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Using a convergent synthetic route to enable multiple points of diversity, a series of glucocorticoid receptor modulators (GRM) were profiled for potency, selectivity, and drug-like properties

Laxity of the upper eyelid skin in the elderly usually leads to an aged appearance and visual field defect, which affects their quality of life. However, there are very few reports on the evaluation and treatment strategy for upper eyelid skin redundancy in elderly Asians. Hence, this article describes an upper eyelid skin laxity correction surgery using an innovative parallel palpebral margin incision to improve ptosis and enlarge the visual field.From August 2012 to March 2021, 87 patients with severe eyelid laxity and ptosis presented to the Plastic Surgery Department of the Zhongda Hospital Affiliated to Southeast University. Upper eyelid skin laxity correction surgery with eyelid marginal incision was performed to correct the excessive tissue between the eyebrow and the upper eyelid and improve patients' vision field. Thereafter, a postoperative follow-up was conducted to observe the results in terms of skin laxity, eyelid shape changes, visual field improvement, postoperative scars, and patients' satisfaction.During the follow-up, information was collected between 3 months and 1 year after surgery. No visible scars were seen in patients after the operation, and the sagging skin of the upper eyelid was corrected. In addition, the effect of correcting visual field defect is stable, with no recurrence within 1 year. The operation was effective, and patients were satisfied.This surgical strategy significantly improved severe upper eyelid skin laxity with inconspicuous postoperative scars. After the operation, patients felt satisfied, and their quality of life was notably improved.

The success rate of dental implants is limited by peri-implant infection and insufficient osseointegration. Therefore, reducing the occurrence of peri-implantitis and promoting osseointegration are in demand. A roughened surface has commonly been applied to improve the osseointegration of implants, but it will accelerate the attachment of bacteria. We have developed novel antibiotic-decorated titanium (Ti) surfaces by the immobilization of dopamine and cefotaxime sodium (CS) simultaneously. Moreover, the surface roughness of the polydopamine (PDA)/CS coating was controlled by the changes in polymerization times as determined by atomic force microscopy. Then, all antibiotic-grafted Ti surfaces could effectively prevent the adhesion and proliferation of both

Purpose: This study aims to translate the English version of the Trans Woman Voice Questionnaire (TWVQ) to simplified Chinese (TWVQ-SC) and to examine its reliability and validity. Method: Standardized translation procedures were strictly followed for the translation of the TWVQ. Two hundred sixty trans woman and 128 cis woman subjects completed sociodemographic investigation, the TWVQ-SC, and the Voice Handicap Index–10 (VHI-10) online. Internal consistency was examined by Cronbach reliability coefficient (Cronbach α). Test–retest reliability was quantified by intraclass correlation coefficient (ICC). Content validity, structural validity, and discriminant validity were examined by expert panel's judgment, factor analysis, Spearman's rank correlation coefficient, and the Mann–Whitney U test. Results: The Cronbach α of the TWVQ-SC was .969 and the ICC was .841, indicating excellent internal consistency and good test–retest reliability. The four principal factors explained 21.345%, 18.592%, 13.551%, and 12.027% of the variance respectively with the cumulative contribution rate 65.514%. There was a strong correlation between the total score of the TWVQ-SC and that of the VHI-10 ( r = .858, p < .001), indicating good structural validity. The total score of the TWVQ-SC of the trans woman subjects was significantly higher than that of the cis woman subjects ( z = 14.590, p < .05), indicating good discriminant validity. Conclusion: The TWVQ-SC exhibits overall high reliability and validity, qualified to be applied as a reliable clinical tool to evaluate trans women's voice in mainland China.

Omphalocele and gastroschisis are the two most common congenital abdominal wall defects; however, no previous study has focused on gastrointestinal and hepatobiliary tract malformations in these two conditions. This study aimed to investigate the demographic characteristics, coexisting congenital gastrointestinal and hepatobiliary tract anomalies, hospital course, and outcomes of patients with gastroschisis and omphalocele.This is retrospective chart review of all patients admitted to one tertiary medical center in Taiwan between January 1, 2000 and June 30, 2020 with a diagnosis of gastroschisis or omphalocele. The medical records were reviewed to obtain demographic data regarding coexisting gastrointestinal and hepatobiliary tract anomalies and outcomes.Of the 51 patients included, 21 had gastroschisis and 30 had omphalocele. Gastroschisis was associated with a significantly younger maternal age and a higher incidence of small for gestational age. Of the 30 patients with omphalocele, twelve had associated gastrointestinal and hepatobiliary anomalies. Seven of the 21 patients with gastroschisis had gastrointestinal anomalies, and none had hepatobiliary anomalies. Among the omphalocele patients, three (10%) had documented malrotation, and one developed midgut volvulus. Among gastroschisis patients, four patients (19%) had malrotation, and two developed midgut volvulus. There were no statistically significant differences in postoperative complications or mortality rates between those with and without gastrointestinal/hepatobiliary tract anomalies.The diversity of coexisting gastrointestinal and hepatobiliary tract anomalies is higher in the omphalocele than in gastroschisis. In addition, we demonstrate that patients with gastroschisis or omphalocele have a higher rate of intestinal malrotation and midgut volvulus.

To compare the hemodynamic response of methylene blue dosing regimens (bolus v bolus plus infusion) for the treatment of vasoplegia.A retrospective cohort analysis.A single-center academic medical center.Patients who underwent cardiac surgery at Cleveland Clinic and received methylene blue between 2016 and 2019. Patients were excluded from the analysis if methylene blue was initiated48 hours after surgery, if the cardiac index was2.0 L/min/mMethylene blue bolus-only regimens versus bolus plus continuous infusion methylene blue regimens.The primary outcome was vasopressor requirement over 48 hours (1, 3, 6, 12, 24, and 48 hours) after methylene blue initiation. Other hemodynamic outcomes evaluated included the rate of methylene blue response, mean arterial pressure (MAP), and systemic vascular resistance (SVR) values over time. In total, 44 patients were included in the analysis, 33 of whom only received a methylene blue bolus. Vasopressor requirements at baseline were 95 (95% CI: 70-122) µg/min norepinephrine equivalent (NE) in the bolus-only group and 100 (86-130) µg/min in the infusion group. Vasopressor requirements decreased at each time point in both groups and were similar throughout (hour 1 mean [95% CI] NE, bolus 79 [67-91] µg/min v bolus plus infusion 84 [63-104] µg/min; p = 0.71). MAP, SVR, and rates of methylene blue response were similar between groups at all time points. Clinical outcomes also were similar between groups.The addition of a methylene blue continuous infusion did not significantly improve hemodynamic response. Bolus-only dosing of methylene blue may be sufficient for the treatment of vasoplegia after cardiac surgery.

