, various digestive symptoms have been frequently reported in patients infected with the virus. In this study, we aimed to further investigate the prevalence and outcomes of COVID-19 patients with digestive symptoms. METHODS: In this descriptive, cross-sectional, multicenter study, we enrolled confirmed patients with COVID-19 who presented to 3 hospitals from January 18, 2020, to February 28, 2020. All patients were confirmed by real-time polymerase chain reaction and were analyzed for clinical characteristics, laboratory data, and treatment. Data were followed up until March 18, 2020. RESULTS: In the present study, 204 patients with COVID-19 and full laboratory, imaging, and historical data were analyzed. The average age was 52.9 years (SD 6 16), including 107 men and 97 women. Although most patients presented to the hospital with fever or respiratory symptoms, we found that 103 patients (50.5%) reported a digestive symptom, including lack of appetite (81 [78.6%] cases), diarrhea (35 [34%] cases), vomiting (4 [3.9%] cases), and abdominal pain (2 [1.9%] cases). If lack of appetite is excluded from the analysis (because it is less specific for the gastrointestinal tract), there were 38 total cases (18.6%) where patients presented with a gastrointestinal-specific symptom, including diarrhea, vomiting, or abdominal pain. Patients with digestive symptoms had a significantly longer time from onset to admission than patients without digestive symptoms (9.0 days vs 7.3 days). In 6 cases, there were digestive symptoms, but no respiratory symptoms. As the severity of the disease increased, digestive symptoms became more pronounced. Patients with digestive symptoms had higher mean liver enzyme levels, lower monocyte count, longer prothrombin time, and received more antimicrobial treatment than those without digestive symptoms. DISCUSSION: We found that digestive symptoms are common in patients with COVID-19. Moreover, these patients have a longer time from onset to admission, evidence of longer coagulation, and higher liver enzyme levels. Clinicians should recognize that digestive symptoms, such as diarrhea, are commonly among the presenting features of COVID-19 and that the index of suspicion may need to be raised earlier in at-risk patients presenting with digestive symptoms. However, further large sample studies are needed to confirm these findings.

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BGLF4 is the only serine/threonine protein kinase identified in Epstein-Barr virus (EBV); it is known to phosphorylate viral DNA polymerase processivity factor, EA-D (BMRF1), EBNA-LP, EBNA-2, cellular EF-1d and nucleoside analogue ganciclovir. However, the expression and biological functions of BGLF4 have not yet been clearly demonstrated in EBV-infected cells. To reveal authentic functions of BGLF4 protein within viral-replicating cells, a panel of specific monoclonal antibodies was generated and characterized. The major immunogenic regions of BGLF4 were mapped to aa 27-70 and 327-429. Using these antibodies, the expression kinetics and localization of BGLF4 were analysed in reactivated EBV-positive lymphoid and epithelial cells. BGLF4 was expressed as a phosphoprotein at the early lytic stage and was detected predominantly in the nucleus of EBV-positive cells, but small amounts of BGLF4 were observed in cytosolic and heavy membrane fractions at the late phase of virus replication. Additionally, it was demonstrated that BGLF4 co-localizes with viral DNA polymerase processivity factor, EA-D (BMRF1), in the virus replication compartment and that it is a virion component. Finally, possible functional domains at the N terminus of BGLF4 were analysed and it was found that aa 1-26 of BGLF4 are dispensable for EA-D phosphorylation, whereas deletion of aa 27-70 reduced kinase activity.

Hierarchical structures combining micropyramids and nanowires with appropriate control of surface carrier recombination represent a class of architectures for radial p-n junction solar cells that synergizes the advantageous features including excellent broad-band, omnidirectional light-harvesting and efficient separation/collection of photoexcited carriers. The heterojunction solar cells fabricated with hierarchical structures exhibit the efficiency of 15.14% using cost-effective as-cut Czochralski n-type Si substrates, which is the highest reported efficiency among all n-type Si nanostructured solar cells. We also demonstrate the omnidirectional solar cell that exhibits the daily generated power enhancement of 44.2% by using hierarchical structures, as compared to conventional micropyramid control cells. The concurrent improvement in optical and electrical properties for realizing high-efficiency omnidirectional solar cells using as-cut Czochralski n-type Si substrates demonstrated here makes a hierarchical architecture concept promising for large-area and cost-effective mass production.

