Incidence and risk factors of postoperative delirium following hepatic resection: a retrospective national inpatient sample database study.

BACKGROUND: Postoperative delirium (POD) is a common complication after major surgery and can cause a variety of adverse effects. However, no large-scale national database was used to assess the occurrence and factors associated with postoperative delirium (POD) following hepatic resection. METHODS: Patients who underwent hepatic resection from 2015 to 2019 were screened using the International Classification of Diseases (ICD) 10th edition clinical modification code from the National Inpatient Sample (NIS) Database. Peri-operative factors associated with delirium were screened and underwent statistical analysis to identify independent predictors for delirium following hepatic resection. RESULTS: A total of 80,070 patients underwent hepatic resection over a five-year period from 2015 to 2019. The overall occurrence of POD after hepatic resection was 1.46% (1039 cases), with a slight upward trend every year. The incidence of elective admission was 6.66% lower (88.60% vs. 81.94%) than that of patients without POD after hepatic resection and 2.34% (45.53% vs. 43.19%) higher than that of patients without POD in teaching hospitals (P < 0.001). In addition, POD patients were 6 years older (67 vs. 61 years) and comprised 9.27% (56.69% vs. 47.42%) more male patients (P < 0.001) compared to the unaffected population. In addition, the occurrence of POD was associated with longer hospitalization duration (13 vs. 5 days; P < 0.001), higher total cost ($1,481,89 vs. $683,90; P < 0.001), and higher in-hospital mortality (12.61% vs. 4.11%; P < 0.001). Multivariate logistic regression identified hepatic resection-independent risk factors for POD, including non-elective hospital admission, teaching hospital, older age, male sex, depression, fluid and electrolyte disorders, coagulopathy, other neurological disorders, psychoses, and weight loss. In addition, the POD after hepatic resection has been associated with sepsis, dementia, urinary retention, gastrointestinal complications, acute renal failure, pneumonia, continuous invasive mechanical ventilation, blood transfusion, respiratory failure, and wound dehiscence / non-healing. CONCLUSION: Although the occurrence of POD after hepatic resection is relatively low, it is beneficial to investigate factors predisposing to POD to allow optimal care management and improve the outcomes of this patient population.

Therapeutic application of human type 2 innate lymphoid cells via induction of granzyme B-mediated tumor cell death.

The therapeutic potential for human type 2 innate lymphoid cells (ILC2s) has been underexplored. Although not observed in mouse ILC2s, we found that human ILC2s secrete granzyme B (GZMB) and directly lyse tumor cells by inducing pyroptosis and/or apoptosis, which is governed by a DNAM-1-CD112/CD155 interaction that inactivates the negative regulator FOXO1. Over time, the high surface density expression of CD155 in acute myeloid leukemia cells impairs the expression of DNAM-1 and GZMB, thus allowing for immune evasion. We describe a reliable platform capable of up to 2,000-fold expansion of human ILC2s within 4 weeks, whose molecular and cellular ILC2 profiles were validated by single-cell RNA sequencing. In both leukemia and solid tumor models, exogenously administered expanded human ILC2s show significant antitumor effects in vivo. Collectively, we demonstrate previously unreported properties of human ILC2s and identify this innate immune cell subset as a member of the cytolytic immune effector cell family.

Identification and validation of aging-related genes in atrial fibrillation.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in the clinic. Aging plays an essential role in the occurrence and development of AF. Herein, we aimed to identify the aging-related genes associated with AF using bioinformatics analysis. Transcriptome profiles of AF were obtained from the GEO database. Differential expression analysis was performed to identify AF-specific aging-related genes. GO and KEGG enrichment analyses were performed. Subsequently, the LASSO, SVM-RFE, and MCC algorithms were applied to screen aging-related genes. The mRNA expression of the screened genes was validated in the left atrial samples of aged rapid atrial pacing-induced AF canine models and their counterparts. The ROC curves of them were drawn to evaluate their diagnostic potential. Moreover, CIBERSORT was used to estimate immune infiltration. A correlation analysis between screened aging-related genes and infiltrating immune cells was performed. A total of 24 aging-related genes were identified, which were found to be mainly involved in the FoxO signaling pathway, PI3K-Akt signaling pathway, longevity regulating pathway, and peroxisome according to functional enrichment analysis. LASSO, SVM-RFE, and MCC algorithms identified three genes (HSPA9, SOD2, TXN). Furthermore, the expression levels of HSPA9 and SOD2 were validated in aged rapid atrial pacing-induced AF canine models. HSPA9 and SOD2 could be potential diagnostic biomarkers for AF, as evidenced by the ROC curves. Immune infiltration and correlation analysis revealed that HSPA9 and SOD2 were related to immune cell infiltrates. Collectively, these findings provide novel insights into the potential aging-related genes associated with AF. HSPA9 and SOD2 may play a significant role in the occurrence and development of AF.