Rationale: Jacobsen syndrome is a rare chromosomal disorder caused by deletions in the long arm of human chromosome 11, resulting in multiple developmental defects including congenital heart defects. Combined studies in humans and genetically engineered mice implicate that loss of ETS1 (E26 transformation specific 1) is the cause of congenital heart defects in Jacobsen syndrome, but the underlying molecular and cellular mechanisms are unknown. Objective: To determine the role of ETS1 in heart development, specifically its roles in coronary endothelium and endocardium and the mechanisms by which loss of ETS1 causes coronary vascular defects and ventricular noncompaction. Methods and Results: ETS1 global and endothelial-specific knockout mice were used. Phenotypic assessments, RNA sequencing, and chromatin immunoprecipitation analysis were performed together with expression analysis, immunofluorescence and RNAscope in situ hybridization to uncover phenotypic and transcriptomic changes in response to loss of ETS1. Loss of ETS1 in endothelial cells causes ventricular noncompaction, reproducing the phenotype arising from global deletion of ETS1. Endothelial-specific deletion of ETS1 decreased the levels of Alk1 (activin receptor-like kinase 1), Cldn5 (claudin 5), Sox18 (SRY-box transcription factor 18), Robo4 (roundabout guidance receptor 4), Esm1 (endothelial cell specific molecule 1) and Kdr (kinase insert domain receptor), 6 important angiogenesis-relevant genes in endothelial cells, causing a coronary vasculature developmental defect in association with decreased compact zone cardiomyocyte proliferation. Downregulation of ALK1 expression in endocardium due to the loss of ETS1, along with the upregulation of TGF (transforming growth factor)-β1 and TGF-β3, occurred with increased TGFBR2/TGFBR1/SMAD2 signaling and increased extracellular matrix expression in the trabecular layer, in association with increased trabecular cardiomyocyte proliferation. Conclusions: These results demonstrate the importance of endothelial and endocardial ETS1 in cardiac development. Delineation of the gene regulatory network involving ETS1 in heart development will enhance our understanding of the molecular mechanisms underlying ventricular and coronary vascular developmental defects and will lead to improved approaches for the treatment of patients with congenital heart disease.

Ischemic stroke (IS) is often comorbid with type 2 diabetes mellitus (T2DM) wherein the determinants of long-term outcomes, beyond the acute stroke phase, are not adequately known. This study identified the determinants of long-term outcomes for diabetic IS patients through a prospective nested case-control study in 624 patients treated with conservative measures (38.60% females, mean age: 63.85 years). After 36-month follow-up, 117 (18.8%) patients with poor outcome were enrolled in the case group. The poor outcome was defined with a modified Rankin Scale (mRS) score ≥3. Meanwhile, 374 (59.9%) patients with good outcome, defined as (mRS score3), were included in the control group. Patients who died (

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with no currently approved treatment. The natural compound silybin (SLN) has versatile hepatoprotective efficacy with negligible adverse effects; however, poor absorption limits its clinical applications. Gut microbiota has been proposed to play a crucial role in the pathophysiology of NAFLD and targeted for disease control. Cyclodextrins, the cyclic oligosaccharides, were documented to have various health benefits with potential prebiotic properties. This study aimed to develop a silybin-2-hydroxypropyl-β-cyclodextrin inclusion (SHβCD) to improve the therapeutic efficacy of SLN and elucidate the mechanisms of improvement. The results showed that SLN formed a 1:1 stoichiometric inclusion complex with HP-β-CD. The solubility of SLN was increased by generating SHβCD, resulting in improved drug permeability and bioavailability. In high-fat diet (HFD)-fed hamsters, SHβCD modulated gut health by restoring the gut microbiota and intestinal integrity. SHβCD showed superior anti-lipid accumulation, antioxidant, and anti-inflammatory effects compared with SLN alone. Transcriptome analysis in the liver tissue implied that the improved inflammation and/or energy homeostasis was the potential mechanism. Therefore, SHβCD may be a promising alternative for the treatment of NAFLD, attributing to the dual functions of HβCD on drug absorption and gut microbial homeostasis.

To evaluate AAPM TG-218 recommended tolerances for IMRT QA for conventional and SBRT delivery.QA analysis was repeated for 150 IMRT/VMAT patients with varying gamma criteria. True composite delivery was utilized, corrected for detector and output variation. Universal tolerance (TLThe IMRT/VMAT TLThe AL

Ets1 deletion in some mouse strains causes septal defects and has been implicated in human congenital heart defects in Jacobsen syndrome, in which one copy of the Ets1 gene is missing. Here, we demonstrate that loss of Ets1 in mice results in a decrease in neural crest (NC) cells migrating into the proximal outflow tract cushions during early heart development, with subsequent malalignment of the cushions relative to the muscular ventricular septum, resembling double outlet right ventricle (DORV) defects in humans. Consistent with this, we find that cultured cardiac NC cells from Ets1 mutant mice or derived from iPS cells from Jacobsen patients exhibit decreased migration speed and impaired cell-to-cell interactions. Together, our studies demonstrate a critical role for ETS1 for cell migration in cardiac NC cells that are required for proper formation of the proximal outflow tracts. These data provide further insights into the molecular and cellular basis for development of the outflow tracts, and how perturbation of NC cells can lead to DORV.

Background: Pulmonary arterial hypertension is an incurable disease, in which the extracellular CaSR (calcium sensing receptor) is mechanistically important. This study was aimed to genetically link the CaSR gene and function to the disease severity. Methods: Sanger sequencing, Sugen/hypoxia pulmonary arterial hypertension rat model, CaSR mutated rat, transcriptional reporter assay and measurement of CaSR activity were used. Results: Sanger sequencing identified a significant association between the variant rs1042636(A>G), located in CaSR exon 7, and idiopathic pulmonary arterial hypertension (IPAH) formation in patients. The frequency of 2968G homozygotes was higher in patients with IPAH compared with healthy individuals (23.6% versus 17.5%; P =0.001, OR=1.864), and the minor alleles of rs6776158, rs1048213, and rs9883099, located in CaSR promoter, raised the IPAH odds ratio to 2.173. Patients with IPAH carrying heterozygotes or homozygotes genotype of rs1042636 showed markedly higher pulmonary artery pressure and reduced survival compared with individuals carrying the wild-type allele. The minor alleles of rs6776158, rs1048213, and rs9883099 increased CaSR expression in reporter assay. In Sugen/hypoxia pulmonary arterial hypertension rats, the point mutation replicating rs1042636 found in IPAH exacerbated pulmonary arterial hypertension severity by promoting the overexpression and the enhanced activity of CaSR. Conclusions: Our functional genomic analysis thus indicates that the CaSR minor alleles of rs1042636, rs6776158, rs1048213, and rs9883099 contribute to the development and severity of IPAH. These findings may benefit clinical prognosis and treatment for IPAH.

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.

Stress urinary incontinence (SUI) is a troublesome hygienic problem that afflicts the female population and is associated with extracellular matrix (ECM). Herein, we investigated the effects of microRNA (miR)-34a on ECM metabolism in fibroblasts of SUI via mediating nicotinamide phosphoribosyl transferase (Nampt/NAmPRTase) and hope to find novel insights in the treatment of SUI. Firstly, the anterior vaginal wall tissues of SUI patients and the female vaginal wall fibroblasts (FVWFs) of non-SUI subjects were collected and identified. Then, FVWFs were treated with 10 ng/mL of interleukin 1 beta (IL-1β) to establish SUI cell models. Subsequently, miR-34a and Nampt expressions in both types of cells were detected via RT-qPCR. It was found that miR-34a was poorly expressed, while Nampt was highly expressed in SUI. Subsequently, IL-1β-treated FVWFs were transfected with miR-34a-mimic and pcDNA3.1-Nampt, respectively. Thereafter, RT-qPCR and Western blot detected that miR-34a overexpression increased COL1A, ACAN, and TIMP-1; decreased MMP-2 and MMP-9; and elevated LC3 II/I ratio, Beclin-1 expression, and the autophagosome number in IL-1β-treated FVWFs, while Nampt upregulation reversed the above outcomes. Then, dual-luciferase reporter gene assay detected that Nampt is a downstream target of miR-34a. Together, miR-34a overexpression promoted autophagy, inhibited ECM degradation in IL-1β-treated FVWFs, and ameliorated SUI via suppressing Nampt.