Epstein-Barr virus (EBV) BKRF3 shares sequence homology with members of the uracil-N-glycosylase (UNG) protein family and has DNA glycosylase activity. Here, we explored how BKRF3 participates in the DNA replication complex and contributes to viral DNA replication. Exogenously expressed Flag-BKRF3 was distributed mostly in the cytoplasm, whereas BKRF3 was translocated into the nucleus and colocalized with the EBV DNA polymerase BALF5 in the replication compartment during EBV lytic replication. The expression level of BKRF3 increased gradually during viral replication, coupled with a decrease of cellular UNG2, suggesting BKRF3 enzyme activity compensates for UNG2 and ensures the fidelity of viral DNA replication. In immunoprecipitation-Western blotting, BKRF3 was coimmunoprecipitated with BALF5, the polymerase processivity factor BMRF1, and the immediate-early transactivator Rta. Coexpression of BMRF1 appeared to facilitate the nuclear targeting of BKRF3 in immunofluorescence staining. Residues 164 to 255 of BKRF3 were required for interaction with Rta and BALF5, whereas residues 81 to 166 of BKRF3 were critical for BMRF1 interaction in glutathione S-transferase (GST) pulldown experiments. Viral DNA replication was defective in cells harboring BKRF3 knockout EBV bacmids. In complementation assays, the catalytic mutant BKRF3(Q90L,D91N) restored viral DNA replication, whereas the leucine loop mutant BKRF3(H213L) only partially rescued viral DNA replication, coupled with a reduced ability to interact with the viral DNA polymerase and Rta. Our data suggest that BKRF3 plays a critical role in viral DNA synthesis predominantly through its interactions with viral proteins in the DNA replication compartment, while its enzymatic activity may be supplementary for uracil DNA glycosylase (UDG) function during virus replication. IMPORTANCECatalytic activities of both cellular UDG UNG2 and viral UDGs contribute to herpesviral DNA replication. To ensure that the enzyme activity executes at the right time and the right place in DNA replication forks, complex formation with other components in the DNA replication machinery provides an important regulation for UDG function. In this study, we provide the mechanism for EBV UDG BKRF3 nuclear targeting and the interacting domains of BKRF3 with viral DNA replication proteins. Through knockout and complementation approaches, we further demonstrate that in addition to UDG activity, the interaction of BKRF3 with viral proteins in the replication compartment is crucial for efficient viral DNA replication.

IMPORTANCE Previous studies have suggested that patients with cancer may be at an increased risk of death from unintentional injury, but to our knowledge, no large studies have examined the rates of death from unintentional injury among patients with cancer. OBJECTIVE To characterize the incidence of death from unintentional injury among patients with cancer in the United States. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study included patients diagnosed with a first primary cancer between January 1, 1973, and December 31, 2015, identified from the Surveillance, Epidemiology, and End Results (SEER) program data. Comparisons with the general US population were based on mortality data collected by the National Center for Health Statistics. Analyses were performed from February 1, 2019, to August 15, 2019. MAIN OUTCOMES AND MEASURES Rates and standardized mortality ratios (SMRs) of death from unintentional injury among patients with cancer. RESULTS A total of 8 271 020 patients with cancer were included in this study (50.2% female; mean [SD] age, 63.0 [15.7] years). Among them, 40 599 deaths from unintentional injury were identified. The rates of death from unintentional injury were 81.90 per 100 000 person-years among patients with cancer and 51.21 per 100 000 person-years in the corresponding US general population. The

