms of DED., Competing Interests: Disclosure: M.H. Ji, None; D.M. Moshfeghi, None; L. Periman (C); D. Kading (C); C. Matossian, None; G. Walman, None; S. Markham, None; A. Mu, None; A. Jayaram, None; M. Gertner, Olympic Ophthalmics, Inc. (F, I); P. Karpecki (C); N.J. Friedman (C, I), (Copyright 2020 The Authors.)

Purpose: To investigate differences between women and men in the repair of rhegmatogenous retinal detachments (RRDs) in the United States., Design: Retrospective cohort study., Methods: Setting: A large insurance claims database., Participants: Subjects with an incident RRD between 2007 and 2015., Data: Demographic data, comorbid ocular conditions associated with RRD, systemic comorbidities, and surgical intervention (pneumatic retinopexy [PR], pars plana vitrectomy [PPV], laser barricade, or scleral buckle [SB]) were collected., Main Outcome Measures: Odds of receipt of surgical intervention for incident RRD, time to repair, type of intervention, and the rate of reoperation by sex., Results: The study period included 133 million eligible records with 61,071 cases of incident RRD among which 43% (n = 26,289) were women. The primary outcome model had 23,933 confirmed RRD cases with a 93% retinal detachment repair rate. Women had 34% reduced odds of receipt of surgical repair of an RRD (odds ratio [OR] 0.66, 95% confidence interval [CI] 0.59, 0.73; P < .001) after adjusting for confounders. This effect persisted in all sensitivity models. Among patients who received repair, women were more often delayed (0.17 days, P = .04). Women were more likely to undergo primary laser barricade (relative risk ratio [RRR] 1.68, P < .001), primary SB (RRR 1.15, P < .001), and PR (RRR 1.07, P < .04) than men. The odds of reoperation were lower in women (OR 0.91, 95% CI 0.85, 0.96; P = .002) after adjustment., Conclusions: Insured women are less likely than insured men to receive surgical intervention for an RRD. Based on the results of this study, if the odds of repair were equal between women and men in the United States, then 781 more women would receive surgery each year, or 7,029 more during the study period. Women are more likely to have the repair performed with scleral buckle, laser barricade, and pneumatic retinopexy. The reason for these sex differences in RRD repair remains unknown and requires further investigation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Although 1000s of immune-related and platelet receptor-related genes have been identified in lung adenocarcinoma, their role in prognosis prediction remains unclear., Methods: We downloaded mRNA data from the Cancer Genome Atlas Dataset (TCGA), and GSE68465 or GSE14814 data sets from the Gene Expression Omnibus (GEO) database., Results: The high-risk group's overall survival (OS) time was lower than that of the low-risk group's in TCGA ( p = 1.15e-03). Additionally, the risk score was an independent prognostic survival factor for lung adenocarcinoma patients in TCGA (HR = 2.136, 95%CI = 1.553-2.937, p < 0.001). The model's prognostic performance was verified with two independent GEO cohorts (GSE68465 and GSE14814). We also developed a nomogram and provided free webpage prediction tools. The mechanism of the high-risk group in this risk score may be have been related to somatic mutations and copy number changes. In addition, this risk score can distinguish the prognosis of the other two cancers (ACC, p < 0.001 and KIRP, p < 0.001). Also, among the other seven cancers, the OS prognosis for high and low risk groups show wide variation ( p < 0.05)., Conclusion: Our research demonstrates that CCNA2 and TGFB2 are potential diagnostic and prognostic biomarkers, as well as therapeutic targets in lung adenocarcinoma (LUAD). We also determined a novel and reliable prognostic score for lung adenocarcinoma prognosis. The online nomogram prediction tool that contains this risk score may also help clinical medical staff., (Copyright © 2020 Zhou, Wang, Lei, Ji, Yang and Xia.)

