In late 2019, a novel human coronavirus – severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) – emerged in Wuhan, China. This virus has caused a global pandemic involving more than 200 ...countries. SARS-CoV-2 is highly adapted to humans and readily transmits from person-to-person.
To investigate the infectivity of SARS-CoV-2 under various environmental and pH conditions. The efficacies of various laboratory virus inactivation methods and home disinfectants against SARS-CoV-2 were investigated.
The residual virus in dried form or in solution was titrated on to Vero E6 cells on days 0, 1, 3, 5 and 7 after incubation at different temperatures. Viral viability was determined after treatment with various disinfectants and pH solutions at room temperature (20–25oC).
SARS-CoV-2 was able to retain viability for 3–5 days in dried form or 7 days in solution at room temperature. SARS-CoV-2 could be detected under a wide range of pH conditions from pH 4 to pH 11 for several days, and for 1–2 days in stool at room temperature but lost 5 logs of infectivity. A variety of commonly used disinfectants and laboratory inactivation procedures were found to reduce viral viability effectively.
This study demonstrated the stability of SARS-CoV-2 on environmental surfaces, and raises the possibility of faecal–oral transmission. Commonly used fixatives, nucleic acid extraction methods and heat inactivation were found to reduce viral infectivity significantly, which could ensure hospital and laboratory safety during the SARS-CoV-2 pandemic.
The ability to make electrical contact to single molecules creates opportunities to examine fundamental processes governing electron flow on the smallest possible length scales. We report experiments ...in which we controllably stretched individual cobalt complexes having spin S = 1, while simultaneously measuring current flow through the molecule. The molecule's spin states and magnetic anisotropy were manipulated in the absence of a magnetic field by modification of the molecular symmetry. This control enabled quantitative studies of the underscreened Kondo effect, in which conduction electrons only partially compensate the molecular spin. Our findings demonstrate a mechanism of spin control in single-molecule devices and establish that they can serve as model systems for making precision tests of correlated-electron theories.
Lipid composition determines the physical properties of biological membranes and can vary substantially between and within organisms. We describe a specific role for the viscosity of ...energy-transducing membranes in cellular respiration. Engineering of fatty acid biosynthesis in
allowed us to titrate inner membrane viscosity across a 10-fold range by controlling the abundance of unsaturated or branched lipids. These fluidizing lipids tightly controlled respiratory metabolism, an effect that can be explained with a quantitative model of the electron transport chain (ETC) that features diffusion-coupled reactions between enzymes and electron carriers (quinones). Lipid unsaturation also modulated mitochondrial respiration in engineered budding yeast strains. Thus, diffusion in the ETC may serve as an evolutionary constraint for lipid composition in respiratory membranes.
In recent years, targeted radionuclide therapy (TRT) has emerged as a promising strategy for cancer treatment. In contrast to conventional radiotherapy, TRT delivers ionizing radiation to tumors in a ...targeted manner, reducing the dose that healthy tissues are exposed to. Existing TRT strategies include the use of
Lu-DOTATATE,
I-metaiodobenzylguanidine, Bexxar, and Zevalin, clinically approved agents for the treatment of neuroendocrine tumors, neuroblastoma, and non-Hodgkin lymphoma, respectively. Although promising results have been obtained with these agents, clinical evidence acquired to date suggests that only a small percentage of patients achieves complete response. Consequently, there have been attempts to improve TRT outcomes through combinations with other therapeutic agents; such strategies include administering concurrent TRT and chemotherapy, and the use of TRT with known or putative radiosensitizers such as poly(adenosine diphosphate ribose) polymerase and mammalian-target-of-rapamycin inhibitors. In addition to potentially achieving greater therapeutic effects than the respective monotherapies, these strategies may lead to lower dosages or numbers of cycles required and, in turn, reduce unwanted toxicities. As of now, several clinical trials have been conducted to assess the benefits of TRT-based combination therapies, sometimes despite limited preclinical evidence being available in the public domain to support their use. Although some clinical trials have yielded promising results, others have shown no clear survival benefit from particular combination treatments. Here, we present a comprehensive review of combination strategies with TRT reported in the literature to date and evaluate their therapeutic potential.
