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Quan-fang Liu,1 Cui-na Shi,1 Jian-hua Tong,1 Kun-peng Li,1 Jian-jun Yang,2 Mu-huo Ji,1 Qing-ren Liu3 1Department of Anesthesiology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 3Department of Anesthesiology, Xishan People’s Hospital of Wuxi City, Wuxi, People’s Republic of ChinaCorrespondence: Qing-ren Liu, Department of Anesthesiology, Xishan People’s Hospital of Wuxi City, Wuxi, People’s Republic of China, Email liuqr5250@163.com Mu-huo Ji, Department of Anesthesiology, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, People’s Republic of China, Email jimuhuo2009@sina.comBackground: The utilization of adjuvants such as dexamethasone and dexmedetomidine in combination with local anesthetics has proven effective in extending analgesia duration. We aimed to investigate the potential efficacy of combining dexmedetomidine and dexamethasone in rhomboid intercostal and sub-serratus (RISS) block for prolonging postoperative analgesia in patients undergoing video-assisted thoracoscopic surgery (VATS).Methods: We did this randomized, double-blind, controlled trial in two tertiary-care hospitals. A total of eighty-eight patients undergoing VATS under general anesthesia were enrolled in this study. They were randomly assigned into four groups: ropivacaine (R) group, ropivacaine + dexmedetomidine (RM) group, ropivacaine + dexamethasone (RS) group, or ropivacaine + dexmedetomidine + dexamethasone (RSM) group. The primary outcome measure was the duration of analgesia. Secondary outcomes included Numeric Rating Scale (NRS) scores, cumulative oxycodone consumption, and adverse effects.Results: The RSM group exhibited a significantly prolonged duration of analgesia at 1073.5 min (932.0– 1283.3) compared to the R group with a duration of 154.5 min (80.5– 199.3) and the RS group with a duration of 282.0 min (195.3– 350.0, P < 0 0.001). The cumulative oxycodone consumption during the 0– 12 hours and 0– 24-hours period was significantly reduced in the RSM group compared to the R group (P < 0.05). There was also a lower incidence of nausea at 48 hours postoperatively in the RSM group compared to the RM group. However, there were no significant differences between the four groups regarding NRS pain scores.Conclusion: The combination of ropivacaine, dexmedetomidine, and dexamethasone in RISS block significantly prolongs the duration of postoperative analgesia following VATS.Keywords: nerve block, pain, postoperative, anesthesia, video-assisted thoracoscopic surgery

Qing-Ren Liu,1 Yu-Chen Dai,2 Mu-Huo Ji,3 Pan-Miao Liu,4 Yong-Yan Dong,4 Jian-Jun Yang4 1Department of Anesthesiology, Xishan People’s Hospital of Wuxi City, Wuxi, 214105, People’s Republic of China; 2Department of Anesthesiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, 210009, People’s Republic of China; 3Department of Anesthesiology, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, 210011, People’s Republic of China; 4Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, People’s Republic of ChinaCorrespondence: Jian-Jun Yang, Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, NO. 1 East Jianshe Road, Zhengzhou, 450052, People’s Republic of China, Email yjyangjj@126.comAbstract: Acute postsurgical pain (APSP) has received growing attention as a surgical outcome. When poorly controlled, APSP can affect short- and long-term outcomes in patients. Despite the steady increase in awareness about postoperative pain and standardization of pain prevention and treatment strategies, moderate-to-severe APSP is frequently reported in clinical practice. This is possibly because pain varies widely among individuals and is influenced by distinct factors, such as demographic, perioperative, psychological, and genetic factors. This review investigates the risk factors for APSP, including gender, age, obesity, smoking history, preoperative pain history, pain sensitivity, preoperative anxiety, depression, pain catastrophizing, expected postoperative pain, surgical fear, and genetic polymorphisms. By identifying patients having an increased risk of moderate-to-severe APSP at an early stage, clinicians can more effectively manage individualized analgesic treatment protocols with a combination of pharmacological and non-pharmacological interventions. This would alleviate the transition from APSP to chronic pain and reduce the severity of APSP-induced chronic physical disability and social psychological distress.Keywords: acute postoperative pain, acute postsurgical pain, risk factors, predictors

Marco H Ji,1 Natalia F Callaway,1 Margaret A Greven,2 Daniel Vail,1 Darius M Moshfeghi1 1Byers Eye Institute, Horngren Family Vitreoretinal Center, Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, California; 2Department of Ophthalmology, Wake Forest University School of Medicine, Winston-Salem, North CarolinaCorrespondence: Darius M Moshfeghi Tel +1 (650) 723-6995Email dariusm@stanford.eduAbstract: Telemedicine has emerged as a potential solution to face the disproportion between infants that need to be screened for retinopathy of prematurity (ROP) and the lack of ophthalmologists. We evaluated its utility in the follow-up after off-label intravitreal injection of bevacizumab. None of the treated infants ended up with bad anatomic outcome. Telemedicine is an alternative safe method to monitor patients after treatment.Keywords: pediatric retina, retina, pediatric ophthalmology