While trimethoprim-sulfamethoxazole (TMP-SMX) is recommended as one of the first-line empiric therapies for treatment of acute uncomplicated cystitis, institutions that observe resistance rates exceeding 20% for Escherichia coli (E. coli) should utilize alternative empiric antibiotic therapy per the Infectious Diseases Society of America (IDSA). Identifying risk factors associated with TMP-SMX resistance in E. coli may help guide empiric antibiotic prescribing for urinary tract infections (UTIs).This multicenter, retrospective study included adult patients who were discharged from 12 emergency departments (EDs) with a urine culture positive for E. coli between January 1, 2019 and December 31, 2019. Logistic regression was used to assess the relationship between potential risk factors and TMP-SMX resistance. The overall institutional antimicrobial resistance rates for E. coli were compared to the rates seen in the study population of ED urinary isolates.Among 427 patients included from a randomized sample of 500 with a urine culture positive for E. coli, 107 (25.1%) were resistant to TMP-SMX. Three predictors of TMP-SMX resistance were identified: recurrent UTI (OR 2.27 [95% CI 1.27-3.99]), genitourinary abnormalities (OR 2.31 [95% CI 1.17-4.49]), and TMP-SMX use within 90 days (OR 8.77 [95% CI 3.19-28.12]). When the antibiotic susceptibilities for this ED cohort were compared to the institutional antibiogram, the TMP-SMX resistance rate was found to be higher in the ED population (25.1% vs 20%).TMP-SMX should likely be avoided as first-line therapy for UTI in patients who have recurrent UTIs, genitourinary abnormalities, or have previously received TMP-SMX within the past 90 days. The use of an ED-specific antibiogram should be considered for assessing local resistance rates in this population.

Pseudo-allergic reactions (PARs) widely occur upon application of drugs or functional foods. Anti-pseudo-allergic ingredients from natural products have attracted much attention. This study aimed to investigate anti-pseudo-allergic compounds in licorice. The anti-pseudo-allergic effect of licorice extract was evaluated in rat basophilic leukemia 2H3 (RBL-2H3) cells. Anti-pseudo-allergic compounds were screened by using RBL-2H3 cell extraction and the effects of target components were verified further in RBL-2H3 cells, mouse peritoneal mast cells (MPMCs) and mice. Molecular docking and human MRGPRX2-expressing HEK293T cells (MRGPRX2-HEK293T cells) extraction were performed to determine the potential ligands of MAS-related G protein-coupled receptor-X2 (MRGPRX2), a pivotal target for PARs. Glycyrrhizic acid (GA) and licorice chalcone A (LA) were screened and shown to inhibit Compound48/80-induced degranulation and calcium influx in RBL-2H3 cells. GA and LA also inhibited degranulation in MPMCs and increase of histamine and TNF-α in mice. LA could bind to MRGPRX2, as determined by molecular docking and MRGPRX2-HEK293T cell extraction. Our study provides a strong rationale for using GA and LA as novel treatment options for PARs. LA is a potential ligand of MRGPRX2.

Objectives. This meta-analysis was to verify the short-time efficacy and safety of abciximab in patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI). Background. Abciximab has long-term efficacy in patients with STEMI undergoing PCI, but the short-term efficacy is still controversial. Methods. We conducted a systematic review and meta-analysis compared with or without abciximab in patients with STEMI undergoing PCI. The relevant randomized controlled trials were included by searching PubMed, EMBASE, Cochrane Library, and Web of Science databases and other sources. The relative risk (RR) and 95% confidence intervals (CI) of outcomes were calculated by the fixed-effects model. Results. Ten randomized controlled trials with 5008 patients met inclusion criteria. There were no significant differences in risk of all-cause death at 30-day (RR 0.79, CI 0.55–1.12, P = 0.18 ), major bleeding (1.37, 0.93–2.03, P = 0.11 ), and transfusion (1.23, 0.94–1.61, P = 0.13 ) between the two groups. However, there were significant differences in risk of all-cause death at 6 months (0.57, 0.36–0.90, P = 0.02 ), recurrent myocardial infarction (0.55, 0.33–0.92, P = 0.02 ), repeat revascularization (0.58, 0.43–0.78, P = 0.0004 ), final TIMI flow P = 0.02 ), minor bleeding (1.29, 1.02–1.63, P = 0.04 ), and thrombocytopenia (2.04, 1.40–2.97, P = 0.0002 ). Conclusions. The application of abciximab can lead to a lower risk of reinfarction, revascularization, and all-cause death at 6 months, but a higher risk of minor bleeding, and thrombocytopenia.

The pathway mediated by jasmonic acid (JA), biosynthesized via 13-lipoxygenases (LOX), plays a central role in both plant development and defense. In rice, there are at least fourteen 13-LOXs. Yet, only two 13-LOXs have been known to be involved in the biosynthesis of JA and plant defenses in rice. Here we cloned a chloroplast-localized 13-LOX gene from rice, OsRCI-1, whose transcripts were upregulated following infestation by brown planthopper (BPH, Nilaparvata lugens), one of the most important pests in rice. Overexpression of OsRCI-1 (oeRCI lines) increased levels of BPH-induced JA, jasmonate-isoleucine, trypsin protease inhibitors and three volatile compounds, 2-heptanone, 2-heptanol and α-thujene. BPHs showed a decreased colonization, fecundity and mass, and developed slowly on oeRCI plants compared with wild-type (WT) plants. Moreover, BPH-infested oeRCI plants were more attractive to the egg parasitoid of BPH, Anagrus nilaparvatae than equally treated WT plants. The decreased attractiveness to BPH and enhanced attractiveness to the parasitoid of oeRCI plants correlated with higher levels of BPH-induced 2-heptanone and 2-heptanol, and 2-heptanone, respectively. Compared with oeRCI plants, WT plants had higher plant height and 1000-grain weight. These results indicate that OsRCI-1 is involved in herbivore-induced JA bursts and plays a role in plant defense and growth.

The aim of this study was to explore the role of galectin-3 in human epidermal growth factor receptor 2 (HER2)-positive breast cancer cells and the potential mechanism.Kaplan-Meier (KM)-plot and The Cancer Genome Atlas (TCGA) databases were used to study the role of galectin-3 in the prognosis of HER2-positive breast cancer. The effects of galectin-3 on cell proliferation, migration, invasion, and colony formation ability in HER2-positive breast cancer cells were examined. The relationship between galectin-3 and important components in the HER2 pathways, including HER2, epidermal growth factor receptor (EGFR), protein kinase B (AKT), and phosphatase and tensin homolog (PTEN), was further studied. Lentivirus and CRISPR/Cas9 were used to construct stable cell lines. Cell counting kit-8 (CCK-8) and apoptosis assays were used to study the relationship between galectin-3 and trastuzumab. The effect of galectin-3 on cell stemness was studied by mammosphere formation assay. The effects of galectin-3 on stemness biomarkers and the Notch1 pathway were examined. Tumorigenic models were used to evaluate the effects of galectin-3 on tumorigenesis and the therapeutic effect of trastuzumab in vivo.HER2-positive breast cancer patients with a high expression level of LGALS3 (the gene encoding galectin-3) messenger RNA (mRNA) showed a poor prognosis. Galectin-3 promoted cancer malignancy through phosphoinositide 3-kinase (PI3K)/AKT signaling pathway activation and upregulated stemness by activating the Notch1 signaling pathway in HER2-positive breast cancer cells. These two factors contributed to the enhancement of trastuzumab resistance in cells. Knockout of LGALS3 had a synergistic therapeutic effect with trastuzumab both in vitro and in vivo.Galectin-3 may represent a prognostic predictor and therapeutic target for HER2-positive breast cancer.