A 2-year-old child was referred to the authors' pediatric retina service for bilateral retinal folds, strabismus, and psychomotor retardation, as well as marked thinning of the corpus callosum. Family history was unremarkable and genetic testing revealed a previously undescribed mutation in the LRP5 gene. Widefield fundus photography, fluorescein angiography, and spectral-domain optical coherence tomography were used to image the retinal fundus. The authors' case suggests a correlation between LRP5 and neurological development, since its variants may lead to a syndromic condition characterized by FEVR-like abnormalities along with neurodevelopmental delay and hypoplasia of the corpus callosum. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:588-591.]., (Copyright 2020, SLACK Incorporated.)

Neuroinflammation plays a key role in the progression of many neurodegenerative diseases, yet the underlying mechanism remains largely unexplored. Using an animal model of neuroinflammation induced by repeated lipopolysaccharide (LPS) injections, we found selectively reduced expression of parvalbumin (PV) but not somatostatin (SST) in the medial prefrontal cortex (mPFC). The reduced PV expression resulted in decreased intensities of vesicular GABA transporter and PV buttons, suggesting disinhibition in the mPFC. These further induced abnormal mPFC neural activities and consequently contributed to cognitive impairments. In addition, gamma oscillations supported by PV interneuron function were positively associated with time spent with the novel object in the novel object recognition test. Notably, down-regulation of neuroinflammation by microglia inhibitor minocycline or boosting gamma oscillations by dopamine 4 receptor agonist RO-10-5824 improved cognitive performance. In conclusion, our study proposes neural network disturbance as a likely mechanistic linker between neuroinflammation and cognitive impairments in neurodegeneration and possibly other psychiatric disorders., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Systemic inflammation induces cognitive impairments via unclear mechanisms. Increasing evidence has suggested complement C3/C3a receptor signaling, a key component of innate immune pathogen defense, plays an important role in cognition and neurodegeneration, whereas its dysfunction is implicated in many neurological disorders. However, it remains unclear whether complement C3/C3a receptor signaling was involved in systemic inflammation-induced cognitive impairments. In the present study, we showed that hippocampal complement C3 levels in astrocytes and C3a receptor expressions in microglia were specifically up-regulated after lipopolysaccharide (LPS) injection. Interestingly, LPS selectively induced inhibitory but not excitatory synapse related protein loss. Notably, C3a receptor antagonist SB290157 trifluoroacetate attenuated LPS-induced hippocampal neuroinflammation and inhibitory synapse related protein loss, contributing to improved cognitive function. In conclusion, our study suggests that complement C3/C3a receptor signaling plays a key role in LPS-induced cognitive impairments, which may serve a therapeutic target for systemic inflammation related cognitive disorders., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

Purpose: The purpose of this study was to explore the use of fluorescein angiography (FA) images in a convolutional neural network (CNN) in the management of retinopathy of prematurity (ROP)., Methods: The dataset involved a total of 835 FA images of 149 eyes (90 patients), where each eye was associated with a binary outcome (57 "untreated" eyes and 92 "treated"; 308 "untreated" images, 527 "treated"). The resolution of the images was 1600 and 1200 px in 20% of cases, whereas the remaining 80% had a resolution of 640 and 480 px. All the images were resized to 640 and 480 px before training and no other preprocessing was applied. A CNN with four convolutional layers was trained on 90% of the images ( n = 752) randomly chosen. The accuracy of the prediction was assessed on the remaining 10% of images ( n = 83). Keras version 2.2.0 for R with Tensorflow backend version 1.11.0 was used for the analysis., Results: The validation accuracy after 100 epochs was 0.88, whereas training accuracy was 0.97. The receiver operating characteristic (ROC) presented an area under the curve (AUC) of 0.91., Conclusions: Our study showed, we believe for the first time, the applicability of artificial intelligence (CNN) technology in the ROP management driven by FA. Further studies are needed to exploit different fields of applications of this technology., Translational Relevance: This algorithm is the basis for a system that could be applied to both ROP as well as experimental oxygen induced retinopathy., Competing Interests: Disclosure: D. Lepore, None; M.H. Ji, None; M.M. Pagliara, None; J. Lenkowicz, None; N.D. Capocchiano, None; L. Tagliaferri, None; L. Boldrini, None; V. Valentini, None; A. Damiani, None, (Copyright 2020 The Authors.)

