Autophagy in dry AMD: A promising therapeutic strategy for retinal pigment epithelial cell damage.

Dry age-related macular degeneration (AMD) is a prevalent clinical condition that leads to permanent damage to central vision and poses a significant threat to patients' visual health. Although the pathogenesis of dry AMD remains unclear, there is consensus on the role of retinal pigment epithelium (RPE) damage. Oxidative stress and chronic inflammation are major contributors to RPE cell damage, and the NOD-like receptor thermoprotein structural domain-associated protein 3 (NLRP3) inflammasome mediates the inflammatory response leading to apoptosis in RPE cells. Furthermore, lipofuscin accumulation results in oxidative stress, NLRP3 activation, and the development of vitelliform lesions, a hallmark of dry AMD, all of which may contribute to RPE dysfunction. The process of autophagy, involving the encapsulation, recognition, and transport of accumulated proteins and dead cells to the lysosome for degradation, is recognized as a significant pathway for cellular self-protection and homeostasis maintenance. Recently, RPE cell autophagy has been discovered to be closely linked to the development of macular degeneration, positioning autophagy as a cutting-edge research area in the realm of dry AMD. In this review, we present an overview of how lipofuscin, oxidative stress, and the NLRP3 inflammasome damage the RPE through their respective causal mechanisms. We summarized the connection between autophagy, oxidative stress, and NLRP3 inflammatory cytokines. Our findings suggest that targeting autophagy improves RPE function and sustains visual health, offering new perspectives for understanding the pathogenesis and clinical management of dry AMD.

Enhanced exclusive enteral nutrition delivery during the first 7 days is associated with decreased 28-day mortality in critically ill patients with normal lactate level: a post hoc analysis of a multicenter randomized trial.

BACKGROUND AND AIMS: Exclusive enteral nutrition (EN) is often observed during the first week of ICU admission because of the extra costs and safety considerations for early parenteral nutrition. This study aimed to assess the association between nutrition intake and 28-day mortality in critically ill patients receiving exclusive EN. METHODS: This is a post hoc analysis of a cluster-randomized clinical trial that assesses the effect of implementing a feeding protocol on mortality in critically ill patients. Patients who stayed in the ICUs for at least 7 days and received exclusive EN were included in this analysis. Multivariable Cox hazard regression models and restricted cubic spline models were used to assess the relationship between the different doses of EN delivery and 28-day mortality. Subgroups with varying lactate levels at enrollment were additionally analyzed to address the potential confounding effect brought in by the presence of shock-related hypoperfusion. RESULTS: Overall, 1322 patients were included in the analysis. The median (interquartile range) daily energy and protein delivery during the first week of enrollment were 14.6 (10.3-19.6) kcal/kg and 0.6 (0.4-0.8) g/kg, respectively. An increase of 5 kcal/kg energy delivery was associated with a significant reduction (approximately 14%) in 28-day mortality (adjusted hazard ratio [HR] = 0.865, 95% confidence interval [CI]: 0.768-0.974, P = 0.016). For protein intake, a 0.2 g/kg increase was associated with a similar mortality reduction with an adjusted HR of 0.868 (95% CI 0.770-0.979). However, the benefits associated with enhanced nutrition delivery could be observed in patients with lactate concentration ≤ 2 mmol/L (adjusted HR = 0.804 (95% CI 0.674-0.960) for energy delivery and adjusted HR = 0.804 (95% CI 0.672-0.962) for protein delivery, respectively), but not in those > 2 mmol/L. CONCLUSIONS: During the first week of critical illness, enhanced nutrition delivery is associated with reduced mortality in critically ill patients receiving exclusive EN, only for those with lactate concentration ≤ 2 mmol/L. TRIAL REGISTRATION: ISRCTN12233792, registered on November 24, 2017.

Novel 2-Amino-1,4-Naphthoquinone Derivatives Induce A549 Cell Death through Autophagy.

