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Background Health care institutions have their own “picklist” for clinicians to document adverse drug reactions (ADRs) into the electronic health record (EHR) allergy list. Whether the lack of a nationally standardized picklist impacts clinician data entries is unknown. Objectives The objective of this study was to assess the impact of defined reaction picklists on clinical documentation and, therefore, downstream analytics and clinical research using these data at two institutions. Methods ADR data were obtained from the EHRs of patients who visited the emergency department or outpatient clinics at Brigham and Women's Hospital (BWH) and University of Colorado Hospital (UCH) from 2013 to 2018. Reported drug class ADR prevalences were calculated. We investigated the reactions on each picklist and compared the top 40 reactions at each institution, as well as the top 10 reactions within each drug class. Results Of 2,160,116 patients, 640,444 (30%) had 928,973 active drug allergies. The most commonly reported drug class allergens were similar between BWH and UCH. BWH's picklist had 48 reactions, and UCH's had 160 reactions; 29 reactions were shared by both picklists. While the top four reactions overall (rash, GI upset/nausea/vomiting, hives, itching) were identical between sites, reactions by drug class exhibited greater documentation diversity. For example, while the summed prevalence of swelling-related reactions to angiotensin-converting-enzyme inhibitors was comparable across sites, swelling was represented by two terms (“swelling,” “angioedema”) at BWH but 11 terms at UCH (e.g., “swelling,” “edema,” by body locality). Conclusion The availability and granularity of reaction picklists impact ADR documentation in the EHR by health care providers; picklists may partially explain variations in reported ADRs across health care systems.

In the new era of competitive smart electronics, the development of compressible multifunctional carbon aerogels is highly needed, but still faces enormous challenges. Here we demonstrate a robust strategy to fabricate multifunctional carbon aerogel via freeze-drying of cellulose nanofibers (CNF) and graphene oxide (GO) co-stabilized Pickering emulsion gel followed by high-temperature annealing. The resulting carbon aerogel exhibits tunable mechanical, hydrophilic and hydrophobic properties due to varying the elemental composition and the pyrolysis of introduced polymers. The carbon aerogel is resilient against high compression strain up to 99 % and has ultralow density (1.82 mg/cm

The Dark Triad (Machiavellianism, psychopathy, narcissism) is associated with online disinhibition and antisocial online behaviors. However, the mediating role between online disinhibition and online trolling has never previously been investigated. We examined direct and indirect associations between online disinhibition and online trolling via the Dark Triad among 1,303 participants. The results showed that online disinhibition is positively correlated with online trolling, and their link is partly mediated by Machiavellianism and psychopathy. Furthermore, men exhibited higher levels of Dark Triad traits and were more likely to engage in online trolling than women. Moderated mediation analyses indicated that gender moderated the relationship between psychopathy and online trolling. The study provided a promising perspective for the intervention of online trolling, namely netizens should be taught to reduce impulsivity and improve empathy and self-control, especially for men.

To develop and validate a nomogram for the prediction of stent dysfunction after transjugular intrahepatic portosystemic shunt (TIPS) placement in patients with hepatitis B cirrhosis.From 2012 to 2020, 355 patients with hepatitis B cirrhosis who underwent TIPS placements were enrolled in this study. A multivariable logistic regression analysis was applied to determine independent risk factors for the nomogram construction. Discrimination, calibration, and clinical usefulness of the prediction model were assessed by using receiver operating characteristic curves, calibration scatter plots, and a decision curve analysis (DCA).Independent factors for TIPS stent dysfunction included diabetes, previous splenectomy, the shunting branch of the portal vein, and stent position, which were used to construct the nomogram. The AUC values in the training and validation cohorts were 0.817 (95% CI: 0.731-0.903) and 0.804 (95% CI: 0.673-0.935), respectively, which suggested a good predictive ability. The calibration curves in both cohorts revealed good agreement between the predictions and actual observations. The DCA curve indicated that when the threshold probability ranged from 2% to 88%, the nomogram could provide clinical usefulness and a net benefit.The nomogram that we developed could be conveniently used to predict TIPS stent dysfunction in patients with hepatitis B cirrhosis.

Objective. To investigate the effects of Compaximab and raizumab on retinal function and serum interleukin-17A level in retinopathy of prematurity. Methods. Sixty cases of retinopathy of prematurity treated in our hospital from February 2019 to April 2021 were selected. The patients were randomly divided into control group ( n = 30 ) and research group ( n = 30 ). The control group was treated with Compaq and the research group was treated with razumab. The curative effect, retinal function, incidence of complications, intraocular pressure at different time, and the level of serum interleukin-17A were compared. Results. Compared with the two groups, the curative effect of the research group 93.33% (28/30) was greater than that of the control group 66.67% (20/30), and the difference was statistically significant ( P < 0.05 ). Compared with the incidence of complications, the incidence of corneal opacity, lens opacity, preretinal and vitreous hemorrhage, endophthalmitis, and traction retinal detachment in the research group was greatly lower, and the difference was statistically significant ( P < 0.05 ). Following the therapy, the IOP of the two groups decreased at different times. The IOP of 1 min, 10 min, and 30 min in the research group was obviously lower, and the difference was statistically significant ( P < 0.05 ). Following treatments, the levels of serum IL-17A were decreased. Compared with the control group, the level of serum IL-17A in the research group was greatly downregulated, and the difference was statistically significant ( P < 0.05 ). Conclusion. Intravitreal injection of razumab is an effective treatment for retinopathy of prematurity, which can effectively improve the retinal function of infants. The level of serum interleukin-17A can be reduced and intraocular pressure can be regulated, which is safe and effective.

Chrysanthemum is one of the most important and popular ornamentals over the world. Chrysanthemum drink is a type of traditional healthy drink like Chinese tea. Owing to the differences in the chemical compositions, different chrysanthemum varieties have different medicinal effects on human health. Thus, the identification of different chrysanthemum varieties is very important and necessary. This study aims to distinguish seven chrysanthemum varieties that are widely used in China. First, total lipids were obtained from chrysanthemums. After that, lipid profiles were characterized using ultra-high-performance liquid chromatography hyphenated with a Q Exactive™ high resolution-accurate-mass mass spectrometer.A total of 163 lipid molecular species from 17 types of lipid classes in seven varieties of chrysanthemums were determined. Principal component analysis indicated that three lipid molecules, lysophosphatidylethanolamine(18:2) (LPE(18:2)), LPE(16:0), and phosphatidic acid(18:2/18:3) (variable importance in projection3, P 0.001), can be used as potential biomarkers to distinguish seven chrysanthemum varieties. Hierarchical cluster analysis showed that the lipid molecular profiles of 'Gongju' were most similar to 'Jinzijianju', followed by 'Huaibaiju', 'Boju', 'Hangbaiju', 'Chuju', and 'Fubaiju'.This comprehensive analysis provided a new method to identify chrysanthemum varieties through the perspective of lipidomics combined with chemometrics. © 2022 Society of Chemical Industry.

Solid pseudopapillary tumor (SPT) is a rare pancreatic tumor. Considering its malignant behaviors, SPT has been classified as a low-grade malignant tumor. Indeed, only 9.2% of all SPT patients are initially diagnosed as malignant with invasion or metastasis. Thus, one of the challenges in managing SPT patients is predicting malignant behavior.To investigate the malignant behavior and tumor-associated macrophage (TAM) infiltration between different histopathologic features of SPT patients.Twenty-five formalin-fixed paraffin-embedded tissue samples from 22 patients pathologically diagnosed with an SPT between 2009 and 2019 at West China Hospital were included in this retrospective study. Integrity of the capsule and growth pattern of the tumor cells was assessed microscopically in hematoxylin-eosin (HE)-stained sections. Based on the histopathological features, the SPT patients were divided into two groups: capsule or invasion. Clinical features, malignant behavior, and TAM infiltration were compared between the two groups.Among the 22 SPT patients, 11 were identified for each group, having either a capsule or invasion histopathologic feature. Malignant behavior was more frequent in the invasion group, including 2 patients who had peripheral organ invasion, 3 with liver metastasis, and 1 with both lymph node and spleen metastases (SPT patients with invasion evident under microscope were more likely to exhibit malignant behavior and TAM infiltration, especially M2-like macrophages. This finding can help in future investigations of the underlying mechanism of TAM-mediated SPT malignant behavior.

