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The flexural performance of a spliced composite slim beam with a slotted web (SCSB-SW) was assessed and prediction formulae of flexural capacity and initial stiffness for the beam were deduced. Through a four-point bending test, the flexural performance of the SCSB-SW was preliminary studied. The experimental results indicated that the section of the SCSB-SW conformed to the plane section assumption in the elastic stage. The beam failed in a ductile failure mode while there was no obvious relative slip between the steel beam and concrete slab in the failure stage. Finite-element models were developed and validated using the test results. A parametric analysis revealed that even if the cross-sectional dimensions and the position of the neutral axis in the beam are changed, the results predicted by the formulae still matched the numerical results well. The material strength, the thickness of the bottom flange of the steel beam and the concrete slab dimensions were found to play key roles in the flexural capacity of the beam, whereas the compressive strength grade of the concrete, the depth of the steel beam web and the dimensions of the concrete flange have significant effects on the initial stiffness of the beam.

This study aims to find out the possible optimal therapy and assess the prognosis properly for patient with spontaneous rupture of hepatocellular carcinoma (HCC).Propensity score matching (PSM) analysis was used to study the data from 325 patients with ruptured HCC (RHCC) and 2,291 patients with non-RHCC.The incidence and hospital mortality of RHCC were 5.1% and 0.8% respectively, with a median overall survival (OS) time of 17 months. There was no difference between ruptured and non-RHCC patients undergoing conservation treatment in terms of OS. Trans-arterial embolization (TAE) was carried out in 69 (21.2%) cases with RHCC, with a median OS of 7 months, which was no difference from that of non-RHCC (pre- and post-PSM). One hundred and sixty-nine (52.0%) RHCC cases underwent one-stage hepatectomy, with a median OS and disease-free survival (DFS) of 30 and 6 months respectively, which were shorter than that of non-RHCC (post-PSM). TAE plus two-stage hepatectomy was performed in 30 RHCC cases, with a median OS and DFS of 28 and 10 months respectively; these outcomes were better than that from RHCC patients undergoing TAE alone or one-stage hepatectomy (post-PSM), which were no difference from that of non-RHCC patients undergoing hepatectomy. The risk of death for RHCC patient undergoing one-stage hepatectomy is 1.545 times higher than that of one undergoing TAE + two-stage hepatectomy.TAE plus two-stage hepatectomy might be the optimal treatment for RHCC patient. Under the premise of the same pathological properties, there is no difference in prognosis between ruptured and non-RHCC patients if the therapy is appropriate.

Background Surgical treatment of severe thoracolumbar kyphosis (TLK) secondary to late osteoporotic vertebral compression fracture (OVCF) presents several challenges to spine surgeons. Proper selection of distal fusion level is an important issue in surgical planning to decrease the likelihood of distal mechanical complications. This study was designed to compare the clinical and radiographic outcomes in elderly patients suffering from severe TLK related with late OVCF between different distal fusion strategies and to recommend a superior distal fusion level for these patients. Methods A total of 57 consecutive subjects with a minimum follow-up of two years were retrospectively reviewed. TLK was defined as the hyperkyphosis with an apex below T10. Severe TLK was defined as the Cobb angle of kyphosis ≥60°. Patients fused to sagittal stable vertebra (SSV) were assigned to Group SSV, while those fused to the vertebra above and below SSV were assigned to Groups SSV- and SSV+, respectively. Bone cement was used to enhance pedicle screw fixation. Clinical and radiographic results were collected and compared between different groups. Results Deformity corrections and living quality improvements at the latest follow-up were superior in Group SSV than Group SSV- with shorter fusion levels, while to the equal extent with Group SSV+ with longer fusion levels. 7 cases of distal complications were observed in Group SSV-. Negatively balanced lowest instrumented vertebra was revealed to be the independent factor predicting distal complications. Patients’ satisfaction of their surgical management was greater in Group SSV than Group SSV- (83.2 ± 4.4% vs. 70.5 ± 10.9%, P = 0.024), while comparable with Groups SSV + SSV+ (84.8 ± 5.7%). Conclusions Fusion to SSV with cement-augmented pedicle screws could limit the development of distal junctional mechanical complications after surgical treatment for severe TLK secondary to late OVCF in elderly patients, while achieves satisfactory deformity correction with the preservation of necessary lumbar motility.

BACKGROUND/PURPOSE Clarithromycin-based standard triple therapy is still commonly adopted by 81.4% of physicians in real-world practice but yields low eradication rates. Therefore, we conducted this study to compare the efficacy of gastric juice-guided therapy for first-line eradication with the standard triple therapy, in order to provide an alternative to real-world practice. METHODS A total of 182 treatment-naive Hp-infected patients were included and randomly allocated to either susceptibility-guided therapy (SGT) with gastric juice PCR or Clarithromycin-based standard triple therapy (STT) for 7 days. RESULTS The intention-to-treat eradication rates were 89% (81/91) in SGT and 75.8% in STT (p < 0.031). The per-protocol eradication rates were 91.0% (81/89) in SGT and 79.3% (69/87) in STT (p < 0.034). Among the subgroups of different antibiotic resistance, patients with SGT demonstrated superior eradication rates (91.7% vs 45.5%, p < 0.027) in the subgroup of both clarithromycin resistance and levofloxacin resistance. CONCLUSION This prospective randomized controlled trial demonstrated the reliable efficacy of susceptibility-guided therapy via gastric juice PCR for the first-line Hp eradication. In Asia-Pacific area, where standard triple therapy is still adopted by the majority of the physicians, it is a recommended alternative to overcome the increasing antibiotic resistance.

Blau syndrome (BS) is a monogenic autoinflammatory disease caused by mutations in nucleotidebinding oligomerization domain containing 2 (NOD2). BS is characterized by the clinical triad of granulomatous dermatitis, arthritis and recurrent uveitis. Due to the low incidence of BS and the lack of treatment studies with large samples, a specific treatment scheme has not been established. We report the case of a patient with BS that was uncontrollable with various immunosuppressive therapies but had a good response to thalidomide. She had the typical triad of rash, arthritis and uveitis. Gene sequencing indicated a NOD2 heterozygous missense variant (c.1759C > T, p.R587C), which has been reported as a pathogenic mutation. The BS diagnosis was confirmed. After treatment with methotrexate, an anti-tumour necrosis factor (TNF)-α inhibitor and corticosteroids, the patient's clinical symptoms and inflammatory indicators remained uncontrolled, and she experienced multiple side effects, such as hypertension and growth retardation attributed to prolonged corticosteroid use. After treatment with thalidomide, her condition was controlled without recurrence or side effects, and corticosteroids were stopped as soon as possible. This report suggests that thalidomide may be effective for BS treatment, but more research is needed to evaluate its long-term efficacy and side effects.

Background This study is designed to evaluate the predictive value of derived monocyte to lymphocyte ratio (dMLR), neutrophil to lymphocyte ratio (NLR) and eosinophil to lymphocyte ratio (ELR) for lymph node metastasis (LNM) in gastric signet ring cell carcinoma (SRCC) patients. Methods We carried out a retrospective analysis for 203 eligible patients who underwent radical gastrectomy between January 2011 and September 2020. Results The diagnostic sensitivity and specificity for dMLR were 60.3% and 72.2%, respectively; while for NLR and ELR were 64.1% and 66.6%, and 91.6% and 23.6%, respectively. The dMLR and NLR were identified as independent predictors of LNM, but ELR was not. A nomogram was developed incorporating dMLR and clinical characteristics with AUC of 0.868, and the outcome of DCA supported good clinical benefit. Conclusions dMLR is a promising novel preoperative biomarker to predict LNM of gastric SRCC.