Lysosome-targeting self-assembling prodrugs had emerged as an attractive approach to overcome the acquisition of resistance to chemotherapeutics by inhibiting lysosomal sequestration. Taking advantage of lysosomal acidification induced intracellular hydrolytic condensation, we developed a lysosomal-targeting self-condensation prodrug-nanoplatform (

Scarring, which develops due to fibroblast activation and excessive extracellular matrix deposition, can cause physical, psychological, and cosmetic problems. Fibroblasts are the main type of connective tissue cells and play important roles in wound healing. However, the underlying mechanisms of fibroblast in reaching scarless wound healing require more exploration. Herein, we systematically reviewed how fibroblasts behave in response to skin injuries, as well as their functions in regeneration and scar formation. Several biocompatible materials, including hydrogels and nanoparticles, were also suggested. Moreover, factors that concern transformation from fibroblasts into cancer-associated fibroblasts are mentioned due to a tight association between scar formation and primary skin cancers. These findings will help us better understand skin fibrotic pathogenesis, as well as provide potential targets for scarless wound healing therapies.

Four cases of cutaneous Balamuthia mandrillaris infection were treated with diminazene aceturate. One patient was cured with mainly monotherapy, 2 patients were cured with diminazene aceturate and excision, and 1 patient died of drug-induced liver damage. This is the first report of B. mandrillaris infection treated with diminazene aceturate.

The purpose of this meta-analysis was to evaluate the efficacy and safety of proton pump inhibitors (PPIs) plus antithrombotic strategy in patients with coronary artery diseases compared with antithrombotic strategy alone. We searched PubMed, EMBASE, Cochrane Library, and Chinese Biomedical Medical Literature databases to retrieve randomized controlled trials investigating PPIs combined with antithrombotic strategy in coronary artery diseases. The primary efficacy outcome was major adverse cardiovascular and cerebrovascular events (MACCE). The primary safety outcome was gastrointestinal events. Secondary outcomes included all-cause death, cardiovascular death, myocardial infarction, stent thrombosis, significant bleeding from gastroduodenal lesions, and gastroduodenal ulcer. Overall, 43,943 patients were enrolled from 19 trials. The incidence of MACCE [relative risk (RR) 1.05; 95% confidence interval (CI) 0.96-1.15], all-cause death (RR 0.84; 95% CI 0.69-1.01), cardiovascular death (RR 0.88; 95% CI 0.69-1.12), myocardial infarction (RR 0.98; 95% CI 0.88-1.09), stent thrombosis (RR 1.01; 95% CI 0.76-1.34), and gastroduodenal ulcer (RR 0.40; 95% CI 0.13-1.29) did not increase significantly in patients receiving PPIs compared with patients without those. There were significant differences in the risk of gastrointestinal events (RR 0.34; 95% CI 0.21-0.54) and significant bleeding from gastroduodenal lesions (RR 0.09; 95% CI 0.03-0.28) between the 2 groups. In patients with coronary artery diseases, PPIs plus antithrombotic strategy could reduce the risk of gastrointestinal events and significant bleeding from gastroduodenal lesions but may not affect the incidence of MACCE, all-cause death, cardiovascular death, myocardial infarction, stent thrombosis, and gastroduodenal ulcer (PROSPERO: CRD42021277899, date of registration October 10, 2021).

In 2016, the British Columbia HIV/AIDS Drug Treatment Program modified its prescriber alert system for antiretroviral therapy (ART) interruptions to include referrals to regional public health nursing teams for direct outreach support for those who remain off treatment for 4 months or longer. We evaluated clinically relevant outcomes of this Re-Engagement and Engagement in Treatment for Antiretroviral Interrupted and Naïve populations (RETAIN) initiative, in comparison to previous time-periods.We analyzed ART interruptions triggering alerts in pre-RETAIN (July 2013-April 2016) and post-RETAIN periods (May 2016-October 2017) with follow-up continuing until October 2018. We compared the proportions of those who restarted ART and achieved viral suppression in pre-RETAIN and post-RETAIN periods and the time to ART restart using generalized estimating equations. Cox proportional hazards modelling was used to examine associations with time-to-ART-restart.A total of 1805 individuals experienced ART interruptions triggering 3219 alerts; 2050 in pre-RETAIN and 1169 in post-RETAIN periods. Participants were predominantly men (74%) and had a median duration of ART of 5 years. Among persons who remained interrupted4 months after an ART interruption alert was sent, the median time from interruption to ART re-initiation declined from 8.7 months to 7.4 months (P0.001) from pre-to post-RETAIN periods. Interruptions in the post-RETAIN era were associated with an increased hazard of restarting ART (adjusted hazard ratio 1.51; 95% CI: 1.34 to 1.69).Public health referrals shortened the length of ART interruptions after alerts sent to prescribers had not resulted in re-engagement. Similar programs should be considered in other jurisdictions.

Visual-spatial working memory (vsWM) impairment in treatment-resistant schizophrenia (TRS) currently has no satisfactory treatment. Our study aimed to improve vsWM function in TRS through intermittent theta burst stimulation (iTBS) using neuronavigation equipment to target the left dorsolateral prefrontal cortex.TRS patients (n = 59) were randomly allocated to receive iTBS (n = 33) or a sham treatment (n = 26) over 2 weeks. The participants including TRS patients and healthy controls (HCs) performed the vsWM n-back task, and TRS patients' neuroimaging data were acquired before and after treatment. All patients also underwent a battery of symptom measures to assess the severity of illness. The main outcome measure was the accuracy (ACC) of n-back target responses, particularly 3-back ACC.The iTBS group showed considerable improvement in n-back ACC compared to the sham group, especially 3-back ACC. After iTBS, performance on the n-back task was comparable to that of HCs. The interaction (group × time) results showed increased fractional amplitude of low frequency fluctuations (fALFF) in the right occipital areas and decreased fALFF in the right precuneus. However, there was a negative correlation between the 3-back ACC and improved clinical symptoms scores. Improvements in 3-back ACC were positively correlated with activity in the right visual cortex.Our study suggested that 2 weeks of iTBS intervention may be a novel, efficacious treatment for vsWM deficits in TRS, which can modulate the activity of local brain regions. iTBS can provide a solution for clinical treatment of TRS and may help patients approach normalcy.

PURPOSE: Mendelian disease genomic research has undergone a massive transformation over the past decade. With increasing availability of exome and genome sequencing, the role of Mendelian research has expanded beyond data collection, sequencing, and analysis to worldwide data sharing and collaboration. METHODS: Over the past 10 years, the National Institutes of Health–supported Centers for Mendelian Genomics (CMGs) have played a major role in this research and clinical evolution. RESULTS: We highlight the cumulative gene discoveries facilitated by the program, biomedical research leveraged by the approach, and the larger impact on the research community. Beyond generating a list of gene-phenotype relationships and participating in widespread data sharing, the CMGs have created resources, tools, and training for the larger community to foster understanding of genes and genome variation. The CMGs have participated in a wide range of data sharing activities, including deposition of all eligible CMG data into the Analysis, Visualization, and Informatics Lab-space (AnVIL), sharing candidate genes through the Matchmaker Exchange and the CMG website, and sharing variants in Genotypes to Mendelian Phenotypes (Geno2MP) and VariantMatcher. CONCLUSION: The work is far from complete; strengthening communication between research and clinical realms, continued development and sharing of knowledge and tools, and improving access to richly characterized data sets are all required to diagnose the remaining molecularly undiagnosed patients.