Background: The relationship between grip strength and cognitive function remains no consensus in the older adults. Objective: To investigate the association of grip strength with cognitive function and cognitive performance in different domains. Methods: Participants of the present cross-sectional study were from the National Health and Nutrition Examination Survey 2011-2014. Grip strength was measured by grip dynamometer, and combined handgrip strength was the sum of the largest reading from each hand. Four cognitive domains (immediate and delayed memory, language, and attention) were assessed by a set of neuropsychological tests. The subjective cognitive decline was determined via self-report. Results: Among 2,618 participants, combined grip strength was positively associated with scores on global cognitive function and each cognitive domain after controlling for demographic characteristics, lifestyle factors, and history of disease. In addition, compared to those with grip strength

The endothelial dysfunction, associated with inflammation and vascular permeability, remains the key event in the pathogenesis of cerebral ischemic stroke. Angiogenesis is essential for neuroprotection and neural repair following stroke. The neuroinflammatory reaction plays a vital role in stroke, and inhibition of inflammation contributes to establishing an appropriate external environment for angiogenesis. Exosomes are the heterogeneous population of extracellular vesicles which play critical roles in intercellular communication through transmitting various proteins and nucleic acids to nearby and distant recipient cells by body fluids and circulation. Recent reports have shown that exosomal therapy is a valuable and potential treatment strategy for stroke. In this review, we discussed the exosomes in complex interaction mechanisms of angiogenesis and inflammation following stroke as well as the challenges of exosomal studies such as secretion, uptake, modification, and application.

Purpose. To evaluate the use of femtosecond laser combined with double-flange polypropylene suture capsular tension ring (CTR) suspension to treat subluxation of lens in Marfan syndrome. The objective is to provide safer and more effective surgical procedures for patients. Setting. Eye Hospital, Aier Eye Hospital of Wuhan University, Wuhan, China Methods. In this retrospective study, we observed sixteen patients (16 eyes) with Marfan syndrome who had undergone this operation. Femtosecond laser incision was performed on the anterior capsule with the lens as the center. The suspending CTR was clipped to anterior capsule to support it, which was secured to the sclera with a double-flange polypropylene suture. Uncorrected visual acuity (UCVA), intraocular pressure (IOP), tilt, and decentration of the intraocular lens (IOL) and postoperative complications were evaluated. Results. All 16 patients were successfully implanted with suspended CTR and IOL after femtosecond laser assisted surgery. Visual acuity improved significantly after surgery ( p < 0.01 ). At 1 month, 3 months and 6 months postoperatively, the tilt of the IOL was 2.70 ± 0.934 , 2.65 ± 0.897 , and 2.66 ± 0.781 , and the decentration of the IOL was 0.30 ± 0.770 , 0.30 ± 0.682 , and 0.29 ± 0.737 ; both had no statistically significant difference between the three groups. After the operation, 4 patients had hyphema and 2 patients experienced a temporary postoperative IOP increase. Only one flange was exposed one month after operation and recovered right after secondary adjustment. Conclusion. Femtosecond laser combined with double-flange polypropylene suture CTR suspension was effective in fixing the lens capsule to the scleral wall in cases of subluxation of lens seen in Marfan syndrome during our short-term observation. The long-term efficacy of this operation needs further observation and follow-up.

Aim: To first explore the prognostic value of MMP11 and MMP15 in hepatocellular carcinoma. Methods: MMP11/MMP15 expression was immunohistochemically detected and correlated with clinicopathologic variables and survival and confirmed in publicly available databases. An MMP-based risk score (MMPRS) was established. Results: Tumoral MMP11/MMP15 expression was higher and univariately associated with crucial clinicopathologic parameters, overall survival and disease-free survival in all patients and/or many subsets. Multivariately, MMP11/MMP15 expression remained significant. Their overexpression and prognostic value were confirmed in the Ualcan and Kaplan–Meier plotter databases. Critically, the novel MMPRS integrating MMP11, MMP15 and tumor–node–metastasis stage identified subgroups with the best and worst prognoses, with much higher predictive power. Conclusion: MMP11 and MMP15 served as prognosticators in hepatocellular carcinoma. MMPRS might work more accurately.

Recently, lactate has been considered as an alternative direct energy substance to glucose for tumor proliferation and metastasis. Meanwhile, mitochondria, as important energy-supplying organelles, are also closely related to tumor progression. Consequently, a new research direction for lactate comprises lactate deprivation coupled with mitochondria-targeted phototherapy to achieve a safer and more effective strategy against tumor metastasis. Herein, linoleic acid-conjugated hyaluronic acid (HL), disulfide bond-rich nanovehicle (mesoporous silica, MOS), mitochondria-targeted IR780 (M780) and lactate oxidase (LOD) are rationally designed as a specific-targeting metabolism nanomodulator (HL/MOS@M780LOD NPs), fulfilling the task of simultaneous depriving cells of lactate and damaging mitochondria to prevent tumor metastasis. Interestingly, M780-mediated photodynamic therapy (PDT) and LOD-mediated starvation therapy can effectively exacerbate the hypoxia state of tumor cells, thereby increasing the free iron levels to activate ferroptosis. On one hand, pyruvic acid and H

Combined methylmalonic acidemia and homocystinuria, is a rare autosomal recessive disorder due to defective intracellular cobalamin metabolism. We report an 18-year-old Chinese male who presented with hypermyotonia, seizures, and congenital heart diseases. Mutation analysis revealed c.365AT and c.482 GA mutations in the

Human herpesvirus 6 (HHV-6) is neurophilic, and its relationship with Alzheimer's disease (AD) remains controversial. This study aimed to examine the relationships between HHV-6 and cognitive abilities in elderly people aged 60 years or above from communities in Shenzhen.We recruited participants from 10 community health service centers in Shenzhen. Participants were divided into case and control groups according to Mini-Mental State Examination (MMSE) scale standards and were included in this study with 1:1 matching based on sex and age (± 3 years). The HHV-6 gene was detected by real-time fluorescent quantitative PCR, and the HHV-6 copy number was quantified.A total of 580 participants (cases, n = 290; controls, n = 290), matched for gender and age was included in this study. A positive HHV-6 test was not associated with a significant difference in global cognitive performance (ORHHV-6 infection significantly associated with orientation, attention and calculation, and language in elderly individuals.

