Assessing Uveitis Risk following Pediatric Down Syndrome Diagnosis: A TriNetX Database Study.

Background and Objectives: The risks of uveitis development among pediatric patients with Down syndrome (DS) remain unclear. Therefore, we aimed to determine the risk of uveitis following a diagnosis of DS. Materials and Methods: This multi-institutional retrospective cohort study utilized the TriNetX database to identify individuals aged 18 years and younger with and without a diagnosis of DS between 1 January 2000 and 31 December 2023. The non-DS cohort consisted of randomly selected control patients matched by selected variables. This included gender, age, ethnicity, and certain comorbidities. The main outcome is the incidence of new-onset uveitis. Statistical analysis of the uveitis risk was reported using hazard ratios (HRs) and 95% confidence intervals (CIs). Separate analyses of the uveitis risk among DS patients based on age groups and gender were also performed. Results: A total of 53,993 individuals with DS (46.83% female, 58.26% white, mean age at index 5.21 ± 5.76 years) and 53,993 non-DS individuals (45.56% female, 58.28% white, mean age at index 5.21 ± 5.76 years) were recruited from the TriNetX database. Our analysis also showed no overall increased risk of uveitis among DS patients (HR: 1.33 [CI: 0.89-1.99]) compared to the non-DS cohort across the 23-year study period. Subgroup analyses based on different age groups showed that those aged 0-1 year (HR: 1.36 [CI: 0.68-2.72]), 0-5 years (HR: 1.34 [CI: 0.75-2.39]), and 6-18 years (HR: 1.15 [CI: 0.67-1.96]) were found to have no association with uveitis risk compared to their respective non-DS comparators. There was also no increased risk of uveitis among females (HR: 1.49 [CI: 0.87-2.56]) or males (HR: 0.82 [CI: 0.48-1.41]) with DS compared to their respective non-DS comparators. Conclusions: Our study found no overall increased risk of uveitis following a diagnosis of DS compared to a matched control population.

Summary of biological research on hepatoblastoma: a scoping review.

Background: Hepatoblastoma is the most prevalent primary hepatic malignancy in children, comprising 80% of pediatric hepatic malignancies and 1% of all pediatric malignancies. However, traditional treatments have proven inadequate in effectively curing hepatoblastoma, leading to a poor prognosis. Methods: A literature search was conducted on multiple electronic databases (PubMed and Google Scholar). A total of 86 articles were eligible for inclusion in this review. Result: This review aims to consolidate recent developments in hepatoblastoma research, focusing on the latest advances in cancer-associated genomics, epigenetic studies, transcriptional programs and molecular subtypes. We also discuss the current treatment approaches and forthcoming strategies to address cancer-associated biological challenges. Conclusion: To provide a comprehensive summary of the molecular mechanisms associated with hepatoblastoma occurrence, this review highlights three key aspects: genomics, epigenetics, and transcriptomics. Our review aims to facilitate the exploration of novel molecular mechanisms and the development of innovative clinical treatment strategies for hepatoblastoma.

Bidirectional two-sample mendelian randomization analysis identifies causal associations of MRI-based cortical thickness and surface area relation to NAFLD.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) patients have exhibited extra-hepatic neurological changes, but the causes and mechanisms remain unclear. This study investigates the causal effect of NAFLD on cortical structure through bidirectional two-sample Mendelian randomization analysis. METHODS: Genetic data from 778,614 European individuals across four NAFLD studies were used to determine genetically predicted NAFLD. Abdominal MRI scans from 32,860 UK Biobank participants were utilized to evaluate genetically predicted liver fat and volume. Data from the ENIGMA Consortium, comprising 51,665 patients, were used to evaluate the associations between genetic susceptibility, NAFLD risk, liver fat, liver volume, and alterations in cortical thickness (TH) and surface area (SA). Inverse-variance weighted (IVW) estimation, Cochran Q, and MR-Egger were employed to assess heterogeneity and pleiotropy. RESULTS: Overall, NAFLD did not significantly affect cortical SA or TH. However, potential associations were noted under global weighting, relating heightened NAFLD risk to reduced parahippocampal SA and decreased cortical TH in the caudal middle frontal, cuneus, lingual, and parstriangularis regions. Liver fat and volume also influenced the cortical structure of certain regions, although no Bonferroni-adjusted p-values reached significance. Two-step MR analysis revealed that liver fat, AST, and LDL levels mediated the impact of NAFLD on cortical structure. Multivariable MR analysis suggested that the impact of NAFLD on the cortical TH of lingual and parstriangularis was independent of BMI, obesity, hyperlipidemia, and diabetes. CONCLUSION: This study provides evidence that NAFLD causally influences the cortical structure of the brain, suggesting the existence of a liver-brain axis in the development of NAFLD.