Acute myocardial infarction (AMI) remains a dominant origin of morbidity, mortality and disability worldwide. Increases in reactive oxygen species (ROS) are key contributor to excessive cardiac injury after AMI. Here we developed an immobilized enzyme with Superoxide Dismutase (SOD) activity cross-link with Zr-based metal-organic framework (ZrMOF) (SOD-ZrMOF) for mitigate ROS-caused injury. In vitro and in vivo evidence indicates that SOD-ZrMOF exhibits excellent biocompatibility. By efficiently scavenging ROS and suppressing oxidative stress, SOD-ZrMOF can protect the function of mitochondria, reduce cell death and alleviate inflammation. More excitingly, long-term study using an animal model of AMI demonstrated that SOD-ZrMOF can reduce the infarct area, protect cardiac function, promote angiogenesis and inhibit pathological myocardial remodeling. Therefore, SOD-ZrMOF holds great potential as an efficacious and safe nanomaterial treatment for AMI., Graphical abstract Image 1, Highlights • We synthesized a superoxide dismutase immobilized nanocomposite with enhanced stability. • We tested the biocompatibility of SOD-ZrMOF and found it could promote the cell viability and proliferation of H9c2 cells. • SOD-ZrMOF shows excellent performance in protecting mitochondrial function of CMs by eliminating excessive ROS under hypoxia. • SOD-ZrMOF exhibited therapeutic effects on MI heart through inhibiting oxidative stress injury by NF-κB/HIF-1α pathway.

In most acute promyelocytic leukemia (APL) cells, promyelocytic leukemia (PML) fuses to retinoic acid receptor α (RARα) due to chromosomal translocation, thus generating PML/RARα oncoprotein, which is a relatively stable oncoprotein for degradation in APL. Elucidating the mechanism regulating the stability of PML/RARα may help to degrade PML/RARα and eradicate APL cells. Here, we describe a deubiquitinase (DUB)-involved regulatory mechanism for the maintenance of PML/RARα stability and develop a novel pharmacological approach to degrading PML/RARα by inhibiting DUB. We utilized a DUB siRNA library to identify the ovarian tumor protease (OTU) family member deubiquitinase YOD1 as a critical DUB of PML/RARα. Suppression of YOD1 promoted the degradation of PML/RARα, thus inhibiting APL cells and prolonging the survival time of APL cell-bearing mice. Subsequent phenotypic screening of small molecules allowed us to identify ubiquitin isopeptidase inhibitor I (G5) as the first YOD1 pharmacological inhibitor. As expected, G5 notably degraded PML/RARα protein and eradicated APL, particularly drug-resistant APL cells. Importantly, G5 also showed a strong killing effect on primary patient-derived APL blasts. Overall, our study not only reveals the DUB-involved regulatory mechanism on PML/RARα stability and validates YOD1 as a potential therapeutic target for APL, but also identifies G5 as a YOD1 inhibitor and a promising candidate for APL, particularly drug-resistant APL treatment.

Primary central nervous system anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is an extremely rare type of primary central nervous system lymphoma (PCNSL). There are only nine cases reported in the literature to date, most of which have an overall survival time of no more than 8 months. Herein, we report such a rare case who has a good outcome with the longest survival time and perform a review of the literature. A 19-year-old male patient was admitted to the hospital complaining of dizziness. CT and MRI imaging showed a heterogeneous enhanced lesion in the left parieto-occipital lobe and the leptomeninges of the occipital lobe and the cerebellum. The lesion was resected and confirmed to be ALK-negative ALCL by pathological examination. Then, the patient received 10 cycles of chemotherapy with high-dose methotrexate (HD-MTX) and whole-brain radiotherapy. The patient recovered well and was regularly followed up. He was free of symptoms without recurrence on imaging examination 3 years later. ALCL is a rare type of PCNSL. HD-MTX combined with radiation is an effective therapeutic approach. However, further prospective studies with a large number of patients are needed to identify the biological characteristics of this rare type of PCNSL.

Background and aims Observational studies showed that coronavirus disease 2019 (COVID-19) attacks universally and its most menacing progression uniquely endangers the elderly with cardiovascular disease (CVD). The causal association between COVID-19 infection or its severity and susceptibility of atrial fibrillation (AF) remains unknown. Methods and results The bidirectional causal relations of COVID-19 (including COVID-19, hospitalized COVID-19 compared with not hospitalized COVID-19, hospitalized COVID-19 compared with population, and severe COVID-19) and AF are determined by using two-sample Mendelian randomization (MR) analysis. Genetically predicted severe COVID-19 was not significantly associated with risk of AF [odds ratio (OR), 1.037; 95% confidence interval (CI), 1.005-1.071; P = 0. 023, q = 0.115]. In addition, genetically predicted AF was also not causally associated with severe COVID-19 (OR, 0.993; 95% CI, 0.888-1.111; P = 0.905, q = 0.905). There was no evidence to support association between of genetically determined COVID-19 and risk of AF (OR, 1.111; 95% CI, 0.971-1.272; P = 0.127, q = 0.318), and vice versa (OR, 1.016; 95% CI, 0.976-1.058; P = 0.430, q = 0.851). Besides, no significant association was observed for hospitalized COVID-19 with AF. MR-Egger indicated no evidence of directional pleiotropy. Conclusion Overall, this MR study provides no clear support that COVID-19 is causally associated with the risk of AF.

Childhood brucellosis present various non-specific clinical symptoms, and limited laboratory data exist for clinical diagnosis. A better understanding of these clinical and laboratory characteristics can avoid clinical misdiagnosis and mistreatment. In this case-series study, a total of 78 children with confirmed diagnosis of brucellosis were evaluated retrospectively. We observed that the incidence rate was higher in the first two quarters every year. The most common symptom was fever. Osteoarticular involvement was found in 44.87% of the patients. Laboratory tests showed that the values of erythrocyte sedimentation rate(ESR), C-reactive protein(CRP), Hemoglobin(Hb), Neutrophils(NEU), Alanine aminotransfease(ALT) and Ferritin in childhood brucellosis with osteoarticular involvement had significant differences than those without osteoarticular involvement or control group (P

An exploration of the underlying mechanisms is necessary to improve nerve myelin-forming cell Schwann cell (SC) differentiation from adipose-derived stem cells (ADSCs). Primary rat ADSCs were isolated and characterised for cell surface markers using flow cytometry analysis. After treatment with a mixture of glial growth factors, ADSCs were induced to differentiate and subsequently identified by immunofluorescence staining and western blotting. A miRNA microarray analysis was performed to explore the genes and signalling pathways regulating ADSC differentiation into SCs. ELISAs were conducted to measure the expression of neurotrophic factors and changes in the level of nerve cell adhesion factor. Dual luciferase reporter assays and RIP assays were performed to explore the potential mechanism of miR-21-5p in ADSC differentiation. The isolated ADSCs were positive for CD29 and CD44 but negative for CD49. After induction with specific cytokines, the differentiated ADSCs presented a spindle-like morphology similar to SCs and expressed S100. RNA-sequencing analyses revealed that 9821 mRNAs of protein-coding genes and 175 miRNAs were differentially expressed in differentiated SC-like cells compared to primary cultures of ADSCs. KEGG and Gene Ontology analyses revealed that the involvement of the Notch signalling pathway and miRNA negative regulation may be associated with the differentiation of ADSCs into SCs. Treatment with a Notch inhibitor promoted the differentiation of ADSCs. Furthermore, mechanistic studies showed that Jag1 bound to miR-21-5p and upregulated its target gene Jag1, thus affecting ADSC differentiation. These results revealed the mechanism underlying the important roles of miRNAs and the Notch signalling pathway in the differentiation of SCs from ADSCs, enabling potential therapeutic applications of ADSCs in peripheral nerve regeneration in the future. miR-21-5p directly decreases levels of Jag1, which inhibits the Notch pathway and subsequently promotes the differentiation of adipose-derived stem cells into myelin-forming Schwann cells. Exploiting this signalling pathway may be an effective new method for the treatment of nerve injury.

To evaluate the ocular and systemic determinants of the choriocapillaris flow deficits percentage (CC FD%) in normal eyes.Observational cross-sectional study.Healthy Chinese participants without ocular or systemic diseases underwent detailed ophthalmic evaluations, including swept-source optical coherence tomography angiography (SS-OCTA) with 6- × 6-mm macular choriocapillaris images. The CC FD% was assessed in circular regions with diameters of 1.0 and 5.0 mm, rings with 1.0- to 2.5-mm diameters, and rings with 2.5- to 5.0-mm diameters.The study included 830 individuals (mean ± SD age 58.66 ± 8.75 years). CC FD% (mean ± SD 22.05% ± 1.13%) was the lowest in the 2.5- to 5.0-mm ring, followed by the 1.0- to 2.5-mm ring, and highest in the 1.0-mm circle. In multivariable analysis, a higher CC FD% was associated with older age (β = 0.16 [95% confidence interval {CI}] 0.08-0.24, P.001), higher intraocular pressure (β = 0.34 [95% CI 0.25-0.42], P.001), higher serum concentrations of high-density lipoprotein cholesterol (β = 0.24 [95% CI 0.17-0.32], P.001), and lower image quality score (β = -0.22 [95% CI -0.30 to -0.14], P.001). CC FD% was also independent of axial length.In healthy adult Chinese individuals, a higher CC FD% was associated with older age, higher intraocular pressure, and higher high-density lipoprotein cholesterol serum concentration. These factors may influence clinical assessments of the choriocapillaris. The lack of an association between CC FD% and axial length is consistent with similar findings for Bruch membrane thickness, macular retinal thickness, and macular retinal pigment epithelium cell density.

