Abstract
Some risk factors for severe coronavirus disease 2019 (COVID-19) have been identified, including age, race, and obesity. However, 20%–50% of severe cases occur in the absence of these ...factors. Cytomegalovirus (CMV) is a herpesvirus that infects about 50% of all individuals worldwide and is among the most significant nongenetic determinants of immune system. We hypothesized that latent CMV infection might influence the severity of COVID-19. Our analyses demonstrate that CMV seropositivity is associated with more than twice the risk of hospitalization due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Immune profiling of blood and CMV DNA quantitative polymerase chain reaction in a subset of patients for whom respiratory tract samples were available revealed altered T-cell activation profiles in absence of extensive CMV replication in the upper respiratory tract. These data suggest a potential role for CMV-driven immune perturbations in affecting the outcome of SARS-CoV-2 infection and may have implications for the discrepancies in COVID-19 severity between different human populations.
Of severe cases of coronavirus disease 2019 (COVID-19), 20%–50% occur in the absence of identified factors. We demonstrated that cytomegalovirus seropositivity is associated with more than twice the risk of hospitalization due to COVID-19, possibly through systemic immune perturbation.
We investigated the ozonation of the antineoplastic drugs cyclophosphamide (CP), ifosfamide (IF), and 5-fluorouracil (5-FU) and of the vasodilator pentoxifylline (PEN) in distilled water, in ...pharmaceutical wastewater, and in hospital effluent at pH 5–11. Under an alkaline pH of 11, all of the target compounds rapidly degraded through the attack of hydroxyl radicals, which resulted in their complete removal within 5 min at an ozone supply rate of 3 g O₃/h. Under acidic pH conditions, such as pH 5.6, CP and IF exhibited slower removal rates; however, compounds with unsaturated C-C bonds, such as 5-FU and PEN, were still removed at rapid rates under acidic conditions. Although the parent compounds were removed within minutes, the resulting ozonation byproducts were resistant to further ozonation and possessed increased Microtox acute toxicity. In distilled water, the resulting ozonation products exhibited minimal mineralization but high acute toxicity, whereas in naturally buffered pharmaceutical and hospital effluents, the byproducts were more amenable to removal and detoxification.
Cancer types with lower mutational load and a non-permissive tumor microenvironment are intrinsically resistant to immune checkpoint blockade. While the combination of cytostatic drugs and ...immunostimulatory antibodies constitutes an attractive concept for overcoming this refractoriness, suppression of immune cell function by cytostatic drugs may limit therapeutic efficacy. Here we show that targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) does not impair dendritic cell-mediated T cell priming and activation. Accordingly, combining MEK inhibitors (MEKi) with agonist antibodies (Abs) targeting the immunostimulatory CD40 receptor results in potent synergistic antitumor efficacy. Detailed analysis of the mechanism of action of MEKi shows that this drug exerts multiple pro-immunogenic effects, including the suppression of M2-type macrophages, myeloid derived suppressor cells and T-regulatory cells. The combination of MEK inhibition with agonist anti-CD40 Ab is therefore a promising therapeutic concept, especially for the treatment of mutant Kras-driven tumors such as pancreatic ductal adenocarcinoma.
Objectives
To assess the quality of published systematic reviews in the urology literature (an extension of our previously reported work), as high‐quality systematic reviews play a paramount role in ...informing evidence‐based clinical practice.
Materials and Methods
Our focus was on systematic reviews in the urology literature that incorporated questions of prevention and therapy. To identify such reviews published during a 36‐month period (2013–2015), we systematically searched PubMed and hand‐searched the table of contents of four major urology journals. Two reviewers independently assessed the methodological quality of those reviews, using the 11‐point ‘Assessment of Multiple Systematic Reviews’ (AMSTAR) instrument. We performed protocol‐driven analyses of the data from our present study's 36‐month period alone, as well as in aggregate with the data from our previously reported work's study periods (2009–2012 and 1998–2008).
Results
In our literature search of the 36‐month period (2013–2015), we initially identified 490 possibly relevant reviews, of which 125 met our inclusion criteria. The most common topic of reviews for the 2013–2015 period was oncology (51.2%; n = 64), followed by voiding dysfunction (21.6%; n = 27). The mean standard deviation (SD) AMSTAR score in the 2013–2015 period (n = 125) was 4.8 (2.4); 2009–2012 (n = 113), 5.4 (2.3); and 1998–2008 (n = 57), 4.8 (2.0) (P = 0.127). In the 2013–2015 period, the mean (SD) AMSTAR score for the BJU International (n = 25) was 5.6 (2.9); for The Journal of Urology (n = 20), 5.1 (2.6); for European Urology (n = 60), 4.5 (2.2); and for Urology (n = 20), 4.4 (2.2) (P = 0.106).
Conclusions
The number of systematic reviews published in the urology literature has exponentially increased, year by year, but their methodological quality has stagnated. To enhance the validity and impact of systematic reviews, all authors and editors must apply established methodological standards.
