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Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are the first-line treatment agents for chronic hepatitis B virus (HBV). Recently, whether the degree to which the risk of hepatocellular carcinoma (HCC) may be reduced by ETV vs TDF has been debated. We compared the incidence of HCC among treatment-naïve patients receiving TDF vs ETV in the United States.From a large administrative medical claims database of commercially insured patients, we identified 166,933 adults with a diagnosis of chronic hepatitis B and a minimum of 12 months of prior enrolment, of whom 3934 and 6127 initiated ETV and TDF respectively. Fine-Gray hazard regression models incorporating treatment propensity scores (PS) were used to estimate the risk of HCC incidence associated with TDF vs ETV; variables considered for adjustment included demographic characteristics, concomitant medication use and baseline comorbidities, as well as competing events including liver transplantation and medication changes.After PS weighting, the TDF and ETV groups were well-matched. During the follow-up, 90 patients developed HCC, including 50 receiving ETV and 40 receiving TDF, giving rise to crude incidence rates of 0.62 per 100 person-years (PY) and 0.30 per 100 PY respectively. In PS-weighted, multivariable analysis, TDF was associated with a subdistribution hazard ratio for HCC of 0.58 (95% confidence interval [CI]: 0.38-0.89) compared to ETV. Results were similar when patients ≥40 years and men and women were analysed separately.Among commercially insured, treatment-naïve patients with chronic hepatitis B in the United States, treatment with TDF was associated with significantly lower risk of HCC than ETV.

We investigated factors associated with rates of recommended monitoring of chronic hepatitis B (HBV) patients for viral DNA and alanine aminotransferase (ALT), and initiation of antiviral treatment among eligible patients, in a US cohort of patients under routine care. Patients were categorised by treatment indication: definite, equivocal or ineligible. Baseline covariates included demographics, clinical characteristics and specialist care status. 'Recommended monitoring' was defined ≥1 ALT or HBV DNA test per year. Logit models, univariate then multivariable, were used to evaluate factors associated with monitoring and treatment. Among 3,830 patients, treatment was received by 67.5% (788/1168 patients) in the 'definite' category, and 34.1% (208/610 patients) in the 'equivocal' category, of whom 109 moved up to 'definite' status at some point during follow-up. Sex, age and specialist care were independently associated with receipt of treatment in 'definite' patients. Routine monitoring rates were high prior to treatment in 'definite/ treated' patients (ALT: 77%; DNA: 85%) but declined afterwards (ALT 63%; DNA 36%). Rates of monitoring were lower in 'definite/ untreated' patients (ALT: 48%; DNA: 32%). Among 'equivocal/ treated' patients, lower age and comorbidity scores were associated with receipt of treatment; ALT monitoring rates were similar before and after treatment initiation (41% and 46%, respectively), while rates of DNA monitoring declined (55% and 29%). Monitoring among 'treatment ineligible' patients was similar to those in the 'equivocal' and untreated 'definite' groups. A large proportion of US HBV patients under routine care did not receive recommended annual laboratory monitoring, especially after initiation of antiviral treatment, and nearly one-third of patients with 'definite' indications for antiviral therapy remained untreated.

In this study, a novel La(III)-based two-dimensional (2D) metal-organic framework, [La

Objective To estimate relative suicidality risk associated with binge‐eating disorder (BED). Methods Retrospective study of patients identified as having BED (N = 1042) and a matched general population cohort (N = 10,420) from the Optum electronic health record database between January 2009 and September 2015. Patients had ≥1 outpatient encounter with a provider who recognized BED during the 12‐month baseline preceding entry date. Incidence and relative risk of suicidality were assessed. Results Incidence per 1000 person‐years (95% CI) of suicidal ideation and suicide attempts, respectively, was 31.1 (23.1, 41.0) and 12.7 (7.9, 19.4) in the BED cohort and 5.8 (4.7, 7.1) and 1.4 (0.9, 2.2) in the comparator cohort. Risk of suicidal ideation and suicide attempts was greater in the BED cohort (HR [95% CIs], 6.43 [4.42, 9.37]) than in the comparator cohort (HR [95% CI], 9.47 [4.99, 17.98]) during follow‐up. After adjusting for psychiatric comorbidities, associations of suicidal ideation and suicide attempts with BED remained elevated in patients with BED having histories of suicidality. Conclusions Findings suggest that history of suicidality may result in an increased risk of suicidal ideation and suicide attempts in patients with BED relative to the general population. Psychiatric comorbidity burden may explain the elevated risk of these conditions in BED.