Background and Objective: To investigate whether surgical management of newly diagnosed rhegmatogenous retinal detachment (RRD) varies if patients are diagnosed during a major national ophthalmology conference., Patients and Methods: This retrospective cohort study included 34,759 patients with incident RRD, of whom, 1,246 (3.6%) were diagnosed during dates of three national ophthalmology conferences, and 1,170 (3.4%) underwent surgery during conference dates. The authors identified patients with primary repair with cryotherapy, laser, scleral buckle, pneumatic retinopexy, or pars plana vitrectomy. Multinomial logistic regression models were used to determine patients' likelihood of receiving each type of repair within 30 days of their diagnosis depending on whether they were diagnosed during a national ophthalmology conference. Linear regression models were used to determine the relationship between the date patients were diagnosed and how long they waited to receive a repair. Main outcome measures included days between diagnosis with RRD and RRD repair, receiving repair on the same day of diagnosis, and reoperation rate within 30 days of the primary repair., Results: Mean time from diagnosis to repair was 1.5 days (standard deviation: ± 2.4 days), and 71% of patients underwent repair within a day of diagnosis. Repairs were followed by a second surgery within 30 days in 11.1% of patients. Patients diagnosed during conferences waited 0.23 days longer between diagnosis and repair compared with patients diagnosed outside of conference dates (P = .001). Patients diagnosed with RRD during conferences were less likely to receive surgical repair within a day of diagnosis compared to patients diagnosed during non-conference dates (P = .037). Patients who were diagnosed with RRD during a conference date and also received surgery during a conference date were more likely to undergo a second surgery within 30 days of the primary procedure (P = .006) CONCLUSIONS: Patients diagnosed with RRD during national ophthalmology conference dates waited slightly longer for surgery, were slightly less likely to receive surgery within a day, and were more likely to undergo a second surgery within 30 days of the primary procedure. The "national meeting effect" phenomenon is present in ophthalmology, albeit to a lesser degree that is likely not visually significant. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:328-337.]., (Copyright 2020, SLACK Incorporated.)

BACKGROUND The metabolic processing of ellagic acid (EA) by cytochrome P450s (CYP450s) expressed in the intestines is unclear. This study aimed to investigate the effects of CYP450s that are highly expressed in HIEC cells on metabolic activity of EA. MATERIAL AND METHODS HIEC cell models expressing 2B6, 2C9, 2D6, and 3A4 were generated by stably transfecting with CYP450 genes using a lentivirus system. PCR and Western blot assay were used to detect expression of CYP450s. Cell Counting Kit-8 (CCK-8) assay was used to examine the cytotoxic effect of EA on CYP450s-expressing HIEC cells. Flow cytometry was employed to evaluate apoptosis of CYP450s-expressing HIEC cells after addition of EA. Metabolic clearance rate of EA in vitro by the constructed HIEC cell models was measured using UPLC-MS method. RESULTS CYP450s expression HIEC cell models, including CYP2B6, CYP2C9, CYP2D6, and CYP3A4, were successfully established. EA treatment at different concentrations (10 μg/mL and 50 μg/mL) remarkably decreased cell viability of HIEC cells expressing CYP2C9 compared to the untreated control (p<0.01), in a concentration-dependent and time-dependent manner. Expression of CYP2C9 significantly increased the apoptosis rate of HIEC cells treated with EA compared to that in HIEC cells without any CYP450s expression (p<0.01). The clearance rate of EA in CYP2B6-expressing (p<0.05) and CYP2C9-expressing (p<0.001) HIEC cell models was remarkably reduced after 120 min. CONCLUSIONS Ellagic acid was effectively activated by CYP2C9 in HIEC cells and caused cytotoxicity and apoptosis of HIEC cells. Therefore, CYP2C9 is main metabolic enzyme of EA when compared to other CYP450 HIEC cell models.