Postoperative neurocognitive disorders (pNCD) are a common neurological complication, especially in elderly following anesthesia and surgery. Yet, the underlying mechanisms of pNCD remain elusive. This study aimed to investigate the molecular mechanisms that compromise synaptic metaplasticity in pNCD development with a focus on the involvement of Nogo-66 receptor 1 (NgR1) in the pathogenesis of pNCD in aged mice. Aged mice subjected to anesthesia and laparotomy surgery exhibited anxiety-like behavior and contextual fear memory impairment. Moreover, the procedure significantly increased NogoA and NgR1 expressions, particularly in the hippocampal CA1 and CA3 regions. This increase led to the depolymerization of F-actin, attributed to the activation of the RhoA-GTPase, resulting in a reduction of dendritic spines and changes in their morphology. Additionally, these changes hindered the efficient postsynaptic delivery of the subunit GluA1 and GluA2 of AMPA receptors (AMPARs), consequently diminishing excitatory neurotransmission in the hippocampus. Importantly, administering the competitive NgR1 antagonist peptide NEP1-40 (Nogo-A extracellular peptide residues 1-40 amino acids of Nogo-66) and Fasudil (a Rho-kinase inhibitor) effectively mitigated synaptic impairments and reversed neurocognitive deficits in aged mice following anesthesia and surgery. Our work indicates that high hippocampal Nogo66-NgR1 signaling disrupts postsynaptic AMPA receptor surface delivery due to F-actin depolymerization in the pathophysiology of pNCD., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Purpose: Central retinal artery occlusion (CRAO) is an ocular emergency that results from acute blockage of the blood supply to the retina and leads to a sudden vision loss. Other forms of ischemic retinopathies include diabetic retinopathy (DR), which involves chronic retinal ischemia and remains the leading cause of blindness in working-age adults. This study is the first to conduct a proteomic analysis of aqueous humor (AH) from patients with CRAO with a comparative analysis using vitreous humor (VH) samples from patients with DR., Methods: AH samples were collected from 10 patients with CRAO undergoing paracentesis and 10 controls undergoing cataract surgery. VH samples were collected from 10 patients with DR and 10 non-diabetic controls undergoing pars plana vitrectomy (PPV). Samples were analyzed using mass spectrometry., Results: Compared with controls, AH levels of 36 differentially expressed proteins (DEPs) were identified in patients with CRAO. Qiagen Ingenuity Pathway Analysis (IPA) revealed 11 proteins linked to ophthalmic diseases. Notably, enolase 2, a glycolysis enzyme isoform primarily expressed in neurons, was upregulated, suggesting neuronal injury and enzyme release. Additionally, clusterin, a protective glycoprotein, was downregulated. ELISA was conducted to confirm proteomics data. VH samples from patients with DR exhibited changes in a distinct set of proteins, including ones previously reported in the literature., Conclusions: The study provides novel insights into CRAO pathophysiology with multiple hits identified. Proteomic results differed between DR and CRAO studies, likely due to the different pathophysiology and disease duration., Translational Relevance: This is the first proteomic analysis of CRAO AH, with the potential to identify future therapeutic targets.

Inflammation plays a crucial role in the initiation and progression of sepsis, and it also induces alterations in brain neurotransmission, thereby contributing to the development of sepsis-associated encephalopathy (SAE). Parvalbumin (PV) interneurons are pivotal contributors to cognitive processes in various central dysfunctions including SAE. Oxytocin, known for its ability to augment the firing rate of gamma-aminobutyric acid (GABA)ergic interneurons and directly stimulate inhibitory interneurons to enhance the tonic inhibition of pyramidal neurons, has prompted an investigation into its potential effects on cognitive dysfunction in SAE. In the current study, we administered intranasal oxytocin to the SAE mice induced by lipopolysaccharide (LPS). Behavioral assessments, including open field, Y-maze, and fear conditioning, were used to evaluate cognitive performance. Golgi staining revealed hippocampal synaptic deterioration, local field potential recordings showed weakened gamma oscillations, and immunofluorescence analysis demonstrated decreased PV expression in the cornu ammonis 1 (CA1) region of the hippocampus following LPS treatment, which was alleviated by oxytocin. Furthermore, immunofluorescence staining of PV co-localization with vesicular glutamate transporter 1 or vesicular GABA transporter indicated a balanced excitation/inhibition effect of neurotransmitters on PV interneurons after oxytocin administration in the SAE mice, leading to improved cognitive function. In conclusion, cognitive function improved after oxytocin treatment. The number of PV neurons in the hippocampal CA1 region and the balance of excitatory/inhibitory synaptic transmission on PV interneurons, as well as changes in local field potential gamma oscillations in the hippocampal CA1 region, may represent its specific mechanisms.