Prevalence of uveitis in syphilis patients in Taiwan.

Few population-based studies have looked at the risk of uveitis among syphilis patients. Our study addresses the knowledge gap by reporting on uveitis risk in syphilis patients through a retrospective cohort study. The Taiwan National Health Insurance database was used for this study, covering the period from January 1st, 2009, to December 31st, 2020. We created a 1:4 propensity score matched cohort between the syphilis patients and controls, which accounted for gender, age, and comorbidities. The primary endpoint was the incidence of newly recorded uveitis. The assessment of uveitis risk in syphilis patients included the use of the Kaplan-Meier method and multivariate Cox proportional hazard model. A total of 31,597 syphilis patients and 126,379 matched comparisons were recruited. The uveitis incidence rate from our syphilis patients was 1.25 per 1000 person-years. The uveitis incidence rate from our non-syphilis group was 0.8 per 1000 person-years. After matching, the syphilis group was found to have a higher risk of developing uveitis (adjusted hazard ratio (aHR) [95% CI]: 1.57 [1.36-1.81], P < .001). Among males and individuals aged 20-34 years, subgroup analysis showed an increased risk of uveitis in the presence of syphilis infection. The Kaplan-Meier survival curve showed a significant difference in uveitis incidence between syphilis and non-syphilis groups (log-rank test P < .001). In summary, our study revealed that Taiwanese syphilis patients were at a higher risk of developing uveitis. These results highlight the need for regular ocular monitoring and screening in individuals with syphilis.

The risk assessment of uveitis after COVID-19 diagnosis: A multicenter population-based study.

Reports on uveitis after COVID-19 have been limited. Our objective was to examine the risk of uveitis among COVID-19 patients. This was a retrospective cohort study based on the TriNetX platform. The exposure group was patients with positive laboratory test result for SARS-CoV-2 and the comparison group was those tested negative for COVID-19 throughout the study period. The endpoint is the new diagnoses of uveitis. This study composed of 2 105 424 patients diagnosed with COVID-19 (55.4% female; 62.5% white; mean age at index 40.7 years) and 2 105 424 patients (55.4% female; 62.4% white; mean age at index 40.7 years) who never had COVID-19. There was significantly increased risk of new diagnosis of uveitis since the first month after diagnosis of COVID-19 compared with matched controls (HR: 1.18, 95% CI: 1.03-1.34) up to 24 months (HR: 1.16, 95% CI: 1.09-1.22). Our findings strengthen those previously raised by case series with a larger and multicenter study. We found that uveitis was significantly associated with COVID-19 infection. Our findings reiterate the need for careful investigation as well as increased awareness from ophthalmologists in considering the possibility of COVID-19 in vulnerable patients with new presentation of uveitis.

Severe congenital neutropenia and liver abscess: Surgical treatment breaks the vicious cycle.

Here, we present a case with genetically confirmed SCN. The main symptom of the child was recurring fever. The combination of antibiotics combined with G-CSF injection was proved to be insufficient, and the patient developed "solid" liver abscess. After undergoing surgical anatomical hepatic lobectomy, the child's infection symptoms showed improvement. The postoperative culture of the purulent material from the liver infection lesion revealed an infection with Staphylococcus aureus. Our case raises the possibility of pathogen sources and routes of infection, clinical characteristics, and effective treatment for SCN patients with concomitant liver abscess.

Association Between Dietary and Serum Cholesterol and Cognitive Function Among the U.S. Elderly from NHANES 2011-2014.