A series of 1,4-naphthoquinone derivatives containing were synthesized as anti-cancer agents and the crystal structure of compound 5a was confirmed by X-ray diffraction. In addition, the inhibitory activities against four cancer cell lines (HepG2, A549, K562, and PC-3) were tested, respectively, and compound 5i showed significant cytotoxicity on the A549 cell line with the IC50 of 6.15 µM. Surprisingly, in the following preliminary biological experiments, we found that compound 5i induced autophagy by promoting the recycling of EGFR and signal transduction in the A549 cell, resulting in the activation of the EGFR signal pathway. The potential binding pattern between compound 5i and EGFR tyrosine kinase (PDB ID: 1M17) was also identified by molecular docking. Our research paves the way for further studies and the development of novel and powerful anti-cancer drugs.

Evidence for Genetic Causal Relationships Between Multiple Immune-Mediated Inflammatory Diseases and Age-Related Macular Degeneration: A Univariable and Multivariable Mendelian Randomization Study.

INTRODUCTION: With the global aging population on the rise, age-related macular degeneration (AMD) poses a growing healthcare burden. Prior research hints at immune-mediated inflammatory diseases (IMIDs) potentially elevating AMD risk via diverse mechanisms. However, causality remains disputed as a result of confounding factors. Hence, our Mendelian randomization (MR) study aims to untangle this link, mitigating confounding effects to explore the IMID-AMD causal relationship. This study aims to investigate the causal relationship between IMIDs and AMD, providing new strategies for the prevention and treatment of AMD in clinical practice. METHODS: This study was registered with PROSPERO, CRD42023469815. We obtained data on IMIDs and AMD from Genome-Wide Association Studies (GWAS) summary statistics and the FinnGen consortium. Rigorous selection steps were applied to screen for eligible instrumental single nucleotide polymorphisms (SNPs). We conducted univariate Mendelian randomization, inverse variance-weighted (IVW), weighted median, Mendelian randomization-Egger (MR-Egger), and multivariate Mendelian randomization (MVMR) analyses. Various sensitivity analysis methods were employed to assess pleiotropy and heterogeneity. The aim was to explore the causal relationships between IMIDs and AMD. RESULTS: The MR analysis revealed that Crohn's disease (CD) (IVW: odd ratios (OR) 1.05, 95% CI (confidence interval) 1.01-1.10, p = 0.007), rheumatoid arthritis (RA) (IVW: OR 1.09, 95% CI 1.04-1.15, p = 0.0001), and type 1 diabetes (T1D) (IVW: OR 1.05, 95% CI 1.02-1.09, p = 0.001) were correlated with an elevated risk of AMD, while multiple sclerosis (MS) (IVW: OR 2.78E-18, 95% CI 2.23E-31 to 3.48E-05, p = 0.008) appeared to be protective against AMD. These findings were supported by an array of MR analysis methodologies and the MVMR approach. CONCLUSION: Our study results, based on MR, provide genetic evidence indicating a causal relationship between specific IMIDs and AMD. CD, RA, and T1D are factors increasing the risk of AMD, while MS may have a protective effect.

Hypoxia-Responsive Polymeric Nanoprodrugs for Combo Photodynamic and Chemotherapy.

Hypoxia in most solid tumors is a major challenge for photodynamic therapy (PDT), and the combination of hypoxia-activated chemotherapy and PDT is a promising approach for enhanced anticancer activity. Herein, we designed hypoxia-responsive polymeric nanoprodrug PNPs to co-deliver photosensitizer 5,10,5,20-tetrakis(4-aminophenyl)-porphine (TAPP) and chlorambucil (CB) to improve the overall therapeutic efficacy. Upon laser irradiation, the central TAPP converted oxygen to produce single oxygen (1O2) for PDT and induced PDT-reduced hypoxia environment, which accelerated the release of activated CB for synergetic cancer cell killing. Consequently, these hypoxia-responsive polymeric nanoprodrugs with a considerable drug-loading content and synergistic therapeutic effect of PDT-CT had great potential for tumor therapy.

Pseudomyopia treated with auricular point sticking combined with periocular needle-embedding therapy and prevention of true myopia: a multicenter randomized controlled trial. / è€³ç©´è´´åŽ‹è”åˆçœ¼å‘¨æ¿é’ˆæŠ€æœ¯é¢„é˜²å‡æ€§è¿‘è§†å‘çœŸæ€§è¿‘è§†è¿›å±•ï¼šå¤šä¸­å¿ƒéšæœºå¯¹ç §è¯•éªŒ.