Advances in MicroRNA Therapy for Heart Failure: Clinical Trials, Preclinical Studies, and Controversies.

Heart failure (HF) is a rapidly growing public health issue with more than 37.7 million patients worldwide and an annual healthcare cost of $108 billion. However, HF-related drugs have not changed significantly for decades, and it is essential to find biological drugs to provide better treatment for HF patients. MicroRNAs (miRNAs) are non-coding RNAs (ncRNAs) with a length of approximately 21 nucleotides and play an important role in the onset and progression of cardiovascular diseases. Increasing studies have shown that miRNAs are widely involved in the pathophysiology of HF, and the regulation of miRNAs has promising therapeutic effects. Among them, there is great interest in miRNA-132, since the encouraging success of anti-miRNA-132 therapy in a phase 1b clinical trial in 2020. However, it is worth noting that the multi-target effect of miRNA may produce side effects such as thrombocytopenia, revascularization dysfunction, severe immune response, and even death. Advances in drug delivery modalities, delivery vehicles, chemical modifications, and plant-derived miRNAs are expected to address safety concerns and further improve miRNA therapy. Here, we reviewed the preclinical studies and clinical trials of HF-related miRNAs (especially miRNA-132) in the past 5 years and summarized the controversies of miRNA therapy.

Two-finger digital rectal examination for the diagnosis of anal fistula: protocol for a randomized controlled trial.

Background: Anal fistula is an anorectal infectious disease caused by a perianal abscess or perianal disease. Accurate anorectal examinations are of great significance. The two-finger digital rectal examination (TF-DRE) has been used in clinical practice, with a lack of comprehensive research on the value of the TF-DRE in the diagnosis of anal fistula. This study will compare the difference in the diagnostic value of the TF-DRE, traditional digital rectal examination (DRE), and anorectal ultrasonography in the diagnosis of anal fistula. Methods: For patients who meet the inclusion criteria, a TF-DRE will be performed to explore the number and location of the external and internal orifices, the number of fistulas, and the relationship between the fistula and the perianal sphincter. A DRE and anorectal ultrasonography will also be performed, and the same data will be recorded. To make a comparison, the final diagnosis results of the clinicians during the operation will be taken as the gold standard, the accuracy of the TF-DRE in diagnosing anal fistula will be calculated, and the significance of the TF-DRE in the preoperative diagnosis of anal fistula will be studied and analyzed. All the statistical results will be analyzed using SPSS22.0 (IBM, USA), and a P value <0.05 will be considered statistically significant. Discussion: The research protocol details the advantages of the TF-DRE compared to the DRE and anorectal ultrasonography in the diagnosis of anal fistula. This study will provide clinical evidence of the diagnostic value of the TF-DRE in the diagnosis of anal fistula. Currently, there is a lack of high-quality research using scientific methods on this innovative anorectal examination method. This study will provide rigorously designed clinical evidence on the TF-DRE. Registration: Chinese Clinical Trials Registry ChiCTR2100045450.

COVID-19 and sarcopenia-related traits: a bidirectional Mendelian randomization study.

Background: Emerging evidence suggested that coronavirus disease 2019 (COVID-19) patients were more prone to acute skeletal muscle loss and suffer sequelae, including weakness, arthromyalgia, depression and anxiety. Meanwhile, it was observed that sarcopenia (SP) was associated with susceptibility, hospitalization and severity of COVID-19. However, it is not known whether there is causal relationship between COVID-19 and SP-related traits. Mendelian randomization (MR) was a valid method for inferring causality. Methods: Data was extracted from the COVID-19 Host Genetic Initiative and the UK Biobank without sample overlapping. The MR analysis was performed with inverse variance weighted, weighted median, MR-Egger, RAPS and CAUSE, MR-APSS. Sensitivity analysis was conducted with MR-Egger intercept test, Cochran's Q test, MR-PRESSO to eliminate pleiotropy. Results: There was insufficient result in the MR-APSS method to support a direct causal relationship after the Bonferroni correction. Most other MR results were also nominally consistent with the MR-APSS result. Conclusions: Our study first explored the causal relationship between COVID-19 and SP-related traits, but the result indicated that they may indirectly interact with each other. We highlighted that older people had better absorb enough nutrition and strengthen exercise to directly cope with SP during the COVID-19 pandemic.