The relationship between brain structure alteration and metabolic product clearance after night shift work with total sleep deprivation (SD) remains unclear. Twenty-two intensive care unit staff on regularly rotating shift work were implemented with structural and diffusion MRI under both rest wakefulness (RW) and SD conditions. Peripheral blood samples were collected for the measurement of cerebral metabolites. Voxel-based morphometry and diffusion tensor imaging analysis were used to investigate the alterations in the gray matter density (GMD) and mean diffusivity (MD) within the participants. Furthermore, correlation analysis was performed to investigate the relationship between the neuroimaging metrics and hematological parameters. A significant increase in the GMD values was observed in the anterior and peripheral areas of the brain under SD. In contrast, a decrease in the values was observed in the posterior regions, such as the bilateral cerebellum and thalamus. In addition, a significant reduction in the total cerebrospinal fluid volume was observed under SD. The Aβ42/Aβ40 levels in participants under SD were significantly lower than those under RW. The mean MD increment values extracted from the region of interest (ROI) of the anterior brain were negatively correlated with the increment of plasma Aβ42/Aβ40 levels (r = -0.658, P = 0.008). The mean GMD decrement values extracted from the posterior ROI were positively correlated with the increment of plasma Aβ-40 levels (r = 0.601, P = 0.023). The findings of this study suggest that one night of shift work under SD induces extensive and direction-specific structural alterations of the brain, which are associated with aberrant brain metabolic waste clearance., Competing Interests: Declaration of Competing Interest The authors declare that there are no competing financial interests in relation to the work described., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Identifying and planning treatment for retinopathy of prematurity (ROP) using telemedicine is becoming increasingly ubiquitous, necessitating a grading system to help caretakers of at-risk infants gauge disease severity. The modified ROP Activity Scale (mROP-ActS) factors zone, stage, and plus disease into its scoring system, addressing the need for assessing ROP's totality of binocular burden via indirect ophthalmoscopy. However, there is an unmet need for an alternative score which could facilitate ROP identification and gauge disease improvement or deterioration specifically on photographic telemedicine exams. Here, we propose such a system (Telemedicine ROP Severity Score [TeleROP-SS]), which we have compared against the mROP-ActS. In our statistical analysis of 1568 exams, we saw that TeleROP-SS was able to return a score in all instances based on the gradings available from the retrospective SUNDROP cohort, while mROP-ActS obtained a score of 80.8% in right eyes and 81.1% in left eyes. For treatment-warranted ROP (TW-ROP), TeleROP-SS obtained a score of 100% and 95% in the right and left eyes respectively, while mROP-ActS obtained a score of 70% and 63% respectively. The TeleROP-SS score can identify disease improvement or deterioration on telemedicine exams, distinguish timepoints at which treatments can be given, and it has the adaptability to be modified as needed., (© 2023. Springer Nature Limited.)

Introduction: Sepsis is a severe host response to infection, which induces both acute and long-term cognitive impairment. Despite its high incidence following sepsis, the underlying mechanisms remain elusive and effective treatments are not available clinically., Area Covered: This review focuses on elucidating the pathological mechanisms underlying cognitive impairment following sepsis. Specifically, the authors discuss the role of systemic inflammation response, blood-brain barrier disruption, neuroinflammation, mitochondrial dysfunction, neuronal dysfunction, and Aβ accumulation and tau phosphorylation in cognitive impairment after sepsis. Additionally, they review current strategies to ameliorate cognitive impairment., Expert Opinion: Potential interventions to reduce cognitive impairment after sepsis include earlier diagnosis and effective infection control, hemodynamic homeostasis, and adequate brain perfusion. Furthermore, interventions to reduce inflammatory response, reactive oxygen species, blood-brain barrier disruption, mitochondrial dysfunction, neuronal injury or death could be beneficial. Implementing strategies to minimize delirium, sleep disturbance, stress factors, and immobility are also recommended. Furthermore, avoiding neurotoxins and implementing early rehabilitation may also be important for preventing cognitive impairment after sepsis.