OBJECTIVES: To observe the clinical effect and safety of auricular point sticking combined with periocular needle-embedding therapy for pseudomyopia and prevention of true myopia. METHODS: A total of 269 children with pseudomyopia were randomized into an observation group (134 cases, 2 cases dropped out) and a control group (135 cases, 5 cases dropped out). In the control group, the healthy education was provided. In the observation group, besides the intervention as the control group, the auricular point sticking was delivered at gan (CO12), pi (CO13), xin (CO15) and yan (LO5) on one ear in each treatment, combined with periocular needle-embedding technique at bilateral Cuanzhu (BL 2), Yuyao (EX-HN 4) and Sibai (ST 2). There were 2 weeks of interval after 4 weeks of treatment. One course of treatment was composed of 6 weeks and 2 courses were required. Separately, before treatment, after 6 and 12 weeks of treatment, and after 12 weeks (the 1st follow-up visit) and 24 weeks (the 2nd follow-up visit) of treatment completion, the spherical equivalent (SE), SE progression, axial length (AL) progression, accommodative amplitude (AMP), the score of the TCM symptom and the general symptom were observed in the two groups. The safety and compliance were evaluated in the two groups. RESULTS: After 6 and 12 weeks of treatment, and in the 1st and 2nd follow-up visits, SE increased when compared with that before treatment in the two groups (P<0.05), and AMP was larger than that before treatment in the observation group (P<0.05). After 12 weeks of treatment, and in the 1st and 2nd follow-up visits, the progression of SE was slower in the observation group compared with that in the control group (P<0.01, P<0.001). After 6 and 12 weeks of treatment, and in the 1st and 2nd follow-up visits, the progression of AL in the observation group was lower than that of the control group (P<0.05, P<0.01, P<0.001); and in the 1st and 2nd follow-up visits, AMP of the observation group was larger when compared with that in the control group (P<0.05, P<0.001). After 6 and 12 weeks of treatment, and in the 1st and 2nd follow-up visits, the total scores of TCM symptom and general symptom were reduced in comparison with those before treatment in the observation group (P<0.05); after 6 and 12 weeks of treatment, the total scores of TCM symptom and general symptom were lower than those before treatment in the control group (P<0.05). In the 1st and 2nd follow-up visits, the difference of the total score of TCM symptom and general symptom in the observation group was larger than that of the control group (P<0.05). In the observation group, compared with the control group, the scores for pale/dark complexion in the 1st and 2nd follow-up visits and that for lassitude in the 2nd follow-up visit were lower (P<0.05), the score for poor concentration after 12 weeks of treatment and that for poor sleep and memory in the 2nd follow-up visit were lower (P<0.05). There were no adverse reactions in the two groups. The compliance was 98.5% in the observation group and was 96.3% in the control group, without statistical difference (P>0.05). CONCLUSIONS: On the basis of health education, auricular point sticking combined with periocular needle-embedding therapy can effectively prevent from true myopia, control the increase of SE, delay the growth of AL and improve AMP in children with pseudomyopia. This compound therapeutic regimen can relieve the general symptom and comprehensively prevent from myopia through multiple approaches, with high safety and satisfactory compliance.

[The value of changes in end-tidal carbon dioxide pressure induced by passive leg raising test in predicting fluid responsiveness in mechanically ventilated patients with septic shock].