Injectable, Hierarchically Degraded Bioactive Scaffold for Bone Regeneration.

Bioactive materials play vital roles in the repair of critical bone defects. However, bone tissue engineering and regenerative medicine are still challenged by the need to repair bone defects evenly and completely. In this study, we functionally simulated the natural creeping substitution process of autologous bone repair by constructing an injectable, hierarchically degradable bioactive scaffold with a composite hydrogel, decalcified bone matrix (DBM) particles, and bone morphogenetic protein 2. This composite scaffold exhibited superior mechanical properties. The scaffold promoted cell proliferation and osteogenic differentiation through multiple signaling pathways. The hierarchical degradation rates of the crosslinked hydrogel and DBM particles accelerated tissue ingrowth and bone formation with a naturally woven bone-like structure in vivo. In the rat calvarial critical defect repair model, the composite scaffold provided even and complete repair of the entire defect area while also integrating the new and host bone effectively. Our results indicate that this injectable, hierarchically degradable bioactive scaffold promotes bone regeneration and provides a promising strategy for evenly and completely repairing the bone defects.

Non-alcoholic fatty liver disease and complications in type 1 and type 2 diabetes: A Mendelian randomization study.

AIM: To investigate the potential causal relationship between non-alcoholic fatty liver disease (NAFLD) and complications in type 1 diabetes (T1D) and type 2 diabetes (T2D). MATERIALS AND METHODS: Two-sample Mendelian randomization (MR) analysis was conducted to appraise after controlling for the confounding factors. Genetic instrument variables for NAFLD surrogated by chronically elevated serum alanine transferase were derived from a recent genome-wide association study. Diabetes-related complications, including diabetic ketoacidosis, nephropathy and retinopathy, were included as outcomes. Four complementary MR methods were used to test reliability. RESULTS: Genetically instrumented NAFLD showed a suggestive causal association with ketoacidosis in T1D (odds ratio [OR]: 1.574; 95% confidence interval [CI]: 1.076, 2.302; P = .019; false discovery rate [FDR] = 0.096) and a significant causal association with early-stage kidney disease in T1D (OR: 1.249; 95% CI: 1.089, 1.432; P = 1.457 × 10-3 , FDR = 0.015). Sensitivity analysis indicated low heterogeneity, low pleiotropy and high reliability of the causal estimates. However, the MR analyses failed to show a causal association between NAFLD and T1D retinopathy, T2D ketoacidosis, nephropathy and retinopathy. CONCLUSIONS: This study supports a causal effect of genetically driven chronic serum alanine aminotransferase-associated NAFLD on early-stage kidney disease in T1D and a suggestive causal effect on ketoacidosis in T1D. However, MR studies did not provide enough evidence to suggest that NAFLD independently increases the risk of retinopathy in T1D and of ketoacidosis, nephropathy and retinopathy in T2D.

Restricted cubic spline model analysis of the association between anal fistula and anorectal abscess incidence and body mass index.

Objective: The epidemiological profile of anal fistula and anorectal abscess has not been well studied. Based on the results of a retrospective cross-sectional survey, we aimed to investigate the potential influential factors associated with anal fistula and anorectal abscess. Methods: We conducted a retrospective analysis of outpatients who visited the proctology department at China-Japan Friendship Hospital between January 2017 and May 2022. A comprehensive questionnaire was designed to collect potential influential factors, and according to formal anorectal examination and the corresponding diagnostic criteria, all the participants were divided into patients with anal fistula or perianal abscess and healthy control group. Multiple logistic regression was used to identify factors in significant association with anal fistula and perianal abscess. Additionally, we combined restricted cubic spline regression to examine the dose-response relationship between factors and the risk of developing anal fistula or anorectal abscess. Results: The present study included 1,223 participants, including 1,018 males and 206 females, with 275 anal fistulas, 184 anorectal abscesses, and 765 healthy controls. We found no statistically significant differences between patients and controls in basic information and preoperative assessment of life factors, except for body mass index. It was indicated that people with overweight or obesity were more prone to anal fistula (OR overweight = 1.35, 95% CI: 1.00-1.82, P = 0.047; OR obesity = 3.44, 95% CI: 2.26-5.26, P < 0.001) or anorectal abscess (OR overweight = 1.41, 95% CI: 1.00-1.99, P = 0.05; OR obesity: 2.24, 95% CI: 1.37-3.67, P = 0.001) than normal-weight individuals. The dose-response research indicated the J-shaped trend between the ascending BMI levels and the higher risk of suffering from anal fistula and anorectal abscess. Conclusions: Our findings indicate that overweight and obesity are risk factors for anal fistula and anorectal abscess, which plays a role in the prevention of anorectal diseases. This provides some theoretical basis for clinicians to provide health education to their patients.