Comprising about 82% of the extant fern species diversity, Polypodiales are generally believed to have diversified in the Late Cretaceous. We estimated the divergence times of Polypodiales using both penalized likelihood and Bayesian methods, based on a dataset consisting of 208 plastomes representing all 28 families and 14 fossil constraints reflecting current interpretations of fossil record. Our plastome phylogeny recovered the same six major lineages as a recent nuclear phylogeny, but the position of Dennstaedtiineae was different. The present phylogeny showed high resolution of relationships among the families of Polypodiales, especially among those forming the Aspleniineae. The divergence time estimates supported the most recent common ancestor of Polypodiales and its closest relative dating back to the Triassic, establishment of the major lineages in the Jurassic, and a likely accelerated radiation during the late Jurassic and the Early Cretaceous. The estimated divergence patterns of Polypodiales and angiosperms converge to a scenario in which their main lineages were established simultaneously shortly before the onset of the Cretaceous Terrestrial Revolution, and further suggest a pre-Cretaceous hidden history for both lineages. The pattern of simultaneous diversifications shown here elucidate an important gap in our understanding of the Terrestrial Revolution that shaped today's ecosystems.

There are limited data examining the relationship between psychosocial factors and receipt of direct‐acting antiviral (DAA) treatment among patients with hepatitis C in large health care organizations in the United States. We therefore sought to determine whether such factors were associated with DAA initiation. We analyzed data from an extensive psychological, behavioral, and social survey (that incorporated several health‐related quality of life assessments) coupled with clinical data from electronic health records of patients with hepatitis C enrolled at four health care organizations during 2017‐2018. Of 2,681 patients invited, 1,051 (39.2%) responded to the survey; of 894 respondents eligible for analysis, 690 (77.2%) initiated DAAs. Mean follow‐up among respondents was 9.2 years. Compared with DAA recipients, nonrecipients had significantly poorer standardized scores for depression, anxiety, and life‐related stressors as well as poorer scores related to physical and mental function. Lower odds of DAA initiation in multivariable analysis (adjusted by age, race, sex, study site, payment provider, cirrhosis status, comorbidity status, and duration of follow‐up) included Black race (adjusted odds ratio [aOR], 0.59 vs. White race), perceived difficulty getting medical care in the preceding year (aOR, 0.48 vs. no difficulty), recent injection drug use (aOR, 0.11 vs. none), alcohol use disorder (aOR, 0.58 vs. no alcohol use disorder), severe depression (aOR, 0.42 vs. no depression), recent homelessness (aOR, 0.36 vs. no homelessness), and recent incarceration (aOR, 0.34 vs. no incarceration). Conclusion: In addition to racial differences, compared with respondents who initiated DAAs, those who did not were more likely to have several psychological, behavioral, and social impairments. Psychosocial barriers to DAA initiation among patients in care should also be addressed to reduce hepatitis C‐related morbidity and mortality., Even among persons with access to care, receipt of direct‐acting antiviral treatment for hepatitis C is suboptimal. We therefore conducted a detailed psychological, behavioral, and social survey among hepatitis C patients in care to determine whether such factors were associated with DAA initiation. Compared with respondents who initiated DAAs, those who did not were more likely to have several psychological, behavioral, and social impairments, suggesting that such factors should be addressed to reduce hepatitis C‐related morbidity and mortality.