Background/aims: Flagellin, which is abundant in gram-negative bacteria, including Pseudomonas , is reported to influence on inflammatory responses in various lung diseases. However, its effect on airway epithelial cells in contribution to asthma pathogenesis is not elucidated yet. We aimed to investigate the effect of TLR5 ligand flagellin on the transcriptomic profile of primary human epithelial cells and to determine the markers of airway inflammation., Methods: Normal human bronchial epithelial (NHBE) cells were grown and differentiated in air-liquid interface (ALI) culture for 14-16 days. The cells were treated with flagellin in vitro at 10 and 100 ng/ml for 3 and 24 h. The conditioned media and cells were harvested to validate inflammatory markers involved in airway inflammation using ELISA, Western blot, and quantitative PCR methods. RNA-sequencing was performed to investigate the transcriptional response to flagellin in ALI-NHBE cells., Results: Altered transcriptional responses to flagellin in differentiated bronchial epithelial cells were determined, including genes encoding chemokines, matrix metalloproteinases, and antimicrobial biomolecules. Pathway analysis of the transcriptionally responsive genes revealed enrichment of signaling pathways. Flagellin induced the mRNA expressions of proinflammatory cytokines and chemokines, and secretion of GM-CSF, CXCL5, CCL5 and CXCL10. Flagellin enhanced the protein expression of MMP-13 in TGF-β1 and TGF-β2 pretreated cell lysates and Wnt/β-catenin signaling., Conclusions: These findings suggest that flagellin could be a potent inducer of inflammatory markers that may contribute to airway inflammation and remodeling., (© 2023 The Author(s).)

Objective: To evaluate the efficacy of ketochromate tromethamine and phloroglucinol combination therapy in early expulsion of ureteral calculi after extracorporeal shockwave lithotripsy (ESWL) in patients with distal ureteral clculi. The clinical and follow-up data of 275 patients with lower ureteral calculi who underwent ESWL were collected retrospectively in Civil Aviation General Hospital from January 1 st 2021 to June 30 th 2021. According to whether adjunctive medication used before ESWL patients were divided into control group and medication group (with ketochromate tromethamine 30 mg and phloroglucinol 80 mg before ESWL). Primary endpoint is the clearance rate of ureteral calculi after ESWL, secondary endpoint are the other outcomes and drug allergy. There were 138 cases in control group [117 were males and mean age (42±13) years]. Meanwhile, there were 137 cases in medication group [118 were males and mean age (42±12) years]. The clearance rate of ureteral calculi at 24 h (67.88% vs 48.55%, P= 0.001)、one week (76.64% vs 57.97%, P= 0.001) and four weeks (89.05% vs 76.08%, P =0.005)after ESWL in medication group were significant higher than that in control group. There was a significant difference in the VAS score of pain scale after ESWL (1.77±0.80 vs 2.06±1.04, P= 0.012) and re-ESWL rate (8.03% vs 17.39%, P =0.02) between two groups, but no difference with gross hematuria in 6 h after ESWL and drug allergy. Conclusions combination use of ketochromate tromethamine and phloroglucinol significantly improve early expulsion of ureteral calculi after ESWL in patients with distal ureteral calculi, with no side effect.

Background: Microglial activation-mediated neuroinflammation is one of the essential pathogenic mechanisms of sepsis-associated encephalopathy (SAE). Mounting evidence suggests that high mobility group box-1 protein (HMGB1) plays a pivotal role in neuroinflammation and SAE, yet the mechanism by which HMGB1 induces cognitive impairment in SAE remains unclear. Therefore, this study aimed to investigate the mechanism of HMGB1 underlying cognitive impairment in SAE., Methods: An SAE model was established by cecal ligation and puncture (CLP); animals in the sham group underwent cecum exposure alone without ligation and perforation. Mice in the inflachromene (ICM) group were continuously injected with ICM intraperitoneally at a daily dose of 10 mg/kg for 9 days starting 1 h before the CLP operation. The open field, novel object recognition, and Y maze tests were performed on days 14-18 after surgery to assess locomotor activity and cognitive function. HMGB1 secretion, the state of microglia, and neuronal activity were measured by immunofluorescence. Golgi staining was performed to detect changes in neuronal morphology and dendritic spine density. In vitro electrophysiology was performed to detect changes in long-term potentiation (LTP) in the CA1 of the hippocampus. In vivo electrophysiology was performed to detect the changes in neural oscillation of the hippocampus., Results: CLP-induced cognitive impairment was accompanied by increased HMGB1 secretion and microglial activation. The phagocytic capacity of microglia was enhanced, resulting in aberrant pruning of excitatory synapses in the hippocampus. The loss of excitatory synapses reduced neuronal activity, impaired LTP, and decreased theta oscillation in the hippocampus. Inhibiting HMGB1 secretion by ICM treatment reversed these changes., Conclusions: HMGB1 induces microglial activation, aberrant synaptic pruning, and neuron dysfunction in an animal model of SAE, leading to cognitive impairment. These results suggest that HMGB1 might be a target for SAE treatment., (© 2023. The Author(s).)