Genomic profiling of bronchoalveolar lavage (BAL) samples may be useful for tumor profiling and diagnosis in the clinic. Here, we compared tumor-derived mutations detected in BAL samples from subjects with non–small cell lung cancer (NSCLC) to those detected in matched plasma samples. Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) was used to genotype DNA purified from BAL, plasma, and tumor samples from patients with NSCLC. The characteristics of cell-free DNA (cfDNA) isolated from BAL fluid were first characterized to optimize the technical approach. Somatic mutations identified in tumor were then compared with those identified in BAL and plasma, and the potential of BAL cfDNA analysis to distinguish lung cancer patients from risk-matched controls was explored. In total, 200 biofluid and tumor samples from 38 cases and 21 controls undergoing BAL for lung cancer evaluation were profiled. More tumor variants were identified in BAL cfDNA than plasma cfDNA in all stages (P < 0.001) and in stage I to II disease only. Four of 21 controls harbored low levels of cancer-associated driver mutations in BAL cfDNA [mean variant allele frequency (VAF) = 0.5%], suggesting the presence of somatic mutations in nonmalignant airway cells. Finally, using a Random Forest model with leave-one-out cross-validation, an exploratory BAL genomic classifier identified lung cancer with 69% sensitivity and 100% specificity in this cohort and detected more cancers than BAL cytology. Detecting tumor-derived mutations by targeted sequencing of BAL cfDNA is technically feasible and appears to be more sensitive than plasma profiling. Further studies are required to define optimal diagnostic applications and clinical utility. Significance: Hybrid-capture, targeted deep sequencing of lung cancer mutational burden in cell-free BAL fluid identifies more tumor-derived mutations with increased allele frequencies compared with plasma cell-free DNA. See related commentary by Rolfo et al., p. 2826

Polycyclic aromatic hydrocarbons (PAHs) are widely existing organic pollutants in the environment, and their persistence in the environment makes us have to pay continuous attention to their health effects. However, since the American Heart Association updated its definition of hypertension in 2017, few studies have explored the relationship. This study aimed to investigate the relationship between PAH exposure and hypertension after the updated definition of hypertension and explore whether body mass index (BMI) moderates this relationship. A total of 6332 adult participants from the 2009-2016 National Health and Nutrition Examination Survey (NHANES) were examined. Multiple logistic regression and restricted cubic splines were used to analyze the association between urinary polycyclic aromatic hydrocarbon metabolites and hypertension, and the dose-response relationship. Weighted quantile sum (WQS) regression was applied to blood pressure to reveal multiple exposure effects and the relative weights of each PAH. The prevalence of hypertension in the study population was 48.52%. There was a positive dose-response relationship between high exposure to 1-hydroxynaphthalene, 23-hydroxyphenanthrene, and the risk of hypertension. Naphthalene metabolites accounted for the most significant proportion of systolic blood pressure, and phenanthrene metabolites accounted for the most significant proportion of diastolic blood pressure. Obese individuals with high PAH exposure were at greater risk for hypertension than individuals with low PAH exposure and normal BMI. Higher prevalence rate and stronger association of metabolites with outcomes were obtained in the general population of the USA under the new guideline. High levels of exposure to PAHs were positively associated with the risk of hypertension, and these effects were modified by BMI.

Haohan Zhou,1,2,&ast; Jiayi Tian,3,&ast; Hongyu Sun,1 Jiaying Fu,1 Nan Lin,1 Danni Yuan,1 Li Zhou,3 Meihui Xia,3 Liankun Sun1 1Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, People’s Republic of China; 2Department of Orthopaedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, 200000, People’s Republic of China; 3First Hospital, Jilin University, Changchun, 130021, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liankun Sun, Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, People’s Republic of China, Email sunlk@jlu.edu.cn Meihui Xia, First Hospital, Jilin University, Changchun, 130021, People’s Republic of China, Email xiamh@jlu.edu.cnPurpose: Magnetic iron oxide nanoparticle (MNP) drug delivery system is a novel promising therapeutic option for cancer treatment. Material issues such as fabrication and functionalized modification have been investigated; however, pharmacologic mechanisms of bare MNPs inside cancer cells remain obscure. This study aimed to explore a systems pharmacology approach to understand the reaction of the whole cell to MNPs and suggest drug selection in MNP delivery systems to exert synergetic or additive anti-cancer effects.Methods: HeLa and SiHa cell lines were used to estimate the properties of bare MNPs in cervical cancer through 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) and enzyme activity assays and cellular fluorescence imaging. A systems pharmacology approach was utilized by combining bioinformatics data mining with clinical data analysis and without a predefined hypothesis. Key genes of the MNP onco-pharmacologic mechanism in cervical cancer were identified and further validated through transcriptome analysis with quantitative reverse transcription PCR (qRT-PCR).Results: Low cytotoxic activity and cell internalization of MNP in HeLa and SiHa cells were observed. Lysosomal function was found to be impaired after MNP treatment. Protein tyrosine kinase 2 beta (PTK2B), liprin-alpha-4 (PPFIA4), mothers against decapentaplegic homolog 7 (SMAD7), and interleukin (IL) 1B were identified as key genes relevant for MNP pharmacology, clinical features, somatic mutation, and immune infiltration. The four key genes also exhibited significant correlations with the lysosome gene set. The qRT-PCR results showed significant alterations in the expression of the four key genes after MNP treatment in HeLa and SiHa cells.Conclusion: Our research suggests that treatment of bare MNPs in HeLa and SiHa cells induced significant expression changes in PTK2B, PPFIA4, SMAD7, and IL1B, which play crucial roles in cervical cancer development and progression. Interactions of the key genes with specific anti-cancer drugs must be considered in the rational design of MNP drug delivery systems.Keywords: drug delivery, anti-cancer drugs, PTK2B, PPFIA4, SMAD7, IL1B

Background and ObjectivesIndividuals with a history of recurrent dream-enactment behaviors, but with subthreshold REM sleep without atonia levels for REM sleep behavior disorder (RBD) diagnosis, are currently classified to have prodromal RBD (pRBD). However, the REM sleep–elevated EMG diagnostic cutoff, progression trajectory, and long-term neurodegenerative outcome of pRBD are not well understood. This study aimed to delineate the evolution of REM sleep EMG levels, determine the EMG cutoff score for diagnosing pRBD, and examine the risk for neurodegenerative diseases of pRBD.MethodsThis retrospective longitudinal case-control study recruited patients with pRBD and age-matched, sex-matched, and follow-up duration–matched controls who were free of neurodegenerative disease at baseline in the Sleep Assessment Unit, the Chinese University of Hong Kong from 1997 to 2018. Patients and controls underwent clinical and video-polysomnography (PSG) assessments at baseline and follow-up(s). REM sleep EMG activity level on mentalis and anterior tibialis (AT) muscles on video-PSG at each visit was scored. The diagnosis of neurodegenerative diseases was confirmed by a neurologist.ResultsA total of 44 patients (age 67.4 ± 8.2 years, 6 females) and 44 controls were recruited. The combined REM sleep EMG level on mentalis and AT muscles of patients with pRBD significantly increased during 8.2 ± 3.3 years of follow-up (from 19.3% ± 9.7% to 47.3% ± 27.4% with estimated annual increase of 3.9%), yielding 29 patients with pRBD (66%) meeting the full-blown RBD diagnostic criteria. Baseline REM sleep mentalis and AT muscles EMG activity of patients who developed full-blown RBD could favorably differentiate pRBD from controls (6.3% for mentalis “any” and 9.1% for combination of mentalis any and bilateral AT muscles phasic EMG with an area under the curve of 0.88 [0.78–0.98] and 0.97 [0.92–1.00], respectively). Patients with pRBD had a higher risk for neurodegenerative diseases (9 developed Parkinson disease and 3 developed dementia with Lewy bodies) when compared with controls (5 developed Alzheimer disease, adjusted hazard ratio = 2.95, 95% CI = 1.02–8.54).DiscussionpRBD has a predictive progression in both pathophysiology and neurodegenerative outcome. This finding has significant implications to the nosological status of pRBD, the current REM sleep-related EMG diagnostic criteria, spectrum concept of RBD, and future neuroprotective intervention.Classification of EvidenceThis study provides Class III evidence that EMG activity during REM sleep predicts the development of pRBD.