Background Genome‐wide association studies have identified over 100 single‐nucleotide polymorphisms (SNPs) associated with prostate cancer (PrCa), and polygenic risk scores (PRS) based on their combined genotypes have been developed for risk stratification. We aimed to assess the contribution of PRS to PrCa risk in a large multisite study. Methods The sample included 1972 PrCa cases and 1919 unaffected controls. Next‐generation sequencing was used to assess pathogenic variants in 14 PrCa‐susceptibility genes and 72 validated PrCa‐associated SNPs. We constructed a population‐standardized PRS and tested its association with PrCa using logistic regression adjusted for age and family history of PrCa. Results The mean age of PrCa cases at diagnosis and age of controls at testing/last clinic visit was 59.5 ± 7.2 and 57.2 ± 13.0 years, respectively. Among 1740 cases with pathology data, 57.4% had Gleason score ≤ 6, while 42.6% had Gleason score ≥ 8. In addition, 39.6% cases and 20.1% controls had a family history of PrCa. The PRS was significantly higher in cases than controls (mean ± SD: 1.42 ± 1.11 vs 1.02 ± 0.76; P

Purpose To perform radiomic analysis of primary tumors extracted from pretreatment contrast-enhanced computed tomography (CE-CT) images for patients with oropharyngeal cancers to identify discriminant features and construct an optimal classifier for the characterization and prediction of human papilloma virus (HPV) status. Materials and methods One hundred and eighty seven patients with oropharyngeal cancers with known HPV status (confirmed by immunohistochemistry-p16 protein testing) were retrospectively studied as follows: Group A: 95 patients (19HPV- and 76HPV+) from the MICAII grand challenge. Group B: 92 patients (52HPV- and 40HPV+) from our institution. Radiomic features (172) were extracted from pretreatment diagnostic CE-CT images of the gross tumor volume (GTV). Levene and Kolmogorov-Smirnov's tests with absolute biserial correlation (>0.48) were used to identify the discriminant features between the HPV+ and HPV- groups. The discriminant features were used to train and test eight different classifiers. Area under receiver operating characteristic (AUC), positive predictive and negative predictive values (PPV and NPV, respectively) were used to evaluate the performance of the classifiers. Principal component analysis (PCA) was applied on the discriminant feature set and seven PCs were used to train and test a generalized linear model (GLM) classifier. Results Among 172 radiomic features only 12 radiomic features (from 3 categories) were significantly different (P 0.48) between the HPV+ and HPV- groups. Among the eight classifiers trained and applied for prediction of HPV status, the GLM showed the highest performance for each discriminant feature and the combined 12 features: AUC/PPV/NPV = 0.878/0.834/0.811. The GLM high prediction power was AUC/PPV/NPV = 0.849/0.731/0.788 and AUC/PPV/NPV = 0.869/0.807/0.870 for unseen test datasets for groups A and B, respectively. After eliminating the correlation among discriminant features by applying PCA analysis, the performance of the GLM was improved by 3.3%, 2.2%, and 1.8% for AUC, PPV, and NPV, respectively. Conclusions Results imply that GTV's for HPV+ patients exhibit higher intensities, smaller lesion size, greater sphericity/roundness, and higher spatial intensity-variation/heterogeneity. Results are suggestive that radiomic features primarily associated with the spatial arrangement and morphological appearance of the tumor on contrast-enhanced diagnostic CT datasets may be potentially used for classification of HPV status.