BACKGROUND: The association between dietary or serum cholesterol and cognitive performance in older adults has not been well-established. OBJECTIVE: This study aimed to investigate the potential association between dietary or serum cholesterol and cognitive performance in the elderly population. METHODS: A cross-sectional analysis was conducted using data from the National Health and Nutrition Examination Survey (NHANES) 2011-2012 and 2013-2014. Diet and supplement cholesterol was estimated based on two non-consecutive 24-hour dietary recalls. Cognitive function was assessed using various statistical tests. Poor cognitive performance was defined as scores below the lowest quartile within age groups. Regression models were adjusted for demographic factors, and subgroup analyses were performed for non-Hispanic White (NHW) and non-Hispanic Black (NHB) individuals. RESULTS: Among 759 participants aged 60 years and above, dietary cholesterol was only associated with dietary saturated fatty acids and serum high-density lipoprotein cholesterol. There was no evidence of an association between dietary cholesterol and cognitive function, except for NHB individuals, where dietary cholesterol showed a positive correlation with cognitive function. In the overall sample and NHW participants, there were consistent positive associations between serum total cholesterol and cognitive performance across statistical tests, while such associations were rare among NHB individuals. Although not statistically significant, NHB individuals had higher dietary/supplementary/total cholesterol intake compared with NHW individuals. CONCLUSION: Within the normal range, increasing serum cholesterol may be a potential factor to prevent or relieve cognitive dysfunction. However, ethnic differences should be taken into account when considering the association between cholesterol and cognitive performance.

Tinnitus as a Potential Risk Factor for Uveitis: A 14-Year Nationwide Population-Based Cohort Study in Taiwan.

BACKGROUND: Tinnitus and uveitis have shared commonality in pathophysiology in terms of autoimmunity. However, no studies that have linked any association between the conditions of tinnitus and uveitis. METHODS: This is a retrospective study conducted from the Taiwan National Health Insurance database in order to investigate whether tinnitus patients are at increased risk of uveitis. Patients newly diagnosed with tinnitus between 2001 and 2014 were recruited and followed up until 2018. The endpoint of interest was a diagnosis of uveitis. RESULTS: A total of 31,034 tinnitus patients and 124,136 matched comparisons were analyzed. Tinnitus patients were found to have a significantly higher cumulative incidence for uveitis than those without the diagnosis of tinnitus with incidence rate of 1.68 (95% CI 1.55-1.82) per 10 000 person-months for tinnitus group and 1.48 (95% CI 1.42-1.54) per 10 000 person-months for non-tinnitus group. CONCLUSION: Tinnitus patients were found to have increased risk of developing uveitis.

Dihydroartemisinin inhibits the activation and proliferation of hepatic stellate cells by regulating miR­29b­3p.

Liver fibrosis is an early pathological feature of hepatic diseases. Hepatic stellate cell (HSC) activation and disordered proliferation are associated with liver fibrosis. The present study identified significant differences in the expression levels of microRNA (miRNA/miR)­29b­3p in clinical samples and multiple miRNA databases. Subsequently, the specific antifibrotic mechanism of miR­29b­3p was further elucidated. Reverse transcription­quantitative PCR, western blot, ELISA and immunofluorescence were used to detect the expression levels of target genes and proteins. Oil red O, Nile red and trypan blue staining were used to evaluate HSC activation and cell viability. A luciferase assay was used to detect the relationship between miR­29b­3p and VEGFA. Adhesion, wound healing, apoptosis double staining and JC­1 assays were used to detect the effects of VEGFR1 and VEGFR2 knockdown on HSCs. Immunoprecipitation and fluorescence colocalization were used to identify interactions between the proteins. Furthermore, a rat fibrosis model was constructed to investigate the effects of dihydroartemisinin (DHA) and miR­29b­3p in vivo and in vitro. The results indicated that miR­29b­3p both inhibited the activation of HSCs and limited the proliferation of activated HSCs via lipid droplet recovery and VEGF pathway regulation. VEGFA was identified as a direct target of miR­29b­3p, and knockdown of VEGFA induced cell apoptosis and autophagy. Notably, VEGFR1 and VEGFR2 knockdown both promoted apoptosis; however, VEGFR1 knockdown inhibited autophagy, whereas VEGFR2 knockdown induced autophagy. Furthermore, it was revealed that VEGFR2 regulated autophagy by mediating the PI3K/AKT/mTOR/ULK1 pathway. VEGFR2 knockdown also led to ubiquitination of heat shock protein 60, ultimately inducing mitochondrial apoptosis. Finally, DHA was identified as a natural agonist of miR­29­3p that effectively prevented liver fibrosis in vivo and in vitro. Overall, the present study determined the molecular mechanism by which DHA inhibited HSC activation and prevented liver fibrosis.