Objective: 5-Hydroxymethylfurfural (5-HMF) is an important component of air pollution, confirmed to be a risk factor for pulmonary inflammation. However, its association with general health is unknown. This article aimed to clarify the effect and mechanism of 5-HMF in the occurrence and aggravation of frailty in mice by investigating whether exposure to 5-HMF was linked to the occurrence and aggravation of mice frailty., Methods: Twelve male C57BL/6 mice (12-month-old, 38 ± 1 g) were randomly divided into the control group and the 5-HMF group. The 5-HMF group was treated with 5-HMF (1 mg/kg/day, respiratory exposure) for 12 months, whereas the control group was treated with equal amounts of sterile water. After the intervention, the ELISA method was used to detect the serum inflammation level of the mice, and the physical performance and frail status were evaluated using a Fried physical phenotype-based assessment tool. The differences in the body compositions were calculated from their MRI images, and the pathological changes in their gastrocnemius muscle were revealed using the H&E staining. Furthermore, the senescence of skeletal muscle cells was evaluated by measuring the expression levels of senescence-related proteins by the western blotting., Results: In the 5-HMF group, serum inflammatory factors IL-6, TNF-α, and CRP levels were significantly raised ( p  < 0.01). Mice in this group had higher frailty scores and significantly reduced grip strength ( p  < 0.001), slower weight gains, less WVgastrocnemius muscle masses, and lower sarcopenia indices (SI). In addition, the cross-sectional areas of their skeletal muscles were reduced, and the levels of their cell senescence-related proteins (p53, p21, p16, SOD1, SOD2, SIRT1, SIRT3) were considerably altered ( p  < 0.01)., Conclusion: 5-HMF may induce chronic and systemic inflammation, which in turn accelerates the progression of the frailty of mice through cell senescence., Competing Interests: 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., (© 2023 The Authors.)

Introduction: Inflammation in early life is a risk factor for the development of neuropsychiatric diseases later in adolescence and adulthood, yet the underlying mechanism remains elusive. In the present study, we performed an integrated proteomic and phosphoproteomic analysis of the hippocampus to identify potential molecular mechanisms of early life inflammation-induced cognitive impairment., Methods: Both female and male mice received a single intraperitoneal injection of 100 μg/kg lipopolysaccharide (LPS) on postnatal day 10 (P10). Behavioral tests, including open field, elevated plus-maze, and Y-maze tests, were performed on P39, P40, and P41, respectively. After behavioral tests, male mice were sacrificed. The whole brain tissues and the hippocampi were harvested on P42 for proteomic, phosphoproteomic, Western blot, and Golgi staining., Results: Early life LPS exposure induced cognitive impairment in male mice but not in female mice, as assessed by the Y-maze test. Therefore, following biochemical tests were conducted on male mice. By proteomic analysis, 13 proteins in LPS group exhibited differential expression. Among these, 9 proteins were upregulated and 4 proteins were downregulated. For phosphoproteomic analysis, a total of 518 phosphopeptides were identified, of which 316 phosphopeptides were upregulated and 202 phosphopeptides were downregulated in the LPS group compared with the control group. Furthermore, KEGG analysis indicated that early life LPS exposure affected the glutamatergic synapse and neuroactive ligand-receptor interaction, which were associated with synaptic function and energy metabolism. Increased level of brain protein i3 (Bri3), decreased levels of PSD-95 and mGLUR5, and dendritic spine loss after early life LPS exposure further confirmed the findings of proteomic and phosphoproteomic analysis., Conclusions: Our findings demonstrated that neuroinflammation and impaired synapse may be involved in early life inflammation-induced cognitive impairment. Future studies are required to confirm our preliminary results., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

In this work, a simple one-step hydrothermal method was employed to prepare the Ce-doped Fe 2 O 3 ordered nanorod arrays (CFT). The Ce doping successfully narrowed the band gap of Fe 2 O 3 , which improved the visible light absorption performance. In addition, with the help of Ce doping, the recombination of electron/hole pairs was significantly inhibited. The external voltage will make the performance of the Ce-doped sample better. Therefore, the Ce-doped Fe 2 O 3 has reached superior photoelectrochemical (PEC) performance with a high photocurrent density of 1.47 mA/cm 2 at 1.6 V vs. RHE (Reversible Hydrogen Electrode), which is 7.3 times higher than that of pristine Fe 2 O 3 nanorod arrays (FT). The Hydrogen (H 2 ) production from PEC water splitting of Fe 2 O 3 was highly improved by Ce doping to achieve an evolution rate of 21 μmol/cm 2 /h.