We hypothesize that segmentectomy is associated with similar recurrence-free and overall survival when compared with lobectomy in the setting of patients with clinical T1cN0M0 non–small cell lung ...cancer (NSCLC; >2-3 cm), as defined by the American Joint Committee on Cancer 8th edition staging system.
We performed a single-institution retrospective study identifying patients undergoing segmentectomy (90) versus lobectomy (279) for T1c NSCLC from January 1, 2003, to December 31, 2016. Univariate, multivariable, and propensity score–weighted analyses were performed to analyze the following endpoints: freedom from recurrence, overall survival, and time to recurrence.
Patients undergoing segmentectomy were older than patients undergoing lobectomy (71.5 vs 68.8, respectively, P = .02). There were no differences in incidence of major complications (12.4% vs 11.7%, P = .85), hospital length of stay (6.2 vs 7 days, P = .19), and mortality at 30 (1.1% vs 1.7%, P = 1) and 90 days (2.2% vs 2.3%, P = 1). In addition, there were no statistical differences in locoregional (12.2% vs 8.6%, P = .408), distant (11.1% vs 13.9%, P = .716), or overall recurrence (23.3% vs 22.5%, P = 1), as well as 5-year freedom from recurrence (68.6% vs 75.8%, P = .5) or 5-year survival (57.8% vs 61.0%, P = .9). Propensity score–matched analysis found no differences in overall survival (hazard ratio HR, 1.034; P = .764), recurrence-free survival (HR, 1.168; P = .1391), or time to recurrence (HR, 1.053; P = .7462).
In the setting of clinical T1cN0M0 NSCLC, anatomic segmentectomy was not associated with significant differences in recurrence-free or overall survival at 5 years. Further prospective randomized trials are needed to corroborate the expansion of the role of anatomic segmentectomy to all American Joint Committee on Cancer 8th Edition Stage 1A NSCLC.
Kaplan–Meier curves depicting time to recurrence in an unmatched cohort of anatomic segmentectomy (red line, n = 90) versus lobectomy (black line, n = 279) for clinical T1cN0M0 non–small cell lung cancer. 95% confidence intervals are represented by the shaded areas (segmentectomy is shown in red, lobectomy in gray). The difference in time to recurrence was not statistically significant (P = .83). NSCLC, Non–small cell lung cancer. Display omitted
The LytR-CpsA-Psr (LCP) proteins are thought to transfer bactoprenol-linked biosynthetic intermediates of wall teichoic acid (WTA) to the peptidoglycan of Gram-positive bacteria. In Bacillus ...subtilis, mutants lacking all three LCP enzymes do not deposit WTA in the envelope, while Staphylococcus aureus Δlcp mutants display impaired growth and reduced levels of envelope phosphate. We show here that the S. aureus Δlcp mutant synthesized WTA yet released ribitol phosphate polymers into the extracellular medium. Further, Δlcp mutant staphylococci no longer restricted the deposition of LysM-type murein hydrolases to cell division sites, which was associated with defects in cell shape and increased autolysis. Mutations in S. aureus WTA synthesis genes (tagB, tarF, or tarJ2) inhibit growth, which is attributed to the depletion of bactoprenol, an essential component of peptidoglycan synthesis (lipid II). The growth defect of S. aureus tagB and tarFJ mutants was alleviated by inhibition of WTA synthesis with tunicamycin, whereas the growth defect of the Δlcp mutant was not relieved by tunicamycin treatment or by mutation of tagO, whose product catalyzes the first committed step of WTA synthesis. Further, sortase A-mediated anchoring of proteins to peptidoglycan, which also involves bactoprenol and lipid II, was not impaired in the Δlcp mutant. We propose a model whereby the S. aureus Δlcp mutant, defective in tethering WTA to the cell wall, cleaves WTA synthesis intermediates, releasing ribitol phosphate into the medium and recycling bactoprenol for peptidoglycan synthesis.