Postoperative cognitive dysfunction is a well-recognized complication after major surgery in the elderly, but its pathophysiological mechanism is not fully understood. In the present study, we used liquid chromatography-tandem mass spectrometry combined with tandem mass tags to identify differentially expressed proteins and perform further functional studies on protein of interest. Here, we showed that hippocampal complement C3 was significantly upregulated after surgery, which was accompanied by marked decreases in synaptic related proteins and density. In aged patients undergoing gastrointestinal surgery, we also found significantly increased plasma level of C3b postoperatively and were negatively associated with cognitive performance. Notably, selective inhibition of complement C3 by compstatin was able to rescue synaptic and cognitive impairments induced by surgery in aged mice. Collectively, our study confirms that surgery can induce cognitive impairments, and the possible mechanisms might be related to abnormal complement signaling and synaptic disruption.

Systemic inflammation induces cognitive impairments via unclear mechanisms. Accumulating evidence has demonstrated that a subset of neurons that express parvalbumin (PV) play a critical role in regulation of cognitive and emotional behavior. Thus, the aim of the present study was to test whether disruption of PV interneuron mediates systemic inflammation-induced depression-like behavior and working memory impairment by lipopolysaccharide (LPS) challenge. Here we showed that LPS induces depression-like behavior and working memory impairment, coinciding with increased PV expression, enhanced GABAergic transmission, and impaired long-term potentiation (LTP) in the hippocampus. Notably, systemic administration of NMDA (N-methyl-D-aspartate) receptor (NMDAR) antagonist ketamine was able to interfere with PV expression and reverse depression-like behavior and working memory impairment, which is probably mediated by reversing impaired LTP. In addition, flumazenil, a competitive antagonist acting at the benzodiazepine binding site of the GABA A receptor, also ameliorated these abnormal behaviors. Collectively, our study added growing evidence to the limited studies that overinhibition mediated by PV interneurons might play a critical role in LPS-induced depression-like behavior and working memory impairment., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Objective: To compare morphologic and functional status at age 4 years for patients treated in one eye with laser photocoagulation and the other eye with intravitreal bevacizumab (IVB) injection for Type 1 retinopathy of prematurity (ROP)., Patients and Methods: In this single-center, randomized, controlled trial, best-corrected visual acuity (BCVA) in logMAR was obtained along with spherical equivalent refraction (SER), fluorescein angiography (FA), optical coherent tomography (OCT), and OCT angiography (OCTA)., Results: Eighteen babies (36 eyes) were selected for this study. BCVA and SER were similar in the two groups, but six patients had anisometropia of 4 diopters or more. IVB-treated eyes tended to have thinner foveal thickness than laser-treated eyes (mean difference: -5.33 pixels; 95% confidence interval, -9.62 to -1.05)., Conclusion: Although the differences found here are minimal between the IVB-treated and laser-treated groups, further long-term evaluation of not only FA, but also OCT and OCTA, are needed in larger studies. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:180-186.]., (Copyright 2020, SLACK Incorporated.)

Background and Objective: To describe a case series of three patients in one family with Von Hippel-Lindau (VHL) disease who presented with vitreoretinal neovascularization and resulting tractional retinal detachments (TRDs). This vitreoretinal phenotype of VHL may benefit from early surgical intervention., Patients and Methods: Descriptive case series of three patients in one family with VHL disease. A review of the literature regarding surgical intervention for VHL was performed., Results: All three patients developed prominent intravitreal neovascularization with fibrovascular growth within the vitreous secondary to a retinal capillary hemangioma. Two subjects with intravitreal neovascularization were treated with laser and cryotherapy but eventually developed a TRD. The final vision in these two patients was light perception and 20/300. The eye that was preemptively treated with vitrectomy to remove the vitreous sustaining the neovascularization had visual acuity of 20/50 after surgery., Conclusion: Intravitreal neovascularization with fibrovascular proliferation may be an indication for vitrectomy prior to the development of retinal detachment. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:109-115.]., (Copyright 2020, SLACK Incorporated.)