In this study, the self-assembled nanoparticles based on Hohenbuehelia serotina polysaccharides (QC-HSP NPs) were fabricated to encapsulate quercetin for improving its bioavailability. The structural characteristics, physicochemical properties as well as the cytotoxicity activities of QC-HSP NPs during gastrointestinal digestion in vitro were respectively investigated. The results showed that QC-HSP NPs possessed the spherical and smooth surface morphology, with the average particle size of 360 nm and zeta potential of -38.8 mV. Moreover, QC-HSP NPs had excellent physiochemical stabilities, and presented sustained-release characteristics during gastrointestinal digestion in vitro. Compared with undigested ones, QC-HSP NPs after gastrointestinal digestion exhibited the more significant anti-proliferative activity on HeLa cells through accumulation of intracellular ROS, arrest of cell cycle at G2/M phase by regulation of cyclin B1, CDK1, p53 and p21 and induction of apoptosis by ER apoptosis pathway. This study provides a new strategy for designing quercetin-loaded nanoparticles based on natural polysaccharides to improve the bioavailability of quercetin.

Understanding the genetic variation underlying transcript splicing is essential for fully dissecting the molecular mechanisms of common diseases. The available evidence from splicing quantitative trait locus (sQTL) studies using pancreatic ductal adenocarcinoma (PDAC) tissues have been limited to small sample sizes. Here we present a genome-wide sQTL analysis to identify SNP that control mRNA splicing in 176 PDAC samples from TCGA. From this analysis, 16,175 sQTLs were found to be significantly enriched in RNA-binding protein (RBP) binding sites and chromatin regulatory elements and overlapped with known loci from PDAC genome-wide association studies (GWAS). sQTLs and expression quantitative trait loci (eQTL) showed mostly nonoverlapping patterns, suggesting sQTLs provide additional insights into the etiology of disease. Target genes affected by sQTLs were closely related to cancer signaling pathways, high mutational burden, immune infiltration, and pharmaceutical targets, which will be helpful for clinical applications. Integration of a large-scale population consisting of 2,782 patients with PDAC and 7,983 healthy controls identified an sQTL variant rs1785932-T allele that promotes alternative splicing of ELP2 exon 6 and leads to a lower level of the ELP2 full-length isoform (ELP2_V1) and a higher level of a truncated ELP2 isoform (ELP2_V2), resulting in decreased risk of PDAC [OR = 0.83; 95% confidence interval (CI), 0.77–0.89; P = 1.16 × 10−6]. The ELP2_V2 isoform functioned as a potential tumor suppressor gene, inhibiting PDAC cell proliferation by exhibiting stronger binding affinity to JAK1/STAT3 than ELP2_V1 and subsequently blocking the pathologic activation of the phosphorylated STAT3 (pSTAT3) pathway. Collectively, these findings provide an informative sQTL resource and insights into the regulatory mechanisms linking splicing variants to PDAC risk.Significance:In pancreatic cancer, splicing quantitative trait loci analysis identifies a rs1785932 variant that contributes to decreased risk of disease by influencing ELP2 mRNA splicing and blocking the STAT3 oncogenic pathway.

Major depressive disorder is the most common mental disorder with significant economic burden and limited treatments. Acupuncture has emerged as a promising non-pharmacological treatment for reducing depressive symptoms. However, the potential mechanisms and clinical effectiveness of acupuncture are not fully understood. This review aimed to: (1) summarize the available evidence on the mechanisms and clinical effectiveness of acupuncture for depression, and then (2) compare with pharmacological interventions, guiding future studies. Studies with animal models of depression and patients have shown that acupuncture could increase hippocampal and network neuroplasticity and decrease brain inflammation, potentially to alleviating depressive disorders. Overall clinical studies indicated that acupuncture could relieve primary depression, particularly milder cases, and was helpful in the management of post-stroke depression, pain-related depression, and postpartum depression both as an isolated and adjunct treatment. It was emphasized that acupuncture combined with antidepressant pharmacological treatment not only enhanced the improvement of primary and secondary depressive symptoms but also reduced the side effects of the medical treatment, which is the main cause for high dropout rates with drug treatment. In summary, substantial evidence from animal and human researches supported the beneficial effect of acupuncture in depression. However, most clinical trials of acupuncture were small, and it is unclear whether their findings can be generalized, so more studies are needed.

Transcriptome sequencing (RNA-seq) is widely used to detect gene rearrangements and quantitate gene expression in acute lymphoblastic leukemia (ALL), but its utility and accuracy in identifying copy number variations (CNVs) has not been well described. CNV information inferred from RNA-seq can be highly informative to guide disease classification and risk stratification in ALL due to the high incidence of aneuploid subtypes within this disease. Here we describe RNAseqCNV, a method to detect large scale CNVs from RNA-seq data. We used models based on normalized gene expression and minor allele frequency to classify arm level CNVs with high accuracy in ALL (99.1% overall and 98.3% for non-diploid chromosome arms, respectively), and the models were further validated with excellent performance in acute myeloid leukemia (accuracy 99.8% overall and 99.4% for non-diploid chromosome arms). RNAseqCNV outperforms alternative RNA-seq based algorithms in calling CNVs in the ALL dataset, especially in samples with a high proportion of CNVs. The CNV calls were highly concordant with DNA-based CNV results and more reliable than conventional cytogenetic-based karyotypes. RNAseqCNV provides a method to robustly identify copy number alterations in the absence of DNA-based analyses, further enhancing the utility of RNA-seq to classify ALL subtype.

The complete mesogastrium excision (CME) based on D2 radical gastrectomy is believed to significantly reduce the local-regional recurrence compared with D2 radical gastrectomy in advanced gastric cancer, and it is widely used in China. This study aimed to explore whether D2 + CME is superior to D2 on surgical outcomes during gastrectomy from Chinese data.Feasible studies comparing the D2 + CME (D2 + CME group) and D2 (D2 group) published up to March 2020 are searched from electronic databases. The data showing surgical and complication outcomes are extracted to be pooled and analyzed.Fourteen records including 1352 patients were included. The D2 + CME group had a shorter mean operative time (weighted mean difference [WMD] = -16.72 min, 95% confidence interval [CI]: -26.56 to -6.87 min, P 0.001), lower mean blood loss (WMD = -39.08 mL, 95% CI: -49.94 to -28.21 mL, P 0.001), higher mean number of retrieved lymph nodes (WMD = 2.13, 95% CI: 0.58-3.67, P = 0.007), shorter time to first flatus (WMD = -0.31 d, 95% CI: -0.53 to - 0.10 d, P = 0.005), and postoperative hospital days (WMD = -1.09, 95% CI: -1.92 to -0.25, P = 0.010) than the D2 group. Subgroup analysis suggested that the advantages from the D2 + CME group were obvious in traditional open radical gastrectomy, proximal gastrectomy, and distal gastrectomy compared with D2 group. The evaluations of post-operative complications showed that the patients who underwent D2 + CME had a lower incidence of post-operative complications than the patients who underwent D2 surgery alone (relative risk [RR] = 0.65, 95% CI: 0.45-0.87, P = 0.003). The D2 radical gastrectomy plus CME improved 3-year overall survival (OS) (RR = 1.16, 95% CI: 1.02-1.32, P = 0.020) and lowered the local recurrence rate (RR = 0.51, 95% CI: 0.28-0.94, P = 0.030). The patients undergoing laparoscopic surgery or total gastrectomy had more significant advantages compared between D2 + CME and D2 groups in 3-year OS.The data from China show that D2 radical gastrectomy plus CME are reliable procedures and safety compared to D2 radical gastrectomy with faster recovery, lower risk, and better prognosis.