Optical Coherence Tomography Biomarkers in Predicting Treatment Outcomes of Diabetic Macular Edema after Ranibizumab Injections.

Background and Objectives: The identification of possible biomarkers that can predict treatment response among DME eyes is important for the individualization of treatment plans. We investigated optical coherence tomography (OCT)-based biomarkers that may predict the one-year real-life outcomes among diabetic macular edema (DME) eyes following treatment by intravitreal ranibizumab (IVR) injections. Materials and Methods: A total of 65 eyes from 35 treatment-naïve patients with DME treated with ranibizumab injection were recruited. Best-corrected visual acuity (BCVA), central retinal thickness (CRT), intraocular pressure (IOP), and OCT scans were retrospectively recorded at baseline before treatment and at 3 months, 6 months, and 12 months after treatment. The OCT scans were evaluated for biomarkers of interest, which included central retinal thickness (CRT), amount and locations of hyperreflective foci (HRF), subretinal fluid (SRF), intraretinal cysts (IRC), large outer nuclear layer cyst (LONLC), ellipsoid zone disruption (EZD), disorganization of retinal inner layers (DRIL), hard exudates (HE), epiretinal membrane (ERM), and vitreomacular interface (VMI). Correlations between these OCT biomarkers and outcome measures (visual and structural) were statistically analyzed. Results: A total of 65 eyes from 35 patients with DME were enrolled. The mean age was 64.2 ± 10.9 years old. Significant improvement in terms of mean BCVA (p < 0.005) and mean CRT was seen at final follow-up compared to baseline. The biomarkers of DRIL, LONLC, and SRF were found to be predictive for at least 50 µm CRT reduction after treatment (with odds ratio of 8.69, 8.5, and 17.58, respectively). The biomarkers of IRC, LONLC, and SRF were predictive for significant improvement in terms of BCVA and CRT after treatment. Finally, the number of HRF was predictive for both BCVA improvement and a CRT reduction of less than 100 µm after treatment. No serious complications were reported during the study. Conclusion: Our study demonstrated the utility of OCT biomarkers as therapeutic predictors of ranibizumab treatment among DME eyes.

The impact of lactating Hu sheep's dietary protein levels on lactation performance, progeny growth and rumen development.

This study aimed to investigate whether lactating Hu sheep's dietary protein levels could generate dynamic effects on the performance of their offspring. Twelve ewes with similar parity were fed iso-energy diets which contained different protein levels (P1: 9.82%, P2: 10.99%) (n = 6), and the corresponding offspring were divided into SP1 and SP2 (n = 12). At 60 days, half of the lambs were harvested for further study: the carcass weight (p = 0.043) and dressing percentage (p = 0.004) in the SP2 group were significantly higher than SP1. The acetic acid (p = 0.007), propionic acid (p = 0.003), butyric acid (p < 0.001) and volatile fatty acids (p < 0.001) in rumen fluid of SP2 were significantly lower than SP1. The expression of MCT2 (p = 0.024), ACSS1 (p = 0.039) and NHE3 (p = 0.006) in the rumen of SP2 was lower than SP1, while the HMGCS1 (p = 0.026), HMGCR (p = 0.024) and Na+/K+-ATPase (p = 0.020) was higher than SP1. The three dominant phyla in the rumen are Bacteroidetes, Proteobacteria and Firmicutes. The membrane transport, amino acid metabolism and carbohydrate metabolism of SP1 were relatively enhanced, the replication and repair function of SP2 was relatively enhanced. To sum up, the increase of dietary protein level significantly increased the carcass weight and dressing percentage of offspring and had significant effects on rumen volatile fatty acids, acetic acid activation and cholesterol synthesis related genes. HIGHLIGHTSIn the early feeding period, the difference in ADG of lambs was mainly caused by the sucking effect.The increase in dietary protein level of ewes significantly increased the carcass weight and dressing percentage of offspring.The dietary protein level of ewes significantly affected the volatile fatty acids (VFAs) and genes related to acetic acid activation and cholesterol synthesis in the rumen of their offspring.The membrane transport, amino acid metabolism and carbohydrate metabolism of the offspring of ewes fed with a low protein diet were relatively enhanced.The replication and repair function of the offspring of ewes fed with a high protein diet was relatively strengthened.