Background: Postoperative cognitive decline (POCD) is a recognized clinical phenomenon characterized by cognitive impairments in patients following anesthesia and surgery, yet its underlying mechanism remains unclear. Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, learning, and memory via activation of TrkB-full length (TrkB-FL) receptors. It has been reported that an abnormal truncation of TrkB mediated by calpain results in dysregulation of BDNF/TrkB signaling and is associated with cognitive impairments in several neurodegenerative disorders. Calpains are Ca 2+ -dependent proteases, and overactivation of calpain is linked to neuronal death. Since one source of intracellular Ca 2+ is N-methyl-d-aspartate receptors (NMDARs) related and the function of NMDARs can be regulated by neuroinflammation, we therefore hypothesized that dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca 2+ /calpain might be involved in the pathogenesis of POCD., Methods: In the present study, 16-month-old C57BL/6 mice were subjected to exploratory laparotomy with isoflurane anesthesia to establish the POCD animal model. For the interventional study, mice were treated with either NMDAR antagonist memantine or calpain inhibitor MDL-28170. Behavioral tests were performed by open field, Y maze, and fear conditioning tests from 5 to 8 days post-surgery. The levels of Iba-1, GFAP, interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), NMDARs, calpain, BDNF, TrkB, bax, bcl-2, caspase-3, and dendritic spine density were determined in the hippocampus., Results: Anesthesia and surgery-induced neuroinflammation overactivated NMDARs and then triggered overactivation of calpain, which subsequently led to the truncation of TrkB-FL, BDNF/TrkB signaling dysregulation, dendritic spine loss, and cell apoptosis, contributing to cognitive impairments in aging mice. These abnormities were prevented by memantine or MDL-28170 treatment., Conclusion: Collectively, our study supports the notion that NMDAR/Ca2+/calpain is mechanistically involved in anesthesia and surgery-induced BDNF/TrkB signaling disruption and cognitive impairments in aging mice, which provides one possible therapeutic target for POCD.

Objective: The aim is to explore the prediction effect of 5 machine learning algorithms on peritoneal metastasis of gastric cancer., Methods: 1080 patients with postoperative gastric cancer were divided into a training group and test group according to the ratio of 7:3. The model of peritoneal metastasis was established by using 5 machine learning (gbm(Light Gradient Boosting Machine), GradientBoosting, forest, Logistic and DecisionTree). Python pair was used to analyze the machine learning algorithm. Gbm algorithm is used to show the weight proportion of each variable to the result., Result: Correlation analysis showed that tumor size and depth of invasion were positively correlated with the recurrence of patients after gastric cancer surgery. The results of the gbm algorithm showed that the top 5 important factors were albumin, platelet count, depth of infiltration, preoperative hemoglobin and weight, respectively. In training group: Among the 5 algorithm models, the accuracy of GradientBoosting and gbm was the highest (0.909); the AUC values of the 5 algorithms are gbm (0.938), GradientBoosting (0.861), forest (0.796), Logistic(0.741) and DecisionTree(0.712) from high to low. In the test group: among the 5 algorithm models, the accuracy of forest, DecisionTree and gbm was the highest (0.907); AUC values ranged from high to low to gbm (0.745), GradientBoosting (0.725), forest (0.696), Logistic (0.680) and DecisionTree (0.657)., Conclusion: Machine learning can predict the peritoneal metastasis in patients with gastric cancer.

Glioma is a common malignant human brain tumor. The progression of glioma is associated with dysregulation of various microRNAs. Previous studies have demonstrated that microRNA-26b-3p (miR-26b-3p) is correlated with the pathogenesis of various tumors, but the functional role of miR-26b-3p and its underlying mechanisms in glioma are not clear. Here, we found that overexpression of miR-26b-3p repressed cell migration and proliferation and promoted apoptosis. In contrast, the opposite effects were observed when miR-26b-3p was inhibited in glioma cells. Anthrax toxin receptor 1 (ANTXR1) was confirmed to be a downstream molecule of miR-26b-3p. Reintroduction of ANTXR1 with an ORF region rescued the suppressive effects of miR-26b-3p on proliferation and migration, and inhibited the apoptosis of glioma cells. Moreover, the downstream target of miR-26b-3p, ANTXR1, was increased in glioma tissues and was inversely correlated with miR-26b-3p. MiR-26b-3p and ANTXR1 were correlated with the severity of glioma. Taken together, these results demonstrate that miR-26b-3p is a critical modulator of glioma via its downstream molecule, ANTXR1. Further, the miR-26b-3p/ANTXR1 axis may serve as a treatment or diagnostic target in glioma., Competing Interests: None., (AJTR Copyright © 2019.)