Rationale and Objectives To detect the diffusion characteristics of lumbosacral nerve roots in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and further to explore their correlations with electrophysiological parameters of lower extremity nerves. Materials and Methods Eighteen CIDP patients and 18 age and sex-matched healthy volunteers were enrolled in this study from August 2019 to August 2020. Axial diffusion tensor imaging (DTI) of lumbosacral plexus was performed in all subjects and fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) of lumbosacral nerve roots were measured. Two-sample t test or Mann–Whitney U test was used to compare the difference of DTI parameters between two groups. Receiver operating characteristic curves were plotted to determine the diagnostic accuracy. All patients also underwent nerve conduction studies. Correlations between DTI parameters of lumbosacral nerve roots and electrophysiological parameters were analyzed with Pearson or Spearman coefficients. Results CIDP patients showed significantly lower FA as well as higher AD, RD, and MD values of lumbosacral nerve roots (FA:0.24±0.054, 0.32±0.044; AD:2.31±0.256, 2.11±0.230 (×10−3mm2/s); RD:1.28±0.189, 1.13±0.106 (×10−3mm2/s); MD:1.68±0.268, 1.45±0.186 (×10−3mm2/s) in CIDP and control group, respectively, all p Conclusion DTI can be used to assess the microstructure alterations of lumbosacral nerve roots in CIDP patients. FA and RD may serve as potential markers reflecting the conduction function of tibial and common peroneal nerves.

Cataract is the leading cause of visual impairment, and posterior capsular opacification (PCO) is the most common long-term complication of modern cataract surgery, which can cause severe visual impairment after surgery. The proliferation, migration, and epithelial-mesenchymal transition (EMT) of residual lens epithelial cells (LECs) stimulated by growth factors and cytokines, are the key pathological mechanisms involved in the development of PCO. This study demonstrated that non-steroidal anti-inflammatory drug (NSAID), bromfenac, was capable of effectively inhibiting cell migration, overexpression of EMT markers, such as fibronectin (FN), matrix metalloproteinase 2 (MMP2), α-smooth muscle actin (α-SMA), and transcription factor Snail, and extracellular signal-regulated kinase (ERK)/glycogen synthase kinase-3β (GSK-3β) signaling induced by transforming growth factor-β2 (TGF-β2) in vitro. The inhibitory effect of bromfenac on TGF-β2-induced EMT was also verified on a primary lens epithelial cell model using human anterior capsules. Furthermore, based on ultrasonic spray technology, we developed a drug-eluting intraocular lens (IOL) using poly (lactic-co-glycolic acid) (PLGA) with sustained bromfenac release ability for the prevention of PCO development. In the rabbit models of cataract surgery, bromfenac-eluting IOL exhibited remarkable PCO prevention and inflammation suppression effects with excellent biocompatibility. In conclusion, bromfenac can inhibit TGF-β2-induced cell migration and the EMT of LECs via ERK/GSK-3β/Snail signaling. The present study offers a novel approach for preventing PCO through PLGA-based drug sustained-release IOLs., Graphical abstract TGF-β2 promoted migration and EMT of lens epithelial cells (LECs) through activation of ERK/GSK-3β/Snail signaling, which could be suppressed by bromfenac. Novel bromfenac-based drug-eluting IOLs exhibited excellent PCO prevention in vivo.Image 1, Highlights • Bromfenac inhibited TGF-β2-induced migration and EMT of LECs through ERK/GSK-3β/Snail signaling. • Drug-eluting IOLs with sustained bromfenac release were developed based on ultrasonic spray technology. • Bromfenac-eluting IOLs exhibited remarkable PCO prevention and inflammation suppression effects in vivo. • Bromfenac-eluting IOLs hold great potential for clinical application of PCO prevention.

It has been challenging to achieve multi-photochromic systems without affecting the individual photoswitching properties of the constituent units. Herein, we present the design and synthesis of a new family of platinum-acetylide dendrimers containing up to twenty-one photochromic dithienylethene (DTE) units that exhibit both high photochromic efficiency and individual switching properties. Upon irradiation with ultraviolet (UV) and visible (vis) light, the resultant metallodendrimers display high conversion yield and good fatigue resistance. More interestingly, cyclization-cycloreversion kinetics revealed that the photochromic property of each DTE unit in these metallodendrimers is unaffected by its neighbor and the full ring-closure of up to twenty-one DTE units in one single dendrimer has been achieved.

Purpose : The association between visual impairment (VI) and the risk of dementia has been poorly understood. We sought to investigate the VI-dementia relationship in the UK Biobank Study. Design : Prospective cohort study Methods : A total of 117,187 volunteers (aged 40-69 years) deemed free of dementia at baseline were included. Habitual distance visual acuity worse than 0.3 logMAR units in the better-seeing eye was used to define VI. The incident dementia was based on electronically linked hospital inpatient and death records. Results : During a median follow up of 5.96 years, the presence of VI was significantly associated with incident dementia (HR=1.78, 95% CI: 1.18-2.68, P=0.006). There was a clear trend between the severity of VI and the risk of dementia (P for trend=0.002). Conclusions : We found VI was associated with increased risk of dementia, with a progressively greater risk among those with worse visual acuity. Our findings suggested that visual impairment might be a modifiable risk factor for dementia and highlighted the potential value of VI elimination to delay the manifestation of dementia.

RATIONALE: In predominantly White populations, early chronic obstructive pulmonary disease (COPD) (i.e., COPD in people aged

Background: Prurigo nodularis (PN) as an extremely pruritic and hyperplastic chronic dermatosis induces psychologically and physiologically stressful responses. PN-induced responses in the hypothalamic-pituitary-adrenal (HPA), hypothalamic-pituitary-gonadal (HPG) axes and endocannabinoid system (ECS) are abnormal. Extant studies on the PN’s pathogenesis mostly focused on the PN’s psychological responses. To date, the PN’s physiological responses remain not been fully uncovered yet. Objectives: To investigate the PN-induced physiological responses via the levels of five steroids and two endocannabinoids combined with their ratios in plasma and examine the association between the psychological and physiological responses. Materials and methods: Thirty-six patients with PN, 36 age- and gender-matched healthy controls were recruited. The PN’s psychological symptoms including pruritus severity, pain and life quality were measured with the visual analogue scale, the prurigo score index, numerical rating scale, verbal rating scale and dermatology life quality index. Their concentrations of steroids and endocannabinoids were determined with liquid chromatography-tandem mass spectrometry. Results: Compared to controls, the PN patients showed lower plasma levels in cortisol, cortisone, N-arachidonoyl-ethanolamine (AEA), and the ratio of DHEA to 1-arachydonoyl glycerol (1-AG), which negatively moderately and over correlated with PN’s symptoms, especially with the pruritus severity. Additionally, the PN patients exhibited higher levels in the ratios of testosterone and 1-AG to cortisol, which positively moderately and over correlated with pruritus severity. Thus, the seven biomarkers would be sensitive and reliable biomarkers for assessing the pruritus severity of PN because they met the screening criteria that the biomarkers show intergroup differences and showed moderate or over correlation with the pruritus severity of PN. Conclusions: To the best of our knowledge, this is the first study exploring PN-induced physiological responses. The findigs suggest that alterations in these three endocrine systems may lead to new insights to psychological mechanisms and responses to prurigo nodularis.