Diabetic retinopathy as a potential risk factor for ptosis: A 13-year nationwide population-based cohort study in Taiwan.

Purpose: To determine the risk of ptosis among diabetic retinopathy (DR) patients. Methods: This is a population-based, retrospective, matched-cohort study where DR patients were recruited from the Taiwan National Health Insurance Research Database (NHIRD) to investigate the risk of developing ptosis. Preexisting co-factors of interest included smoking status and medical comorbidities of hyperlipidemia and hypertension. Statistical analysis was performed using T-test, Cox-proportional hazard ratios adjusted for comorbidities (aHR), Wilcoxon rank sum test, Kaplan-Meier estimators, and log rank tests. Results: Follow-up data of 9,494 patients with DR and 37,976 matched control cohort (non-DR) from 2000 to 2012 were analyzed. DR patients were found to have significantly increased risk of developing ptosis (adjusted hazard ratio (HR) [95% CI]: 2.76 [1.74-4.38], p < 0.001) when compared to the control cohort. From analysis in different strata, adult age and non-smokers were shown to have higher risk for ptosis development among DR patients. Furthermore, DR patients was also found to have increased risk of developing ptosis when compared to matched controls, regardless of whether they had medical comorbidities of lipid metabolism disorders or hypertension. Conclusions: In this large-scale study using real-world data, our results showed that DR patients were found to have increased risk of developing ptosis. Female gender, adult age, and non-smokers were also shown to increase the risk of ptosis among DR patients. This has implications towards the care of diabetic patients, complications such as ptosis should be properly screened for when encountering such patients. Before ptosis surgery, the possibility of underlying diabetes or DR should be also scrutinized and treated properly to avoid undesirable postoperative dissension.

Identification of a 5-lncRNA-Based Signature for Immune Characteristics and Prognosis of Lung Squamous Cell Carcinoma and Verification of the Function of lncRNA SPATA41.

Lung squamous cell carcinoma (LUSC) is one of the most lethal cancers worldwide. Traditional tumor-node-metastasis (TNM) staging system has many insufficiencies in predicting immune characteristics, overall survival (OS), and prognosis of LUSC. LncRNA is currently found involved in tumor development and effectively predicts tumor prognosis. We screened potential tumor-related lncRNAs for immune characteristics and constructed a nomogram combining lncRNA and traditional clinical indicators for prognosis prediction. We obtained the large-scale gene expression profiles of samples from 492 LUSC patients in The Cancer Genome Atlas database. SPATA41, AL034550.2, AP003721.2, AC106786.1, and AC078889.1 were finally screened to construct a 5-lncRNA-based signature. The risk score of the signature divided patients into subgroups of high-risk and low-risk with significant differences in OS. Their area under the curve (AUC) reached more than 0.70 in 1, 3, and 5 years. In addition, compared with the high-risk subgroup, the low-risk subgroup exhibited a remarkably favorable prognosis and TME score, along with a higher immune infiltration score and lower TIDE score. The signature also significantly related to chemotherapy response, especially in cisplatin, vinorelbine, and paclitaxel. Importantly, the nomogram we constructed had good reliability with the assessment of the calibration chart and consistency index (c-index). GO and KEGG enrichment analysis indicated that co-expression mRNAs of the 5 lncRNAs were mainly focused on RNA splicing, DNA replication, and protein serine/threonine kinase activity. Functional assays demonstrated that SPATA41, one of the five OS-related lncRNAs, regulated invasion, migration, proliferation, and programmed death in vitro. In summary, our 5-lncRNA-based signature has a good performance in predicting immune characteristics and prognosis of LUSC patients.

Changes of Estimated Glomerular Filtration Rate and Glycated Hemoglobin A1c in Diabetic Macular Edema Patients Treated by Ranibizumab and Aflibercept in the Tertiary Referral Hospital.