Sepsis-associated encephalopathy (SAE) is a potentially irreversible acute cognitive dysfunction with unclear mechanism. Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific phosphatase which normally opposes synaptic strengthening by regulating key signaling molecules involved in synaptic plasticity and neuronal function. Thus, we hypothesized that abnormal STEP signaling pathway was involved in sepsis-induced cognitive impairment evoked by lipopolysaccharides (LPS) injection. The levels of STEP, phosphorylation of GluN2B (pGluN2B), the kinases extracellular signal-regulated kinase 1/2 (pERK), cAMP-response element binding protein (CREB), synaptophysin, brain derived neurotrophic factor (BDNF), and post-synaptic density protein 95 (PSD95) in the hippocampus, prefrontal cortex, and striatum were determined at the indicated time points. In the present study, we found that STEP levels were significantly increased in the hippocampus, prefrontal cortex, and striatum following LPS injection, which might resulted from the disruption of the ubiquitin-proteasome system. Notably, a STEP inhibitor TC-2153 treatment alleviated sepsis-induced memory impairment by increasing phosphorylation of GluN2B and ERK1/2, CREB/BDNF, and PSD95. In summary, our results support the key role of STEP in sepsis-induced memory impairment in a mouse model of SAE, whereas inhibition of STEP may provide a novel therapeutic approach for this disorder and possible other neurodegenerative diseases.

Sepsis-associated encephalopathy induces cognitive dysfunction via mechanisms that commonly involve neuroinflammation and synaptic plasticity impairment of the hippocampus. The β2-adrenoceptor (β2-AR) is a G-protein coupled receptor that regulates immune response and synaptic plasticity, whereas its dysfunction has been implicated in various neurodegenerative diseases. Thus, we hypothesized abnormal β2-AR signaling is involved in sepsis-induced cognitive impairment. In the present study, C57BL/6 mice were subjected to cecal ligation and puncture (CLP) to mimic the clinical human sepsis-associated encephalopathy. The levels of hippocampal β2-AR, proinflammatory cytokines tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), IL-6, cAMP-response element binding protein (CREB), brain derived neurotrophic factor (BDNF), post-synaptic density protein 95 (PSD95), and NMDA receptor 2 B subtypes (GluN2B) were determined at 6, 12, 24 h and 7 and 16 days after CLP. For the interventional study, mice were treated with β2-AR agonist clenbuterol in two ways: early treatment (immediately following CLP) and delayed treatment (on the 8th day following CLP). Neurobehavioral performances were assessed by open field and fear conditioning tests. Here, we found that hippocampal β2-AR expression was significantly decreased starting from 12 h and persisted until 16 days following CLP. Besides, sepsis mice also exhibited increasing neuroinflammation, down-regulated CREB/BDNF, decreasing PSD95 and GluN2B expression, and displayed hippocampus-dependent cognitive impairments. Notably, early clenbuterol treatment alleviated sepsis-induced cognitive deficits by polarizing microglia toward an anti-inflammatory phenotype, reducing proinflammatory cytokines including IL-1β, TNF-α, and up-regulating CREB/BDNF, PSD95, and GluN2B. Intriguingly, delayed clenbuterol treatment also improved cognitive impairments by normalization of hippocampal CREB/BDNF, PSD95, and GluN2B. In summary, our results support the beneficial effects of both early and delayed clenbuterol treatment, which suggests that activation of β2-AR has a translational value in sepsis-associated organ dysfunction including cognitive impairments.