The role of ribavirin (RBV) in the era of direct-acting antivirals (DAA) is not clear, and DAA studies have been largely genotype- and regimen-specific. Using data from the Chronic Hepatitis Cohort Study, we evaluated the role of RBV and increased DAA treatment duration among patients with chronic hepatitis C (HCV) in routine clinical care. We performed multivariable analysis of data from 4133 patients receiving any of the following: sofosbuvir (SOF); daclatasvir + SOF; grazoprevir + elbasvir; paritaprevir/ritonavir + ombitasvir; simeprevir + SOF; and SOF + ledipasvir; SOF + velpatasvir ± voxilaprevir; and glecaprevir + pibrentasvir—all with/ without RBV. Inverse probability treatment weighting was used to adjust for treatment selection bias. Sustained virological response (SVR) was defined by undetectable HCV RNA 12 weeks after end of therapy. The overall SVR rate was 95%. Mean treatment duration was 12 ± 4.5 weeks. The final model included treatment duration and diabetes, as well as the interaction of RBV with previous treatment status (treatment naïve, interferon treatment failure [TF] or previous DAA TF), cirrhosis status, and HCV genotype (GT). Each one-month increment of treatment duration increased odds of SVR by 99% (aOR = 1.99). Diabetes, previous DAA TF, and decompensated cirrhosis significantly reduced odds of SVR. RBV significantly increased the likelihood of SVR among patients with decompensated cirrhosis (aOR = 5.05), previous DAA treatment failure (aOR = 5.43), and GT3 (aOR = 13.28). Among RBV-free regimens, patients with GT3 were less likely to achieve SVR than those with GT1 or 2 (aOR 0.07). Diabetes, decompensated cirrhosis, and prior DAA TF independently reduced the likelihood of SVR. Longer treatment duration increased likelihood of SVR. Conclusion: RBV increased likelihood of SVR among patients with GT3, previous DAA TF, or decompensated cirrhosis.

A natural colourant derived from purple‐fleshed sweet potato (PFSP) by ultrasound‐assisted solvent extraction was examined in terms of its anthocyanins and 6‐month storage stability under different conditions: avoid from light at 25 (AL25) and 37 °C (AL37) and under fluorescent light at 25 °C (FL25). This PFSP colourant mainly contained the following peonidin anthocyanins: peonidin 3‐p‐hydroxybenzoyl sophoroside‐5‐glucoside, peonidin 3‐feruloyl sophoroside‐5‐glucoside, peonidin 3‐caffeoyl sophoroside‐5‐glucoside, peonidin dicaffeoyl sophoroside‐5‐glucoside, peonidin 3‐caffeoyl‐p‐hydroxybenzoyl sophoroside‐5‐glucoside and peonidin caffeoyl‐feruloyl sophoroside‐5‐glucoside. The degradation ratios of PFSP anthocyanins (PFSPAs) under AL25, AL37 and FL25 were around 50.7%, 89.0% and 87.0% respectively. The FL25 and AL37 conditions had similar effects on the colourant's total colour change (ΔEab). The degradation kinetics followed the zero‐order reaction models. The PFSPAs were more stable during storage than other anthocyanins because they mainly consist of di‐acylated and double glycosylated forms of peonidin derivatives. These results may promote the application of PFSPAs as a novel natural colourant in food industry.

Most organic semiconductors (OSCs) consist of conjugated skeletons with flexible peripheral chains. Their weak intermolecular interactions from dispersion and induction forces result in environmental susceptibilities and are unsuitable for many multifunctional applications where direct exposure to external environments is unavoidable, such as gas absorption, chemical sensing, and catalysis. To exploit the advantages of inorganic semiconductors in OSCs, ion-in-conjugation (IIC) materials are proposed. An IIC material refers to any conjugated material (molecules, polymers, and crystals) in Kekule's structural formula containing stoichiometric ionic states in its conjugated backbone in the electronic ground state. In this review, the definitions, structures, synthesis, properties, and applications of IIC materials are described briefly. Four types of IIC material, including zwitterionic conjugated molecules/polymers, conjugated ionic dyes, π-d conjugated molecules and polymers, and coordinatively doped polymers, are reported. Their applications in gas sensing, humidity sensing, resistive memory devices, and thermal/photo-/electro-catalysis are demonstrated. The challenges and opportunities for future research are also discussed. It is expected that this work will inspire the design of new organic electronic information materials.