While genetic alterations in several regulators of the cell cycle have a significant impact on the gastric carcinogenesis process, the prognostic role of them remains to be further elucidated. The TCGA-STAD training set were downloaded and the mRNA expression matrix of cell cycle genes was extracted and corrected for further analysis after taking the intersection with GSE84437 dataset. Differentially expressed mRNAs were identified between tumor and normal tissue samples in TCGA-STAD. Univariate Cox regression analysis and lasso Cox regression model established a novel seven-gene cell cycle signature (including GADD45B, TFDP1, CDC6, CDC25A, CDC7, SMC1A and MCM3) for GC prognosis prediction. Patients in the high-risk group shown significantly poorer survival than patients in the low-risk group. The signature was found to be an independent prognostic factor for GC survival. Nomogram including the signature shown some clinical net benefit for overall survival prediction. The signature was further validated in the GSE84437 dataset. In tissue microarray, CDC6 and MCM3 protein expression were significant differences by the immunohistochemistry-based H-score between tumor tissues and adjacent tissues, and CDC6 is an independent prognostic factor for GC. Interestingly, our GSEA revealed that low-risk patients were more related to cell cycle pathways and might benefit more from therapies targeting cell cycle. Our study identified a novel robust seven-gene cell cycle signature for GC prognosis prediction that may serve as a beneficial complement to clinicopathological staging. The signature might provide potential biomarkers for the application of cell cycle regulators to therapies and treatment response prediction.

Clinical drug interaction studies with itraconazole and rifampicin have demonstrated that acalabrutinib is a sensitive substrate of CYP3A. A physiologically based pharmacokinetic (PBPK) model was developed based on the data of these studies. One of the active CYP3A metabolites, ACP-5862, was identified but never studied in a drug interaction scenario. This study aims to evaluate both parent and metabolite exposure change with coadministration of moderate CYP3A inhibitors and its impact on safety and efficacy.In an open label, randomized, 2-period study, we investigated the effect of coadministration of fluconazole or isavuconazole on the pharmacokinetics of acalabrutinib. Bruton tyrosine kinase receptor occupancy and safety were compared between different treatments. Experimental data were compared to PBPK simulation results.Least square means of acalabrutinib maximum plasma concentration and area under the curve increased 1.37 (1.14-1.64) and 1.60 (1.45-1.77)-fold in the presence of isavuconazole and 1.48 (1.10-1.98) and 2.16 (1.94-2.40)-fold in the presence of fluconazole, respectively. For ACP-5862, these values are 0.72 (0.63-0.82) and 0.91 (0.86-0.97) fold for isavuconazole and 0.65 (0.49-0.87) and 0.95 (0.91-0.99) fold for fluconazole coadministration. The PBPK model was able to recover acalabrutinib and ACP-5862 PK profiles in the study. Bruton tyrosine kinase receptor occupancy change was minimal in the presence of isavuconazole. There were no deaths, serious adverse events (AEs), or subject discontinuation due to AEs in this study. Only mild (Grade 1) AEs were reported during the study, by 17% of the study population.Our results demonstrate the impact of fluconazole and isavuconazole on the pharmacokinetics of acalabrutinib and ACP-5862, and suggest that no dose adjustment is needed for concomitant administration with moderate CYP3A inhibitors. the current PBPK model can be used to propose dose adjustment for drug interactions via CYP3A.

The pathological roles of long non-coding RNAs (lncRNAs) in colorectal carcinoma (CRC) have been corroborated. To date, the pathological contributions of LINC01315 in the epithelial-mesenchymal transition (EMT) property of CRC are still ambiguous. By silencing LINC01315, we disclosed that LINC01315 promoted the growth, metastatic characteristics, and the EMT of CRC cells

Background/Aim: Long noncoding RNA TARID (lncRNA TARID) can activate the tumor suppressor TCF21 in tumorigenesis by inducing promoter demethylation. However, the impact on lncRNA TARID and its variants of coronary artery disease (CAD) are poorly understood. Methods We performed a case-control study enrolling 949 case patients and 892 controls to assess genotype. Five variants were genotyped by TaqMan assay. 20 case patients and 20 controls were used to evaluate the expression of lncRNA TARID. The qRT-PCR and cell cycle analysis were applied to examined cell proliferation and cell distribution. Results This study indicated that rs2327433 GG genotype was associated with CAD risk adjusting for traditional risk factors (OR=2.74, 95%CI: 1.10-6.83, P=0.03). Our results analyses revealed that the genotype of rs2327433 was related to the proportion of CAD patients with left anterior descending artery disease and left circumflex artery disease (P=0.025 and P=0.025, respectively). The results showed that the minor allele frequency of rs2327433 was significantly correlated with the severity of the disease (P=0.029). The eQTL analysis showed that rs2327433 may affect the transcription factors TCF21 regulated by lncRNA TARID. We found that TARID silencing regulated the cell proliferation and altered cell cycle progression by induced upregulation of CDK1 and PCNA. Conclusions SNP rs2327433 in lncRNA TARID was associated with CAD risk and the severity of CAD in Chinese Han population. Furthermore, SNP rs2327433 may affect the expression of atherosclerosis-related transcription factor TCF21 regulated by lncRNA TARID. Finally, our study provided a new lncRNA-dictated regulatory mechanism participating in cell proliferation.

We aimed to determine the utility of biopsy data and anemia for the prediction of renal outcomes in Chinese patients with type 2 diabetes. In total, 441 Chinese patients with type 2 diabetes and biopsy-confirmed diabetic nephropathy (DN) were enrolled in a retrospective study. Their renal pathology was assessed using the Renal Pathology Society system. Cox proportional hazards models were used to estimate hazard ratios (HRs) for end-stage renal disease (ESRD), and immunofluorescence staining was used to assess the expression of hypoxia-inducible factor (HIF)-α in patients' kidneys. We found that glomerular pathology classification was an independent pathological predictor of low hemoglobin concentration, according to linear and logistic regression analyses. Each 1 g/dL decrease in baseline hemoglobin concentration was associated with a 42% higher risk of an adverse renal outcome, after adjustment for clinical and pathologic covariates. In patients with severe glomerular lesions, the risk of progression to ESRD was significantly higher if mild or moderate/severe anemia was present, but in patients with mild glomerular lesions, the risk was only significantly higher in those with moderate or severe anemia than in the absence of anemia. Harrell's C Concordance was improved, but the Akaike information criterion was worsened by adding the glomerular pathology classification to the use of anemia status and clinical data. Immunofluorescence staining revealed that renal HIF-1α and HIF-2α expression was significantly higher in classes II-IV than class I. Thus, the addition of glomerular pathology classification increases the value of anemia status for the prediction of the progression to ESRD.

To investigate the prognostic value of metabolic syndrome (MetS) and its relationship with renal structure changes in patients with type 2 diabetes and associated diabetic nephropathy (DN).411 Chinese patients with type 2 diabetes and biopsy-confirmed DN were enrolled in this retrospective study. MetS was defined according to the modified criteria of the 2005 International Diabetes Federation. Baseline demographics and clinical information at the time of renal biopsy were extracted from the hospital's electronic medical records system. Renal pathological findings were assessed according to Renal Pathology Society system. Univariate and multivariate logistic regression analyses were performed to define the pathological covariates associated with MetS. A competing risk model, with death as the competing risk, was used to estimate the sub-distribution hazard ratio (SHR) of MetS for end-stage kidney disease (ESKD).224 (55%) patients had MetS. Patients with MetS had poor renal function and more severe interstitial fibrosis tubular atrophy scores (IFTA) than those without MetS. Multivariate logistic regression analysis revealed that IFTA was significantly associated with MetS (odds ratio per score increase 1.45, 95% confidence interval [CI] 1.02-2.05). Of the patients with DN at risk, 40% of patients progressed to ESKD. After adjusting for renal function and pathological parameters, the presence of MetS was an independent predictor for progression to ESKD (SHR 1.93, 95% CI 1.34-2.79). The SHRs for progression to ESKD also increased as the number of MetS components increased. Additionally, adding the IFTA scores improved the prognostic power of a model that only contained MetS and clinical covariates for predicting future ESKD.MetS is an independent prognostic predictor of ESKD in patients with T2D and DN, while adding the IFTA scores increased the prognostic value of MetS for renal outcome.