Five-field 130° wide-angle imaging is the standard of care for retinopathy of prematurity (ROP) screening with an ideal hypothetical composite field-of-view (FOV) of 180°. We hypothesized that in many real-world scenarios the effective composite FOV is considerably less than ideal. This observational retrospective study analyzed the effective FOV of fundus photos of patients screened for ROP as part of the Stanford University Network for Diagnosis of Retinopathy of Prematurity (SUNDROP) initiative. Five fundus photos were selected from each eye per image session. Effective FOV was defined as the largest circular area centered on the optic disc that encompassed retina in each of the four cardinal views. Seventy-three subjects were analyzed, 35 without ROP and 34 with ROP. Mean effective FOV was 144.55 ± 6.62° ranging from 130.00 to 153.71°. Effective FOV was not correlated with the presence or absence of ROP, gestational age, birth weight, or postmenstrual age. Mean effective FOV was wider in males compared to females. Standard five-field 130° fundus photos yielded an average effective FOV of 144.54° in the SUNDROP cohort. This implies that an imaging FOV during ROP screening considerably less than the hypothetical ideal of 180° is sufficient for detecting treatment warranted ROP., (© 2022. The Author(s).)

Background: Postoperative delirium (POD), one of the most common complications following major surgery, imposes a heavy burden on patients and society. The objective of this exploratory study was to conduct a secondary analysis to identify whether there exist novel and reliable serum biomarkers for the prediction of POD., Methods: A total of 131 adult patients (≥ 65 years) undergoing lower extremity orthopedic surgery with were enrolled in this study. Cognitive function was assessed preoperatively with Mini-Mental State Examination (MMSE). Delirium was diagnosed according to the Confusion Assessment Method (CAM) criteria on preoperative day and postoperative days 1-3. The preoperative serum levels of a panel of 16 biochemical parameters were measured by ELISA., Results: Thirty-five patients developed POD, with an incidence of 26.7%. Patients in POD group were older (P = 0.001) and had lower preoperative MMSE scores (P = 0.001). Preoperative serum levels of prostaglandin E2 (PGE2, P < 0.001), S100β (P < 0.001), glial fibrillary acidic protein (P < 0.001) and neurofilament light (P = 0.002) in POD group were significantly increased. Logistic regression analysis showed that advanced age (OR = 1.144, 95%CI: 1.008 ~ 1.298, P = 0.037), higher serum neurofilament light (OR = 1.003, 95%CI: 1.000 ~ 1.005, P = 0.036) and PGE2 (OR = 1.031, 95%CI: 1.018 ~ 1.044, P < 0.001) levels were associated with the development of POD. In addition, serum level of PGE2 yielded an area under the ROC curve (AUC) of 0.897 to predict POD (P < 0.001), with a sensitivity of 80% and a specificity of 83.3%., Conclusions: Our study showed that higher preoperative serum PGE2 level might be a biomarker to predict the occurrence of POD in elderly patients undergoing elective orthopedic surgery., Trial Registration: NCT03792373 www., Clinicaltrials: gov ., (© 2022. The Author(s).)

Recent evidence has shown that presenilin enhancer 2 (Pen2; Psenen) plays an essential role in corticogenesis by regulating the switch of apical progenitors (APs) to basal progenitors (BPs). The hippocampus is a brain structure required for advanced functions, including spatial navigation, learning and memory. However, it remains unknown whether Pen2 is important for hippocampal morphogenesis. To address this question, we generated Pen2 conditional knockout (cKO) mice, in which Pen2 is inactivated in neural progenitor cells (NPCs) in the hippocampal primordium. We showed that Pen2 cKO mice exhibited hippocampal malformation and decreased population of NPCs in the neuroepithelium of the hippocampus. We found that deletion of Pen2 neither affected the proliferative capability of APs nor the switch of APs to BPs in the hippocampus, and that it caused enhanced transition of APs to neurons. We demonstrated that expression of the Notch1 intracellular domain (N1ICD) significantly increased the population of NPCs in the Pen2 cKO hippocampus. Collectively, this study uncovers a crucial role for Pen2 in the maintenance of NPCs during hippocampal development., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Background: Patients undergoing coronary artery bypass graft (CABG) are at high risk for developing postoperative delirium (POD). A simple prediction rule may benefit patients from early identification of POD followed by adequate preventive strategies. The purpose of the current study was to develop and validate a POD prediction rule for patients undergoing CABG (POD-CABG), by considering all possible perioperative factors., Methods: In this prospective cohort study, patients who underwent first elective isolated CABG were continuously enrolled from May 2014 to November 2015 in a tertiary hospital. Delirium was assessed using the Confusion Assessment Method for Intensive Care Unit. Patients' perioperative risk factors were collected through interviews and review of medical records. The area under receiver-operating characteristic curve (AUC) was used to assess the overall performance of the predictive rule., Results: A total of 242 and 148 patients were enrolled in the derivation and validation cohorts, respectively. Multiple logistic regression analysis identified seven variables that were independently associated with POD: age (≥65 years), gender (female), history of myocardial infarction and diabetes mellitus, postoperative atrial fibrillation, the use of intra-aortic balloon pump, and serum interleukin-6 ≥478 pg/ml at 18 hours after surgery. The AUC of the POD-CABG was 0.84 (95% CI, 0.79-0.90) in the derivation cohort, and was 0.86 (95% CI, 0.80-0.91) after bootstrap resampling. The AUC was 0.81 (95% CI, 0.73-0.88) after the POD-CABG was applied to the validation cohort., Conclusions: The POD-CABG with inclusion of interleukin-6 demonstrated good performance in predicting POD., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest, (Copyright © 2021. Published by Elsevier Ltd.)