Microvascular invasion (MVI) in hepatocellular carcinoma (HCC) is an independent predictor of poor outcomes subsequent to surgical resection or liver transplantation (LT); however, MVI currently ...cannot be adequately determined preoperatively. Radiogenomic venous invasion (RVI) is a contrast‐enhanced computed tomography (CECT) biomarker of MVI derived from a 91‐gene HCC “venous invasion” gene expression signature. Preoperative CECTs of 157 HCC patients who underwent surgical resection (N = 72) or LT (N = 85) between 2000 and 2009 at three institutions were evaluated for the presence or absence of RVI. RVI was assessed for its ability to predict MVI and outcomes. Interobserver agreement for scoring RVI was substantial among five radiologists (κ = 0.705; P < 0.001). The diagnostic accuracy, sensitivity, and specificity of RVI in predicting MVI was 89%, 76%, and 94%, respectively. Positive RVI score was associated with lower overall survival (OS) than negative RVI score in the overall cohort (P < 0.001; 48 vs. >147 months), American Joint Committee on Cancer tumor‐node‐metastasis stage II (P < 0.001; 34 vs. >147 months), and in LT patients within Milan criteria (P < 0.001; 69 vs. >147 months). Positive RVI score also portended lower recurrence‐free survival at 3 years versus negative RVI score (P = 0.001; 27% vs. 62%). Conclusion: RVI is a noninvasive radiogenomic biomarker that accurately predicts histological MVI in HCC surgical candidates. Its presence on preoperative CECT is associated with early disease recurrence and poor OS and may be useful for identifying patients less likely to derive a durable benefit from surgical treatment. (Hepatology 2015;62:792–800)
The purpose of this study is to examine the effects of the coronavirus disease 2019 (COVID-19) pandemic on adult lung transplants and report practice changes in the United States.
A retrospective ...analysis of a public dataset from the United Network for Organ Sharing was performed regarding adult lung transplantation (January 19, 2020-June 30, 2020). Data were stratified into 3 periods: pre-COVID-19 (January 19, 2020-March 14, 2020), first COVID-19 era (March 15, 2020-May 8, 2020), and second COVID-19 era (May 9, 2020-June 30, 2020). Weekly changes in waitlist inactivations (COVID-19 precautions or not), waitlist additions, transplant volume, and donor recovery were examined across eras and changes across era were correlated.
During the first COVID-19 era, 301 patients were added to the waitlist, representing a 40% decrease when compared to the prior 8-week period. This was followed by a significant increase in listing during the second COVID-19 era (t = 2.16, P = 0.032). Waitlist inactivations decreased in the second COVID-19 era from the first COVID-19 era (t = 3.60, P < 0.001). There was no difference in waitlist inactivations between the pre-COVID era and the second COVID-19 era (P = 0.10). Weekly volume was not associated with trends in COVID-19 cases across any era, but was negatively associated with waitlist inactivations due to COVID-19 precautions entering the first COVID-19 era (r = -0.73, P = 0.04) and second COVID-19 era (r = -0.89, P = 0.003).
Due to the COVID-19 pandemic, the United States experienced a decrease in lung transplant volume. While overall volume has returned to normal, additional studies are needed to identify areas of improvement to better prepare for future pandemics.
A microdose cocktail containing midazolam, dabigatran etexilate, pitavastatin, rosuvastatin, and atorvastatin has been established to allow simultaneous assessment of a perpetrator impact on the most ...common drug metabolizing enzyme, cytochrome P450 (CYP)3A, and the major transporters organic anion‐transporting polypeptides (OATP)1B, breast cancer resistance protein (BCRP), and MDR1 P‐glycoprotein (P‐gp). The clinical utility of these microdose cocktail probe substrates was qualified by conducting clinical drug interaction studies with three inhibitors with different in vitro inhibitory profiles (rifampin, itraconazole, and clarithromycin). Generally, the pharmacokinetic profiles of the probe substrates, in the absence and presence of the inhibitors, were comparable to their reported corresponding pharmacological doses, and/or in agreement with theoretical expectations. The exception was dabigatran, which resulted in an approximately twofold higher magnitude for microdose compared to conventional dosing, and, thus, can be used to flag a worst‐case scenario for P‐gp. Broader application of the microdose cocktail will facilitate a more comprehensive understanding of the roles of drug transporters in drug disposition and drug interactions.
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