The 2016 WHO classification introduced the category of high-grade B-cell lymphoma (HGBL), which includes one poorly understood subset, blastoid-HGBL. Establishing the diagnosis and distinguishing blastoid-HGBL from B-acute lymphoblastic leukemia (B-ALL) in bone marrow can be challenging. We assessed 31 cases of blastoid-HGBL diagnosed initially in bone marrow and compared this group to 36 cases of B-ALL using immunophenotyping, fluorescence in situ hybridization, and targeted next generation sequencing analysis. The 31 blastoid-HGBL cases included 14 HGBL with MYC and BCL2 and/or BCL6 rearrangements (double hit lymphoma, DHL), 13 HGBL, not otherwise specified (NOS), and four cases with TdT expression that were difficult to classify. Compared with B-ALL, blastoid-HGBL cases more often showed increased intensity/bright expression of CD20, CD38, CD45, BCL-6, and MYC, and less frequent bright expression of CD10 and TdT. Cases of blastoid-HGBL also more frequently had MYC rearrangement, a complex karyotype and TP53 mutation (p

Echinococcosis is a zoonotic parasitic disease that is highly endemic to the Qinghai province of China. Limited data are available on the prevalence of the causal pathogen, Echinococcus spp., in definitive hosts in this region. Thus, the aim of this study was to evaluate the prevalence of Echinococcus spp. in wild foxes and stray dogs in Qinghai province. Five hundred and twenty-eight feces from wild foxes and 277 from stray dogs were collected from 11 counties in the Golog, Yushu, and Haixi prefectures and screened for Echinococcus spp. using copro-DNA polymerase chain reaction (PCR). In total, 5.5% of wild foxes and 15.2% of stray dogs tested positive for Echinococcus spp. The prevalence rates of Echinococcus spp. in wild foxes in Golog, Yushu, and Haixi were 7.3%, 5.2%, and 1.9%, respectively. In stray dogs, these rates were 13.3%, 17.3%, and 0%, respectively. Sequencing analysis determined that Echinococcus multilocularis was the most prevalent species, occurring in 4.0% and 12.6% of wild foxes and stray dogs, respectively. Echinococcus shiquicus was observed in 1.5% of wild foxes and 0.7% of stray dogs. Echinococcus granulosus was observed only in wild dogs, with a prevalence rate of 1.8%. To our knowledge, this is the first report on the prevalence of E. shiquicus in dogs in Qinghai province. The current results improve our understanding of the transmission and dissemination of human echinococcosis and suggest that exposure to the eggs of E. multilocularis harbored by wild foxes and stray dogs may pose a great risk of alveolar echinococcosis to humans in Qinghai province.

OBJECTIVE Previous studies have suggested the use of 1.0 g/kg of 20% mannitol at the time of skin incision during neurosurgery in order to improve brain relaxation. However, the incidence of brain swelling upon dural opening is still high with this dose. In the present study, the authors sought to determine a better timing for mannitol infusion. METHODS One hundred patients with midline shift who were undergoing elective supratentorial tumor resection were randomly assigned to receive early (immediately after anesthesia induction) or routine (at the time of skin incision) administration of 1.0 g/kg body weight of 20% mannitol. The primary outcome was the 4-point brain relaxation score (BRS) immediately after dural opening (1, perfectly relaxed; 2, satisfactorily relaxed; 3, firm brain; and 4, bulging brain). The secondary outcomes included subdural intracranial pressure (ICP) measured immediately before dural opening; serum osmolality and osmole gap (OG) measured immediately before mannitol infusion (T0) and at the time of dural opening (TD); changes in serum electrolytes, lactate, and hemodynamic parameters at T0 and 30, 60, 90, and 120 minutes thereafter; and fluid balance at TD. RESULTS The time from the start of mannitol administration to dural opening was significantly longer in the early administration group than in the routine administration group (median 66 [IQR 55–75] vs 40 [IQR 38–45] minutes, p < 0.001). The BRS (score 1/2/3/4, n = 14/26/9/1 vs 3/25/18/4, p = 0.001) was better and the subdural ICP (median 5 [IQR 3–6] vs 7 [IQR 5–10] mm Hg, p < 0.001) was significantly lower in the early administration group than in the routine administration group. Serum osmolality and OG increased significantly at TD compared to levels at T0 in both groups (all p < 0.001). Intergroup comparison showed that serum osmolality and OG at TD were significantly higher in the routine administration group (p < 0.001 and = 0.002, respectively). Patients who had received early administration of mannitol had more urine output (p = 0.001) and less positive fluid balance (p < 0.001) at TD. Hemodynamic parameters, serum lactate concentrations, and incidences of electrolyte disturbances were comparable between the two groups. CONCLUSIONS Prolonging the time interval between the start of mannitol infusion and dural incision from approximately 40 to 66 minutes can improve brain relaxation and decrease subdural ICP in elective supratentorial tumor resection.

Osteoinductive, osteoconductive, and antibacterial properties of bone repair materials play important roles in regulating the successful bone regeneration. In the present work, we developed pH-sensitive gelatin methacryloyl (GelMA)-oxidized sodium alginate (OSA) hydrogels for dual-release of gentamicin sulfate (GS) and phenamil (Phe) to enhance the antibacterial activity and to promote large bone defect repair. Controlled release of GS was achieved through physical blending with GelMA-OSA solution before photo-polymeriaztion, while Phe was encapsulated into mesoporous silicate nanoparticles (MSN) within the hydrogels. In vitro antibacterial studies against Staphylococcus aureus and Escherichia coli indicated the broad-spectrum antibacterial property. Moreover, in vitro cell tests verified the synergistically enhanced osteogenic differentiation ability. Furthermore, in vivo studies revealed that the hydrogels significantly increased new bone formation in a critical-sized mouse cranial bone defect model. In summary, the novel dual-network hydrogels with both antibacterial and osteoinductive properties showed promising potential applications in bone tissue engineering.

Background Alpha-1 antitrypsin deficiency (AATD) is an autosomal co-dominant condition that predisposes to emphysema, cirrhosis, panniculitis, and vasculitis. Under-recognition has prompted efforts to enhance early detection and testing of at-risk individuals. Direct-to-consumer (DTC) genetic testing represents an additional method of detection. Research Question The study addressed three questions: 1) Does a DTC testing service identify previously undetected individuals with AATD? 2) What was the time interval between initial AATD-related symptoms and initial diagnosis of AATD in such individuals? and 3) What was the behavioral impact of learning about a new diagnosis of AATD through a DTC test? Study Design and Methods In this cross-sectional study, 195,014 individuals responded to a survey within the 23andMe, Inc. research platform. Results Among 195,014 study participants, the allele frequency for either the PI*S and PI*Z AATD variants was 21.6% (6.5% for PI*Z and 15.1% for PI*S); 0.63% were PI*ZZ, half of whom reported having a physician confirm the diagnosis. Approximately 27% of those with physician-diagnosed AATD reported first becoming aware of AATD through the DTC test. Among those newly-aware participants, the diagnostic delay interval was 22.3 years. Participants frequently shared their DTC test results with healthcare providers (HCPs) and the reported impact of learning a diagnosis of AATD was high. For example, 51.1% of PI*ZZ individuals shared their DTC result with an HCP. The odds ratio for PI*ZZ smokers to report smoking reduction as a result of receiving the DTC result was 1.7 [CI 1.4, 2.2] compared to those without a Z allele and for reduced alcohol consumption was 4.0 [CI 2.6, 5.9]. Interpretation In this largest available report on DTC testing for AATD, this test, in combination with clinical follow-up, can help to identify previously undiagnosed AATD patients. Moreover, receipt of the DTC AATD report was associated with positive behavior change, especially among those with risk variants.

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of pathologies, ranging from steatosis to nonalcoholic steatohepatitis (NASH). The factors promoting the progression of steatosis to NASH are still unclear. Recent studies suggest that mitochondrial lipid composition is critical in NASH development. Here, we showed that CDP-DAG synthase 2 (Cds2) was downregulated in genetic or diet-induced NAFLD mouse models. Liver-specific deficiency of Cds2 provoked hepatic steatosis, inflammation and fibrosis in five-week-old mice. CDS2 is enriched in mitochondria-associated membranes (MAMs), and hepatic Cds2 deficiency impaired mitochondrial function and decreased mitochondrial PE levels. Overexpression of phosphatidylserine decarboxylase (PISD) alleviated the NASH-like phenotype in Cds2f/f;AlbCre mice and abnormal mitochondrial morphology and function caused by CDS2 deficiency in hepatocytes. Additionally, dietary supplementation with an agonist of peroxisome proliferator-activated receptor alpha (PPARα) attenuated mitochondrial defects and ameliorated the NASH-like phenotype in Cds2f/f;AlbCre mice. Finally, Cds2 overexpression protected against high-fat diet-induced hepatic steatosis and obesity. Thus, Cds2 modulates mitochondrial function and NASH development.