OBJECTIVE: To test whether the changes of partial end-tidal carbon dioxide pressure (PETCO2) during passive leg raising (PLR) predict fluid responsiveness in mechanically ventilated patients with septic shock. METHODS: Forty-two mechanically ventilated patients with septic shock admitted from January 2012 to November 2012 were prospectively recruited.Hemodynamic parameters monitored by a pulse indicator continuous cardiac output (PiCCO) device and PETCO2 monitored by an expiratory-CO2 device were studied at baseline, after PLR, and after volume expansion. Fluid responsiveness was defined as an increase in cardiac index (CI) of 15% or greater after volume expansion. The correlation between PLR-induced CI change (ΔCIPLR) and PETCO2 (ΔPETCO2-PLR) was analyzed. The value of ΔPETCO2-PLR to predict fluid responsiveness was evaluated by receiver operating characteristic (ROC) curves. RESULTS: A total of 42 patients were enrolled in this study, of whom, 24 had a CI increase of ≥ 15% after volume expansion (responders). After PLR, CI and PETCO2 were both significantly increased in the response group compared with baseline [(21.4 ± 12.9)% of CI and (9.6 ± 4.7)% of PETCO2, P < 0.05], while no significant changes were observed (P > 0.05) in the non-response group. Both ΔCIPLR and ΔPETCO2-PLR were significantly higher in responder group than in the non-responder group (both P < 0.05). ΔCI and ΔPETCO2 after PLR were strongly correlated (r = 0.64, P < 0.05). In responders after PLR, the area under ROC curve of ΔPETCO2-PLR was 0.900 ± 0.056 (95%CI 0.775-1.000, P < 0.05). An increase of ≥ 5% in ΔPETCO2-PLR predicted fluid responsiveness with a sensitivity of 88.0% and specificity of 88.2%. CONCLUSIONS: The change of PETCO2 induced by passive leg raising is a non-invasive and easy way to predict fluid responsiveness in mechanically ventilated patients with septic shock.

Is compromised intestinal barrier integrity responsible for the poor prognosis in critically ill patients with pre-existing hyperglycemia?

BACKGROUND: Compromised intestinal barrier integrity can be independently driven by hyperglycemia, and both hyperglycemia and intestinal barrier injury are associated with poor prognosis in critical illness. This study investigated the intestinal barrier biomarkers in critically ill patients, to explore the role of compromised intestinal barrier integrity on the prognosis of critically ill patients with pre-existing hyperglycemia. METHODS: This was a retrospective observational study. The relationships between intestinal barrier biomarkers and glycated hemoglobin A1c (HbA1c), fasting blood glucose (FBG), indicators of clinical characteristics, disease severity, and prognosis in critically ill patients were investigated. Then the metrics mentioned above were compared between survivors and non-survivors, the risk factors of 90-day mortality were investigated by logistic regression analysis. Further, patients were divided into HbA1c < 6.5% Group and HbA1c ≥ 6.5% Group, metrics mentioned above were compared between these two groups. RESULTS: A total of 109 patients with critical illness were included in the study. D-lactate and lipopolysaccharide (LPS) were associated with sequential organ failure assessment (SOFA) score and 90-day mortality. LPS was an independent risk factor of 90-day mortality. DAO, NEU (neutrophil) proportion, temperature, lactate were lower in HbA1c ≥ 6.5% Group while D-lactate, LPS, indicators of disease severity and prognosis showed no statistical difference between HbA1c < 6.5% Group and HbA1c ≥ 6.5% Group. CONCLUSIONS: Intestinal barrier integrity is associated with the disease severity and prognosis in critical illness. Compromised intestinal barrier integrity might be responsible for the poor prognosis in critically ill patients with pre-existing hyperglycemia.

[Evaluation of extravascular lung water in patients with acute respiratory distress syndrome by syndecan-1 combined with lung ultrasonography].