Objective. To elucidate the therapeutic efficacy of needle-warming moxibustion (NWM) combined with hyperbaric oxygen therapy (HBOT) in the treatment of patients with ischemic stroke and its effect on neurological function. Methods. One hundred patients with ischemic stroke admitted to the Xuzhou Medical University Affiliated Hospital of Lianyungang from January 2019 to July 2021 were enrolled. Among them, 45 patients treated with NWM were set as the control group, and the rest 55 patients treated by NWM combined with HBOT were included in the research group. The curative effect, neurological deficit score, activity of daily living (ADL), balance ability, and the levels of serum proinflammatory factors in both groups were observed and recorded. Of them, the neurological deficit of patients was evaluated by the National Institutes of Health Stroke Scale (NHISS), the ADL ability was determined by the Barthel index score, and the balance ability was assessed by the Berg balance scale. Results. The total effective rate of the research group was higher than that of the control group. Better ADL and balance ability and milder neurologic impairment were determined in the research group compared with the control group. After treatment, the secretion levels of proinflammatory factors such as C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-8 (IL-8) in the serum of patients in the research group were statistically lower than those before treatment and the control group. Conclusions. NWM combined with HBOT is effective in the treatment of patients with ischemic stroke, which can not only improve patients’ neurological function, ADL, and balance ability but also inhibit serum inflammatory reactions.

Performing immediate radical cystectomy in all patients with the highest-risk non-muscle invasive bladder cancer results in overtreatment. We confirm whether the substratification of highest-risk patients can more effectively select suitable patients for radical cystectomy.Patients with primary T1 high grade bladder cancer from two centers were included and roughly stratified into high-risk or highest-risk. The highest-risk patients were further substratified according to the number of risk factors. Endpoints were tumor recurrence and progression. The predictive accuracy was assessed with internal validation that consists of time-dependent receiver operating characteristic curve and calibration curves.A total of 262 patients were included. Although highest-risk patient had a poor prognosis, after further substratification, we found that those with only one factor showed the same prognosis with high-risk patients (recurrence: hazard ratio 1.79, P = 0.105; progression: hazard ratio 1.38, P = 0.532), while those with ≥2 factors had worst prognosis than high-risk patients. The 3-year area under the curve showed that the predictive accuracy of substratification in terms of recurrence and progression were superior to that of non-substratification (0.685 vs 0.622 and 0.666 vs 0.599, respectively). Additionally, calibration curves showed perfect agreement between the predicted and the actual recurrence and progression.Substratification of highest-risk enables us to further optimize the surgical decisions-making. Highest-risk patients with one factor show the similar outcomes as high-risk patients and deserve to try bladder-sparing treatment, whereas those with ≥2 risk factors were strongly recommended to undergo radical cystectomy.

LY01008 had been identified as being highly similar to the bevacizumab reference product in the pharmacy and pharmacology terms. The primary objective of this study was to compare the pharmacokinetic characteristics of the biosimilar candidate LY01008 with that of the bevacizumab (AvastinIn this double-blind, parallel-group, phase I study, 102 male subjects aged 18-45 years were randomized 1:1 to receive a single intravenous infusion of 3 mg/kg LY01008 or bevacizumab. Before the pivotal section, 12 healthy male subjects receiving a single intravenous (IV) infusion of 0.5 mg/kg or 1.5 mg/kg LY01008 were screened to verify the safety and tolerability of LY01008. Primary endpoints included the area under the concentration-time curve (AUC) from time zero to the last quantifiable time point (AUCThe geometric mean ratios (GMRs) (90% confidence intervals, CIs) of AUCLY01008, a recombinant humanized monoclonal antibody (mAb) against vascular endothelial growth factor (VEGF), displayed pharmacokinetic similarity to bevacizumab, and good safety and tolerability profiles. The data from this trial provide fundamental information for further development.Clinical trial registration ID: CTR20170191.

The wide-scale adoption of electronic health records (EHRs) provides extensive information to support precision medicine and personalized health care. In addition to structured EHRs, we leverage free-text clinical information extraction (IE) techniques to estimate optimal dynamic treatment regimes (DTRs), a sequence of decision rules that dictate how to individualize treatments to patients based on treatment and covariate history. The proposed IE of patient characteristics closely resembles "The clinical Text Analysis and Knowledge Extraction System" and employs named entity recognition, boundary detection, and negation annotation. It also utilizes regular expressions to extract numerical information. Combining the proposed IE with optimal DTR estimation, we extract derived patient characteristics and use tree-based reinforcement learning (T-RL) to estimate multistage optimal DTRs. IE significantly improved the estimation in counterfactual outcome models compared to using structured EHR data alone, which often include incomplete data, data entry errors, and other potentially unobserved risk factors. Moreover, including IE in optimal DTR estimation provides larger study cohorts and a broader pool of candidate tailoring variables. We demonstrate the performance of our proposed method via simulations and an application using clinical records to guide blood pressure control treatments among critically ill patients with severe acute hypertension. This joint estimation approach improves the accuracy of identifying the optimal treatment sequence by 14-24% compared to traditional inference without using IE, based on our simulations over various scenarios. In the blood pressure control application, we successfully extracted significant blood pressure predictors that are unobserved or partially missing from structured EHR.

Background We have limited information about neuroendocrine carcinoma (NEC) of the gallbladder. The purpose of this paper is to compare clinical and pathological features between different age groups and prognostic factors for gallbladder NEC and how it differs from adenocarcinoma (ADC) of the gallbladder. Patients and methods This study included 28 gallbladder NEC patients and 137 ADC patients whose clinical characteristics and pathological findings were retrospectively collected. Propensity score matching and Cox regression analysis were used for the analysis of prognostic factors. Results We divided NEC patients into two groups based on the age more than or less than 60 years. Most of the NEC patients less than 60 years old complained of abdominal pain or discomfort (p = 0.038), and more younger patients accepted adjuvant therapy (p = 0.020) than older patients did. CD56 was positive in all patients more than 60 years old, which is significantly higher than that of younger patients (p = 0.039). The mean age was similar between NEC and ADC patients. After eliminating confounding factors between NEC and ADC patients, the overall survival rates were still lower in NEC patients. Univariate analysis extracted six possible risk factors. Multivariate analysis indicated that surgery type, tumor size, and existence of gallstones were independent prognostic factors. Conclusion The overall survival of gallbladder NEC is not associated with age. In this study, surgical method and tumor size were found to be independent risk factors for NECs. In addition, NEC patients have a worse prognosis than ADC patients with similar clinical and pathological features.

Increased abnormal spindle‐like microcephaly (ASPM) expression has been linked to clinical stage and poor prognosis in cancers, but the molecular mechanisms by which ASPM promotes cell metastasis in colorectal cancer (CRC) has not been identified. This study showed that the abilities of cell migration, invasion, and epithelial–mesenchymal transition (EMT) were attenuated in ASPM‐deficient CRC cell lines. Furthermore, we reported that attenuation of ASPM expression inhibited CRC cell metastasis in vivo. Additionally, the expression of ASPM was positively correlated with β‐catenin level in CRC tissues. Mechanistically, ASPM can upregulate β‐catenin transcription by stimulating the β‐catenin promoter and enhancing the nuclear translocation of β‐catenin in CRC cells, which leads to the activation of the Wnt/β‐catenin pathway. Finally, we showed that ASPM effectively induced CRC cell migration and invasion in a β‐catenin‐dependent manner.