Free-standing gallium nitride (GaN) substrates are in high demand for power devices, laser diodes, and high-power light emitting diodes (LEDs). SixPoint Materials Inc. has begun producing 2" GaN substrates through our proprietary Near Equilibrium AmmonoThermal (NEAT) growth technology. In a single 90 day growth, eleven c -plane GaN boules were grown from free-standing hydride vapor phase epitaxy (HVPE) GaN substrates. The boules had an average X-ray rocking curve full width at half maximum (FWHM) of 33 ± 4 in the 002 reflection and 44 ± 6 in the 201 reflection using 0.3 mm divergence slits. The boules had an average radius of curvature of 10.16 ± 3.63 m. The quality of the boules was highly correlated to the quality of the seeds. A PIN diode grown at Georgia Tech on a NEAT GaN substrate had an ideality factor of 2.08, a high breakdown voltage of 1430 V, and Baliga's Figure of Merit of >9.2 GW/cm 2 . These initial results demonstrate the suitability of using NEAT GaN substrates for high-quality MOCVD growth and fabrication of high-power vertical GaN switching devices.

Background: Systemic inflammation impairs cognitive performance, yet the brain networks mediating this process remain to be elucidated. The purpose of the current study was to use resting-state functional magnetic resonance imaging (fMRI) to explore changes in the functional connectivity in a lipopolysaccharide- (LPS-) induced systemic inflammation animal model., Materials and Methods: We used the regional homogeneity (ReHo) method to examine abnormal brain regions between the control and LPS groups and then considered them as seeds of functional connectivity analysis., Results: Compared with the control group, our study showed that (1) LPS impaired mood function, as reflected by a depression-like behavior in the forced swim test; (2) LPS induced significantly increased ReHo values in the anterior cingulate cortex (ACC) and caudate putamen (CPu); (3) the ACC seed showed increased functional connectivity with the retrosplenial cortex, superior colliculus, and inferior colliculus; and (4) the right CPu seed showed increased functional connectivity with the left CPu. Linear regression analysis showed a LPS-induced depression-like behavior which was associated with increased ReHo values in the ACC and right CPu. Moreover, the LPS-induced depression-like behavior was related to increased functional connectivity between the right CPu and left CPu., Conclusion: This is the first study to show that systemic inflammation impairs mood function that is associated with an altered resting-state functional network based on ReHo analysis, providing evidence of the abnormal regional brain spontaneous activity which might be involved in inflammation-related neurobehavioral abnormalities.

Sepsis-associated encephalopathy (SAE) is a common complication that leads to long-term cognitive impairments and increased mortality in sepsis survivors. The mechanisms underlying this complication remain unclear and an effective intervention is lacking. Accumulating evidence suggests the nucleotide-binding domain-like receptor protein3 (NLRP3)/caspase-1 pathway is involved in several neurodegenerative diseases. Thus, we hypothesized that the NLRP3/caspase-1 pathway is involved in NLRP3-mediated pyroptosis, maturation and release of inflammatory cytokines, and cognitive deficits in SAE. We used the NLRP3 inhibitor MCC950 and the caspase-1 inhibitor Ac-YVAD-CMK to study the role of the NLRP3/caspase-1 pathway in pyroptosis and cognitive deficits in a mouse model of SAE. Mice were randomly assigned to one of six groups: sham+saline, sham+MCC950, sham+Ac-YVAD-CMK, cecal ligation and puncture (CLP)+saline, CLP+MCC950, and CLP+Ac-YVAD-CMK. Surviving mice underwent behavioral tests or had hippocampal tissues collected for histochemical analysis and biochemical assays. Our results show that CLP-induced hippocampus-dependent memory deficits are accompanied by increased NLRP3 and caspase-1 positive cells, and augmented protein levels of NLRP3, caspase-1, gasdermin-D, and pro-inflammatory cytokines in the hippocampus. In addition, administration of MCC950 or Ac-YVAD-CMK rescues cognitive deficits and ameliorates increased hippocampal NLRP3-mediated neuronal pyroptosis and pro-inflammatory cytokines. Our results suggest that the NLRP3/caspase-1 pathway-induced pyroptosis mediates cognitive deficits in a mouse model of SAE.