Background: A low-fermentable oligo-, di-, monosaccharides, and polyols (FODMAP) diet has been reported to be associated with improving the symptoms of irritable bowel syndrome (IBS); however, its efficacy as evaluated by different studies remains controversial.Objective: A systematic review and meta-analysis of randomized controlled trials (RCTs) were conducted to explore the efficacy of a low-FODMAP diet (LFD) in alleviating the symptoms of IBS.Methods: A search of the literature for RCTs that assessed the efficacy of an LFD in treating IBS patients was conducted using the electronic databases PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science. The searches in each database were conducted from the inception of the database to February 2021. Two independent reviewers screened citations and a third reviewer resolved disagreements. Two independent reviewers also performed eligibility assessments and data extraction. The RCTs that evaluated LFDs vs. a normal IBS or usual diet and assessed changes of IBS symptoms were included in the search. Data were synthesized as the relative risk of global symptoms improvement, mean difference of IBS Severity Scoring System (IBS-SSS) score, sub-items of IBS-SSS irritable bowel syndrome-related quality of life (IBS-QOL), hospital anxiety and depression scale (HADS), stool consistency/frequency, and body mass index (BMI) using a random effects model. The risk of bias was assessed using Risk of Bias Tool 2 (RoB 2). The bias of publication was assessed based on Egger's regression analysis. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology.Results: A total of 2,768 citations were identified. After full-text screening, a total of 10 studies were eligible for the systematic review and were subsequently used to compare an LFD with various control interventions in 511 participants. An LFD was associated with the improvement of global symptoms [n = 420; Risk Ratio (RR) = 1.54; 95% Confidence Interval (CI) 1.18 to 2; I2 = 38%], improvement of stool consistency [n = 434; Mean difference (MD) = −0.25; 95% CI −0.44 to −0.06; I2= 19%), and a reduction trend of stool frequency (n = 434; MD = −0.28; 95% CI −0.57 to 0.01; I2 = 68%) compared with control interventions. There was no statistically significant change in IBS-QOL (n = 484; MD = 2.77; 95% CI −2 to 7.55; I2 = 62%), anxiety score (n = 150; MD = −0.45; 95% CI −3.38 to 2.49; I2 = 86%), depression score (n = 150; MD = −0.05; 95% CI −2.5 to 2.4; I2 = 88%), and BMI (n = 110; MD = −0.22; 95% CI −1.89 to 1.45; I2 = 14%). The overall quality of the data was “moderate” for “global improvement of IBS symptom,” “stool consistency,” “stool consistency for IBS with diarrhea (IBS-D),” and “stool frequency for IBS-D,” and “low” or “very low” for other outcomes according to GRADE criteria.Conclusion: An LFD is effective in reducing the global symptoms and improving the bowel habits of adult IBS patients. The efficacy for IBS-D patients can also be more pronounced.Systematic Review Registration: CRD42021235843.

Modification of human herpesvirus DNA polymerase processivity factors (PFs) by phosphorylation occurs frequently during viral lytic replication. However, functional regulation of the herpesvirus PFs through phosphorylation is not well understood. In addition to processivity, the PF BMRF1 of Epstein-Barr virus can function as a transactivator to activate the BHLF1 promoter within the lytic origin of replication (oriLyt), which is assumed to facilitate DNA replication through remodelling viral chromatin structure. BMRF1 is known to be phosphorylated by the viral BGLF4 kinase, but its impact on BMRF1 function is unclear. Seven candidate BGLF4 target sites were predicted within a proline-rich region between the DNA-processivity and nuclear-localization domains of BMRF1. We show that four of these residues, Ser-337, Thr-344, Ser-349 and Thr-355, are responsible for the BGLF4-induced hyperphosphorylation of BMRF1. In functional analyses, a phosphorylation-mimicking mutant of BMRF1 shows similar nuclear localization, as well as DNA-binding ability, to the wild type; however, it displays stronger synergistic activation of the BHLF1 promoter with Zta. Notably, BGLF4 downregulates BMRF1 transactivation and enhances the transactivation activity of Zta and the synergistic activation of BMRF1 and Zta on the BHLF1 promoter. Our findings suggest that BGLF4 may modulate the activation of the oriLyt BHLF1 promoter coordinately through multiple mechanisms to facilitate optimal oriLyt-dependent viral DNA replication. INTRODUCTIONEpstein-Barr virus (EBV) is a gamma-1 human herpesvirus that infects most of the human population worldwide. EBV infection is associated closely with several human malignant diseases, including Burkitt's lymphoma, nasopharyngeal carcinoma (NPC) and Hodgkin's disease (Cohen, 2000;Young & Rickinson, 2004). Even though the virus is present in a latent form in most cancer tissues, elevated serum antibody titres against some EBV lytic antigens have been used as diagnostic markers for NPC (Chien et al., 2001) and the serum viral DNA load is an important prognostic parameter for NPC patients (Lin et al., 2004). Thus, the progression of lytic replication is important for the pathogenesis of EBV-associated malignancy.Transcription-coupled viral DNA replication is a common phenomenon among human herpesviruses for the initiation of lytic replication. The promoters within lytic origin of replication (oriLyt) regions, which have been identified in human cytomegalovirus, Kaposi's sarcoma-associated virus (KSHV or human herpesvirus 8) and EBV, are crucial for viral lytic replication (AuCoin et al., 2004;Hammerschmidt & Sugden, 1988;Xu et al., 2004). Because the promoter regions within oriLyt are important for viral replication and can be substituted by other functional promoters, the transcription machinery has been suggested to remodel the viral chromatin structure and thereby facilitate the binding of the DNA polymerase complex to the viral DNA template (Xu et al., 2004).In addition to DNA polymerase, functional replic...