This research is an exploratory study that evaluates the affordances of WeChat for the development of a community of inquiry (CoI) in semi-synchronous language exchange supported by WeChat. WeChat is ...an instant messenger that facilitates a multimodal environment in which interaction can happen synchronously, semi-synchronously and asynchronously through text, audio, video conferencing and a variety of pedagogically facilitating affordances. Differing from most existing studies in CoI, this research investigates all three presences in the CoI framework, that is, teaching, social, and cognitive presence, as they emerged in the language exchange between students of Mandarin Chinese and students of English. The findings from this research confirm the establishment of the three presences in CoI, but with features specific to WeChat-supported semi-synchronous language exchange. Recommendations for future research into CoI facilitated by WeChat are also put forward. Author abstract
Treatment with acetyl-CoA carboxylase inhibitors (ACCi) in nonalcoholic steatohepatitis (NASH) may increase plasma triglycerides (TGs), with variable changes in apoB concentrations. ACC is rate ...limiting in de novo lipogenesis and regulates fatty acid oxidation, making it an attractive therapeutic target in NASH. Our objectives were to determine the effects of the ACCi, firsocostat, on production rates of plasma LDL-apoB in NASH and the effects of combined therapy with fenofibrate. Metabolic labeling with heavy water and tandem mass spectrometric analysis of LDL-apoB enrichments was performed in 16 NASH patients treated with firsocostat for 12 weeks and in 29 NASH subjects treated with firsocostat and fenofibrate for 12 weeks. In NASH on firsocostat, plasma TG increased significantly by 17% from baseline to week 12 (P = 0.0056). Significant increases were also observed in LDL-apoB fractional replacement rate (baseline to week 12: 31 ± 20.2 to 46 ± 22.6%/day, P = 0.03) and absolute synthesis rate (ASR) (30.4–45.2 mg/dl/day, P = 0.016) but not plasma apoB concentrations. The effect of firsocostat on LDL-apoB ASR was restricted to patients with cirrhosis (21.0 ± 9.6 at baseline and 44.2 ± 17 mg/dl/day at week 12, P = 0.002, N = 8); noncirrhotic patients did not change (39.8 ± 20.8 and 46.3 ± 14.8 mg/dl/day, respectively, P = 0.51, N = 8). Combination treatment with fenofibrate and firsocostat prevented increases in plasma TG, LDL-apoB fractional replacement rate, and ASR. In summary, in NASH with cirrhosis, ACCi treatment increases LDL-apoB100 production rate and this effect can be prevented by concurrent fenofibrate therapy.
Graphical abstract: ACCi treatment alone (green arrow) leads to increased apoB particle production in the liver as shown by increased production of LDL-apoB. Fenofibrate combined with ACCi treatment (red inhibitory symbol) prevented the increased LDL-apoB particle production. Display omitted
Angelman syndrome (AS) is a neurodevelopmental disorder that is caused by maternal genetic deficiency of a gene that encodes E6-AP ubiquitin-protein ligase (gene symbol UBE3A) mapping to chromosome ...15q11-q13. AS leads to stiff and jerky gait, excess laughter, seizures, and severe intellectual disability. In some parts of the brain, the paternally inherited UBE3A gene is subject to genomic imprinting by the action of the UBE3A-antisense transcript (UBE3A-ATS) on the paternally inherited allele. Consequently, only the maternally inherited UBE3A gene is expressed in mature neurons. AS occurs due to deletions of the maternal 15q11 - 13 region, paternal uniparental disomy (UPD), imprinting center defects, mutations in the maternal UBE3A gene, or other unknown genetic malfunctions that result in a silenced maternal UBE3A gene in the specific imprinted regions of the brain.
A potential treatment strategy for AS is to increase methylation of UBE3A-ATS to promote expression of the paternal UBE3A gene and thus ameliorate the clinical phenotypes of AS. We treated two sets of male identical twins with class I deletions with a 1 year treatment trial of either betaine and folic acid versus placebo. We found no statistically significant changes in the clinical parameters tested at the end of the 1 year trial, nor did we find any significant adverse events.
This study tested the hypothesis that by increasing the methylation of the UBE3A-antisense transcript in Angelman syndrome to promote expression of the silenced paternal UBE3A gene we may ameliorate the clinical phenotypes of AS. We treated two sets of identical twins with placebo versus betaine and folic acid. Although this study represented a novel approach to treating Angelman syndrome, the differences in the developmental testing results was not significant. This paper also discusses the value of monozygotic twin studies in minimizing confounding variables and its utility in conducting small treatment studies.
NCT00348933 . Registered 6 July 2006.
BACKGROUNDCOVID-19 remains a global health emergency with limited treatment options, lagging vaccine rates, and inadequate healthcare resources in the face of an ongoing calamity. The disease is ...characterized by immune dysregulation and cytokine storm. Cyclosporine A (CSA) is a calcineurin inhibitor that modulates cytokine production and may have direct antiviral properties against coronaviruses.METHODSTo test whether a short course of CSA was safe in patients with COVID-19, we treated 10 hospitalized, oxygen-requiring, noncritically ill patients with CSA (starting at a dose of 9 mg/kg/d). We evaluated patients for clinical response and adverse events, measured serum cytokines and chemokines associated with COVID-19 hyperinflammation, and conducted gene-expression analyses.RESULTSFive participants experienced adverse events, none of which were serious; transaminitis was most common. No participant required intensive care unit-level care, and all patients were discharged alive. CSA treatment was associated with significant reductions in serum cytokines and chemokines important in COVID-19 hyperinflammation, including CXCL10. Following CSA administration, we also observed a significant reduction in type I IFN gene expression signatures and other transcriptional profiles associated with exacerbated hyperinflammation in the peripheral blood cells of these patients.CONCLUSIONShort courses of CSA appear safe and feasible in patients with COVID-19 who require oxygen and may be a useful adjunct in resource-limited health care settings.TRIAL REGISTRATIONThis trial was registered on ClinicalTrials.gov (Investigational New Drug Application no. 149997; ClinicalTrials.gov NCT04412785).FUNDINGThis study was internally funded by the Center for Cellular Immunotherapies.
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