With the help of non-orthogonal multiple access (NOMA), the number of connections of the beamspace multiple-input multiple-output (MIMO) systems can be improved with enhanced sum-rate performance, which constitutes beamspace MIMO-NOMA. Thus, most relevant papers focus on improving the system sum rate, which may inflict unbearable rate loss to weak users. To ensure the achievable rates of weak users, we maximize and analyze the minimal rate of the system in the single-beam case as well as the multi-beam case, where two completely different phenomena are revealed. Particularly, in the single-beam case, the maximized minimal rate of the beamspace MIMO-NOMA always grows rapidly with the signal-to-noise-ratio (SNR), and is larger than that of the beamspace MIMO using orthogonal multiple access (beamspace MIMO-OMA). However, in the multi-beam case, the maximized minimal rate of the beamspace MIMO-NOMA grows slower and slower in the high-SNR region, where it is smaller than that of the beamspace MIMO-OMA. To explain this difference, it is disclosed that the intra-beam interference in the single-beam case is of successive pattern, which is proved to have no limit on the max-min rate. In contrast, the inter-beam interference in the multi-beam case is of mutual pattern, which is proved to restrict the max-min rate to a derived upper bound.

Background & Aims Hepatocellular carcinoma (HCC) is characterized by intratumoral accumulation of regulatory T-cells (Tregs), which suppresses antitumor immunity. This study was designed to investigate how microRNAs regulate immunosuppression in HCC. Methods FVB/NJ mice were hydrodynamically injected with AKT/Ras or c-Myc and Sleeping Beauty transposon to induce HCC. The Sleeping Beauty system was used to deliver microRNA-15a/16-1 into livers of mice. Flow cytometry and immunostaining were used to determine changes in the immune system. Results Hydrodynamic injection (HDI) of AKT/Ras or c-Myc into mice resulted in hepatic enrichment of Tregs, reduced cytotoxic T cells (CTLs) and HCC development. HCC impaired microRNA-15a/16-1 biogenesis in Kupffer cells (KCs) of AKT/Ras and c-Myc mice. HDI of microRNA-15a/16-1 fully prevented HCC in AKT/Ras and c-Myc mice, while 100% of control mice died from HCC. Therapeutically, microRNA-15a/16-1 promoted a regression of HCC in both mouse models. MicroRNA-15a/16-1 impaired hepatic enrichment of Tregs and increased hepatic CTLs. Mechanistically, a significant increase was observed in serum C-C motif chemokine 22 (CCL22) and transcription of Ccl22 in KCs of AKT/Ras and c-Myc mice. MicroRNA-15a/16-1 prevented KCs from overproducing CCL22 by inhibiting NF-κB that activates transcription of Ccl22. By reducing CCL22 binding to CCR4 on Tregs, microRNA-15a/16-1 impaired Treg chemotaxis. Disrupting the interaction between microRNA-15a/16-1 and NF-κB impaired the ability of microRNA-15a/16-1 to prevent hepatic Treg accumulation and HCC. Depletion of CD8+ T cells and additional treatment of CCL22 recovered growth of HCC that was fully prevented by miR-15a/16. Conclusion MicroRNA-15a/16-1 attenuates immunosuppression by disrupting CCL22-mediated communication between KCs and Tregs. MicroRNA-15a/16-1 represents a potential immunotherapy against HCC.

Background: Little is known about the association between macronutrient intake and incident dementia. Objective: To identify an optimal range of macronutrient intake associated with reduced risk of dementia. Methods: Our analysis included 93,389 adults aged 60–75 years from the UK Biobank. Diet was assessed using a web-based 24-h recall questionnaire between 2009–2012. Dementia was ascertained using hospital inpatient, death records, and self-reported data up to January 2021. We calculated a macronutrient score based on associations between an individual’s macronutrient intake and incident dementia. Results: During a median follow-up of 8.7 years, 1,171 incident dementia cases were documented. We found U-shape relationships for carbohydrate, fat, and protein intake with incident dementia. Compared to individuals with optimal carbohydrate intake, those with high intake (HR (95%CI): 1.48(1.15–1.91)) but not low intake (1.19(0.89–1.57)) had a higher risk of dementia. In the multivariable analysis, a low-fat intake (HR (95%CI): 1.42(1.11–1.82)) was associated with a higher risk of all-cause dementia. After adjustment for covariates, a high (HR (95%CI): 1.41(1.09–1.83)) but not low protein intake (1.22(0.94–1.57)) was associated with an increased risk of dementia. Individuals in quintiles 3–5 of optimal macronutrient score had a lower risk of dementia compared with those in quintile 1 (HR (95%CI): 0.76(0.64–0.91) for quintile 3, 0.71(0.60–0.85) for quintile 4, 0.74(0.61–0.91) for quintile 5). The association between macronutrient score and incident dementia was significant across subgroups of age, gender, education, and smoking. Conclusion: Moderate intakes of carbohydrate, fat, and protein were associated with the lowest risk of incident dementia.

Osteoarthritis (OA) affects approximately 12% of the aging Western population. The sirtuin/forkhead box O (SIRT/FOXO) signaling pathway plays essential roles in various biological processes. Despite it has been demonstrated that ubiquitin-specific protease 3 (USP3) inhibits chondrocyte apoptosis induced by interleukin (IL)-1β, the role of USP3/SIRT3/FOXO3 in the senescence of chondrocytes in OA is unclear. This study initially isolated articular chondrocytes and investigated the role of USP3 in IL-1β-induced senescence of chondrocytes. After USP3 was overexpressed or silenced by lentivirus, expressions of genes and proteins were detected using quantitative polymerase chain reaction and immunoblotting, respectively. Cell cycle analysis was performed using flow cytometry. Reactive oxygen species (ROS) levels and senescence were analyzed. Then, SIRT3 was inhibited or overexpressed to explore the underlying mechanism. We found that overexpression of USP3 hindered IL-1β-mediated cell cycle arrest, ROS generation, and chondrocyte senescence. The inhibition of SIRT3 blocked the protective effect of USP3 on cell senescence, whereas the overexpression of SIRT3 abolished USP3-silencing-induced cell senescence. Furthermore, SIRT3 attenuated cell senescence, probably by deacetylating FOXO3. USP3 upregulated SIRT3 to deacetylate FOXO3 and attenuated IL-1β-induced chondrocyte senescence. This study demonstrated that USP3 probably attenuated IL-1β-mediated chondrocyte senescence by deacetylating FOXO3 via SIRT3.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the pandemic respiratory infectious disease COVID-19. However, clinical manifestations and outcomes differ significantly among COVID-19 patients, ranging from asymptomatic to extremely severe, and it remains unclear what drives these disparities. Here, we studied 159 sequentially enrolled hospitalized patients with COVID-19-associated pneumonia from Brescia, Italy using the VirScan phage-display method to characterize circulating antibodies binding to 96,179 viral peptides encoded by 1,276 strains of human viruses. SARS-CoV-2 infection was associated with a marked increase in immune antibody repertoires against many known pathogenic and non-pathogenic human viruses. This antiviral antibody response was linked to longitudinal trajectories of disease severity and was further confirmed in additional 125 COVID-19 patients from the same geographical region in Northern Italy. By applying a machine-learning-based strategy, a viral exposure signature predictive of COVID-19-related disease severity linked to patient survival was developed and validated. These results provide a basis for understanding the role of memory B-cell repertoire to viral epitopes in COVID-19-related symptoms and suggest that a unique anti-viral antibody repertoire signature may be useful to define COVID-19 clinical severity.