Background and Objectives: Intravitreal injections (IVI) of vascular endothelial growth factor (VEGF) inhibitors are guideline-indicated treatments for diabetic macular edema (DME). However, some recent data have suggested that IVI VEGF inhibitors might, through systemic absorption, lead to a reduction in renal function. Our study aims to compare changes in glycated hemoglobin A1c (HbA1c) and estimated glomerular filtration rate (eGFR) between patients who received IVI ranibizumab and aflibercept treatment and patients who have not received IVI treatments. Materials and Methods: There were 17,165 DME patients with documented ophthalmology visits in the China Medical University Hospital-Clinical Research Data Repository. Those with a history of ESRD or bevacizumab treatment history, and those with missing information on HbA1c or eGFR, were excluded. After matching by age (±2 years), gender, and the year of clinical visit, 154 patients with medical treatment (including ranibizumab and aflibercept) and 154 patients without medical treatment were included in the study. The difference between HbA1c and eGFR at baseline and 3 and 12 months after the index date between the two groups was assessed. Results: Mean HbA1c and eGFR decreased between baseline and 12 months after the index date in both groups (p < 0.05). Compared with the non-treatment group, the treatment group had significantly lower HbA1c 3 and 12 months after the index date. There was no significant difference in eGFR between the two groups. In the generalized estimating equations (GEE) model, HbA1c in the treatment group was lower than the non-treatment group (−0.44%, 95% CI = −0.75, −0.14), but eGFR was similar after adjusting for age, gender, and index-year. HbA1c and eGFR decreased with the time in the adjusted GEE model (p < 0.0001) in both groups. Conclusions: This study showed that eGFR decreased with age and time and was not related to IVI anti-VEGF treatments in our tertiary referral hospital. IVI anti-VEGF therapy was also associated with better HbA1c control. It is suggested that DME patients can receive intravitreal VEGF inhibitors without inducing more renal impairment.

Optical Coherence Tomography Biomarkers in Predicting Treatment Outcomes of Diabetic Macular Edema After Dexamethasone Implants.

Purpose: To identify optical coherence tomography (OCT) biomarkers that may predict functional and anatomical outcomes in diabetic macular edema (DME) patients treated with intravitreal dexamethasone (DEX) implant. Materials and Methods: Sixty-four eyes from 50 patients with DME were enrolled. Best-corrected visual acuity (BCVA) and OCT biomarkers including central retinal thickness (CRT), subretinal fluid (SRF), intraretinal cysts (IRC), ellipsoid zone disruption (EZD), disorganization of retinal inner layers (DRIL), hard exudate (HE), hyperreflective foci (HRF), epiretinal membrane (ERM), and vitreomacular interface (VMI) changes were evaluated at baseline and at 3, 6, and 12 months after treatment. Multiple logistic analysis was performed to evaluate each OCT biomarker as a predictive factor for functional and anatomical improvement at the end of treatment. Results: The presence of SRF at baseline was associated with a favorable outcome, with CRT improving by more than 100 µm after treatment from multivariate logistic regression analysis [odds ratio 6.16 (1.75-21.6)]. In addition, baseline SRF predicted a greater CRT improvement from multiple regression analysis (model R-square 0.11, p = 0.006). The reduction of DRIL, SRF, LONLC, IRC, and EZD were correlated with better CRT improvement (more than 100 µm) (P < 0.05). SRF and EZD recovery can also predict better visual prognosis (P < 0.05). Conclusion: OCT biomarkers can be used to predict who may benefit the most after DEX treatment. We suggest that the DEX implant should be considered as a first line treatment in DME patients with SRF.

Curcumol alleviates liver fibrosis by inducing endoplasmic reticulum stress-mediated necroptosis of hepatic stellate cells through Sirt1/NICD pathway.

Liver fibrosis is a repair response process after chronic liver injury. During this process, activated hepatic stellate cells (HSCs) will migrate to the injury site and secrete extracellular matrix (ECM) to produce fibrous scars. Clearing activated HSCs may be a major strategy for the treatment of liver fibrosis. Curcumol isolated from plants of the genus Curcuma can effectively induce apoptosis of many cancer cells, but whether it can clear activated HSCs remains to be clarified. In the present study, we found that the effect of curcumol in treating liver fibrosis was to clear activated HSCs by inducing necroptosis of HSCs. Receptor-interacting protein kinase 3 (RIP3) silencing could impair necroptosis induced by curcumol. Interestingly, endoplasmic reticulum (ER) stress-induced cellular dysfunction was associated with curcumol-induced cell death. The ER stress inhibitor 4-PBA prevented curcumol-induced ER stress and necroptosis. We proved that ER stress regulated curcumol-induced necroptosis in HSCs via Sirtuin-1(Sirt1)/Notch signaling pathway. Sirt1-mediated deacetylation of the intracellular domain of Notch (NICD) led to degradation of NICD, thereby inhibiting Notch signalling pathway to alleviate liver fibrosis. Specific knockdown of Sirt1 by HSCs in male ICR mice further exacerbated CCl4-induced liver fibrosis. Overall, our study elucidates the anti-fibrotic effect of curcumol and reveals the underlying mechanism between ER stress and necroptosis.