Preeclampsia remains a high cause of incidence and death for mothers and fetuses in developing nations. Preeclampsia has numerous clinical and biochemical markers that have been tested, but they have failed to provide a conclusive diagnosis in the different phases of the disease's progression. Herein, our team intended to determine potential diagnostic biomarkers for preeclampsia and analyzed associations with immune cells. Two microarray data from mankind's preeclampsia and control specimens were acquired from GSE75010 and GSE44711 datasets. Differentially expressed genes (DEGs) were identified between77 normal samples and 80 preeclampsia samples. Candidate biomarkers were discovered using the least absolute shrinkage and selection operator (LASSO) and the support vector machine recursive feature elimination (SVM-RFE) analysis. The expressions and diagnostic values of genes in preeclampsia were further demonstrated in the GSE44711 dataset (8 control samples and 8 preeclampsia samples). The correlation of critical genes with the proportion of immune cells was analyzed. We identified 20 DEGs in preeclampsia. Diseases enriched by DEGs were mainly related to preeclampsia, gestational diabetes, ovarian disease, female reproductive system disease, and endocrine system disease. COL17A1, FLT1, FSTL3, and SERPINA3 were identified as diagnostic genes of preeclampsia and validated in the GSE44711 datasets. Immune cell infiltration assays suggested that COL17A1, FLT1, FSTL3, and SERPINA3 were related to several immune cells. Overall, we identified four critical diagnostic genes in preeclampsia. Furthermore, more well-designed research studies with larger cohorts were warranted to confirm the value of the four genes for the diagnosis and outcome of preeclampsia patients., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2022 Mu-yi Yang et al.)

Few studies have investigated factors associated with acute postsurgical pain (APSP) trajectories, and whether the APSP trajectory can predict chronic postsurgical pain (CPSP) remains unclear. We aimed to identify the predictors of APSP trajectories in patients undergoing gastrointestinal surgery. Moreover, we hypothesised that APSP trajectories were independently associated with CPSP. We conducted a prospective cohort study of 282 patients undergoing gastrointestinal surgery to describe APSP trajectories. Psychological questionnaires were administered 1 day before surgery. Meanwhile, demographic characteristics and perioperative data were collected. Average pain intensity during the first 7 days after surgery was assessed by a numeric rating scale (NRS). Persistent pain intensity was evaluated at 3 and 6 months postoperatively by phone call interview. CPSP was defined as pain at the incision site or surrounding areas of surgery with a pain NRS score ≥ 1 at rest. The intercept and slope were calculated by linear regression using the least squares method. The predictors for the APSP trajectory and CPSP were determined using multiple linear regression and multivariate logistic regression, respectively. Body mass index, morphine milligram equivalent (MME) consumption, preoperative chronic pain and anxiety were predictors of the APSP trajectory intercept. Moreover, MME consumption and preoperative anxiety could independently predict the APSP trajectory slope. The incidence of CPSP at 3 and 6 months was 30.58% and 16.42% respectively. APSP trajectory and age were predictors of CPSP 3 months postoperatively, while female sex and preoperative anxiety were predictive factors of CPSP 6 months postoperatively. Preoperative anxiety and postoperative analgesic consumption can predict APSP trajectory. In addition, pain trajectory was associated with CPSP. Clinicians need to stay alert for these predictors and pay close attention to pain resolution., (© 2022. The Author(s).)