Osteoporosis and sarcopenia-related traits: A bi-directional Mendelian randomization study.

Background: With the advancement of world population aging, age-related osteoporosis (OP) and sarcopenia (SP) impose enormous clinical and economic burden on society. Evidence from accumulating studies indicates that they mutually influence one another. However, an observational study may be affected by potential confounders. Meanwhile, a Mendelian randomization (MR) study can overcome these confounders to assess causality. Objectives: The aim of this study was to evaluate the causality between OP and SP, informing new strategies for prevention, diagnosis, and treatment of osteosarcopenia. Methods: Instrumental variables (IVs) at the genome-wide significance level were obtained from published summary statistics, and the inverse variance weighted method and several other MR methods were conducted to evaluate the bi-directional causality between SP and OP. Myopia was analyzed as a negative control outcome to test the validity of IVs. Results: Femoral neck bone mineral density (FN BMD), lumbar spine BMD (LS BMD), and forearm BMD (FA BMD) had a direct causal effect on appendicular lean mass (ALM) [FA BMD-related analysis: odds ratio (OR) = 1.028, 95% confidence interval (CI) = (1.008,1.049), p = 0.006; FN BMD-related analysis: OR (95% CI) = 1.131 (1.092,1.170), p = 3.18E-12; LS BMD-related analysis: OR (95% CI) = 1.080 (1.062,1.098), p = 2.86E-19]. ALM had a significant causal effect on LS BMD [OR (95% CI) = (1.033,1.147), p = 0.001]. There was no evidence for causal association between BMD and low grip strength. Conclusions: OP and SP might mutually have a significant causal effect on each other. Our results supported the idea that the patient with severe OP was more susceptible to lose ALM and severe ALM loss might reduce LS BMD.

Hydrostatic Pressure Modulates Intervertebral Disc Cell Survival and Extracellular Matrix Homeostasis via Regulating Hippo-YAP/TAZ Pathway.

Established studies proved that hydrostatic pressure had multiple effects on the biological behavior of the intervertebral disc (IVD). However, the conclusions of the previous studies were inconsistent, due to the difference in hydrostatic loading devices and observing methods used in these studies. The current study is aimed at investigating the role of dynamic hydrostatic pressure in regulating biological behavior of the notochordal nucleus pulposus (NP) and fibrocartilaginous inner annulus fibrosus (AF) and its possible mechanism using our novel self-developed hydrostatic pressure bioreactor. The differences in the biological behavior of the rabbit IVD tissues under different degree of hydrostatic pressure were evaluated via histological analysis. Results revealed that low-loading dynamic hydrostatic pressure was beneficial for cell survival and extracellular matrix (ECM) homeostasis in notochordal NP and fibrocartilaginous inner AF via upregulating N-cadherin (N-CDH) and integrin ß1. In comparison, high-magnitude dynamic hydrostatic pressure aggravated the breakdown of ECM homeostasis in NP and inner AF via enhancing the Hippo-YAP/TAZ pathway-mediated cell apoptosis. Moreover, inner AF exhibited greater tolerance to physiological medium-loading degree of hydrostatic pressure than notochordal NP. The potential mechanism was related to the differential expression of mechanosensing factors in notochordal NP and fibrocartilaginous inner AF, which affects the fate of the cells under hydrostatic pressure. Our findings may provide a better understanding of the regulatory role of hydrostatic pressure on the cellular fate commitment and matrix metabolism of the IVD and more substantial evidence for using hydrostatic pressure bioreactor in exploring the IVD degeneration mechanism as well as regeneration strategies.