Manipulating the activities of E3 ubiquitin ligases with chemical ligands holds promise for correcting E3 malfunctions and repurposing the E3s for induced protein degradation in the cell. Herein, we report an alternative strategy to proteolysis-targeting chimeras (PROTACs) and molecular glues to induce protein degradation by constructing and screening a γ-AA peptide library for cyclic peptidomimetics binding to the HECT domain of E6AP, an E3 ubiquitinating p53 coerced by the human papillomavirus and regulating pathways implicated in neurodevelopmental disorders such as Angelman syndrome. We found that a γ-AA peptide P6, discovered from the affinity-based screening with the E6AP HECT domain, can significantly stimulate the ubiquitin ligase activity of E6AP to ubiquitinate its substrate proteins UbxD8, HHR23A, and β-catenin in reconstituted reactions and HEK293T cells. Furthermore, P6 can accelerate the degradation of E6AP substrates in the cell by enhancing the catalytic activities of E6AP. Our work demonstrates the feasibility of using synthetic ligands to stimulate E3 activities in the cell. The E3 stimulators could be developed alongside E3 inhibitors and substrate recruiters such as PROTACs and molecular glues to leverage the full potential of protein ubiquitination pathways for drug development.

Non-small cell lung cancer (NSCLC) is one of the deadliest cancers in the world. Metastasis is considered one of the leading causes of treatment failure and death in NSCLC patients. A crucial factor of promoting metastasis in epithelium-derived carcinoma has been considered as epithelial-mesenchymal transition (EMT). Rictor, one of the components of mTORC2, has been reportedly involved in EMT and metastasis of human malignancies. However, the regulatory mechanisms of Rictor, Rictor-mediated EMT and metastasis in cancers remain unknown. Our present study indicates that Rictor is highly expressed in human NSCLC cell lines and tissues and is regulated, at least partially, at the transcriptional level. Knockdown of Rictor expression causes phenotype alterations through EMT, which is accompanied by the impairment of migration and invasion ability in NSCLC cells. Additionally, we have cloned and identified the human

Here we studied expression and potential functions of Gαi3 in cervical cancer. The bioinformatics analysis together with the results from local patients' tissues revealed that Gαi3 expression was remarkably elevated in human cervical cancer tissues and different cervical cancer cells, and was associated with poor overall survival and poor disease-specific survival of patients. Gαi3 depletion resulted in profound anti-cervical cancer activity. In primary or immortalized cervical cancer cells, Gαi3 shRNA or CRISPR/Cas9-caused Gαi3 knockout/KO largely hindered cell proliferation and migration, and provoked apoptosis. On the contrast, ectopic Gαi3 overexpression further enhanced cervical cancer proliferation and migration. Akt-mTOR activation in primary cervical cancer cells was significantly reduced after Gαi3 silencing or KO, but was augmented following Gαi3 overexpression. Further studies revealed that the transcription factor GATA4 binding to Gαi3 promoter region was significantly enhanced in cervical cancer tissues and cells. Gαi3 expression was decreased by GATA4 shRNA, but upregulated following GATA4 overexpression.

Exploring the cross-talk between the immune system and advanced biomaterials to treat SARS-CoV-2 infection is a promising strategy. Here, we show that ACE2-overexpressing A549 cell-derived microparticles (AO-MPs) are a potential therapeutic agent against SARS-CoV-2 infection. Intranasally administered AO-MPs dexterously navigate the anatomical and biological features of the lungs to enter the alveoli and are taken up by alveolar macrophages (AMs). Then, AO-MPs increase the endosomal pH but decrease the lysosomal pH in AMs, thus escorting bound SARS-CoV-2 from phago-endosomes to lysosomes for degradation. This pH regulation is attributable to oxidized cholesterol, which is enriched in AO-MPs and translocated to endosomal membranes, thus interfering with proton pumps and impairing endosomal acidification. In addition to promoting viral degradation, AO-MPs also inhibit the proinflammatory phenotype of AMs, leading to increased treatment efficacy in a SARS-CoV-2-infected mouse model without side effects. These findings highlight the potential use of AO-MPs to treat SARS-CoV-2-infected patients and showcase the feasibility of MP therapies for combatting emerging respiratory viruses in the future.

Colorectal cancer (CRC) is one of the most common malignancies worldwide, yet successful treatment still remains a challenge. In this study, we found that oxiconazole (OXI), a broad-spectrum antifungal agent, exhibits certain anti-tumor effect against CRC. Autophagy arrest and subsequent apoptosis are characterized as pivotal events involving OXI-induced growth suppression of CRC cells. Mechanistically, OXI downregulates the protein levels of peroxiredoxin-2 (PRDX2), an antioxidant enzyme, for reactive oxygen species (ROS) detoxication, to initiate autophagy by inactivating the Akt/mTOR pathway and inhibiting RAB7A-mediated fusion of autophagosome and lysosome, which lead to extreme accumulation of autophagosomes and subsequent growth suppression of CRC cells. Consistently, interfering with autophagy or overexpressing PRDX2 significantly impedes OXI-induced growth suppression of CRC cells. Moreover, OXI plus oxaliplatin, a mainstay drug for CRC treatment, achieves an improved anti-tumor effect. Taken together, our findings bring novel mechanistic insights into OXI-induced autophagy arrest and the growth inhibitory effect on CRC cells, and suggest a promisingly therapeutic role of OXI for CRC treatment.

Objectives Hemophilic arthropathy is the most common complication of severe hemophilia A. This study aims to investigated joint status and related risk factors in patients with severe hemophilia A (PWSHA). Methods This single-center study included 31 patients. Six index joints (both elbows, knees, and ankles) were evaluated using the Hemophilia Early Arthropathy Detection with UltraSound in China (HEAD-US-C) and Hemophilia Joint Health Score (HJHS). Treatment adherence was measured using the Validated Hemophilia Regimen Treatment Adherence Scale-Prophylaxis (VERITAS-Pro). We analyzed the influence of age, treatment delay (the interval between diagnosis and the initiation of treatment), prophylaxis, and treatment adherence on joint outcomes. Results All patients were male (median age, 22 years). The median age at diagnosis was 1 year; that at initial treatment was 5 years. All patients experienced joint bleeding. HEAD-US-C and HJHS scores were positively correlated (R = 0.70, P 1 year treatment delay was close to significant (P = 0.055). HJHS scores were significantly different between these two groups (P = 0.03). Joint assessment scores were not significantly different between on-demand and low-dose prophylaxis groups. VERITAS-Pro scores were correlated with both HEAD-US-C and HJHS scores (P = 0.046 and P = 0.005, respectively). Conclusions Hemophilic arthropathy was pervasive in PWSHA. Age and poor adherence were significantly correlated with joint damage. Prompt treatment and adherence improvement may reduce severity.

Online trolling is aggressive online behavior that has severe consequences for the mental health of internet users. Online trolling can be influenced by personal factors and psychological states. Based on the General Aggression Model, moral disengagement was examined as a moderator of the direct and indirect relations between mindfulness and online trolling via social media fatigue. A total of 1123 college students completed questionnaires regarding their experience with online trolling, mindfulness, social media fatigue, and moral disengagement. The results showed that individuals with high mindfulness were less likely to troll others online, which was mediated by their social media fatigue. Furthermore, moral disengagement moderated the indirect relationship between mindfulness and online trolling. Specifically, the relationship between mindfulness and social media fatigue became weaker for individuals with high moral disengagement. The relationship between social media fatigue and online trolling became strengthened for individuals with high moral disengagement. These findings elucidate the role of personal factors and the present internal state in online trolling and suggest that comprehensive intervention programs may be promising for reducing online trolling.