Background The Chinese government has worked out the “Rural Oriented Medical Students Training Project” to address physician maldistribution, which attempted to train physicians for rural areas. The present study attempted to evaluate the job satisfaction of the graduates of this project in Jiangsu Province, China. Methods Online questionnaires were sent to the graduates of the “Rural Oriented Medical Students Training Project” (group A) and their colleagues, who were rural physicians recruited from different sources (group B). The study was approved by the Ethics Committee of Xuzhou Medical University, and the approval number was 2,018,057. Information on demographic characteristics, work conditions, and self-reported satisfaction was collected to compare the satisfaction differences between the two recruited rural physicians using the Chi-square test and Mann–Whitney U test. Additionally, factors correlated to the satisfaction of group A were assessed using multivariate linear regression. Statistical analysis was performed using SPSS 23.0 (SPSS Inc., Chicago, IL, USA). P Results Group A exhibited moderate satisfaction (2.81 ± 0.687). The satisfaction score from the highest to the lowest was for occupational ecology, life satisfaction, stress, competency, and internal environment. Positive factors related to the satisfaction of group A were area, monthly income, working hours per week, professional title, and post. Conclusion The satisfaction of the graduates of the “Rural Oriented Medical Students Training Project” was moderate. Factors related to satisfaction included economic incentives, workload, and professional confidence. Possible solutions for increasing satisfaction should consist of economic support and possible ways to improve the professional identification of these graduates.

Traffic restriction policy (TRP) is common practice to alleviate urban congestion and air pollution. However, effects of TRP for non-local vehicles and elevated expressways on local and regional air quality are understudied. Using air pollutant data collected by ground-based national and roadside environmental monitoring stations and field measurements, comparative research design and regression discontinuity analysis were performed to investigate the local and regional variations in air pollutant concentrations with and without the TRP. Results indicate that traffic restriction significantly decreased the local and regional concentration levels of primary gaseous pollutants (e.g., NOX and CO), particularly under more stringent TRP during China International Import Expo, which also brought an ozone increase due to the reduced effect of NOX titration. However, the TRP only exhibited limited impacts on mitigating regional particulate pollution. These findings suggest that the air quality improvements due to the non-local TRP highly depend on the types of pollutants and the spatial locations.

Aerosol liquid water content (ALWC) dictates the hygroscopicity of aerosol particles. To date, measurements of ALWC have been confined primarily to ground-based observations, although vertical profiles of ALWC are crucial for understanding its interactions with meteorology. This study proposes a novel method for deriving profiles of ALWC using data acquired by a lidar, a microwave radiometer, and a suite of aerosol instruments measuring aerosol physical and chemical properties, deployed during a five-month field experiment in Guangzhou, China. The retrieval approach is based on a machine-learning model named the gradient-boosted decision tree model. The inversion accuracy and stability are assessed through comparisons with ALWC data acquired on the ground and at the top of the Guangzhou Tower of 532 m above ground. The agreements are encouraging: with the coefficient of determination (R2) = 0.870 and root-mean-square error (RMSE) = 3.28 μg m-3 for all data; R2 = 0.776 and RMSE = 2.18 μg m-3 for tower data; and R2 = 0.872 and RMSE = 4.1μg m-3 for ground data. From the vertical distribution of the retrieved ALWC in Guangzhou, ALWC is higher in the lower boundary layer, especially when air pollution is severe. The proportion of liquid water in aerosol particles is closely related to the relative humidity in the environment, which will affect the morphology of aerosol particles (with about every 10% increase in liquid water, the depolarization ratio decreases by 0.02). The model may be of general use for studying air pollution and secondary aerosol generation.

Huntington's Disease is a fatal neurodegenerative disorder caused by an inherited mutation in the huntingtin gene (HTT) comprising an expanded cytosine-adenine-guanine (CAG) trinucleotide repeat sequence that results in a pathogenic huntingtin protein. AAV gene therapy containing a primary artificial microRNA (pri-amiRNA) specifically targeting HTT mRNA has the potential to provide long-lasting therapeutic benefit, via durable reduction of mutant HTT expression after a single administration. The efficiency and precision of processing of the pri-amiRNA precursor to the mature guide strand by transduced cells is critical for specific and potent HTT lowering. The selection of the optimized pri-amiRNA comprised a series of in vitro studies followed by in vivo studies in small and then large mammals. Our studies demonstrate the predictivity of certain cell culture systems and rodent models for nonhuman primates (NHP) with respect to some, but not all key features of pri-amiRNA processing. In addition, our results show that the processing of pri-amiRNAs to the mature guide strand can differ greatly across different scaffolds and sequences while providing the same levels of target lowering. Importantly, our data demonstrate that there is a combinatorial effect of guide and passenger strand sequences, together with the scaffold, on pri-amiRNA processing, with different guide and passenger strand sequences within the same scaffold dramatically altering pri-amiRNA processing. Taken together, our results highlight the importance of optimizing not only target lowering, but also the efficiency and precision of pri-amiRNA processing in vitro, in rodents and in large mammals to identify the most potent and selective AAV gene therapy that harnesses the endogenous miRNA biogenesis pathway for target lowering without perturbing the endogenous cellular miRNA profile. The optimized pri-amiRNA was selected with this focus on efficiency and precision of pri-amiRNA processing in addition to its pharmacological activity on HTT lowering, and general tolerability in vivo.

In this work, an edible cellulose-based antibacterial material was prepared by cross-linking α-cellulose and kanamycin sulfate via glutaraldehyde to form kanamycin sulfate-glutaraldehyde-cellulose. Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy and X-ray diffraction results indicated that the kanamycin sulfate molecule was cross-linked with the molecular chain of cellulose. The optimal mass ratio of kanamycin sulfate to α-cellulose was 1:100 and the degree of substitution reached 1.11%. The optimal kanamycin sulfate-glutaraldehyde-cellulose material showed an excellent inhabitation against both Gram-positive and Gram-negative bacteria. Meantime, the optimal kanamycin sulfate-glutaraldehyde-cellulose had a marked resistance to gastric acid and had low cell cytotoxicity. To promote the application of the kanamycin sulfate-glutaraldehyde-cellulose material, the porous microspheres were prepared via the sol-gel method. The particle size of the homogeneous porous microspheres is mainly distributed between 1.5 and 2.0 μm. Therefore, the kanamycin sulfate-glutaraldehyde-cellulose described herein is a potential edible, eco-friendly, potent, stable, inexpensive, and antibacterial carrier material for delivering drugs, proteins, or vaccines.

Early detrimental experiences increase the risk of psychiatric disorders, including posttraumatic stress disorder (PTSD). In a previous experiment, we demonstrated that traumatic stress in adolescence triggers changes in the expression of the epigenetic marker H3K9me2 in the hippocampus and prefrontal cortex of adolescent and adult rats, which suppresses transcription of the brain-derived neurotrophic factor (Bdnf) gene that promotes dendrite development and synaptic growth. However, corresponding changes in the amygdala in response to traumatic stress in early life have not yet been fully elucidated. In the current study, we used the inescapable foot shock (IFS) procedure to establish a PTSD model. Half an hour after the end of electric shocks, intraperitoneal injection of the G9a enzyme inhibitor Unc0642, a small molecule inhibitor of EHMT2 that can decrease H3K9me2 expression, was applied to reverse the corresponding epigenetic changes. Exploratory behaviors, anxiety-like behavior, social communication ability, spatial exploration and memory were determined using the open field test (OFT), elevated plus maze (EPM) test, three-chamber sociability test (SIT), Morris water maze (MWM) test, and Y maze test (YMZ), respectively. Additionally, the levels of H3K9me2 and BDNF were measured by quantitative reverse transcription-polymerase chain reaction (qPCR) and Western blotting. Furthermore, neuronal development was examined using Golgi staining. The results showed that the IFS procedure induced anxiety-like and depression-like behaviors, social skills dysfunction, and spatial exploration and memory disorders. It also decreased the mRNA expression of BDNF and BDNF and increased the expression of H3K9me2 in the amygdala. More importantly, compared to unstressed animals, traumatic stress during adolescence induced dendrite maldevelopment in adolescent and adult rats. In summary, the present study indicates that early-life stress alters the epigenetic marker expression of H3K9me2 and decreases levels of BDNF in the amygdala, resulting in dendrite maldevelopment and a higher risk of mental disorders.