Stroke volume variation for predicting responsiveness to fluid therapy in patients undergoing cardiac and thoracic surgery: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the reliability of stroke volume variation (SVV) for predicting responsiveness to fluid therapy in patients undergoing cardiac and thoracic surgery. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, EMBASE, Cochrane Library, Web of Science up to 9 August 2020. METHODS: Quality of included studies were assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 tool. We conducted subgroup analysis according to different anaesthesia and surgical methods with Stata V.14.0, Review Manager V.5.3 and R V.3.6.3. We used random-effects model to pool sensitivity, specificity and diagnostic odds ratio with 95% CI. The area under the curve (AUC) of receiver operating characteristic was calculated. RESULTS: Among the 20 relevant studies, 7 were conducted during thoracic surgery, 8 were conducted during cardiac surgery and the remaining 5 were conducted in intensive critical unit (ICU) after cardiac surgery. Data from 854 patients accepting mechanical ventilation were included in our systematic review. The pooled sensitivity and specificity were 0.73 (95％ CI: 0.59 to 0.83) and 0.62 (95％ CI: 0.46 to 0.76) in the thoracic surgery group, 0.71 (95％ CI: 0.65 to 0.77) and 0.76 (95％ CI: 0.69 to 0.82) in the cardiac surgery group, 0.85 (95％ CI: 0.60 to 0.96) and 0.85 (95％ CI: 0.74 to 0.92) in cardiac ICU group. The AUC was 0.73 (95% CI: 0.69 to 0.77), 0.80 (95% CI: 0.77 to 0.83) and 0.88 (95% CI: 0.86 to 0.92), respectively. Results of subgroup of FloTrac/Vigileo system (AUC=0.80, Youden index=0.38) and large tidal volume (AUC=0.81, Youden index=0.48) in thoracic surgery, colloid (AUC=0.85, Youden index=0.55) and postoperation (AUC=0.85, Youden index=0.63) in cardiac surgery, passive leg raising (AUC=0.90, Youden index=0.72) in cardiac ICU were reliable. CONCLUSION: SVV had good predictive performance in cardiac surgery or ICU after cardiac surgery and had moderate predictive performance in thoracic surgery. Nevertheless, technical and clinical variables may affect the predictive value potentially.

Modification of lysine deacetylation regulates curcumol-induced necroptosis through autophagy in hepatic stellate cells.

The excessive deposition of extracellular matrix (ECM) is the main characteristic of liver fibrosis, and hepatic stellate cells (HSCs) are the main source of ECM. The removal of activated HSCs has a reversal effect on liver fibrosis. Western blot and MTT analysis indicated that curcumol could relieve hepatic fibrosis by promoting HSCs receptor-interacting protein kinase 1/3 (RIP1/RIP3)-dependent necroptosis. Importantly, autophagy flow was monitored by constructing the mRFP-GFP-LC3 plasmid, and it was found that curcumol cleared activated HSCs in a necroptosis manner that was dependent on autophagy. Our study suggested that the activation of necrosome formed by RIP1 and RIP3 depended on Atg5, and that autophagosomes were also necessary for curcumol-induced necroptosis. Furthermore, microscale thermophoresis and co-immunoprecipitation assay results proved that curcumol could target Sirt1 to regulate autophagy by reducing the acetylation level of Atg5. The HSCs-specific silencing of Sirt1 exacerbated CCl4 -induced liver fibrosis in mice. The deacetylation of Atg5 not only accelerated the accumulation of autophagosomes but also enhanced the interaction between Atg5 and RIP1/RIP3 to induce necroptosis. Overall, our study indicated that curcumol could activate Sirt1 to promote Atg5 deacetylation and enhanced its protein-protein interaction function, thereby inducing autophagy and promoting the necroptosis of HSCs to reduce liver fibrosis.