Background Diminished ovarian reserve (DOR) is the precursor state of ovarian failure and can cause the decline of women’s reproductive function. DOR also leads to poor outcome of in vitro fertilization and embryo transfer (IVF-ET) by affecting the oocytes, high qualified embryo rate, pregnancy rate, etc. Some studies have demonstrated that acupuncture can improve ovarian function. But to date, there is limited evidence indicating that acupuncture or electro-acupuncture is efficient to DOR. This trial aims to evaluate the efficiency and safety of electro-acupuncture for the ovarian function and the following outcome of IVF-ET in DOR patients. Methods This will be a multicenter randomized controlled clinical trial. A total of more than 338 women with DOR will be randomly allocated to treatment and control groups in 1:1 ratio receiving acupuncture before undergoing IVF-ET. The primary outcome will be the clinical pregnancy rate per cycle of IVF-ET after acupuncture. The secondary outcomes will be ovarian reserve function, outcomes of IVT-ET, blood biochemical index, Massachusetts General Hospital Acupuncture Sensation Scale (MASS), scores from the self-rating anxiety and depression scale, quality of life, and pregnancy outcomes. The safety of acupuncture will also be assessed. Discussion The results of this trial may provide high-quality evidence regarding the effectiveness of electro-acupuncture in the treatment of DOR and following outcomes of IVF-ET. This will also help patients with DOR and their physicians by offering a new treatment option. Trial registration Chinese Clinical Trial Registry ChiCTR1900024626. Registered on 19 July 2019.

Ginsenoside compound K (CK) is the major intestinal bacterial metabolite of ginsenosides that exhibits anticancer potential in various cancer cells both in vitro and in vivo. The anticancer types, mechanisms, and effects of CK in the past decade have been summarized in this review. Briefly, CK exerts anticancer effects via multiple molecular mechanisms, including the inhibition of proliferation, invasion, and migration, the induction of apoptosis and autophagy, and anti-angiogenesis. Some signaling pathways play a significant role in related processes, such as PI3K/Akt/mTOR, JNK/MAPK pathway, and reactive oxygen species (ROS). Moreover, the effects of CK combined with nanocarriers for anticancer efficiency are discussed in this review. Furthermore, we aimed to review the research progress of CK against cancer in the past decade, which might provide theoretical support and effective reference for further research on the medicinal value of small molecules, such as CK.

BACKGROUND Because of their cancer and treatment adverse effects, most pediatric oncology patients will experience 1 or more symptoms at one time that can seriously affect their quality of life. Because these children are attached to parents, their symptom burden directly influences the parental stress level and parental interpretations of their children's quality of life. OBJECTIVE The aim of this study was to examine the association between child-reported symptom burden and the pediatric quality of life reported by children with cancer and their parents, and whether parental perceived stress mediates these relationships. METHODS In a cross-sectional design, convenience sampling was used to recruit 80 parent-child dyads. Advanced statistical methods were adopted to analyze the mediating effects of parental stress between children's symptom burden and their quality of life. RESULTS The results revealed that parental stress was the mediator in the relationship between child-reported symptom burden and children's quality of life reported by parents. The results also showed that parental stress was not a mediator in the relationship between child-reported symptom burden and their quality of life. This underscored the differences in interpretations of quality of life reported by children and their parents. CONCLUSION Children's symptom burden is an important factor in predicting parental stress level and the quality of life reported by the children. Children's voice should be incorporated whenever possible. IMPLICATIONS FOR PRACTICE The knowledge gained from this study will facilitate intervention development to enhance parents' abilities in stress management and symptom management for their children with the support of the nursing profession.

Background Some pain, fatigue, and gastrointestinal adverse events were observed in potential association with injection of COVID-19 vaccines, while there was no preventive intervention for it. We aim to investigate the efficacy of auricular acupressure (AA) therapy in preventing and relieving AEFI after injection of COVID-19 vaccine. Methods The study design is a randomized, multicentre, three-arm controlled, single-blind trial. Participants meeting the inclusion criteria will be advertised and enrolled and assigned in the medical institutions randomly for post-injection observation. No less than 360 participants will be randomized into one of three groups: auricular acupressure group, sham auricular acupressure group, and wait-list group. Interventions will be performed immediately and will happen 4 to 5 times per day for 5 days. The primary clinical outcomes will be quality and quantity evaluation among participants who reported any AEFI and who reported local pain at injection site. Secondary outcomes will concern headache, muscle and (or) joint pain, fatigue, nausea, vomiting, diarrhoea, and other potential events. All the outcomes will be assessed at baseline and 1, 3, 5, 7, and 14 days after the injection. Both intention-to-treat and per-protocol analyses will be performed, with significance level determined as 5%. Discussion Results of this trial will help to clarify the value of auricular acupressure therapy in preventing and relieving overall and certain adverse events following immunization after injection of COVID-19 vaccine. Trial registration China Clinical Trial Registry (ChiCTR) (ChiCTR2100043210). Registered on 8 February, 2021.

Identification of cancer-predisposing germline variants in childhood cancer patients is important for therapeutic decisions, disease surveillance and risk assessment for patients, and potentially, also for family members. We investigated the spectrum and prevalence of pathogenic germline variants in selected childhood cancer patients with features suggestive of genetic predisposition to cancer. Germline DNA was subjected to exome sequencing to filter variants in 1048 genes of interest including 176 known cancer predisposition genes (CPGs). An enrichment burden analysis compared rare deleterious germline CPG variants in the patient cohort with those in a healthy aged control population. A subset of predicted deleterious variants in novel candidate CPGs was investigated further by examining matched tumor samples, and the functional impact of AXIN1 variants was analyzed in cultured cells. Twenty-two pathogenic/likely pathogenic (P/LP) germline variants detected in 13 CPGs were identified in 19 of 76 patients (25.0%). Unclear association with the diagnosed cancer types was observed in 11 of 19 patients carrying P/LP CPG variants. The burden of rare deleterious germline variants in autosomal dominant CPGs was significantly higher in study patients versus healthy aged controls. A novel AXIN1 frameshift variant (Ser321fs) may impact the regulation of β-catenin levels. Selection of childhood cancer patients for germline testing based on features suggestive of an underlying genetic predisposition could help to identify carriers of clinically relevant germline CPG variants, and streamline the integration of germline genomic testing in the pediatric oncology clinic.

BackgroundThere is a paucity of data on whether steatosis impacts autoimmune hepatitis (AIH) treatment response. We aimed to evaluate the influence of baseline steatosis on the biochemical response, fibrosis progression, and adverse longterm outcomes of AIH.MethodsSteatosis was diagnosed by a controlled attenuation parameter (CAP) ≥ 248 dB / m. Only patients who underwent immunosuppressive therapy with available liver histological material at diagnosis and qualified CAP within seven days of the liver biopsy were included. Univariate and multivariate analyses were subsequently conducted.ResultsThe multicentre and retrospective cohort enrolled 222 subjects (88.3% female, median age 54 years, median follow-up 48 months) in the final analysis, and 56 (25.2%) patients had hepatic steatosis. Diabetes, hypertension, and significant fibrosis at baseline were more common in the steatosis group than in the no steatosis group. After adjusting for confounding factors, hepatic steatosis was an independent predictor of insufficient biochemical response (OR: 8.07) and identified as an independent predictor of long-term adverse outcomes (HR: 4.07). By subgroup multivariate analysis (different degrees of steatosis, fibrosis, and prednisone dose), hepatic steatosis independently showed a relatively stable correlation with treatment response. Furthermore, in contrast to those without steatosis, a significant increase in liver stiffness (LS) was observed in patients with steatosis (4.1%/year vs. -16%/year, P < 0.001).ConclusionsConcomitant hepatic steatosis was significantly associated with poor response to treatment in AIH patients. Routine CAP measurements are therefore essential to guide the management of AIH.