Myocardial infarction (MI) is one of the fatal diseases in humans. Its incidence is constantly increasing annually all over the world. The problem is accompanied by the limited regenerative capacity of cardiomyocytes, yielding fibrous scar tissue formation. The propagation of electrical impulses in such tissue is severely hampered, negatively influencing the normal heart pumping function. Thus, reconstruction of the internal cardiac electrical connection is currently a major concern of myocardial repair. Conductive biomaterials with or without cell loading were extensively investigated to address this problem. This article introduces a detailed overview of the recent progress in conductive biomaterials and fabrication methods of conductive scaffolds for cardiac repair. After that, the advances in myocardial tissue construction in vitro by the restoration of intercellular communication and simulation of the dynamic electrophysiological environment are systematically reviewed. Furthermore, the latest trend in the study of cardiac repair in vivo using various conductive patches is summarized. Finally, we discuss the achievements and shortcomings of the existing conductive biomaterials and the properties of an ideal conductive patch for myocardial repair. We hope this review will help readers understand the importance and usefulness of conductive biomaterials in cardiac repair and inspire researchers to design and develop new conductive patches to meet the clinical requirements. Statement of significance After myocardial infarction, the infarcted myocardial area is gradually replaced by heterogeneous fibrous tissue with inferior conduction properties, resulting in arrhythmia and heart remodeling. Conductive biomaterials have been extensively adopted to solve the problem. Summarizing the relevant literature, this review presents an overview of the types and fabrication methods of conductive biomaterials, and focally discusses the recent advances in myocardial tissue construction in vitro and myocardial repair in vivo, which is rarely covered in previous reviews. As well, the deficiencies of the existing conductive patches and their construction strategies for myocardial repair are discussed as well as the improving directions. Confidently, the readers of this review would appreciate advantages and current limitations of conductive biomaterials/patches in cardiac repair.

Introduction: Sodium taurocholate cotransporting polypeptide has been identified as the hepatitis B virus (HBV) entry receptor. However, information regarding the role of sodium taurocholate cotransporting polypeptide variants in the development of HBV-related advanced cirrhosis and hepatocellular carcinoma is limited. Methodology: Overall, 581 patients with chronic HBV infection were divided into the liver fibrosis or cirrhosis group based on the Fibrosis-4 index. Further, 183 patients with hepatocellular carcinoma were distributed into early/intermediate and advanced/end stage groups based on Barcelona Clinic Liver Cancer Staging approach. Three single nucleotide polymorphisms were genotyped by high resolution melting curve method. Serum biomarkers of liver function were detected, and hepatocellular carcinoma properties were collected as well. Results: Subjects with GA+AA genotypes at the rs4646287 polymorphism site were associated with a significantly higher rate of fibrosis development (rs4646287 GA+AA genotypes were 13.7% and 20.0% in the non-fibrosis and fibrosis group, respectively; p = 0.038). There were no significant differences between sodium taurocholate cotransporting polypeptide polymorphisms and hepatocellular carcinoma progression. The GA+AA genotype carriers of rs7154439 had relatively high albumin levels (p = 0.035). The rs2296651 GA genotype carriers tended to have solitary tumor nodule and without metastasis (p = 0.004 and 0.015, respectively). Conclusions: Rs4646287 was associated with HBV-related fibrosis development. Sodium taurocholate cotransporting polypeptide polymorphisms were correlated with serum albumin level as well as hepatocellular carcinoma multifocality and metastasis. Therefore, integrating sodium taurocholate cotransporting polypeptide polymorphisms to a risk stratification algorithm may help clinicians manage the chronic HBV infection patients better.

The study objective was to compare the effectiveness of microwave ablation (MWA) and laparoscopic liver resection (LLR) on solitary 3-5-cm HCC over time.From 2008 to 2019, 1289 patients from 12 hospitals were enrolled in this retrospective study. Diagnosis of all lesions were based on histopathology. Propensity score matching was used to balance all baseline variables between the two groups in 2008-2019 (n = 335 in each group) and 2014-2019 (n = 257 in each group) cohorts, respectively. For cohort 2008-2019, during a median follow-up of 35.8 months, there were no differences in overall survival (OS) between MWA and LLR (HR: 0.88, 95% CI 0.65-1.19, p = 0.420), and MWA was inferior to LLR regarding disease-free survival (DFS) (HR 1.36, 95% CI 1.05-1.75, p = 0.017). For cohort 2014-2019, there was comparable OS (HR 0.85, 95% CI 0.56-1.30, p = 0.460) and approached statistical significance for DFS (HR 1.33, 95% CI 0.98-1.82, p = 0.071) between MWA and LLR. Subgroup analyses showed comparable OS in 3.1-4.0-cm HCCs (HR 0.88, 95% CI 0.53-1.47, p = 0.630) and 4.1-5.0-cm HCCs (HR 0.77, 95% CI 0.37-1.60, p = 0.483) between two modalities. For both cohorts, MWA shared comparable major complications (both p 0.05), shorter hospitalization, and lower cost to LLR (all p 0.001).MWA might be a first-line alternative to LLR for solitary 3-5-cm HCC in selected patients with technical advances, especially for patients unsuitable for LLR.

Background The average body weight of the Chinese population is rising rapidly over the past two decades and the old 2001 body mass index (BMI) cut-off value for malnutrition may underestimate malnutrition diagnosis. We explored the BMI cut-off value for malnutrition diagnosis based on national BMI data over the past 30 years and applied it to the Global Leadership Initiative on Malnutrition (GLIM) criteria when investigating malnutrition in hospitalized older adult patients. Methods To explore the BMI cut-off value for malnutrition, we established a linear stepwise model to predict the annual increasing BMI trend based on data from the national BMI dataset (1990-2009). The new cut-off value was applied to a large-scale dataset from a cross-sectional study pertaining to older hospitalized patients (≥65) recruited from 30 large hospitals in China. Results The average BMI increased from 21.8 to 23 kg/m2 in two decades. Using the linear model, we calculated that the net BMI increase will be 1.49 kg/m2 from 2009 to 2019. We subsequently proposed that the BMI cut-off value for malnutrition should rise to 20 kg/m2 . This cut-off value was applied to the validation dataset, containing 8,725 patients, and the GLIM-determined malnutrition rate was 24.58% (using the NRS-2002) and 23.32% (using the MNA-SF). The results significantly differed from those obtained using the 2001 Chinese BMI criteria (p Conclusion The GLIM tool has good applicability in Asian populations, especially in Chinese older adult patients. The BMI cut-off value for malnutrition should be adjusted to 20 kg/m2 for Chinese adults. This article is protected by copyright. All rights reserved.

Objective To assess the effectiveness of pulsed electromagnetic field (PEMF) on pain and physical function in patients with low back pain. Data sources A search of PubMed, Embase, Cochrane Library, and Web of Science was conducted up to December 2021. Methods We included randomized controlled trials that investigated the effectiveness of PEMF in patients with low back pain. The primary outcome was pain intensity and the secondary outcome was physical function, both were evaluated by assessment scales. Standardized mean difference (SMD) and 95% confidence interval (CI) were calculated for the summary statistics analysis. The registration number of this systematic review in PROSPERO is CRD42020213829. Results Fourteen trials involving 618 participants were included. The PEMF treatment showed more significant pain alleviation than placebo or other therapy alone in patients with low back pain (SMD = −1.01, 95% CI −1.42 to −0.6, P 2 = 31%; SMD = −0.36, 95% CI −0.62 to −0.11, P = 0.005, I2 = 37%, respectively.) In addition, a significant difference in pain alleviation was observed in patients with chronic low back pain (SMD = −0.6, 95%CI − 0.94 to −0.25, p 2 = 67%), whereas no significant difference was observed in patients with acute low back pain (SMD = −0.46, 95%CI − 0.99 to 0.07, p = 0.09, I2 = 0%). PEMF did not improve physical function compared with the control treatment (SMD = −0.45, 95% CI − 0.98 to 0.07, p = 0.09, I2 = 86%). Conclusion PEMF is beneficial for alleviating pain in patients with chronic low back pain despite having no advantage in improving physical function.