Immunotherapy has delivered impressive outcomes in combating tumor malignancies. However, insufficient immune infiltration and poor immunogenicity within the tumor microenvironment (TME) greatly compromise patient response rates. Here, a photoactivatable silencing extracellular vesicle (PASEV) is developed for sensitized cancer immunotherapy. p21-Activated kinase 4 (PAK4) is a newly identified tumor-cell-intrinsic "guard" associated with immune exclusion. Small interfering RNA against PAK4 (siPAK4) is designed and assembled with a photoactivatable reactive-oxygen-species (ROS)-sensitive polymer to form the nanocomplex core, which is further camouflaged by extracellular vesicles from M1 macrophages. The PASEV not only serves as a vehicle for packaging, tumor accumulation, and ROS-responsive release of siPAK4 for potent PAK4 silencing, but also primes the TME through immunogenic phototherapy, thereby simultaneously boosting intratumoral infiltration and immune activation. The combined immunotherapy elicits robust anticancer immunity, thus showing great promise for fighting cancers. This work opens a new avenue to simultaneously boost intratumoral infiltration and immune activation for sensitized cancer immunotherapy.

Aims Autism spectrum disorder (ASD) is a wide range of neurodevelopmental disorders involving deficits in social interaction and communication. Unfortunately, autism remains a scientific and clinical challenge owing to the lack of understanding the cellular and molecular mechanisms underlying it. This study aimed to investigate the pathophysiological mechanism underlying leukocyte-endothelial adhesion in autism-related neurovascular inflammation. Methods Male BTBR T+tf/J mice were used as an autism model. The dynamic pattern of leukocyte-endothelial adhesion in mouse cerebral vessels was detected by two-photon laser scanning microscopy (TPLSM). Using FACS, RT-PCR, and Western blotting, we explored the expression of cell adhesion molecules, the mRNA expression of endothelial chemokine, the protein levels of cathepsin B, and inflammatory mediators. Results We found a significant increase in leukocyte-endothelial adhesion in BTBR mice, accompanied by elevated expression of the adhesion molecule neutrophils CD11b and endothelial ICAM-1. Our data further indicate that elevated neutrophil cathepsin B levels contribute to elevated endothelial chemokine CXCL7 levels in BTBR mice. The pharmacological inhibition of cathepsin B reverses the enhanced leukocyte-endothelial adhesion in the cerebral vessels of autistic mice. Conclusion Our results revealed the prominent role of cathepsin B in modulating leukocyte-endothelial adhesion during autism-related neurovascular inflammation and identified a promising novel approach for autism treatment.

Neuritin is a neurotrophic factor that is activated by neural activity and neurotrophins. Its major function is to promote neurite growth and branching; however, the underlying mechanisms are not fully understood. To address this issue, this study investigated the effects of neuritin on neurite and spine growth and intracellular Ca2+ concentration in rat cerebellar granule neurons (CGNs). Incubation of CGNs for 24 h with neuritin increased neurite length and spine density; this effect was mimicked by insulin and abolished by inhibiting insulin receptor (IR) or mitogen‐activated protein kinase kinase/extracellular signal‐regulated kinase (ERK) activity. Calcium imaging and western blot analysis revealed that neuritin enhanced the increase in intracellular Ca2+ level induced by high K+, and stimulated the cell surface expression of CaV1.2 and CaV1.3 α subunits of the L‐type calcium channel, which was suppressed by inhibition of IR or mitogen‐activated protein kinase kinase/ERK. Treatment with inhibitors of L‐type calcium channels, calmodulin, and calcineurin (CaN) abrogated the effects of neuritin on neurite length and spine density. A similar result was obtained by silencing nuclear factor of activated T cells c4, which is known to be activated by neuritin in CGNs. These results indicate that IR and ERK signaling as well as the Ca2+/CaN/nuclear factor of activated T cells c4 axis mediate the effects of neuritin on neurite and spine growth in CGNs. Open Practices Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/ Cover Image for this issue: doi: 10.1111/jnc.14195.