Overexpression of survivin is frequently observed in human malignancies and is associated with poor prognosis. The present study found that survivin is highly expressed in nasopharyngeal carcinoma (NPC) tumor tissues. Depleting survivin with shRNA inhibited cell viability, colony formation, and in vivo tumorigenesis of NPC cells. With a natural product screening, we identified Butein as a potential anti-tumor compound for NPC by reducing survivin protein level. Butein shortened the half-life of survivin and enhanced ubiquitination-mediated degradation. The mechanism study showed that Butein promoted the interaction between survivin and E3 ligase Fbxl7, and the knockdown of Fbxl7 compromised Butein-induced survivin ubiquitination. Butein suppressed the Akt-Wee1-CDK1 signaling and decreased survivin Thr34 phosphorylation, facilitating E3 ligase Fbxl7-mediated survivin ubiquitination and degradation. Moreover, Butein exhibited a strong in vivo anti-tumor activity, as the tumor volume of Butein-treated xenografts was reduced significantly. Butein alone or combined with cisplatin (CDDP) overcame chemoresistance in NPC xenograft tumors. Overall, our data indicate that Butein is a promising anti-tumor agent for NPC treatment.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare systemic vasculitis, which often starts with respiratory symptoms such as asthma, and it is difficult to make early clinical diagnosis.This study aims to improve the therapeutic level of EGPA with lung involvement via analyzing the clinical characteristics, diagnosis, and treatment .We retrospectively analyzed the clinical data of 13 EGPA patients with lung involvement who were diagnosed from February 1, 2014 to July 31, 2021 in the Second Xiangya Hospital, Central South University.The ratio of male to female in 13 patients was 7꞉6. The patients were diagnosed at median age 52 (46-68) years old and 6 had been diagnosed as "bronchial asthma". Pulmonary clinical manifestations mainly included cough, expectoration, wheezing, and shortness of breath; while extra-pulmonary manifestations mainly included rash and subcutaneous mass, fever, limb numbness, muscle and joint pain, abdominal pain, etc. Peripheral blood tests of all patients showed that 11 patients had eosinophils ≥10%, 10 had elevated inflammatory indicators, and 3 were anti-neutrophil cytoplasmic antibody (ANCA) positive. The major lung imaging features were patches or strips of increased density, multiple nodules, bronchiectasis, bronchial wall thickening, exudation, mediastinal lymph nodes, and so on. Eight patients had sinusitis and 9 with abnormal electromyography. Extravascular eosinophil infiltration was found in 9 patients. Six patients with lung biopsy showed eosinophil, lymphocyte, and plasma cell infiltration, 3 patients were involved in small blood vessels, and 1 had granuloma. Pulmonary function tests were performed in 7 patients, 5 of them showed different degrees of pulmonary ventilation dysfunction, and 4 of them had diffusion dysfunction. Almost all patients respond well to glucocorticoid and immunosuppressant.EGPA is rare in clinical, often involving multiple systems with great harm and may combine with asthmatic manifestations. Pulmonary involvement is relatively common. However, due to insufficient recognition of this disease and huge heterogeneity of pulmonary imaging manifestations, misdiagnosis and missed diagnosis are easy to occur. Relevant laboratory, imaging, and biopsy examination should be performed as early as possible with comprehensive consideration of extrapulmonary involvement. Early identification has great significance to improve the diagnosis rate and prognosis of diseases.

There was growing evidence that inflammatory responses played significant roles in malignancies. However, the impact of pro-inflammatory-to-anti-inflammatory factor ratio in tumor tissues has not been investigated in gastric cancer (GC) yet. We collected patient data from The Cancer Genome Atlas (TCGA) database. A total of 270 stomach adenocarcinoma (STAD) patients without distant metastasis were included in the study. After screening 12 candidate pro-inflammatory-to-anti-inflammatory pairs, only the IL-6/IL-10 mRNA expression ratio in tumor tissues had a significant effect on overall survival (OS) of STAD patients (P = 0.014). X-tile analysis showed that the greatest survival differences were obtained when the cutoff value of IL-6/IL-10 mRNA expression ratio was set at 1.3 and 5.5. With the low-ratio group (IL-6/IL-10 mRNA expression ratio: IL-6/IL-10 mRNA expression ratio: 1.3–5.5) and the high-ratio group (IL-6/IL-10 mRNA expression ratio: > 5.5) was significantly shorter (P IL-6/IL-10 mRNA expression ratio was an independent prognostic factor for OS and disease-specific survival (DSS). These findings provided a novel and powerful tool for a more rational management of GC patients.

Background: Patients with extremely high-risk ASCVD usually suffered poor prognosis, bilirubin is considered closely related to cardiovascular outcomes. However, there is controversy over the relationship between bilirubin and coronary artery disease. This study aimed to evaluate the predictive value of the DIBIL ratio in patients with extremely high-risk ASCVD. Methods: 10,260 consecutive patients with extremely high-risk ASCVD were enrolled in this study. All patients were divided into three groups according to their DIBIL ratio. The incidence of MACCEs was recorded, and in a competing risk regression, the incidence of MACCEs and their subgroups were recorded. The direct-indirect bilirubin ratio (DIBIL ratio) was calculated by the direct bilirubin (umol/L)/indirect bilirubin (umol/L) ratio, all laboratory values were obtained from the first fasting blood samples during hospitalization. Results: The area under the ROC curve of the DIBIL ratio to predict the occurrence of all-cause death was 0.668, the cut-off value of which is 0.275. Competing risk regression indicated that DIBIL ratio was positively correlated with all-cause death [1.829 (1.405–2.381), p Conclusion: The DIBIL ratio was an excellent tool to predict poor prognosis, suggesting that this index may be developed as a biomarker for risk stratification and prognosis in extremely ASCVD patients.

Background Infection is one of the most common causes of death in patients with hematological malignancies during chemotherapy. Due to its special location, local warmth and humidity, repeated pollution with stool and urine, and characteristically wrinkled anatomical structure within which bacteria can hide, the perianal becomes a site with a high incidence of infection. Such infection also has a high recurrence rate and high mortality, increasing the economic burden of patients, delaying the time of treatment and reducing the quality of life. In severe cases, sepsis occurs and endangers the patient’s life. Previous studies have confirmed the effectiveness of povidone iodine (PI) in the prevention of perianal infection in patients with hematological malignancies during chemotherapy, but these reports have not documented in detail the adverse events associated with sitz bathing and the lack of randomized controlled trials of different concentrations of dilute povidone iodine sitz bathing. Therefore, the evidence is insufficient. Hence, the objective of this paper is to determine whether a povidone iodine diluent sitz bath can reduce the incidence of perianal infection compared with conventional perianal cleaning care and to observe the incidence of perianal infection, the severity of perianal infection, and the complications related to the sitz bath among groups treated with different concentrations of povidone iodine diluent, especially in high-risk patients prone to perianal infection, to screen for the optimal concentration. Methods The trial is designed as a single-center, parallel, randomized, controlled and intervention trial with four parallel groups, and a primary endpoint of perianal infection occurred after this hospitalization chemotherapy. Randomization will be performed as simple randomization with a 1:1:1:1 allocation. This study received full ethics committee approval. The first patient was enrolled on May 1, 2021. A total of 268 patients with hematological malignancies undergoing chemotherapy who have risk factors for perianal infection will be enrolled with informed consent and randomly allocated to one of the four arms receiving (1) perianal cleaning care (control group D), (2) 1:100 PI diluted sitz bath (intervention group A), (3) 1:200 PI diluted sitz bath (intervention group B), and (4) 1:300 PI diluted sitz bath (intervention group C). The primary endpoint of the trial was the incidence of perianal infection. The secondary endpoints of the study will be the results of anal swab bacterial culture, the severity of perianal infection, the incidence of perianal adverse events (dryness, peeling, pigmentation, burning sensation), and pain scores. The length of hospitalization in days and hospitalization expenses will be recorded. Safety will be assessed with consideration of all adverse and severe adverse events related to the study treatment. Discussion We hypothesized that patients with hematological malignancies during chemotherapy would benefit from a povidone iodine diluted sitz bath. This study will provide evidence-based recommendations for clinicians and nurses. Trial registration Chinese Clinical Trial Registry (registration ID: ChiCTR2000041073). Registered on December 17, 2020. The protocol version number is V1.0,20201217. http://www.chictr.org.cn/edit.aspx?pid=66044&htm=4