Viral immunotherapies are being recognized in cancer treatment, with several currently approved or undergoing clinical testing. While contemporary approaches have focused on oncolytic viral therapies, our efforts center on the development of plant virus-based cancer immunotherapies. In a previous work, we demonstrated the potent efficacy of the cowpea mosaic virus (CPMV), a plant virus that does not replicate in animals, applied as an in situ vaccine. CPMV is an immunostimulatory drug candidate, and intratumoral administration remodels the tumor microenvironment leading to activation of local and systemic antitumor immunity. Efficacy has been demonstrated in multiple tumor mouse models and canine cancer patients. As wild-type CPMV is infectious toward various legumes and because shedding of infectious virus from patients may be an agricultural concern, we developed UV-inactivated CPMV (termed inCPMV) which is not infectious toward plants. We report that as a monotherapy, wild-type CPMV outperforms inCPMV in mouse models of dermal melanoma or disseminated colon cancer. Efficacy of inCPMV is less than that of CPMV and similar to that of RNA-free CPMV. Immunological investigation using knockout mice shows that inCPMV does not signal through TLR7 (toll-like receptor); structure-function studies indicate that the RNA is highly cross-linked and therefore unable to activate TLR7. Wild-type CPMV signals through TLR2, -4, and -7, whereas inCPMV more closely resembles RNA-free CPMV which signals through TLR2 and -4 only. The structural features of inCPMV explain the increased potency of wild-type CPMV through the triple pronged TLR activation. Strikingly, when inCPMV is used in combination with an anti-OX40 agonist antibody (administered systemically), exceptional efficacy was demonstrated in a bilateral B16F10 dermal melanoma model. Combination therapy, with in situ vaccination applied only into the primary tumor, controlled the progression of the secondary, untreated tumors, with 10 out of 14 animals surviving for at least 100 days post tumor challenge without development of recurrence or metastatic disease. This study highlights the potential of inCPMV as an in situ vaccine candidate and demonstrates the power of combined immunotherapy approaches. Strategic immunocombination therapies are the formula for success, and the combination of in situ vaccination strategies along with therapeutic antibodies targeting the cancer immunity cycle is a particularly powerful approach.

Kidney renal clear cell carcinoma (KIRC) is the most common and aggressive subtype of renal cell carcinoma. N6-methyladenosine (m6A) RNA methylation is the most prevalent epigenetic RNA modification. Long non-coding RNAs (lncRNAs) have emerged as a key role in regulating cancer progression. However, little has been learned about the molecular functions of m6A-related lncRNAs in KIRC. The prognostic value of m6A-related ln-cRNAs was investigated in KIRC samples downloaded from The Cancer Genome Atlas (TCGA) dataset. The m6A-related lncRNAs were further screen out by Pearson correlation test. Then, 27 m6A-related lncRNAs were confirmed as potential prognostic factors through univariate Cox regression analysis. They were entered into Lasso and multivariate Cox regression to build a m6A-related lncRNA prognostic signature, including 14 m6A-related lncRNAs determined as independent prognostic factors. Additionally, a risk score calculated according to the prognostic model could divide KIRC patients into low- and high-risk groups depending on median risk score as cut-off. A prognostic nomogram, derived from the prognostic model and integrating clinical characteristics of patients, was constructed. Three distinct clusters were identified with different immune signatures through consensus clustering analysis according to the expression pattern of m6A-related lncRNAs. Twenty-seven prognostic m6A-related lncRNAs were determined as prognostic lncRNAs from TCGA-KIRC cohort. The m6A-related lncRNA prognostic signature containing 14 independent prognostic lncRNAs exhibited good accuracy in predicting overall survival of KIRC patients. We correlated the three distinct clusters with immune infiltration signature of KIRC for the first time. We found that the worse prognosis of cluster2 was probably mediated by immune evasion. In summary, our study identified a m6A-related lncRNAs prognostic signature which had great clinical value in prognosis assessment. We classified TCGA-KIRC samples into three clusters with distinct immune signatures, which could be considered as potential targets of immunotherapy for KIRC treatment in the future.

Biomedical device-associated infection (BAI) is one of the main reasons for the function failure of implants in clinical practice. Development of high-efficiency antibacterial materials is of great significance in reducing the incidence of BAI and prolonging the function of the implants as well as alleviate the suffering of patients. In this work, a hierarchical polymer brush modified surface that can self-adapt to bacterial stimuli for exhibiting synergistic antibacterial activities was constructed, and it consisted of upper poly(sulfobetaine methacrylate) (pSBMA) brushes and antimicrobial peptide (AMP) tethered bottom brushes. Under physiological pH conditions, the hydration layer formed by the upper pSBMA can not only effectively resist the initial adhesion of bacteria, but also mask the toxicity of the underlying AMPs and improve biocompatibility. Once bacteria colonized the surface, the release of MTL could be activated for timely bactericidal activity

We present the finding of a dimeric ACE2 peptide mimetic designed through side chain cross-linking and covalent dimerization. It has a binding affinity of 16 nM for the SARS-CoV-2 spike RBD, and effectively inhibits the SARS-CoV-2 pseudovirus in Huh7-hACE2 cells with an IC

Stress urinary incontinence (SUI) is defined as involuntary urinary leakage happening in exertion. Nicotinamide phosphoribosyltransferase (Nampt) is seldom researched in the pathogenesis of SUI. Accordingly, the current study set out to elucidate the role of Nampt in SUI progression. Firstly, we determined Nampt expression patterns in SUI patients and rat models. In addition, fibroblasts were obtained from the anterior vaginal wall tissues of non-SUI patients and subjected to treatment with different concentrations of interleukin-1β (IL-1β), followed by quantification of Nampt expressions in fibroblasts. Subsequently, an appropriate concentration of IL-1β was selected to treat anterior vaginal wall fibroblasts. Nampt was further silenced in IL-1β-treated fibroblasts to assess the role of Nampt in autophagy and extracellular matrix (ECM) degradation. Lastly, functional rescue assays were carried out to inhibit autophagy and evaluate the role of autophagy in the mechanism of Nampt modulating IL-1β-treated fibroblast ECM degradation. It was found that Nampt was highly-expressed in SUI patients and rat models and IL-1β-treated fibroblasts. On the other hand, Nampt silencing was found to suppress ECM degradation and promote SUI fibroblast autophagy. Additionally, inhibition of autophagy attenuated the inhibitory effects of Nampt silencing on SUI fibroblast ECM degradation. Collectively, our findings revealed that Nampt was over-expressed in SUI, whereas Nampt silencing enhanced SUI fibroblast autophagy, and thereby inhibited ECM degradation.

We present a deep clustering-based MS data visualization strategy (MCnebula), integrated with the influential open-source automatic MS annotation platform SIRIUS and in vivo and in vitro methods, to screen and validate potential lead compounds from natural products.

The lymphatic system provides a main route for the dissemination of most malignancies, which was related to high mortality in cancer patients. Traditional intravenous chemotherapy is of limited effectiveness on lymphatic metastasis due to the difficulty in accessing the lymphatic system. Herein, a novel lymphatic-targeting nanoplatform is prepared by loading doxorubicin (DOX) into sub-50 nm polypyrrole nanovesicles (PPy NVs). The PPy NVs possessed hollow spherical morphologies and a negative surface charge, leading to high drug loading capacity. These vesicles can also convert near-infrared (NIR) light into heat and thus can be used for tumor thermal ablation. DOX loaded PPy NVs (PPy@DOX NVs) along with NIR illumination are highly effective against 4T1 breast cancer cells