Treatment outcomes in retinopathy of prematurity (ROP) are closely correlated with the location (i.e. zone) of disease, with more posterior zones having poorer outcomes. The most posterior zone, Zone I, is defined as a circle centered on the optic nerve with radius twice the distance from nerve to fovea, or subtending an angle of 30 degrees. Because the eye enlarges and undergoes refractive changes during the period of ROP screening, the absolute area of Zone I according to these definitions may likewise change. It is possible that these differences may confound accurate assessment of risk in patients with ROP. In this study, we estimated the area of Zone I in relation to different ocular parameters to determine how variability in the size and refractive power of the eye may affect zoning. Using Gaussian optics, a model was constructed to calculate the absolute area of Zone I as a function of corneal power, anterior chamber depth, lens power, lens thickness, and axial length (AL), with Zone I defined as a circle with radius set by a 30-degree visual angle. Our model predicted Zone I area to be most sensitive to changes in AL; for example, an increase of AL from 14.20 to 16.58 mm at postmenstrual age 32 weeks was calculated to expand the area of Zone I by up to 72%. These findings motivate several hypotheses which upon future testing may help optimize treatment decisions for ROP., (© 2022. The Author(s).)

Background : The pathophysiological mechanisms underlying postoperative cognitive dysfunction (POCD) remain unclear over the years. Neuroinflammation caused by surgery has been recognized as an important element in the development of POCD. Many studies also suggest that the vagus nerve plays an important role in transmitting peripheral injury signals to the central nervous system (CNS) and the resultant neuroinflammation. Previously, we have demonstrated that brain mast cells (BMCs), as the "first responders", play a vital role in neuroinflammation and POCD. However, how the vagus nerve communicates with BMCs in POCD has not yet been clarified. Methods : In the current study, we highlighted the role of the vagus nerve as a conduction highway in surgery-induced neuroinflammation for the first time. In our model, we tested if mice underwent unilateral cervical vagotomy (VGX) had less neuroinflammation compared to the shams after laparotomy (LP) at an early stage. To further investigate the roles of mast cells and glutamate in the process, we employed Kit W-sh mice and primary bone marrow-derived MCs to verify the glutamate-NR2B axis on MCs once again. Results : Our results demonstrated that there were higher levels of glutamate and BMCs activation as early as 4 h after LP. Meanwhile, vagotomy could partially block the increases and reduce neuroinflammation caused by peripheral inflammation during the acute phase. Excitingly, inhibition of NR2B receptor and knockout of mast cells can attenuateneuroinflammation induced by glutamate. Conclusion : Taken together, our findings indicate that the vagus is a high-speed pathway in the transmission of peripheral inflammation to the CNS. Activation of BMCs triggered a neuroinflammatory cascade. Inhibition of NR2B receptor on BMCs can reduce glutamate-induced BMCs activation, neuroinflammation, and memory impairment, suggesting a novel treatment strategy for POCD., 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 © 2022 Yang, Dong, Liu, Ji, Zhang, Dai, Sun, Liu, Zhou, Sha, Qian, Li, Yao and Li.)

Background: Regional anesthesia has been used to reduce acute postsurgical pain and to  prevent chronic pain. The best technique, however, remains controversial., Objectives: The aim of this study was to assess the short- and long-term postoperative analgesic efficacy of ultrasound-guided quadratus lumborum block (QLB) in open gastrointestinal surgery., Study Design: A randomized, double-blinded, controlled trial., Setting: Operating room; postoperative recovery room and ward., Methods: One hundred eighteen patients underwent elective gastrointestinal surgery randomly assigned into 2 groups (QLB group or control group). Before anesthetic induction, QLB was performed bilaterally under ultrasound guidance using 20 mL of 0.375% ropivacaine or saline solution at each abdominal wall. The primary outcome was cumulative oxycodone consumption within 24 h after surgery. The secondary outcomes were acute pain intensity, incidence of chronic pain, and incidence of postoperative nausea or vomiting (PONV), dizziness, and pruritus., Results: The cumulative oxycodone consumption was significantly lower in the QLB group during the first 6, 6-24, 24, and 48 h postoperatively when compared to the control group. At rest or during coughing, the numeric rating scale scores were significantly lower at 1, 3, 6, and 12 h postoperatively in the QLB group compared to the control group. There were no significant differences between the 2 groups regarding the incidence of chronic postoperative pain at 3 or 6 months after surgery. Significant differences were found in the incidence of PONV between the two groups, but other complications, such as dizziness and pruritus, did not differ significantly., Limitations: We did not confirm the QLB effectiveness with sensory level testing after local anesthetic injection. Cumulative oxycodone consumption could have been affected by the patients' use of oxycodone for nonsurgical pain., Conclusions: Ultrasound-guided QLB provided superior short-term analgesia and reduced oxycodone consumption and the incidence of PONV after gastrointestinal surgery. However, the incidence of chronic pain was not significantly affected by this anesthetic technique.

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.

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).

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.

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.)

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.)

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 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.

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 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.