ObjectiveTo evaluate the long-term cost effectiveness of insulin degludec/insulin aspart (IDegAsp) vs. biphasic insulin aspart 30 (BIAsp 30) for the treatment of people with type 2 diabetes mellitus (T2DM) inadequately managed on basal insulin in China.MethodsThe CORE (the Center for Outcomes Research) Diabetes Model, which has been published and verified, was used to simulate disease progression and calculate the total direct medical costs, life years (LYs) and quality-adjusted life years (QALYs) over 30 years, from the perspective of Chinese healthcare system. The patient demographic information and clinical data needed for the model were gathered from a phase III treat-to-target clinical trial (NCT02762578) and other Chinese cohort studies. Medical costs on treating diabetes were calculated based on clinical trial and local sources. The diabetes management and complications costs were derived from published literature. A discounting rate of 5% was applied to both health and cost outcomes. And one-way and probabilistic sensitivity analyses were carried out to test the reliability of the results.ResultsCompared with BIAsp 30, treatment with IDegAsp was associated with an incremental benefit of 0.001 LYs (12.439 vs. 12.438) and 0.280 QALYs (9.522 vs. 9.242) over a 30-year time horizon, and increased CNY (Chinese Yuan) 3,888 (390,152 vs. 386,264) for total costs. IDegAsp was cost-effective vs. BIAsp 30 therapy with an incremental cost-effectiveness ratio of CNY 13,886 per QALY gained. Results were robust across a range of sensitivity analyses.ConclusionCompared with BIAsp 30, IDegAsp was a cost-effective treatment option for people with T2DM with inadequate glycemic management on basal insulin in China.

We reviewed the effects of hypertension and the means to prevent and treat it across the spectrum of a woman's lifespan and identified gaps in sex-specific mechanisms contributing to hypertension in women that need to be addressed.Hypertension continues to be an important public health problem for women across all life stages from adolescence through pregnancy, menopause, and older age. There remain racial, ethnic, and socioeconomic differences in hypertension rates not only overall but also between the sexes. Blood pressure cutoffs during pregnancy have not been updated to reflect the 2017 ACC/AHA changes due to a lack of data. Additionally, the mechanisms behind hypertension development in menopause, including sex hormones and genetic factors, are not well understood. In the setting of increasing inactivity and obesity, along with an aging population, hypertension rates are increasing in women. Screening and management of hypertension throughout a women's lifespan are necessary to reduce the burden of cardiovascular disease, and further research to understand sex-specific hypertension mechanisms is needed.

To investigate the clinical features and laboratory characteristics of primary autoimmune hemolytic anemia (AIHA) patients with negative results of direct antiglobulin test (DAT) by tube test but positive results by microcolumn gel assay, in order to provide references for the diagnosis of these patients.59 patients diagnosed with primary AIHA in our hospital from January 2015 to December 2020 were retrospectively analyzed. According to the results of tube test and microcolumn gel assay, the cases were divided into 3 groups, and the clinical and laboratory characteristics of each group were compared.The cases were grouped as follows: Group I, cases with negative results by both methods of DAT (n=5); Group II, cases with negative results by tube test but positive results by microcolumn gel assay (n=26); Group III, cases with positive results by both methods of DAT (n=28). There was no significant difference in age and sex between Group II and other groups, whereas the positive rate of anti-IgG + anti-C3d of Group II was lower than that in Group III (P=0.015). The main clinical manifestations of Group II were chest tightness, shortness of breath, fatigue, as well as yellow skin and sclera or dark urine, but the incidence rate of these symptoms was not significantly different from other groups. Anemia related indexes in Group II such as red blood cell (RBC) count and hemoglobin (Hb) were lower than the reference intervals, but there was no significant difference compared with other groups. Hemolysis related indexes in Group II such as reticulocyte (Ret) ratio, indirect bilirubin (IBIL), lactate dehydrogenase (LDH) and free-hemoglobin (F-Hb) were higher than the reference intervals, and the latter two items were signficantly higher than those in Group I (P=0.031 and P=0.036). Serum complement C3 and C4 in Group II were higher than those in Group III (P=0.010 and P=0.037).Anemia severity of primary AIHA patients who were negative of DAT by tube test but positive by microcolumn gel assay was similar to those with negative or positive results by both DAT methods, but the mechanism and degree of complement system involved in hemolysis might be different. Results above may be helpful for laboratory diagnosis of this kind of patients.DAT试管法阴性而微柱凝胶法阳性的原发自身免疫性溶血性贫血患者的临床与实验室特征.探讨直接抗人球蛋白试验（DAT）试管法阴性而微柱凝胶法阳性的原发自身免疫性溶血性贫血（AIHA）患者的临床与实验室特征，为此类患者的诊断提供借鉴。.回顾性分析2015年1月至2020年12月在本院就诊的原发AIHA患者59例。根据DAT试管法和微柱凝胶法结果将研究对象分为3组，比较各组的临床与实验室特征。.将研究对象分为DAT两方法均阴性组（Ⅰ组，n=5）、DAT试管法阴性而微柱凝胶法阳性组（Ⅱ组，n=26）、DAT两方法均阳性组（Ⅲ组，n=28）。Ⅱ组与其他组别相比，年龄、性别组成均无显著差异，DAT微柱凝胶法抗IgG+抗C3d阳性比例低于Ⅲ组（P=0.015）。Ⅱ组临床表现以胸闷、憋气、乏力等贫血相关症状以及皮肤、巩膜黄染或尿色加深等溶血相关症状为主，但发生率与其他组别无显著差异。Ⅱ组的红细胞数（RBC）、血红蛋白（Hb）等贫血相关指标低于参考范围，但与Ⅰ组、Ⅲ组相比差异无统计学意义。Ⅱ组的网织红细胞（Ret）比率、间接胆红素（IBIL）、乳酸脱氢酶（LDH）、游离血红蛋白（F-Hb）等溶血相关指标高于参考范围，其中后2项显著高于Ⅰ组（P=0.031和P=0.036）。Ⅱ组的血清补体C3、C4水平均高于Ⅲ组（P=0.010和P=0.037）。.DAT试管法阴性而微柱凝胶法阳性的原发AIHA患者与两方法均阴性和均阳性患者相比，贫血程度接近，但补体系统参与溶血的机制和程度可能不同。这一结果可能对此类患者的实验室诊断与鉴别提供帮助。.

BackgroundOverweight and obesity among college students have become an emergent public health concern, which may be effectively prevented by diet self-management (DSM). The purpose of this explorative study was to explore college students' experiences and perspectives on diet self-management (DSM), as well as its influencing factors.MethodThirty-three college students were recruited from different universities in China. A qualitative method was used to conduct semi-structured interviews with audio recording to explore their DSM experience and factors that influence DSM. Data were analyzed using thematic analysis to develop themes related to DSM.ResultIn the perception of what "good DSM" means, three themes and ten subthemes were identified: characteristics of good DSM (including 5 subthemes: regularity, balanced diet, no picky eating, good eating habits, and scientificity), method of good DSM (including three subthemes: self-control, adjusting, and making plans), and content of good DSM (including two subthemes: nutrition management and safety management). The influencing factors of DSM can be categorized into four levels of themes and 34 subthemes: individual, family, school, and social levels.ConclusionThe results of this qualitative research highlighted the complexity and multi-dimension of DSM and its influencing factors. Our findings may help to inform diverse and needs-based intervention approaches to improve DSM and promote healthy diet among college students so as to prevent overweight and obesity.