The asymmetric synthesis of 3-sec-substituted pyrrole derivatives through vinylogous imine intermediates generated in situ from 2,5-dimethyl-3-[1-(arylsulfonyl)alkyl]pyrroles with high activity and enantioselectivity (up to 98 % ee) was examined. Employing a cinchona alkaloid based chiral bifunctional organocatalyst, the reaction of tritylthiol to sulfonylpyrroles delivered a series of highly enantioselective sulfur-containing 3-sec-substituted pyrroles.

Introduction Noninvasive measures of bone activity include intact parathyroid hormone (iPTH) and bone-specific alkaline phosphatase (BSAP). Whether BSAP measurement alone or in combination with other biochemical data provides more reliable information about bone turnover than iPTH alone in African Americans on hemodialysis is unknown. Methods This cross-sectional study aimed to determine the optimal predictor and cutoff points for BSAP, iPTH, calcium and phosphorus in classifying bone biopsy findings. Forty-three African American hemodialysis patients were available for analysis. Biochemical data on the day of biopsy across a spectrum of qualitative histologic bone features were compared. Classification and regression tree analysis was used to determine both the optimal predictor and cutoff points for BSAP, iPTH, calcium and phosphorus in identifying bone turnover status. Findings Seven subjects had adynamic disease, 31 had mild/moderate hyperparathyroid bone features, and five had severe hyperparathyroid bone disease. BSAP was the optimal predictor of bone biopsy with a cutoff point of 22 ng/mL. Calcium and phosphorus had no predictive value. At BSAP ≤ 22 ng/mL, subjects had either adynamic bone disease or mild/moderate hyperparathyroid bone disease but iPTH was not useful in further classifying biopsy findings. When BSAP was >22 ng/mL, subjects had either mild/moderate or severe hyperparathyroid bone disease, and iPTH was useful in further classifying biopsy findings. With BSAP > 22 ng/mL and iPTH

Scope Egg ovotransferrin (OVT) is considered a functional food ingredient for its various bioactivities. The objective of this work is to explore the potential biological activity of OVT on the gut health. Methods and results Both young (3 week old) and adult (8 week old) mouse models are utilized in this research. Each group receives a standard diet containing either OVT (experimental group) or distilled water (control group) for a 14 day period. Transcriptome and 16S rDNA sequencing analyses are applied to characterize the gene expression in colonic epithelial cells and gut microbiota composition. In the young groups, OVT suppresses the genes correlated with lipid metabolism and signal transduction. The regulated genes in the adult groups encompass various biological processes, including lipid metabolism, signal transduction, endocrine system, and others. OVT increases the proportion of some beneficial bacteria significantly, especially Akkermansia, and inhibits some harmful bacteria. Furthermore, OVT affects mucosal morphology positively via increasing the crypt depth. OVT also increases the expression of tight junction protein occludin by 3.0- and 5.2-folds in young and adult groups, respectively. Conclusion OVT exhibits some beneficial effects on the gut environment. These positive findings provide new insight into the understanding of OVT as an excellent functional ingredient.

Scope Insects are a potentially environmentally friendly alternative dietary protein source to supplement mammalian and fish sources, but potential allergenic risks are a concern. Consumption of insects may result in anaphylaxis and has been implicated in cross-reactivity with shellfish. Many allergenic proteins may be involved in cross-reactivity, including tropomyosin (TM). The uniformity of TM cross-reactivity among edible insects is unknown. Candidate edible insects for variability in shellfish IgE cross-reactivity are investigated. Methods and results Selected insects and known related sources of allergens are extracted and probed by immunoblot with sera/plasma from patients sensitized to insects or shellfish. Quantification of TM in these extracts is performed using mass spectrometry. A comparison of the quantity of TM and the IgE reactivity of TM from these insects is performed. Distinct patterns of IgE cross-reactivity are observed with three insect species showing diminished reactivity. This pattern is not consistent with the amount of TM present in these insects, or with overall sequence homology. Conclusion Insects display a diversity of TM-associated IgE reactivity. It is likely that minor sequence features and/or structural effects are primarily responsible. Additionally, it is demonstrated that some insect species may present significantly less IgE cross-reactivity to shrimp than do others.