Background The Liver Imaging Reporting and Data System (LI-RADS) assigns a risk category for hepatocellular carcinoma (HCC) to imaging observations. Establishing the contributions of major features can inform the diagnostic algorithm. Purpose To perform a systematic review and individual patient data meta-analysis to establish the probability of HCC for each LI-RADS major feature using CT/MRI and contrast-enhanced US (CEUS) LI-RADS in patients at high risk for HCC. Materials and Methods Multiple databases (MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Scopus) were searched for studies from January 2014 to September 2019 that evaluated the accuracy of CT, MRI, and CEUS for HCC detection using LI-RADS (CT/MRI LI-RADS, versions 2014, 2017, and 2018; CEUS LI-RADS, versions 2016 and 2017). Data were centralized. Clustering was addressed at the study and patient levels using mixed models. Adjusted odds ratios (ORs) with 95% CIs were determined for each major feature using multivariable stepwise logistic regression. Risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) (PROSPERO protocol: CRD42020164486). Results A total of 32 studies were included, with 1170 CT observations, 3341 MRI observations, and 853 CEUS observations. At multivariable analysis of CT/MRI LI-RADS, all major features were associated with HCC, except threshold growth (OR, 1.6; 95% CI: 0.7, 3.6; P = .07). Nonperipheral washout (OR, 13.2; 95% CI: 9.0, 19.2; P = .01) and nonrim arterial phase hyperenhancement (APHE) (OR, 10.3; 95% CI: 6.7, 15.6; P = .01) had stronger associations with HCC than enhancing capsule (OR, 2.4; 95% CI: 1.7, 3.5; P = .03). On CEUS images, APHE (OR, 7.3; 95% CI: 4.6, 11.5; P = .01), late and mild washout (OR, 4.1; 95% CI: 2.6, 6.6; P = .01), and size of at least 20 mm (OR, 1.6; 95% CI: 1.04, 2.5; P = .04) were associated with HCC. Twenty-five studies (78%) had high risk of bias due to reporting ambiguity or study design flaws. Conclusion Most Liver Imaging Reporting and Data System major features had different independent associations with hepatocellular carcinoma; for CT/MRI, arterial phase hyperenhancement and washout had the strongest associations, whereas threshold growth had no association. © RSNA, 2021 Online supplemental material is available for this article.

Purpose: The purpose of this study was to investigate the influencing factors for chest CT hysteresis and severity of coronavirus disease 2019 (COVID-19). Methods: The chest CT data of patients with confirmed COVID-19 in 4 hospitals were retrospectively analyzed. An independent assessment was performed by one clinician using the DEXIN FACT Workstation Analysis System, and the assessment results were reviewed by another clinician. Furthermore, the mean hysteresis time was calculated according to the median time from progression to the most serious situation to improve chest CT in patients after fever relief. The optimal scaling regression analysis was performed by including variables with statistical significance in univariate analysis. In addition, a multivariate regression model was established to investigate the relationship of the percentage of lesion/total lung volume with lymphocyte and other variables. Results: In the included 166 patients with COVID-19, the average value of the most serious percentage of lesion/total lung volume was 6.62, of which 90 patients with fever had an average hysteresis time of 4.5 days after symptom relief, with a similar trend observed in those without fever. Multivariate analysis revealed that lymphocyte count in peripheral blood and transcutaneous oxygen saturation decreased with the increase of the percentage of lesion/total lung volume. Conclusion: There is a hysteresis effect in the improvement of chest CT image relative to fever relief in patients with COVID-19. The pulmonary lesions may be related to the severity as well as decreased lymphocyte count or percutaneous oxygen saturation.

Background: HIV-related stigma poses a crucial barrier to HIV therapy and prevention worldwide. Stigma taking place in healthcare settings has also been a global challenge for years. Objective: To measure HIV-related stigma among health care facilities in Baoan, Shenzhen and to take decision regarding stigma-reduction intervention. Methods: We conducted a cross-sectional survey in Shenzhen Baoan Women's and Children's Hospital, China in February 2019. We collected data on HIV-related stigma from 207 hospital staff randomly selected for an anonymous survey online by a standardized questionnaire. We analyzed the influence factors on HIV-related stigma taking place in health facilities using the statistical method. Results: The percentages of worry expressed when touching clothing, dressing wound, and drawing blood for PLWH were 60.9%, 84.5%, and 82.6%, respectively. 76.3% of respondents reported at least one form of extra precautions taken during service provision to PLWH. Younger hospital employees with less working experience were more likely concerned about occupation risk of HIV infection (P Conclusion: HIV-related stigma in health facilities remains a significant challenge, and evidence- based interventions at both systematic and individual levels are needed for improvements.

Aims It is unknown whether Epstein-Barr virus (EBV) infection can occur in high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, also known as double-hit or triple-hit lymphoma (DHL/THL). Methods and results Here we report 16 cases of EBV+ DHL/THL from screening 846 cases of DHL/THL and obtaining additional EBV+ cases through multi-institutional collaboration: 8 MYC/BCL2 DHL, 6 MYC/BCL6 DHL, and 2 THL. There were 8 men and 8 women with a median age of 65 years (range, 32-86). Two patients had a history of follicular lymphoma and one had AIDS. Nine of 14 patients had an International Prognostic Index of ≥3. Half of the cases showed high-grade/Burkitt-like morphology and the other half diffuse large B-cell lymphoma morphology. By immunohistochemistry, the lymphoma cells were positive for MYC (n=14/16), BCL2 (n=12/16), BCL6 (n=14/16), CD10 (n=13/16), and MUM1 (n=6/14). By Hans algorithm, 13 cases were classified as GCB and 3 as non-GCB. The lymphomas frequently showed an EBV latency type I with a median EBV-encoded small RNAs of 80% positive cells (range, 20-100%). After a median follow-up of 36.3 months (range, 2.0-41.6), 7 patients died with a median survival of 15.4 months (range, 3.4-47.3) after diagnosis of EBV+ DHL/THL. Five of 6 patients with MYC/BCL6 DHL were alive including 4 in complete remission. In contrast, only 4/10 patients with MYC/BCL2 DHL or THL were alive including 2 in complete remission. The median survival in patients with MYC/BCL6 DHL was unreached and was 21.6 months in patients with MYC/BCL2 DHL or THL. Conclusions EBV infection in DHL/THL is rare (~1.5%). Cases of EBV+ DHL/THL are largely similar to their EBV-negative counterparts clinicopathologically. Our findings expand the spectrum of EBV+ B-cell lymphomas currently recognized in the WHO classification and suggest differences between EBV+ MYC/BCL2 and MYC/BCL6 DHL that may have therapeutic implications.

In recent years, cancer phototherapy has been extensively studied as noninvasive cancer treatment. To present efficient recognition toward cancer cells, most photosensitizers (PSs) are required to couple with tumor-targeted ligands. Interestingly, the heptamethine cyanine IR780 displays an intrinsic tumor-targeted feature even without modification. However, the photothermal efficacy and photostability of IR780 are not sufficient enough for clinical use. Herein, we involve a twisted structure of tetraphenylethene (TPE) between two molecules of IR780 to improve the photothermal conversion efficiency (PCE). The obtained molecule T780T shows strong near-infrared (NIR) fluorescence and improved PCE (38.5%) in the dispersed state. Also, the photothermal stability and ROS generation capability of T780T at the NIR range (808 nm) are both promoted. In the aqueous phase, the T780T was formulated into uniform nanoaggregates (∼200 nm) with extremely low fluorescence and PTT response, which would reduce in vivo imaging background and side effect of PTT response in normal tissues. After intravenous injection into tumor-bearing mice, the T780T nanoaggregates display high tumor accumulation and thus remarkably inhibit the tumor growth. Moreover, the enhanced photostability of the T780T allows for twice irradiation after one injection and leads to more significant tumor inhibition. In summary, our study presents a tumor-targeted small-molecule PS for efficient cancer therapy and brings a new design of heptamethine cyanine PS for potential clinical applications.