OBJECTIVE: To investigate the value of plasma syndecan-1 (SDC-1) combined with lung ultrasonography in evaluating the degree of extravascular lung water in patients with acute respiratory distress syndrome (ARDS). METHODS: From July 2018 to July 2019, 50 patients with ARDS admitted to the department of intensive care unit of Wuxi People's Hospital Affiliated to Nanjing Medical University were enrolled. After admission, pulse indicator continuous cardiac output (PiCCO) catheter was established for all patients. PiCCO indexes, including extravascular lung water index (EVLWI) and pulmonary vascular permeability index (PVPI) were monitored by one doctor. Another doctor performed lung ultrasound examination, and calculated the sum of the number of B-lines under 10 ultrasound sections of upper blue point, lower blue point, diaphragm point, Plaps point and rear blue point of both lungs. Then the level of plasma SDC-1 was detected by enzyme linked immunosorbent assay (ELISA). Pearson correlation method was used to analyze the correlation between the number of ultrasonic B-lines, plasma SDC-1 level and EVLWI and PVPI. Taking 10 mL/kg EVLWI as the boundary value, the degree of pulmonary edema in patients with ARDS was divided into mild pulmonary edema and severe pulmonary edema. The receiver operator characteristic curve (ROC curve) was drawn, and the number of B-lines, SDC-1 and the predictive value of the combination of the above two indicators on the severity of pulmonary edema in patients with ARDS were analyzed. RESULTS: The cardiac index (CI) and central venous pressure (CVP) of 50 patients with ARDS were (46.84±6.00) mL×s-1×m-2 and (8.12±1.80) mmHg (1 mmHg = 0.133 kPa), cardiogenic pulmonary edema was excluded. In 50 patients with ARDS, EVLWI was (10.82±2.92) mL/kg, PVPI was 3.02±0.69, the number of ultrasound B-lines was 40.90±13.05, and plasma SDC-1 was (568.25±118.14) µg/L. Pearson correlation analysis showed that the number of ultrasound B-lines in patients with ARDS was significantly positively correlated with EVLWI and PVPI (r1 = 0.802, r2 = 0.799, both P < 0.01). Plasma SDC-1 was also positively correlated with EVLWI and PVPI (r1 = 0.732, r2 = 0.576, both P < 0.01). ROC curve analysis showed that the number of B-lines and SDC-1 had good predictive value for the severity of pulmonary edema in patients with ARDS. The area under ROC curve (AUC) and 95% confidence interval (95%CI) were 0.891 (0.803-0.979) and 0.875 (0.772-0.978), respectively. When the cut-off of B-lines was 40.50, the sensitivity and specificity were 82.1% and 86.4%, respectively. When the cut-off of SDC-1 was 559.37 µg/L, the sensitivity and specificity were 85.7% and 81.8%, respectively. Combining the number of B-lines with SDC-1 could further improve the predictive value of pulmonary water in patients with ARDS. The AUC (95%CI) was 0.958 (0.890-1.000), and the sensitivity and specificity were 92.9% and 91.8%, respectively. CONCLUSIONS: The level of plasma SDC-1 and the number of pulmonary ultrasonic B-lines have a good correlation with the degree of extravascular lung water in patients with ARDS. The combined application of the two noninvasive indexes can be used to evaluate the degree of extravascular lung water in patients with ARDS.

Mingjing granule, a traditional Chinese medicine in the treatment of neovascular age-related macular degeneration: study protocol for a randomized controlled trial.

BACKGROUND: Neovascular age-related macular degeneration (nAMD) is the most common cause of irreversible vision loss and blindness among the older people aged 50 and over. Although anti-vascular endothelial growth factor (anti-VEGF) therapies have resulted in improving patient outcomes, there are limitations associated with these treatments. In China, traditional Chinese medicine (TCM) has been used to treat eye diseases for more than 2000 years. Previous studies have shown that TCM may be beneficial for nAMD patients. However, explicit evidence has not been obtained. The purpose of the present trial is to examine the efficacy and safety of the Mingjing granule, a compound Chinese herbal medicine, for nAMD patients. METHODS/DESIGN: This is a double-blind, placebo-controlled, randomized trial of Mingjing granule as an add-on to intravitreous ranibizumab for nAMD. One hundred eighty nAMD patients from six hospitals in China will be enrolled according to the inclusion and exclusion criteria and randomly allocated into two groups, 90 in each. All participants will receive a 24-week treatment and then be followed up for another 24 weeks. The primary outcome is the mean change of best-corrected visual acuity at week 24 and 48 as compared to the baseline. The secondary outcomes include mean change in central retinal thickness, area of retinal hemorrhage and exudation, and TCM syndrome score, mean number of intravitreal ranibizumab injection, and total cost of the treatment. Indexes of safety include blood regular test, urine regular test, liver function test, renal function test, and electrocardiogram from baseline to weeks 24 and 48. Qualitative control and some standard operating processes will be formed throughout the trial. Any ocular or systemic adverse events will be treated suitably, and related data will be recorded accurately and completely in the case report form. DISCUSSION: Based on previous empirical and animal laboratory studies, this study will address the question of whether Mingjing granule could contribute to improving efficacy, safety, and efficiency with need for fewer intravitreal injections of anti-VEGF, improving compliance and visual outcomes in the management of persons with nAMD. TRIAL REGISTRATION: Chinese Clinical Trial Registry ( http://www.chictr.org.cn ), ChiCTR2000035990 . Registered on 21 August 2020.