Deficiency of MIF Accentuates Overloaded Compression-Induced Nucleus Pulposus Cell Oxidative Damage via Depressing Mitophagy.

Established studies proved that mechanical compression loading had multiple effects on the biological behavior of the intervertebral disc (IVD). However, the regulating mechanism involved in this process remains unclear. The current study is aimed at exploring the potential bioregulators and signaling pathways involved in the compression-associated biological changes of nucleus pulposus (NP) cells. Tandem mass tag- (TMT-) based quantitative proteomics was exerted to analyze the differentially expressed proteins (DEPs) and signal pathways among the different groups of NP cells cultured under noncompression, low-compression (LC), and high-compression (HC) loading. Eight potential protective bioregulators for the NP cell survival under different compression loading were predicted by the proteomics, among which macrophage migration inhibitory factor (MIF) and oxidative stress-related pathways were selected for further evaluation, due to its similar function in regulating the fate of the cartilage endplate- (CEP-) derived cells. We found that deficiency of MIF accentuates the accumulation of ROS, mitochondrial dysfunction, and senescence of NP cells under overloaded mechanical compression. The potential molecular mechanism involved in this process is related to the mitophagy regulating role of MIF. Our findings provide a better understanding of the regulatory role of mechanical compression on the cellular fate commitment and matrix metabolism of NP, and the potential strategies for treating disc degenerative diseases via using MIF-regulating agents.

The effects of IL-17/IL-17R inhibitors on atherosclerosis in psoriasis and psoriatic arthritis: A protocol for systematic review and meta analysis.

BACKGROUND: Psoriasis (PSO) is a systemic inflammatory disorder that presents with erythematous scaling of the skin and is associated with autoimmune dysfunction. Atherosclerosis is one of the major comorbidities of PSO. PSO-associated inflammatory factor IL-17 could lead to vascular endothelial cell injury and atherosclerosis. While some research results show that IL-17 helps stabilize plaque formation. Efficacy and safety on PSO and psoriatic arthritis (PSA) of existing IL-17/IL-17R biologics (secukinumab, ixekizumab, brodalumab, and bimekizumab) have been clinically validated, but whether they can improve atherosclerotic outcomes in psoriatic patients remains controversial. METHODS: Seven electronic search engines will be searched from inception to December 1, 2020, including PubMed, Embase, Scopus, PsycINFO, Global Health, Web of Science and the Cochrane Library. Clinical trial registries, potential grey literature, relevant conference abstracts, and reference lists of identified studies will also be searched. Literature selection, data extraction, and quality assessment will be done by 2 independent authors. Based on the heterogeneity test, the fixed effect or random effect model will be used for data synthesis. Changes in lung function will be evaluated as the primary outcome. Assessment of symptoms, quality of life, medication use, exacerbations and adverse events will be assessed as secondary outcomes. RevMan V. 5.3.5 (The Nordic Cochrane Centre, Copenhagen, Denmark) will be used for meta-analysis. RESULTS: This study will provide a synthesis of current evidence of IL-17/IL-17R inhibitors on atherosclerosis in PSO and PSA. CONCLUSION: The conclusion of our study will provide updated evidence to judge whether IL-17/IL-17R inhibitors is an effective solution to atherosclerosis as comorbidity of PSO and PSA. PROSPERP REGISTRATION NUMBER: CRD42020209897.

The role of exosome lipids in central nervous system diseases.

Central nervous system (CNS) diseases are common diseases that threaten human health. The CNS is highly enriched in lipids, which play important roles in maintaining normal physiological functions of the nervous system. Moreover, many CNS diseases are closely associated with abnormal lipid metabolism. Exosomes are a subtype of extracellular vesicles (EVs) secreted from multivesicular bodies (MVBs) . Through novel forms of intercellular communication, exosomes secreted by brain cells can mediate inter-neuronal signaling and play important roles in the pathogenesis of CNS diseases. Lipids are essential components of exosomes, with cholesterol and sphingolipid as representative constituents of its bilayer membrane. In the CNS, lipids are closely related to the formation and function of exosomes. Their dysregulation causes abnormalities in exosomes, which may, in turn, lead to dysfunctions in inter-neuronal communication and promote diseases. Therefore, the role of lipids in the treatment of neurological diseases through exosomes has received increasing attention. The aim of this review is to discuss the relationship between lipids and exosomes and their roles in CNS diseases.