8-methylene-tert-butylamine-3',5,7-trihydroxy-4'-methoxyflavanone (MTBH), a novel hesperidin derivative, has potential in the prevention of hepatic disease, however, its effects on cytochrome P450 isoforms (P450s) remains unexplored. The purpose was to investigate the effects of MTBH on the mRNA, protein levels and activities of six P450s (1A2, 2C11/9, 2D2/6, 3A1/4, 2C13/19 and 2E1) in vitro and in vivo.In vitro study, rat and human liver microsomes were adopted to elucidate the inhibitory effect of MTBH on six P450s using probe drugs. In vivo study, Sprague-Dawley male rats were treated with MTBH (25, 50 or 100 mg/kg for 28 consecutive days), phenobarbital (80 mg/kg for 12 consecutive days) or 0.5% CMC-Na solution (control group) by intragastric administration, then, the mRNA, protein levels and activities of liver P450s were analyzed by real-time PCR, western blotting and probe-drug incubation systems, respectively.The in vitro study indicated that MTBH inhibits the activities of CYP3A1/4 and CYP2E1 in rat and human liver microsomes. In vivo data showed that MTBH inhibits mRNA, protein levels and activities of CYP3A1 and CYP2E1 in medium- and high-dose MTBH groups.MTBH has the potential to cause drug-drug interactions when co-administered with drugs that are metabolized by CYP3A1/4 and CYP2E1.

Background & Aims Intratumor molecular heterogeneity is a key feature of tumorigenesis and is linked to treatment failure and patient prognosis. Herein, we aimed to determine what drives tumor cell evolution by performing single-cell transcriptomic analysis. Methods We analyzed 46 hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) biopsies from 37 patients enrolled in interventional studies at the NIH Clinical Center, with 16 biopsies collected before and after treatment from 7 patients. We developed a novel machine learning-based consensus clustering approach to track cellular states of 57,000 malignant and non-malignant cells including tumor cell transcriptome-based functional clonality analysis. We determined tumor cell relationships using RNA velocity and reverse graph embedding. We also studied longitudinal samples from 4 patients to determine tumor cellular state and its evolution. We validated our findings in bulk transcriptomic data from 488 patients with HCC and 277 patients with iCCA. Results Using transcriptomic clusters as a surrogate for functional clonality, we observed an increase in tumor cell state heterogeneity which was tightly linked to patient prognosis. Furthermore, increased functional clonality was accompanied by a polarized immune cell landscape which included an increase in pre-exhausted T cells. We found that SPP1 expression was tightly associated with tumor cell evolution and microenvironmental reprogramming. Finally, we developed a user-friendly online interface as a knowledge base for a single-cell atlas of liver cancer. Conclusions Our study offers insight into the collective behavior of tumor cell communities in liver cancer as well as potential drivers of tumor evolution in response to therapy. Lay summary Intratumor molecular heterogeneity is a key feature of tumorigenesis that is linked to treatment failure and patient prognosis. In this study, we present a single-cell atlas of liver tumors from patients treated with immunotherapy and describe intratumoral cell states and their hierarchical relationship. We suggest osteopontin, encoded by the gene SPP1, as a candidate regulator of tumor evolution in response to treatment.

Advanced Non-alcoholic fatty liver disease (NAFLD) is associated with increased risk of cardiovascular disease (CVD).We determine whether combinations of ultrasound graphic steatosis grades, fibrosis scores and apolipoprotein levels add value to CVD risk prediction in NAFLD patients.The retrospective cohort study enrolled 10,453 individuals (3519 NAFLD; 6934 non NAFLD) from 2004 to 2018. Hepatic ultrasound measurements, lipid and apolipoprotein profiles, Fibrosis-4 and the NAFLD fibrosis scores (NFS) were assessed. The primary outcome included both clinical and subclinical CVD.During 116-month follow-up period, there were 957 clinical and 752 subclinical CVD events. NAFLD patients had a higher incidence of CVD than non NAFLD patients as the steatosis degree, NFS, and FIB4 scores increased (25.1% vs 11.9%, Log Rank: p 0.001). For the lipid and apolipoprotein profiles excluding triglyceride or ApoE, subjects with varied steatosis severity in the upper two tertiles had different risk of CVD (p for interaction 0.001). A nomogram model combination of Framingham Risk Score (FRS), NFS and apolipoprotein profiles presented a higher AUC than FRS in a time-dependent ROC curve (0.816 vs 0.752, p 0.001).The novel risk score considering ultrasonography-defined steatosis grades, non-invasive liver fibrosis scores and apolipoprotein profiles accurately predicted the 10-year risk of CVD.

Aims: This study aims to evaluate the differences in the characteristics of atherosclerotic plaques in the proximal, curved, and distal segments of the curved basilar artery (BA) through high-resolution magnetic resonance imaging(HR-MRI). Methods: The imaging and clinical data of 146 patients were retrospectively analyzed. On the basis of three-dimensional (3D) time -of -flight magnetic resonance angiography (3D-TOF-MRA), 51 patients with BA curvature were selected for the study. The BA plaque is divided into three groups: proximal, curved, and distal. Plaques were identified and analyzed according to spin echo acquisition imaging via T1-weighted 3D volumetric isotropic Tse acquisition (T1W-3D -VISTA), and compare the differences in clinical related factors and plaque characteristics between groups. Diffusion-weighted imaging (DWI) and/or T2WI identified brainstem infarction. The patients were divided into symptomatic and asymptomatic groups. The correlation between plaque location and symptoms was identified and analyzed. Results: Among 51 patients, a total of 376 plaques were detected. Plaques in the proximal and curved segments are more common than those in the distal segments. Proximal plaques are more likely to have intraplaque hemorrhage ( P =0.002 ＜0.05). There was no significant difference in the distribution of criminal plaques and non-criminal plaques between each group ( P =0.36 ＞0.05). Conclusion: Plaques in the proximal and curved segments of the BA are more common than those in the distal segments. The proximal plaque is more prone to intraplaque hemorrhage.

Background: Epidemiological studies have suggested that elevated serum uric acid may contribute to the progression of chronic kidney disease. However, no large prospective study has examined whether hyperuricemia is an independent risk factor for the progression of autosomal dominant polycystic kidney disease (ADPKD). Methods: We measured uric acid in stored serum samples from the 2-year study visit of 671 participants from the HALT PKD multicenter trials. Participants were categorized according to uric acid tertiles. For Study A (participants aged 15-49 years with preserved kidney function, n=350), we used linear mixed effects models to examine the association between uric acid and repeated measures of height-adjusted total kidney volume (htTKV), the primary outcome for Study A. For Study B (participants aged 18-64 with decreased kidney function, n=321), we used Cox proportional hazards models to assess the hazard for the combined endpoint of 50% loss in estimated glomerular filtration rate (eGFR), end-stage kidney disease (ESKD), or death, the primary outcome for Study B. To assess the association of uric acid with the slope of eGFR decline (secondary outcome of HALT A and B), we used linear mixed effects models for the combined population of Study A and B. Results: In the unadjusted model, the annual change in htTKV was 2.7% higher in the highest uric acid tertile compared to the lowest (p Conclusion: Elevated serum uric acid is not an independent risk factor for disease progression in ADPKD.

Objective To conduct a nationwide evaluation of vaccine bidding, procurement and distribution management for understanding and improving the current situation well in mainland China. Methods An institution survey was carried out to collect information on tendering, procurement, distribution and related issues to vaccines by structured questionnaires administered to 31 provinces in mainland China from April to July 2019. Results In 13 (41.9%) of 31 provinces, centralized bidding of National Immunization Program (NIP) vaccines was accomplished, and others conducted independent tendering and purchasing in 2018. For non-NIP vaccines, all provinces implemented unified bidding at the provincial level and over half (18, 58.1%) of them chose provincial public resource trading platforms, but their modes varied over provinces. Then procurement was undertaken by the district-level centers for disease control and prevention (CDC) while they were unable to choose the best option of too many vaccines targeted by the province-level CDC for local populations. The distribution modes of NIP and non-National Immunization Program (non-NIP) vaccines were similar overall in a province but very different over provinces. Main mode was that CDCs at different levels delivered about two thirds (64.5%) of NIP vaccines distribution and more than one third (35.5%) of non-NIP vaccines. Another distribution mode was occupied as fully buying the service from third parties in 3 municipalities. Some provinces mixed both modes, too. The total distribution volume of vaccines was 430.7 million doses in 2018. The top five non-NIP vaccines delivered in 2018 were human rabies vaccine, varicella vaccine, EV71 hand foot mouth disease vaccine, hepatitis B vaccine and influenza vaccine. Conclusion The vaccine biding, procurement and distribution management varied over provinces in mainland China in 2018, especially for non-NIP vaccines. Specific policies and measures should be developed for different regions to improve the immunization management better.