[Prognostic value of oxygen challenge test for patients with cardiogenic shock receiving extracorporeal membrane oxygenation].

OBJECTIVE: To investigate the prognostic value of oxygen challenge test (OCT) for patients with cardiogenic shock receiving extracorporeal membrane oxygenation (ECMO). METHODS: A retrospective analysis was conducted. Seventy-eight patients diagnosed with cardiogenic shock receiving veno-arterial (V-A) ECMO admitted to Department of intensive care unit (ICU) of Wuxi People's Hospital Affiliated to Nanjing Medical University from June 2012 to May 2017 were enrolled. Ten-minute OCT was implemented by transcutaneous oximetry at 6 hours after ECMO initiation. The basic data of patients (gender, age, primary disease); the acute physiology and chronic health evaluation II (APACHE II) score, sequential organ failure assessment (SOFA) score, left ventricular ejection fraction (LVEF), mean arterial pressure (MAP) at the start of ECMO treatment; arterial blood gas analysis index, dose of vasoactive agents, transcutaneous oxygen pressure (PtO2), 10-minute OCT value (OCT10), oxygen challenge index (OCI) at 6 hours after ECMO initiation; and the ECMO support time, duration of mechanical ventilation and its parameters, and application of intra-aortic balloon pump (IABP) within 60 days were recorded. Patients were divided into the survival group and the death group according to their 60-day mortality status, and the differences between the two groups were compared. Receiver operating characteristic curve (ROC) analysis was used to analyze the prognostic value of OCT10 and OCI. According to the best boundary value of OCT10 and OCI, Kaplan-Meier survival curve was drawn and the 60-day cumulative survival rate was compared. The risk factors affecting prognosis were analyzed by multivariate Logistic regression. RESULTS: Sixty-seven patients were finally enrolled in the study, with 31 in the survival group and 36 in the death group. Compared with the survival group, APACHE II score, SOFA score, use of IABP in death group were higher, PtO2, OCT10 and OCI were lower, and duration of ECMO and ventilation were longer, but there was no significant difference in gender, age, primary disease, LVEF, MAP, ventilator settings, dose of vasoactive agents, or results of arterial blood gas between the two groups. OCT10, OCI, APACHE II score and SOFA score were predictive values for 60-day deaths, and the area under ROC curve (AUC) of OCT10 was 0.866±0.042 [95% confidence interval (95%CI) = 0.760-0.937], the AUC of OCI was 0.829±0.051 (95%CI = 0.717-0.910), the AUC of APACHE II score was 0.860±0.043 (95%CI = 0.754-0.933), and the AUC of SOFA score was 0.821±0.049 (95%CI = 0.708-0.904) (all P < 0.01). The cut-off point for OCT10 was ≥70.0 mmHg (1 mmHg = 0.133 kPa) with the sensitivity of 91.67% and the specificity of 67.74%. The cut-off point for OCI was ≥0.68 with the sensitivity of 88.68% and the specificity of 71.58%. According to the cut-off point for OCT10 or OCI, the 60-day cumulative survival rate of patients with high OCT10 was significantly higher than that of low OCT10 [58.06% (18/31) vs. 36.11% (13/36), χ2 = 5.425, P = 0.020]; the survival rate in high OCI group was significantly higher than that in low OCI group [55.17% (16/29) vs. 39.47% (15/38), χ2 = 5.119, P = 0.024]. It was shown by multivariate Logistic regression that OCT10 [odds ratio (OR) = 0.883, 95%CI = 0.791-0.965, P = 0.006] and OCI (OR = 0.011, 95%CI = 0.001-0.087, P = 0.005) were independent risk factors for 60-day mortality. CONCLUSIONS: OCT could predict the prognosis of patients with cardiogenic shock receiving ECMO.